WO2007099392A2

WO2007099392A2 - Convergent synthesis of carbohydrate building blocks

Info

Publication number: WO2007099392A2
Application number: PCT/IB2006/003357
Authority: WO
Inventors: Peter Seeberger; Alexander Adibekian; Mattheus S. M. Timmer
Original assignee: Eidgenoessische Technische Hochschule Zurich ETHZ
Current assignee: Eidgenoessische Technische Hochschule Zurich ETHZ
Priority date: 2005-09-27
Filing date: 2006-09-27
Publication date: 2007-09-07
Anticipated expiration: 2008-03-27
Also published as: WO2007099392A3

Abstract

The invention relates to a process for preparing carbohydrate building blocks by combining two carbon fragments to form a protected linear or branched open chain carbohydrate. The protected linear or branched open chain carbohydrate is then cyclized to form a carbohydrate building block.

Description

Convergent Synthesis of Carbohydrate Building Blocks

RELATED APPLICATIONS

This application claims the benefit of the filing date of United States Provisional Patent Application serial number 60/720,910, filed September 27, 2005.

BACKGROUND OF THE INVENTION

Recognition of the biological importance of carbohydrates has dramatically increased the demand for pure, synthetically derived oligosaccharides. Sophisticated glycosylation reactions that allow for the installation of even the most difficult glycosidic linkages with high degrees of selectivity have been developed. See e.g., Preparative Carbohydrate Chemistry, S. Hanessian, Marcel Dekker Inc., New York, 1997; Carbohydrates in Chemistry and Biology, B. Ernst, G. W. Hart, P. Sinay, Eds. Wiley-VCH, Weinheim, 2000, Vol. 1; B. Davies, J. Chem. Soc, Perkin Trans. 1 2000, 2137-2160 and PJ. Garegg^v. Carb. Chem. Biochem. 2004, 59, 69-113. An automated method for the rapid combination of monosaccharide building blocks on solid phase has been reported. See e.g., T. Kanemitsu, O. Kanie, Trends Glycosci. Glyc. 1999, 11, 267-276; P.H. Seeberger, W.C. Haase, Chem. Rev. 2000, 100, 4349-4394; OJ. Plante, E.R. Palmacci, P.H. Seeberger Science 2001, 291, 1523-1527; P. Sears, C-H. Wong Science 2001, 291, 2344- 2350; OJ. Plante, E.R. Palmacci, R.B. Andrade, P.H. Seeberger J. Am. Chem. Soc. 2001, 123, 9545-9554; Solid Support Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries, P.H. Seeberger, Wiley, New York, 2001; K.D. Randell, A. Barkley, P. Arya Comb. Chem. High Throughput Screening 2002, 5, 179-193; T. Kanemitsu, O. Kanie, Comb. Chem. High Throughput Screening 2002, 5, 339-360; S.M. Khersonsky, CM. Ho, M.A. Garcia, Y.T. Chang Curr. Top. Med Chem. 2003, 3, 617-643; R. Franzen, J. Tois Comb. Chem. High Throughput Screening 2003, 6, 433-444. Moreover, the time required to assemble an oligosaccharide has been reduced more than one-hundred fold. Therefore, the need for substantial quantities of and rapid access to fully-functionalized building blocks has increased dramatically.

In certain instances, lengthy syntheses have been required to produce such building blocks. Therefore, efforts to synthesize orthogonally protected monosaccharides from non- carbohydrate precursors were undertaken. Syntheses of hexoses by Masamune and Sharpless were facilitated by the availability of synthetic methods to introduce specific stereogenic centers, selectively. S.Y. Ko, A.W.M. Lee, S. Masamune, L.A. Reed, K.B. Sharpless, FJ. Walker Science 1983, 220, 949. Later, the aldol reaction proved to be a useful tool to create hexoses from simple precursors. Mukaiyama et al. reported stereoselective syntheses of pentoses and hexoses using silyl enol ethers in aldol condensations to furnish partially protected pentoses and hexoses. T. Mukaiyama, I. Shiina, S. Kobayashi Chem. Lett. 1990, 12, 2201-2204; T. Mukaiyama, H. Anan, I. Shiina, S. Kobayashi Bull. Soc. CMm. Fr. 1993, 130, 388-394; A.B. Northrup, D.W.C. MacMillan Science 2004, 305, 1752-1755. More recently, proline-catalized aldol reactions fashioned precursors to be used in Mukaiyama-type aldol reactions to synthesize partially protected glucose, mannose and allose monosaccharides. See e.g., A.B. Northrup, D.W.C. MacMillan Science 2004, 305, 1752-1755; D. Enders, C. Grondal Angew. Chem. Int. Ed. 2005, 44, 1210-1212. The yields and selectivities reported for these transformations were highly dependent upon the specific protective groups. The need exists for monosaccharide building blocks that contain practical protective group patterns and a readily available anomeric leaving group.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a method for the preparation of carbohydrate building blocks by cyclization of a linear or branched open chain carbohydrate derivative, obtained by combining two 3 C fragments and cyclization of the linear or branched open chain carbohydrate to form a hexopyranose of the general formulas depicted below:

wherein

A represents acetimidoyl, substituted acetimidoyl, halogen, trichloroacetimidoyl, thiocarbamoyl, sulfoxide, -OR', -SR', or -SeR';

R' is selected independently for each occurrence from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, and substituted aryl; X₂, X₃, X₄ and X₅ are independently selected from the group consisting of H, -O-, -CN₅ -NH-, -NO₂, and N₃;

X₆ represents independently for each occurrence, -CH₂O-, -CH₂NH-, -CH₃, -CH₂NO₂, -CH₂N₃, -COO-, -CONH-, -CN, or -COS-;

B, C, D, E, and F are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates and substituted carbohydrates;

Y₁, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, and =C(R)_2;

X is independently for each occurrence selected from the group consisting of O,

NH, NR, S, and Se;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, X₄ or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

Another aspect of the present invention relates to a method of preparing carbohydrate building blocks, comprising the formation of a linear or branched open chain carbohydrate by combining two C2 fragments and cyclization of the linear or branched open chain carbohydrate to form a furanose carbohydrate building block as depicted below: condensation followed

^Y4>3 ^{3 + Y2}>1¹ ; by one or more " steps

wherein

R' is selected independently for each occurrence from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, and substituted aryl;

X₂, and X₃ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and -N₃;

B, C, and E are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates and substituted carbohydrates;

X is independently for each occurrence selected from the group consisting of O, NH, NR, S, and Se;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂ or X₃ is H, -CN, -NO₂, or -N₃, the corresponding B, C or E is absent.

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining a C2 and a C3 fragment and cyclization of the linear or branched open chain carbohydrate to form a furanose carbohydrate building block as depicted below:

wherein

X₂ and X₃ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and -N₃;

X₆ represents independently for each occurrence, -CH₂O-, -CH₂NH-, -CH₃, -CH₂NO₂, -CH₂N₃, -COO-, -CONH-, -CN or -COS-;

B, C, E, and F are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates and substituted carbohydrates;

Y₁, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR)₅ =C(XR)₂, and =C(R)_2;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Yi, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂ or X₃ is H, -CN, -NO₂, or -N₃, the corresponding B, C, or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining a C2 and a C3 fragment and cyclization of the linear or branched open chain carbohydrate to form a furanose carbohydrate building block as depicted below: condensation _{Hn γ R}

EX₅ followed "V j*^u cyclization FX₆-γ^υy-A

Y₄-^Y₃ ^{+ 2>1} by one or more ^F*⁶ jV^Yi " x V \ _R steps ^X3C ^X3C X2B wherein

X₂, X₃, and X₅ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and -N₃;

Yi, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, and =C(R)_2;

X is independently for each occurrence selected from the group consisting of O, NH, NR, S, and Se; R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, or X₅ is H, -CN, -NO₂, or ₇N₃, the corresponding B, C, or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining two C3 fragments and cyclization of the linear or branched open chain carbohydrate to form a hexafuranose carbohydrate building block as depicted below: condensation _H0 χ,B

EX₅ X₂B followed _cγ T I cyclization

Y₄ Y3 Y2 Yi by one or more Λ X _c steps ^{EXs X3}°

wherein

X₆ represents independently for each occurrence, -CH₂O-, -CH₂NH-, -CH₃, -CH₂NO₂, -CH₂N₃, -COO-, -CONH-, -CN or -COS-; B, C, D, E, and F are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates or substituted carbohydrates;

X is independently for each occurrence selected from the group consisting of O,

NH, NR, S, and Se;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, - CN or -CH₂N₃, the corresponding F is absent.

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining a C2 and a C4 fragment and cyclization of the linear or branched open chain carbohydrate to form a hexafuranose carbohydrate building block as depicted below:

wherein

A represents acetimidoyl, substituted acetimidoyl, halogen, trichloroacetimidoyl, thiocarbamoyl, sulfoxide, -OR', -SR', or -SeR'; R' is selected independently for each occurrence from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;

X₂, X₃, X₄ and X₅ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, or -N₃;

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining a C2 and a C4 fragment and cyclization of the linear or branched open chain carbohydrate to form a hexopyranose carbohydrate building block as depicted below:

wherein

X₂, X₃, and X₄ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and -N₃;

Y₁, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, or =C(R)_2;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, or X₄ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

cyclization

wherein

X₂, X₃, X₄ and X₅ are independently selected from the group consisting of H, -O-,

-CN, -NH-, -NO₂, or N₃;

B, C, D, E₅ and F are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates or substituted carbohydrates;

X is independently for each occurrence selected from the group consisting of O, NH, NR, S, and Se; R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, X₄ or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said condensation is an aldol condensation.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said condensation comprises a Lewis acid.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said condensation comprises MgBr₂OEt.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said one or more steps comprises one or more reductions, protections or deprotections.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide. A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein said cyclization comprises N-iodosuccinimide (NIS).

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein A is -SR'; and R¹ is alkyl.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein A is -SEt.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₂ is -O-.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₂ is -O-; and B is H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₃ is -O-.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₃ is -O-; and C is H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₄ is -O-.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₄ is -O-; and D is H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₅ is -O-. A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₅ is -O-; and E is H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₆ is -CH₂O-.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₆ is -CH₂O-; and F is H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₁ is -C(XR)₂H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₁ is -C(SR)₂H; and R is alkyl.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₁ is -C(SEt)₂H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₂ is -C(=0)H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₃ is =C(XR)H. A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₃ is =C(OR)H; and R is silyl.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₃ is =C(OTBDMS)H.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₄ is -C(X)XR.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₄ is -C(H)OR.

A further aspect of the present invention relates to the aforementioned methods and any of the attendant definitions, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining a Cl and a C5 fragment and cyclization of the linear or branched open chain carbohydrate to form a hexopyranose carbohydrate building block as depicted below:

wherein

A represents acetimidoyl, substituted acetimidoyl, halogen, tricliloroacetimidoyl, thiocarbamoyl, sulfoxide, -OR', -SR', or -SeR';

X₂, X₃, and X₄ are independently selected from the group consisting of H, -0-, -CN, -NH-, -NO₂, or N₃;

B, C, D, E, and F are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates and substituted carbohydrates; Y₁, and Y₂ are independently for each occurrence selected from the group consisting Of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, and =C(R)_2;

Y₃ is selected from the group consisting of C(X)R₂, C(X)(XR)₂, C(R)₄, C(R)₃(XR), CR₂(XR)₂, C(XR)₄, C(R)₃N₃, RCN, and C(R)₃NO₂;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁ and Y₂ have the appropriate bond order; provided that when any occurrence OfX₂, X₃, or X₄ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, - CN or -CH₂N₃, the corresponding F is absent.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said condensation is an aldol condensation.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said condensation comprises a Lewis acid.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said condensation comprises MgBr₂OEt. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said one or more steps comprises one or more reductions, protections or deprotections.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cyclization comprises N-iodosuccinimide (NIS).

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein A is -SR¹; and R¹ is alkyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein A is -SEt.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -O-.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -O-; and B is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₃ is -O-.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₃ is -O-; and C is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₄ is -O-. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₄ is -O- ; and D is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₆ is -CH₂O-.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₆ is -CH₂O-; and F is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₁ is -C(XR)₂H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₁ is -C(SR)₂H; and R is alkyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₁ is -C(SEt)₂H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₂ is -C(=O)H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is RCN. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is RCN; and R is silyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is TMSCN.

wherein

-CN₅ -NH-, -NO₂, and N₃;

B, C, D, E, and F are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates or substituted carbohydrates;

Y₃ and Y₄ are independently for each occurrence selected from the group consisting Of-C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, or =C(R)_2;

Y₁ is selected from the group consisting OfC(X)R₂, C(X)(XR)₂, C(R)₄, C(R)₃(XR), CR₂(XR)₂, C(XR)₄, C(R)₃N₃, RCN, or C(R)₃NO₂; X is independently for each occurrence selected from the group consisting of O, NH, NR, S, and Se;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, or substituted metal; and the connecting carbon atoms to Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, X₄ or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said condensation comprises MgBr₂OEt.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said one or more steps comprises one or more reductions, protections or deprotections.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cyclization comprises N-iodosuccinimide (NIS).

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein A is -SR'; and R' is alkyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -O- ; and B is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₄ is -O-.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₄ is -O-; and D is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₅ is -O-. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₅ is -O-; and E is H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1-,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₁ is C(X)R₂.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is =C(XR)H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is =C(0R)H; and R is silyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is =C(0TBDMS)H.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₄ is -C(X)XR. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₄ is -C(H)OR.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

Another aspect of the present invention relates to a method for the preparation of carbohydrate building blocks comprising the formation of a linear or branched open chain carbohydrate by combining a C4 and a C2 fragment and cyclization of the linear or branched open chain carbohydrate to form a hexafuranose carbohydrate building block as depicted below:

_Y ^Y4._{Y3 + V} ^γ ₂

wherein

X₂, and X₃ are independently selected from the group consisting of H, -0-, -CN, -NH-, -NO₂, and N₃;

B and C are selected independently for each occurrence, from the group consisting of H, protecting groups, carbohydrates or substituted carbohydrates;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, subsituted carboxide, orthoester, subsituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, or substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂ or X₃ is H, -CN, -NO₂, or -N₃, the corresponding B or C is absent.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cyclization comprises acid.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cyclization comprises trifluoroacetic acid (TFA).

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -0-.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -0-; and B is H. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein B or C is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-1,2,3- triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Yi is -C(SR)₂H; and R is alkyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₂ is -C(=O)OR; and R is alkyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₂ is -C(=O)OMe.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₃ is -C(=O)H. A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₄ is -CR₃; and R is hydrogen or alkyl.

A further aspect of the present invention relates to the aforementioned method and any of the attendant definitions, wherein Y₄ is -CH₃.

BRIEF DESCRIPTION OF THE FIGURES Figure IA depicts a retrosynthetic analysis of uronic acid thioglycosides.

Figure IB depicts the synthesis of differentially protected aldehyde dithioacetals from L-arabinose. a) EtSH, cone. aq. HCl, 10 min, 77%. b) 2,2-dimethoxypropane, pyridinium/7-toluenesulfonate (cat.), acetone, 1.5 h, 81%. c) BnBr, TBAI (cat.), NaH, DMF, 0 ⁰C, 4 h. d) W-Bu₂SnO, toluene, Dean-Stark trap, then BnBr, CsF, TBAI (cat.), DMF. e) Ac₂O, pyridine, 46% (2 steps), f) AcOHTH₂O (1/1, v/v), 50 °C, 1 h, 6: 62% (2 steps: c and f), 7: 92 %. g) NaIO₄, H₂O/THF, 0 °C, 15 min, 8: 82%, 9: 80%.

Figure 2 A depicts the synthesis of L-glucuronic acid, L-iduronic acid and L- altruronic acid building blocks, a) Method A: BF₃-Et₂O, DCM, 0 °C, 15 min., 93% (11:14:17 = 1:1:1). Method B: MgBr₂-Et₂O, toluene, -78 ⁰C to -30 °C, 1 h, quant, (only 11). b) 1. FmocCl, pyridine, 2 h. 2. HF-pyridine, THF, 16 h, 12: 83%, 15: 89%, 18: 84% (2 steps), c) NIS, DCM, 15 min, quant. (13, 16 and 19).

Figure 2B depicts the synthesis of selectively protected D-glucuronic and L-iduronic acid building blocks, a) Method A: BF₃-Et₂O, DCM, 0 °C, 15 min., 95% (20:23 = 3:2). Method B: MgBr₂-Et₂O, toluene, -78 °C to -30 °C, 1 h, 98% (only 20). b) a. FmocCl, pyridine, 2 h. b. HF-pyridine, THF, 16 h, 21: 79%, 24: 76% (2 steps), c) NIS, DCM, 15 min, quant. (22 and 25), (α/β = 1:1).

DETAILED DESCRIPTION OF THE INVENTION

A typical carbohydrate building block used in oligosaccharide assembly is equipped with different protecting groups to mask the hydroxyl functions and/or amine functions, and an anomeric leaving group that can be activated to induce the formation of a glycosidic linkage. These differentially protected and functionalized monosaccharides have traditionally been accessed from naturally occurring sugar starting materials through a series of protection-deprotection maneuvers in order to establish the desired protecting group pattern. This process typically requires between six and twenty transformations depending upon the sugar, the protecting group pattern and the anomeric leaving group. T. Ogawa Chem. Soc. Rev. 1994, 23, 397-407; SJ. Danishefsky, M.T. Bilodeau Angew. Chem. Int. Ed. 1996, 35, 1480-1520; and T. Hudlicky, D. A. Entwistle, K.K. Pitzer, AJ. Thorpe Chem. Rev. 1996, 96, 1195-1220.

In certain embodiments, the invention provides a improved universal method for the preparation of carbohydrate building blocks by cyclization of a linear or branched open chain carbohydrate, obtained by combining two fragments. The reaction scheme for the synthesis of each building block is designed so as to specify the different protecting groups to mask hydroxyl and amine functions, thereby allowing selective deprotection of the hydroxyls elected for ensuing glycosylation and permanent protection of the remainder of hydroxyl and/or amine functions. The anomeric leaving group is selected based on the eventual activation protocol of choice.

Definitions

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.

The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non- limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. ) In the claims, as well as in the specification above, all transitional phrases such as

"comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. As used herein, a "carbohydrate" (or, equivalently, a "sugar") is a saccharide (including monosaccharides, oligosaccharides and polysaccharides) and/or a molecule (including oligomers or polymers) derived from one or more monosaccharides, e.g., by reduction of carbonyl groups, by oxidation of one or more terminal groups to carboxylic acids, by replacement of one or more hydroxy group(s) by a hydrogen atom, an amino group, a thiol group or similar heteroatomic groups, etc. The term "carbohydrate" also includes derivatives of these compounds. Non-limiting examples of carbohydrates include allose ("All"), altrose ("Alt"), arabinose ("Ara"), erythrose, erythrulose, fructose ("Fru"), fucosamine ("FucN"), fucose ("Fuc"), galactosamine ("GaIN"), galactose ("Gal"), glucosamine ("GIcN"), glucosaminitol ("GlcN-ol"), glucose ("GIc"), glyceraldehyde, 2,3- dihydroxypropanal, glycerol ("Gro"), propane- 1,2,3-triol, glycerone ("1,3- dihydroxyacetone"), 1,3-dihydroxypropanone, gulose ("GuI"), idose ("Ido"), lyxose ("Lyx"), mannosamine ("ManN"), mannose ("Man"), psicose ("Psi"), quinovose ("Qui"), quinovosamine, rhamnitol ("Rha-ol"), rhamnosamine ("RhaN"), rhamnose ("Rha"), ribose ("Rib"), ribulose ("RuI"), sialic acid ("Sia" or "Neu"), sorbose ("Sor"), tagatose ("Tag"), talose ("TaI"), tartaric acid, erythraric/threaric acid, threose, xylose ("XyI"), or xylulose ("XuI"). In some cases, the carbohydrate may be a pentose (i.e., having 5 carbons) or a hexose (i.e., having 6 carbons); and in certain instances, the carbohydrate may be an oligosaccharide comprising pentose and/or hexose units, e.g., including those described above.

A "monosaccharide," is a carbohydrate or carbohydrate derivative that includes one saccharide unit. Similarly, a "disaccharide," a "trisaccharide," a "tetrasaccharide," a "pentasaccharide," etc. respectively has 2, 3, 4, 5, etc. saccharide units. An "oligosaccharide," as used herein, has 1-20 saccharide units, and the saccharide units may be joined in any suitable configuration, for example, through alpha or beta linkages, using any suitable hydroxy moiety, etc. The oligosaccharide may be linear, or branched in certain instances. A "polysaccharide," as used herein, typically has at least 4-20 saccharide units. For instance, the polysaccharide may have at least 25 saccharide units, at least 50 saccharide units, at least 75 saccharide units, at least 100 saccharide units, etc. In some cases, the carbohydrate is mulitmeric, i.e., comprising more than one saccharide chain.

It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form," as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group).

By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH₃,-OAc).

For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (C(^O)) is converted to a diether (C(OR)₂), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (-NRC(=0)R) or a urethane (-NRC(=0)0R), for example, as: a methyl amide (-NHC(=0)CH₃) ; a benzyloxy amide (-NHC(=O)OCH₂C₆H₅NHCbz) ; as a t-butoxy amide (-NHC=(=O)OC(CH₃)₃,-NHBoc); a 2-biphenyl-2-propoxy amide

(-NHC(=O)OC(CH₃)₂C₆H₄C₆H₅NHBoc), as a 9-fluorenyhnethoxy amide (-NHFmoc), as a 6-nitroveratryloxy amide (-NHNvoc), as a 2-trimethylsilylethyloxy amide (-NHTeoc), as a 2,2,2-trichloroethyloxy amide (-NHTroc), as an allyloxy amide (-NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (-NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical.

For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-SCH₂NHC(=O)CH₃).

The term "Lewis acid" is art-recognized and refers to an atom, compound or complex capable of accepting a pair of electrons from another atom, compound or complex. The term "nucleophile" is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons.

The term "electrophile" is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above, or from a Lewis base. Electrophilic moieties useful in the method of the present invention include halides and sulfonates.

The term "electron-withdrawing group" is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron- withdrawing capability is given by the Hammett sigma (σ) constant. This well known constant is described in many references, for instance, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259. The Hammett constant values are generally negative for electron donating groups (σ[P] = -0.66 for NH₂) and positive for electron withdrawing groups (σ[P] = 0.78 for a nitro group), σ[P] indicating para substitution. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, cyano, chloride, and the like. Exemplary electron-donating groups include amino, methoxy, and the like.

The term "catalytic amount" is recognized in the art and means a substoichionietric amount of a reagent relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent reagent relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent reagent to reactant.

A "polar solvent" means a solvent which has a dielectric constant (ε) of 2.9 or greater, such as DMF, THF, ethylene glycol dimethyl ether (DME), DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether. Preferred solvents are DMF, DME, NMP, and acetonitrile.

A "polar, aprotic solvent" means a polar solvent as defined above which has no available hydrogens to exchange with the compounds of this invention during reaction, for example DMF, acetonitrile, diglyme, DMSO, or THF.

An "aprotic solvent" means a non-nucleophilic solvent having a boiling point range above ambient temperature, preferably from about 25°C to about 19O⁰C, more preferably from about 8O⁰C to about 16O⁰C, most preferably from about 8O⁰C to 15O⁰C, at atmospheric pressure. Examples of such solvents are acetonitrile, toluene, DMF, diglyme, THF or DMSO.

The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups, hi certain embodiments, a straight chain or branched chain alkyl has about 80 or fewer carbon atoms in its backbone (e.g., C₁-C₈₀ for straight chain, C₃-C₈₀ for branched chain), and alternatively, about 30 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure. As used herein, "fluoroalkyl" denotes an alkyl where one or more hydrogens have been replaced with fluorines; "perfluoroalkyl" denotes an alkyl where all the hydrogens have been replaced with fluorines.

Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term "aryl" is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, trifluoromethyl, cyano, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms "heterocyclyl", "heteroaryl", or "heterocyclic group" are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.

The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings {e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.

The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term "ring atom", as used herein, refers to a backbone atom that makes up the ring. Such ring atoms are selected from C, N, O or S and are bound to 2 or 3 other such ring atoms (3 in the case of certain ring atoms in a bicyclic ring system). The term "ring atom" does not include hydrogen.

The term "nitro" is art-recognized and refers to -NO₂; the term "halogen" is art- recognized and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is art-recognized and refers to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-recognized and refers to -SO₂ ^". "Halide" designates the corresponding anion of the halogens, and "pseudohalide" has the definition set forth on page 560 of "Advanced Inorganic Chemistry" by Cotton and Wilkinson, that is, for example, monovalent anionic groups sufficiently electronegative to exhibit a positive Hammett sigma value at least equaling that of a halide (e.g., CN, OCN, SCN, SeCN, TeCN, N₃, and C(CN)₃).

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

R50 ^R5°

/ + N N R53

^R51 R52 wherein R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH₂)_m-R61, or R50 and R51 or R52, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH₂)_m-R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group. The term "acylamino" is art-recognized and refers to a moiety that may be represented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH₂)_m-R61, where m and R61 are as defined above.

The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH₂)_m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.

The term "carboxyl" is art recognized and includes such moieties as may be represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH₂)_m-R61or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH₂)_m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularyl when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thiolformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group.

The term "carbamoyl" refers to -0(C=O)NRR¹, where R and R' are independently H, aliphatic groups, aryl groups or heteroaryl groups.

The term "oxo" refers to a carbonyl oxygen (=0).

The terms "oxime" and "oxime ether" are art-recognized and refer to moieties that may be represented by the general formula:

wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH₂)_m-R61. The moiety is an "oxime" when R is H; and it is an "oxime ether" when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH₂)_m-R61.

The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -0-alkynyl, -O-(CH₂)_m-R61, where m and R61 are described above.

The term "sulfonate" is art recognized and refers to a moiety that may be represented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl. The term "sulfate" is art recognized and includes a moiety that may be represented by the general formula:

in which R57 is as defined above.

The term "sulfonamido" is art recognized and includes a moiety that may be represented by the general formula:

O N S OR56

R50 O in which R50 and R56 are as defined above.

The term "sulfamoyl" is art-recognized and refers to a moiety that may be represented by the general formula:

in which R50 and R51 are as defined above.

The term "sulfonyl" is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "sulfoxido" is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is defined above.

Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

The term "selenoalkyl" is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto. Exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH₂)_m-R61, m and R61 being defined above.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms trifiate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations .

Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. AU such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereonieric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, "Handbook of Chemistry and Physics", 67th Ed., 1986-87, inside cover.

While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein, hi addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.

Exemplary Embodiments

A convergent route to orthogonally protected D-glucuronic and L-iduronic acid thioglycoside building blocks, commonly used in heparin oligosaccharide assembly, is described. The approach relies on a selective Mukaiyama aldol reaction between a silyl enol ether and a dithioacetal-containing aldehyde. NIS promoted cyclization results in the differentially protected pyranose uronic acid thioglycosides as competent glycosylating agents. Rapid access to sufficient quantities of these key intermediates feeds the growing need for monosaccharide building blocks for use in the assembly of bioactive oligosaccharides.

Described is a remarkable convergent route to orthogonally protected D-glucuronic and L-iduronic acid thioglycoside building blocks, commonly used in heparin oligosaccharide assembly. The approach relies on a selective Mukaiyama aldol reaction between a silyl enol ether and a dithioacetal-containing aldehyde. NIS promoted cyclization results in the differentially protected pyranose uronic acid thioglycosides as competent glycosylating agents. Rapid access to sufficient quantities of these key intermediates feeds the growing need for monosaccharide building blocks for use in the assembly of bioactive oligosaccharides. Retrosynthetic analysis of uronic acids A (Figure IA) reveals that the fully protected uronic acid thioglycosides could be obtained via cyclization of linear hexoses B. The open chain hexoses can be formed in turn via a Mukaiyama aldol reaction of an appropriately protected ketene acetal C with a dithioacetal-cntaining aldehyde D.

Synthesis of the key aldehyde dithioacetals 8 and 9 commenced with readily available L-arabinose (1, Figure IB). Conversion of the aldehyde into the corresponding dithioacetal was achieved by reaction with ethanethiol in the presence of hydrochloric acid. Subsequent protection of the 4,5-diol with 2,2-dimethoxypropane furnished crystalline acetonide 2. At this stage, the protecting group patterns for the 2-OH and 3-OH hydroxyls were selected. Reaction of 2 with NaH in the presence of excess benzyl bromide afforded dibenzyl-arabinoside 3, while formation of a tin ketal of the diol 2. and subsequent monobenzylation gave 4. After acetylation of the remaining hydroxyl group in 4, selectively protected 5 was isolated in 46% overall yield, together with 45% of the 2-O- benzyl-3-O-acetyl regioisomer. Cleavage of the acetal protective groups in 3 and 5 was followed by sodium periodate-mediated cleavage of the ensuing vicinal diols to form the desired aldehydes 8 and 9 in very good overall yield. It should be noted that these two key intermediates are derived from cheap commercially available starting materials, using straightforward and high yielding transformations that are readily scalable.

Having established an efficient route toward aldehyde dithioacetals, the aldol reaction/cyclization sequence was explored (Figure 2A). The BF₃-Et₂O mediated aldol reaction of aldehyde 8 with silylenolether 10 gave a 1:1:1 mixture of three products, as judged by the ¹H-NMR signals of the crude product mixture. Each of the three individual aldol products was isolated by column chromatography and identified after conversion to the corresponding pyranosides. Therefore, the free hydroxyls of 11, 14 and 17 were transformed into 9-fluorenylmethyl carbonates, followed by cleavage of the silyl ether under the agency of pyridine-HF to obtain alcohols 12, 15 and 18 in good overall yields. Although initial attempts to effect cyclization using various acidic conditions proved to be challenging, NIS-promoted activation of the mercaptane led to the clean formation of pyranose carbohydrates 13, 16 and 19 in quantitative yields. At this stage, the absolute configuration of the pyranoses was established by the ¹H-NMR coupling patterns of the carbohydrate ring protons. For compound 13, the large (8-10 Hz) coupling constants between H-2, H-3, H-4 and H-5 protons provided the evidence to assign gluco- configuration. The /do-configuration of 16 was assigned based on the presence of characteristically small coupling constants (1-3 Hz) for all protons form H-2 through H-5. The configuration was further corroborated by the W-coupling ⁴J_2>4 = 1.0 Hz, typical of a 2,4-diaxial substituted pyranose. The. coupling pattern for the less common altruronic acid 19 was in full accordance with the reported coupling constants for altroses. It should be noted that no trace of the galacto uronic acid, the fourth possible isomer, was found. This seemingly remarkable absence can be rationalized by assuming a non-chelating, open chain transition state that allows only for the three C-C bond formations observed, and not for the sterically demanding Si-Si attack that would lead to the galacto isomer.

With the absolute configurations of the aldol products determined, the selectivity of the aldol reaction was further explored. It has been shown that stereoselectivities can be significantly improved by the use of metal Lewis acids in a chelation controlled Mukaiyama aldol reaction. We envisaged that Felkin-Anh addition of silylenolether and aldehyde in an open transition state should preferentially furnish glucuronic acid. Indeed, MgBr₂-Et₂O promoted aldol reaction of aldehyde 8 and ketene acetal 10 (Method B, Figure 2A) afforded glucuronic acid 11 in quantitative yield as a single diastereoisomer.

In order to examine the aldol reaction between the differentially protected aldehyde 9 and ketene acetal 10, the BF₃-Et₂O mediated reaction was performed (Figure 2B). Surprisingly, analysis of the crude reaction mixture by ¹H-NMR showed a 3:2 ratio of two diastereomers, and only traces of a third. Separation of the individual isomers followed by protecting group manipulations and NIS-mediated cyclization led to the isolation of the pyranoses 22 and 25. Comparison of the ¹H-NMR coupling constants with those for pyranosides 13 and 16, thioglycoside 22 was identified as D-glucuronic acid and 25 as L- iduronic acid. Finally, aldol reaction between aldehyde 9 and ketene acetal 10 led to the exclusive formation of the g/wco-configured product (Method B, Figure 2B).

Remarkably, a highly convergent route to orthogonally protected D-glucuronic and L-iduronic acid thioglycoside building blocks has been developed. Rapid access to sufficient quantities of monosaccharides that contain practical protective group patterns and a readily activatable anomeric leaving group will greatly facilitate oligosaccharide assembly using automated methods.

EXEMPLIFICATION

The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Example 1 — Synthesis of Two Exemplary C₄ Fragments

L-Arabinose di(ethylthio)acetal. L-Arabinose (50 g, 330 mmol) was added to a vigorously stirred mixture of ethane thiol (50 mL) and cone. aq. HCl (50 mL). After the exothermic reaction starts, the slightly pink solution was cooled (0° C) and stirring was continued for 10 min upon which the product crystalizes. The suspension was filtered and the residue was washed with cold water (3 x 50 mL), dried by suction, washed with ether (3 x 50 mL) and dried again. The resulting white powder could be used without further purification or recrystallized from ethyl acetate to obtain L-arabinose di(ethylthio)acetal 2 (65 g, 254 mmol, 77%) as white platelets. Mp 125-126°C; α_D ²⁰ = 11 (c = 1.0); IR (CHCl₃): 3414, 2967, 1432, 1260, 1076, 1024, 940, 877 cm^"1; ¹H-NMR (300 MHz, CD₃OD): δ 4.03 (d, J= 9.2 Hz, IH), 3.97 (d, J= 8.3 Hz, IH), 3.84 (d, J= 9.2 Hz, IH), 3.78 (dd, J= 2.9, 10.7 Hz, IH), 3.68 (ddd, J= 2.9, 5.9, 8.3 Hz, IH), 3.68 (dd, J= 5.9, 10.8 Hz, IH), 2.78- 2.58 (m, 4H), 1.24 (t, J= 7.4 Hz, 3H), 1.23 (t, J= 7.4 Hz, 3H); ¹³C-NMR (75 MHz, CD₃OD): δ 73.1, 72.7, 71.9, 65.1, 56.2, 25.4, 15.0, 14.9; ESI-MS (m/z): 279.2 [M+Na]⁺, 535.2 [2M+Na]⁺, 301.2 [M+HC0₃]^".

4,5-0-Isopropylidene-L-arabinose di(ethylthio)acetal (2). 2,2-Dimethoxypropane (25 mL, 200 mL, 2.0 equiv.) and

(2.0 g, cat.) were added to a suspension of L-arabinose di(ethylthio)acetal (25.6 g, 100 mmol) in acetone (400 mL). After obtaining a homogenous solution and stirring for an additional hour, sat. aq. NaHCO₃ (50 mL) and water (50 mL) were added and the mixture was concentrated to a volume of approximately 150 mL. The residue was extracted with ethyl acetate (3 x 100 mL), dried (MgSO₄) and concentrated. The resulting residue was crystallized from ethyl acetate, filtered and washed with cold hexanes to obtain pure isopropylidene-arabinose 2 (24 g, 81 mmol, 81%) as white needles. α_D ²⁰ = 64 (c = 1.0); IR (CHCl₃): 3548, 3456, 3008, 2933, 1454, 1377, 1373, 1262, 1153, 1070, 844 cm-¹; ¹H-NMR (SOO MHz, CDCl₃): 5 4.14-3.94 (m, 5H), 3.74 (dd, J= 1.0, 9.3 Hz, IH), 3.27 (bs, IH), 2.81-2.60 (m, 4H), 2.36 (bs, IH), 1.42 (s, 3H), 1.35 (s, 3H), 1.27 (t, J= 7.4, 3H), 1.27 (t, J= 7.4, 3H); ¹³C-NMR (75 MHz₅ CDCl₃): δ 109.2, 76.1, 71.0, 70.0, 67.1, 55.6, 26.9, 25.6, 25.4, 23.5, 14.6, 14.5; ESI-MS (m/z): 319.2 [M+Na]⁺, 615.2 [2M+Na]⁺, 341.2 JMfHCO₃]^".

2,3-Di-0-benzyl-4,5-0-isopropylidene-L-arabinose di(ethylthio)acetal (3).

Arabinose 2 (2.38 g, 5.0 mmol) was coevaporated with DMF and dissolved in DMF (25 mL). After cooling the solution to 0°C, benzyl bromide (1.4 mL, 11.5 mmol, 2.3 equiv.), sodium hydride (0.440 g, 60% in oil, 11.0 mmol, 2.2 eq.) and TBAI (cat.) were added and the reaction mixture was allowed to stir for 4 h. The reaction mixture was quenched with methanol, concentrated in vacuo, dissolved in ethyl acetate, washed with water, sat. aq. NaHCO₃ and brine, dried (MgSO₄), filtered and concentrated in vacuo. The residue was used in the next step without further purification. α_D ²⁰ = -22.4 (c = 1.0); IR (CHCl₃): 3065, 2988, 2929, 2872, 1496, 1454, 1373, 1346, 1263, 1158, 1070, 1028, 915, 856 cm^"1; ¹H- NMR (300 MHz, CD₃OD): δ 7.41-7.24 (m, 10H), 4.92 (d, J= 10.9 Hz, IH), 4.81 (d, J= 11.4 Hz, IH), 4.75 (d, J= 11.4 Hz, IH), 4.74 (d, J= 10.9 Hz, IH), 4.25 (app q, J= 6.3 Hz, IH), 4.18-4.14 (m, 2H), 4.04 (dd, J= 6.3, 8.3 Hz, IH), 3.89 (dd, J= 6.6, 8.3 Hz, IH), 3.81 (dd, J= 4.3, 6.5 Hz, IH), 2.77-2.61 (m, 4H), 1.43 (s, 3H), 1.35 (s, 3H), 1.24 (t, J= 7.4 Hz, 3H), 1.23 (t, J= 7.4 Hz, 3H) ; ESI-MS (m/z): 494.0 [M+NH₄]⁺, 499.2 [MfNa]⁺.

2,3-Di-6>-benzyl-L-arabinose di(ethylthio)acetal (6). Crude 3 was dissolved in 80% AcOH in H₂O, stirred for 1 h at 50°C and concentrated. Purification of the residue by column chromatography (ethyl acetate/light petroleum ether, 1/4, v/v) yielded pure 6 (1.36 g, 3.15 mmol, 63% over two steps) as a colorless oil. α_D ²⁰ = -15.9 (c = 1.0); IR (CHCl₃): 3580, 3498, 3007, 2973, 2929, 2872, 1496, 1454, 1377, 1264, 1097, 1062, 913 cm^"1; ¹H- NMR (300 MHz, CD₃OD): δ 7.41-7.28 (m, 10H), 4.89 (d, J = 11.3 Hz, IH), 4.76 (d, J = 11.3 Hz, IH), 4.67 (d, J = 11.3 Hz, IH), 4.60 (d, J= 11.3 Hz, IH), 4.16 (d, J= 4.1 Hz, IH), 4.02 (dd, J = 4.1, 4.3 Hz, IH), 3.96 (ddd, J= 3.2, 4.3, 7.8 Hz, IH), 3.89 (dd, J= 4.3, 7.8 Hz, IH), 3.77 (dd, J = 3.2, 11.3 Hz, IH), 3.68 (dd, J = 4.3, 11.4 Hz, IH), 2.78 (dq, J = 12.4, 7.4 Hz, IH), 2.98 (bs, IH), 2.70 (dq, J = 12.4, 7.4 Hz, IH), 2.64 (dq, J = 12.2, 7.4 Hz, IH), 2.59 (dq, J = 12.2, 7.4 Hz, IH), 2.06 (bs, IH), 1.26 (t, J = 7.4 Hz, 3H), 1.23 (t, J = 7.4 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 137.6, 137.5, 128.3, 128.2, 127.9, 127.8, 127.7, 82.2, 78.6, 74.4, 74.1, 71.2, 63.5, 52.2, 25.8, 25.5, 14.5, 14.4; ESI-MS (m/z): 454.1 [M+NH₄]⁺, 481.1 [MH-HCO₃]^'.

(2R,3i?)-2,3-Bis(benzyloxy)-4,4-bis(ethylthio)butanal (8). A solution OfNaIO₄ (80 mg, 0.40 mmol, 1.1 equiv.) in H₂O (1 niL) was added dropwise to a cooled (0°C) and stirred mixture of diol 6 (150 mg, 0.34 mmol) in THF (4 mL). After 10 minutes, the reaction mixture was diluted with hexanes (10 mL) and extracted with sat. aq. NaHCO₃ (2 x 20 mL) and brine (20 mL), dried (MgSO₄), filtered and concentrated. Column chromatography (hexanes → 5% ethyl acetate in hexanes) gave pure aldehyde 8 (123 mg, 0.28 mmol, 82%) as a colorless oil. α_D ²⁰ = 23.9 (c = 1.0); IR (CHCl₃): 3007, 2973, 2929, 2872, 1727, 1496, 1454, 1377, 1264, 1097, 1070, 1028, 912 cm^'1; ¹H-NMR (300 MHz, CDCl₃): δ 9.80 (d, J= 1.0 Hz, IH), 7.35-7.28 (m, 10H), 4.81 (d, J= 11.2 Hz, IH), 4.76 (d, J = 11.8 Hz, IH), 4.62 (d, J= 11.2 Hz, IH), 4.61 (d, J= 11.8 Hz, IH), 4.17-4.09 (m, 3H), 4.04 (dd, J= 4.8, 5.0 Hz, IH), 2.72-2.56 (m, 4H), 1.26 (t, J= 7.4 Hz, 3H), 1.25 (t, J= 7.4 Hz, 3H); ¹³C-NMR (75 MHz, QDCl₃): δ 201.3, 137.2, 137.0, 128.4, 128.2, 128.1, 128.0, 127.8, 83.0, 82.9, 76.4, 74.6, 73.7, 60.4, 52.3, 26.1, 25.4, 14.4, 14.3; ESI-MS (m/z): 405.2 [M+H]⁺, 427.2 [M+Na]⁺.

2-0-Acetyl-3-0-benzyl-4,5-CMsopropylidene-L-arabinose di(ethylthio) acetal

(5). Diol 2 (4.1 g, 14.8 mmol) was dissolved in toluene (60 mL). Dibutyltin oxide (4.1 g, 16 mmol, 1.1 equiv.) was added and the reaction mixture was heated under reflux for 1.5 h while water was removed azeotropically using a Dean-Stark trap. The solution was concentrated in vacuo and the residue was redissolved in DMF. Caesium fluoride (2.4 g, 16 mmol, 1.1 equiv.), benzyl bromide (2.0 mL, 16 mmol, 1.1 equiv.) and a catalytic amount of TBAI were added. After stirring for 16 h, the reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic layer was washed twice with aqueous KF (IM) and once with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude mixture of monobenzylated arabinose 4 together with its 2-O-benzyl regioisomer were dissolved in pyridine (50 mL) and acetic anhydride (50 mL) was added. After stirring overnight, the mixture was concentrated and traces of solvent were removed by coevaporation with toluene (3 x 100 mL). Purification by column chromatography (hexanes —> 2.5% ethyl acetate in hexanes) yielded compound 5 (2.92 g, 6.8 mmol, 46%) and its 2- O-benzyl regioisomer (2.84 g, 6.6 mmol, 45%). α_D ²⁰ = -26.3 (c = 1.0); IR (CHCl₃): 2988, 2930, 2872, 1742, 1455, 1373, 1248, 1158, 1064, 1021, 858 cm^'1; ¹H-NMR (300 MHz): δ 7.36-7.27 (m, 5H), 5.20 (dd, J= 3.5, 8.2 Hz, IH), 4.86 (d, J= 11.3 Hz, IH), 4.76 (d, J= 11.3 Hz, IH), 4.33 (dd, J= 3.5, 4.4 Hz, IH)₅ 4.15 (dt, J= 3.5, 6.6 Hz, IH), 4.11 (d, J= 8.2 Hz, IH), 3.97 (dd, J= 6.6, 8.1 Hz, IH), 3.90 (dd, J= 6.6, 8.1 Hz, IH), 2.75-2.55 (m, 4H), 2.08 (s, 3H), 1.42 (s, 3H)₅ 1.31 (s, 3H)₅ 1.23 (t, J= 7.4 Hz₅ 3H)₅ 1.21 (t₅ J= 7.4 Hz₅ 3H); ¹³C-NMR (75 MHz): δ 169.9, 138.1, 128.3, 127.7, 127.6, 108.5, 77.6, 77.2, 75.0, 74.O₅ 65.4, 51.9, 26.4, 24.7, 24.6, 24.4, 20.9, 14.2, 14.0; ESI-MS (m/z): 446.3 [M+NILtf^1", 451.1 [M+Naf; HRMS m/z calcd for C₂₁H₃₂O₅S₂Na⁺: 451.1583, obsd: 451.1577.

2-0-Acetyl-3-0-benzyI-L-arabinose di(ethylthio)acetal (7). Acetonide 5 (167 mg, 0.39 mmol) was dissolved in 50% AcOH in H₂O, stirred for 1 h at 5O⁰C and concentrated. Purification of the residue by column chromatography (ethyl acetate/light petroleum ether, 1/4, v/v) yielded pure 7 (141 mg, 0.36 mmol, 92%) as a colorless oil. α_D ²⁰ = -22.4 (c = 1.0); IR (CHCl₃): 3589, 3514, 2969, 2930, 2873, 2253, 1730, 1497, 1455, 1375, 1248, 1095, 1044, 907, 650 cm^"1; ¹H-NMR (300 MHz): δ 7.35-7.25 (m, 5H), 5.26 (dd, J= 2.6, 8.9 Hz, IH), 4.81 (d, J= 11.4 Hz₅ IH)₅ 4.72 (d, J= 11.4 Hz, IH)₅ 4.15 (dd, J= 2.6, 8.1 Hz, IH), 4.13 (d, J= 8.9 Hz, IH), 3.81 (dd, J= 3.0, 11.4 Hz, IH), 3.67 (dd, J= 5.0, 11.4 Hz, IH), 3.58 (ddd, J= 3.0, 5.0, 8.1 Hz, IH), 2.75-2.55 (m, 4H), 2.14 (s, 3H), 1.23 (t, J= 7.4 Hz, 3H), 1.22 (t, J= 7.4 Hz, 3H); ¹³C-NMR (75 MHz): δ 171.8, 137.9, 128.4, 127.8, 127.7, 77.7, 74.7, 74.4, 71.0, 63.2, 51.9, 24.7, 24.3, 20.9, 14.2. HRMS m/z calcd for C₂₃H₃₂O₅S₂Na⁺: 411.1270, obsd: 411.1278.

(2R,3i?)-3-Acetoxy-2-benzyloxy-4,4-bis(ethylthio)butanal (9). A solution of NaIO₄ (80 mg, 0.40 mmol, 1.1 equiv.) in H₂O (1 mL) was added dropwise to a cooled (0°C) and stirred mixture of diol 7 (141 mg, 0.36 mmol) in THF (4 mL). After 10 minutes, the reaction mixture was diluted with hexanes (10 mL) and extracted with sat. aq. NaHCO₃ (2 x 20 mL) and brine (20 mL), dried (MgSO₄), filtered and concentrated. Column chromatography (hexanes —> 5% ethyl acetate in hexanes) gave pure aldehyde 9 (103 mg, 0.29 mmol, 80%) as a colorless oil. α_D ²⁰ = 5.5 (c = 1.0); IR (CHCl₃): 2976, 2930, 2874, 1743, 1492, 1454, 1373, 1248, 1090, iO52, 1027 cm^"1; ¹H-NMR (SOO MHz): δ 9.65 (d, J= 0.6 Hz, IH), 7.40-7.30 (m, 5H), 5.40 (dd, J= 3.7, 7.5 Hz, IH), 4.80 (d, J= 11.5 Hz, IH), 4.67 (d, J= 11.5 Hz, IH), 4.40 (dd, J= 0.6, 3.7 Hz, IH), 4.17 (d, J= 7.5 Hz, IH), 2.73-2.54 (m, 4H), 2.09 (s, 3H), 1.25 (t, J= 7.4 Hz, 3H), 1.22 (t, J= 7.4 Hz, 3H); ¹³C-NMR (75 MHz): δ 199.8, 169.6, 136.6, 128.5, 128.3, 128.2, 82.0, 73.9, 73.6, 51.1, 25.1, 25.0, 20.7, 14.3, 14.1; ESI-MS (m/z): 357.0 [M+NH₄]⁺, 379.1 [M+Na]⁺; HRMS m/z calcd for C₂₃H₃₂O₅S₂Na⁺: 379.1008, obsd: 379.1005. Example 2 — Synthesis of Three Exemplary Carbohydrate Building Blocks

11 R¹ = H, R² = TBS 14 R¹ = H, R² = TBS 17 R¹ = H, R² = TBS

C 12 R¹ = Fmoc, R² = H C 15 R¹ = Fmoc, R² = H C 18 R¹ = Fmoc, R² = H

13 16 19

Method A: BF₃ ^»Et₂0 (1.5 equiv.) was added to a solution of the silyl enol ether 10 (1.5 equiv.) and the aldehyde 8 (1.0 equiv.) in CH₂Cl₂ (5 niL/mmol) at 0°C. After stirring for 15 min, the reaction mixture was quenched with sat. aq. NH₄Cl and diluted with CH₂Cl₂. The organic layer was separated and washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄) and filtered. After concentration and purification of the residue by column chromatography (hexanes → hexanes/CH₂Cl₂, 1/3, v/v), the pure aldol products 11, 14 and 17 were obtained as colorless oils.

Method B: The silyl enol ether 10 (1.5 equiv.) was added to a suspension of MgBr₂^Et₂O (3 equiv.) in toluene (5 mL/mmol) at -78°C. After stirring for 30 min, the aldehyde 8 (1.0 equiv.) was added and the mixture was stirred for another 2 h at the same temperature. The solution was then warmed up to room temperature and stirring was continued until the starting material was completely consumed (TLC analyses). After quenching with sat. aq. NH₄Cl, the reaction mixture was extracted three times with EtOAc, the combined organic layers were washed with brine, dried (MgSO₄) and filtered. After concentration and purification of the residue by column chromatography (hexanes → hexanes/CH₂Cl₂, 1/3, v/v), the pure aldol product 11 was obtained as a colorless oil.

2,3-di-0-benzyl uronic acid di(ethylthio)acetals 11, 14 and 17: Aldehyde 8 (0.30 g, 0.75 mmol) and enol ether 10 were subjected to method A to give glucuronate 11: (0.14 g, 0.23 mmol, 31%), iduronate 14: (0.14 g, 0.23 mmol, 31%) and altruronate 17: (0.13 g, 0.22 mmol, 29%). Aldehyde 8 (40 mg, 0.10 mmol) and enol ether 10 were subjected to method B to give glucuronate 11: (61 mg, 0.10 mmol, quant.). Methyl 2,3-di-0-benzyl-5-0-tert-butyldimethylsilyl-D-glucuronate di(ethylthio)acetal (11). α_D ²⁰ = -8.5 (c = 1.0); IR (CHCl₃): 3600, 2954, 2930, 2858, 1745, 1600, 1496, 1454, 1361, 1260, 1116, 1066, 1027, 839 cm^"1; ¹H-NMR (300 MHz): δ 7.36- 7.26 (m, 10H), 4.92 (d, J = 11.0 Hz, IH), 4.87 (d, J = 11.0 Hz, IH), 4.76 (d, J = 11.0 Hz, IH), 4.65 (d, J = 11.0 Hz, IH), 4.29 (d, J = 7.6 Hz, IH), 4.16 (dd, J = 1.0, 7.6 Hz, IH), 4.08 (dd, J= 2.9, 7.6 Hz, IH), 3.99 (d, J = 2.9 Hz, IH), 3.86 (ddd, J = 1.0, 7.6, 10.0 Hz, IH), 3.73 (s, 3H), 2.82-2.60 (m, 5H), 1.25 (t, J = 7.2 Hz, 3H), 1.24 (t, J= 7.2 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³C-NMR (75 MHz): δ 173.6, 139.1, 138.7, 128.4, 128.3,

128.0, 127.6, 127.4, 84.2, 79.5, 77.8, 77.4, 77.0, 76.1, 74.8, 73.7, 71.2, 53.9, 52.0, 26.4,

26.0, 26.2, 18.5, 14.9, 14.7, -4.7, -5.2; ESI-MS (m/z): 608.3 [M+H]⁺, 626.3 [M+NH₄]⁺; HRMS m/z calcd for C₃₁H₄₈O₆S₂SiNa: 631.2554, obsd: 631.2545.

Methyl 2,3-di-0-benzyl-5-0-tert-butyldimethylsilyI-L-iduronate di(ethylthio)acetal (14). α_D ²⁰ = +50 (c = 1.0); IR (CHCl₃): 3600, 2953, 2930, 2858, 1752, 1602, 1497, 1454, 1362, 1263, 1141, 1065, 1006, 981, 910, 840 cm^"1; ¹H-NMR (300 MHz): δ 7.36-7.21 (m, 10H), 4.97 (d, J = 10.8 Hz, IH), 4.92 (d, J = 11.3 Hz, IH), 4.78 (d, J = 10.8 Hz, IH), 4.59 (d, J = 11.3 Hz, IH), 4.35 (d, J= 6.4 Hz, IH), 4.27 (dd, J = 2.5, 8.1 Hz, IH), 4.12 (dd, J= 2.0, 8.1 Hz, IH), 4.03 (d, J= 2.5 Hz, IH), 3.95 (ddd, J = 2.0, 6.4, 9.5 Hz, IH), 3.59 (d, J= 9.5 Hz, IH), 3.32 (s, 3H), 2.84-2.66 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 0.95 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); ¹³C-NMR (75 MHz)^': 8

173.1, 138.7, 138.3, 128.1, 128.0, 127.7, 127.3, 127.1, 127.0, 83.9, 79.2, 75.9, 74.5, 73.4, 70.9, 53.7, 51.8, 26.3, 25.7, 25.0, 18.4, 14.7, 14.5, -4.8, -5.2; ESI-MS (m/z): 608.3 [M+H]⁺, 626.3 [M+NH₄f; HRMS m/z calcd for C₃₁H₄₈O₆S₂SiNa: 631.2554, obsd: 631.2543.

Methyl 2,3-di-O-benzyl-5-O-tert-butyIdimethylsilyl-L-altruronate di(ethylthio)acetal (17). α_D ²⁰ = -26 (c = 1.0); IR (CHCl₃): 3600, 2953, 2930, 2858, 1752, 1602, 1497, 1454, 1361, 1257, 1125, 1006, 1006, 910, 839 cm^"1; ¹H-NMR (300 MHz): δ 7.38-7.23 (m, 10H), 4.82 (d, J = 11.2 Hz, IH), 4.78 (d, J= 11.2 Hz, IH), 4.65 (d, J= 11.2 Hz, IH), 4.55 (d, J = 11.2 Hz, IH), 4.45 (ddd, J = 2.5, 4.8, 8.3 Hz, IH), 4.43 (d, J = 2.5 Hz, IH), 4.19 (d, J= 4.0 Hz, IH), 4.03 (dd, J= 4.0, 8.3 Hz, IH), 3.99 (t, J = 4.0 Hz, IH), 3.48 (s, 3H), 2.82-2.64 (m, 2H), 2.62-2.46 (m, 2H), 2.94 (d, J= 4.8, IH), 1.26 (t, J = 7.2 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H), 0.98 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H); ¹³C-NMR (75 MHz): δ 171.4, 138.1, 137.7, 128.1, 128.0, 127.9, 127.7, 127.6, 127.3, 82.3, 76.8, 74.2,

74.1, 73.7, 73.7, 52.1, 51.5, 25.8, 25.7, 25.3, 18.5, 14.4, -4.8, -5.0; ESI-MS (m/z): 608.3 [M+H]⁺, 626.3 [M+NH₄]⁺; HRMS m/z calcd for C₃₁H₄₈O₆S₂SiNa: 631.2554, obsd: 631.2544.

General procedure for Fmoc protection and cyclization: FmocCl (2 equiv.) was added to a solution of the alcohol (1 equiv.) in pyridine (1 mL/mmol) and the mixture was stirred for 2 h at room temperature. The mixture was concentrated and traces of solvent were removed by coevaporation with toluene. Column chromatography (hexanes/CH₂Cl₂, 1/1, v/v) of the residue gave the homogeneous ester as a colorless oil. The residue was dissolved in THF (5 mL/mmol) and HF .pyridine (1 mL) was added. After stirring for 16 h, the reaction mixture was diluted with ether and quenched with sat. aq. NaHCO₃. The organic layer was washed successively with sat. aq.NH₄Cl and brine, dried (MgSO₄), filtered and concentrated. Column chromatography (CH₂Cl₂) of the residue gave the pure alcohol as a colorless oil. The residue was dissolved in CH₂Cl₂ (5 mL/mmol) and NIS (1 equiv.) was added. After stirring for 10 min, the deep red reaction mixture was diluted with CH₂Cl₂ and quenched with IM aq. Na₂S₂O₃. After stirring for 15 min, the organic layer was separated, washed with brine, dried (MgSO₄), filtered and concentrated. Column chromatography (toluene → toluene/ethyl acetate, 200/1, v/v) of the residue gave the cyclized uronic acid as a colorless oil.

Methyl (ethyl 2,3-di-0-benzyI-4-0-fluoren-9~ylmethyloxycarbonyl-l-thio-α-D- glucopyranoside)uronate (13). Di(ethylthio)acetal 11 (0.10 mmol, 61 mg) was subjected to the general procedure for the Fmoc protection and cyclization to give ethyl thioglycoside 13 (54 mg, 83 μmol, 83%). α_D ²⁰ = 34 (c - 0.5); TR (CHCl₃): 3010, 2954, 2944, 2858, 1758, 1451, 1385, 1263, 1099, 1003, 969, 846 cm^"1; ¹H-NMR (SOO MHz): δ 7.77-7.75 (m, 2H), 7.63-7.59 (m, 2H), 7.41-7.21 (m, 16H), 5.41 (d, J= 5.0 Hz, IH), 4.95 (dd, J= 8.4, 9.7 Hz, IH), 4.85 (d, J= 11.4 Hz, IH), 4.79 (d, J= 9.7 Hz, IH)₃ 4.70 (d, J= 11.4 Hz, IH), 4.69 (s, 2H), 4.41 (dd, J= 7.3, 10.3 Hz, IH), 4.29 (dd, J= 7.6, 10.3 Hz, IH), 4.24 (bt, J= 7.4 Hz, IH), 3.91 (dd, J = 8.4, 9.2 Hz, IH), 3.87 (dd, J= 5.0, 9.1 Hz, IH), 3.64 (s, 3H), 2.62 (dq, J = 12.9, 7.4 Hz, IH), 2.56 (dq, J = 12.9 Hz, 7.4 Hz, IH), 1.29 (t, J = 7.4 Hz, 3H); ¹³C-NMR (75 MHz): δ 168.5, 154.1, 143.1, 143.0, 141.1, 137.9, 137.2, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.1, 127.0, 125.1, 125.0, 119.9, 83.3, 78.5, 78.0, 77.2, 75.4, 74.8, 72.8, 70.3, 68.7, 52.7, 46.6, 24.2, 14.8; ESI-MS (m/z): 672.1 [M+NH₄]⁺; HRMS m/z calcd for C₃₈H₃₈O₈SNa⁺: 677.2180, obsd: 677.2190.

Methyl (ethyl 2,3-di-0-benzyl-4-0-fluoren-9-yImethyloxycarbonyl-l-thio-α-L- idopyranoside)uronate (16). Di(ethylthio)acetal 14 (0.10 mmol, 61 mg) was subjected to the general procedure for the Fmoc protection and cyclization to give ethyl thioglycoside 16 (58 mg, 89 μmol, 89%). α_D ²⁰ = 48 (c = 0.5); IR (CHCl₃): 3012, 2953, 2930, 2858, 1752, 1454, 1263, 1065, 1006, 981, 910, 840 cm^"1; ¹H-NMR (SOO MHz): δ 7.77-7.73 (m, 2H), 7.63-7.57 (m, 2H), 7.41-7.18 (m, 16H), 5.03 (ddd, J= 3.0, 1.7 Hz, ⁴J= 1.0 Hz, IH), 4.94 (d, J= 1.7 Hz, IH), 4.67 (d, J= 11.9 Hz, IH), 4.61 (d, J= 2.0 Hz, IH), 4.51 (d, J= 11.9 Hz, IH), 4.50 (d, J= 12.3 Hz, IH), 4.43 (d, J= 12.3 Hz, IH), 4.37 (dd, J= 7.9, 10.3 Hz, IH), 4.31 (dd, J= 7.9, 10.3 Hz, IH), 4.18 (bt, J= 7.9 Hz, IH), 3.95 (t, J = 3.0 Hz, IH), 3.78 (s, 3H), 3.46 (ddd, J = 3.0, 1.7 Hz, ⁴J= 1.0 Hz, IH), 2.81 (dq, J= 12.7, 7.4 Hz, IH), 2.74 (dq, J = 12.7 Hz, 7.4 Hz, IH), 1.33 (t, J= 7.4 Hz, 3H); ¹³C-NMR (75 MHz): δ 168.5, 154.8, 143.5, 142.8, 141.4, 141.3, 137.6, 137.2, 128.8, 128.4, 128.3, 128.2, 128.0, 127.4, 125.5, 120.1, 83.7, 77.4, 75.0, 74.6, 73.2, 72.7, 71.3, 70.7, 70.3, 52.6, 46.8, 26.0, 15.3; ESI- MS (m/z): 672.2 [M+NH₄f; HRMS m/z calcd for C₃₈H₃₈O₈SNa⁺: 677.2180, obsd: 677.2191.

Methyl (ethyl 2,3-di-0-benzyl-4-0-fluoren-9-yImethyloxycarbonyI-l-thio-α-L- altropyranoside)uronate (19). Di(ethylthio)acetal 17 (0.10 mmol, 61 mg) was subjected to the general procedure for the Fmoc protection and cyclization to give ethyl thioglycoside 19 (55 mg, 84 μmol, 84%). α_D ²⁰ = 19 (c = 0.5); IR (CHCl₃): 3032, 2954, 2927, 2858, 1751, 1452, 1386, 1262, 1096, 991, 930, 846 cm^"1; ¹H-NMR (300 MHz): δ 7.78-7.73 (m, 2H), 7.64-7.58 (m, 2H), 7.43-7.21 (m, 16H), 5.31 (dd, J= 9.6, 3.0 Hz, IH), 5.07 (d, J= 1.8 Hz, IH), 4.63 (s, 2H), 4.53 (d, J= 11.8 Hz, IH), 4.49 (d, J= 9.6 Hz, IH), 4.45 (d, J= 11.8 Hz, IH), 4.44 (dd, J= 7.1, 10.2 Hz, IH), 4.33 (dd, J= 7.5, 10.2 Hz, IH), 4.24 (bt, J= 7.4 Hz, IH), 4.01 (dd, J= 4.4, 3.0 Hz, IH), 3.74 (s, 3H), 3.67 (dd, J= 4.4, 1.8 Hz, IH), 2.73 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); ¹³C-NMR (75 MHz): δ 168.4, 154.0, 143.5, 143.1, 141.4, 141.3, 137.5, 137.3, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.2, 125.3, 125.2, 120.1, 83.1, 77.2, 73.6, 73.4, 73.3, 73.2, 72.1, 70.1, 52.4, 46.7, 29.7, 25.9, 15.0; ESI- MS (m/z): 672.2 [M+NH₄]⁺; HRMS m/z calcd for C₃₈H₃₈O₈SNa⁺: 677.2180, obsd: 677.2189. Example 3 Synthesis of Two Exemplary Carbohydrate Building Blocks

22 25

2-0-acetyl-3-di-0-benzyl uronic acid di(ethylthio)acetals 20 and 23: Aldehyde 9 (0.30 g, 0.84 mmol) and enol ether 10 were subjected to method A of example 2 to give glucuronate 20: (0.27 g, 0.48 mmol, 57%) and iduronate 23: (0.17 g, 0.31 mmol, 38%) in 95% combined yield. Aldehyde 9 (0.10 g, 0.28 mmol) and enol ether 10 were subjected to method B of example 2 to give glucuronate 20: (0.15 g, 0.27 mmol, 98%).

Methyl 2-0-acetyI-3-0-benzyl-5-0-tert-butyldimethylsilyl-D-glucuronate di(ethylthio)acetal (20). α_D ²⁰ = -22 (c = 1.0); IR (CHCl₃): 3556, 3008, 2955, 2930, 2858, 1744, 1454, 1438, 1372, 1221, 1115, 1028, 840 cm^"1; ¹H-NMR (300 MHz): δ 7.37-7.27 (m, 5H), 5.45 (dd, IH, J = 5.6, 5.8 Hz), 4.77 (s, 2H), 4.28 (d, IH, J = 6.6 Hz), 4.25 (dd, IH, J = 2.7, 5.8 Hz), 4.05 (d, IH, J = 5.6 Hz), 3.89 (ddd, IH, J = 2.7, 6.6, 9.0 Hz), 3.75 (s, 3H), 2.79-2.59 (m, 5H), 2.03 (s, 3H), 1.25 (t, IH, J = 7.4 Hz), 1.23 (t, IH, J = 7.4 Hz), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³C-NMR (75 MHz): δ 172.1, 170.3, 138.0, 128.4, 127.7, 127.4, 77.1, 75.2, 74.3, 73.6, 73.3, 52.0, 51.6, 29.7, 25.6, 25.3, 25.1, 20.9, 18.1, 14.2, -5.0, - 5.3; ESI-MS (m/z): 561.3 [M+H]⁺, 578.3

HRMS m/z calcd for C₂₆H₄₄O₇S₂SiNa⁺: 583.2190, obsd: 583.2181.

Methyl 2-6>-acetyI-3-O-benzyl-5-O-tert-butyldimethyIsilyl-L-iduronate di(ethylthio)acetal (23). α_D ²⁰ = -8.6 (c = 1.0); IR (CHCl₃): 3556, 3025, 2955, 2929, 2858, 1743, 1455, 1438, 1372, 1253, 1143, 1087, 840 cm^"1; ¹H-NMR (SOO MHz): δ 7.33-7.23 (m, 5H), 5.65 (dd, IH₅ J = 4.1, 7.2 Hz), 4.69 (d, IH₅ J= 11 Hz), 4.63 (d, IH₅ J= 11 Hz), 4.32 (d, IH, J = 5.3 Hz), 4.16 (dd, IH, J = 3.3, 7.2 Hz), 4.11 (d, IH, J= 4.1 Hz), 3.99 (ddd, IH, J= 3.3, 5.2, 10.6 Hz), 3.43 (d, IH, J = 10.6 Hz), 3.30 (s, 3H)₅ 2.79-2.59 (m, 4H), 2.04 (s, ' 3H), 1.26 (t, IH, J = 7.4 Hz), 1.25 (t, IH, J= 7.4 Hz), 0.97 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); ¹³C-NMR (75 MHz): δ 172.6, 170.2, 138.1, 128.3, 127.2, 78.0, 75.0, 74.4, 73.8, 70.7, 51.9, 51.2, 26.0, 25.9, 25.8, 25.3, 21.0, 18.4, 14.4, 14.3, -4.7, -5.3; ESI-MS (m/z): 561.3 [M+Hf, 578.3 [M+NH₄]⁺; HRMS m/z calcd for C₂₆H₄₄O₇S₂SiNa⁺: 583.2190, obsd: 583.2181.

Methyl (ethyl 2-0-acetyl-3-0-benzyl-4-0-fluoren-9-ylmethyIoxycarbonyl-l- thio-α/β-D-g!ucopyranoside)uronate (22). Di(ethylthio)acetal 20 (0.10 mmol, 56 mg) was subjected to the general procedure for the Fmoc protection and cyclization of example 2 to give ethyl thioglycoside 22 (48 mg, 79 μmol, 79%). α_D ²⁰ = 43 (c = 1); IR (CHCl₃): 3008, 1752, 1451, 1374, 1261, 1075, 1012, 966, 822 cm^"1; ¹H-NMR (300 MHz): α-anomer: δ 7.78-7.74 (m, 2H), 7.62-7.59 (m, 2H), 7.40-7.23 (m, 9H), 5.73 (d, J= 4.6 Hz, IH), 5.06- 5.13 (m, IH), 5.00 (dd, J= 4.6, 8.0 Hz, IH), 4.79 (d, J= 7.6 Hz, IH), 4.71-4.57 (m, 2H), 4.49-4.41 (m, IH), 4.38-4.31 (m, IH), 4.23 (t, J= 7.2 Hz, IH), 3.96 (t, J= 7.6 Hz, IH), 3.66 (s, 3H), 2.80-2.58 (m, 2H), 2.04 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H); β-anomer: δ 7.78- 7.74 (m, 2H), 7.62-7.59 (m, 2H), 7.40-7.23 (m, 9H), 5.06-5.13 (m, 2H), 4.71-4.57 (m, 2H), 4.49-4.41 (m_s m), 4.43 (d, J= 10.0 Hz, IH), 4.38-4.31 (m, IH), 4.23 (t, J= 7.2 Hz, IH),

4.05 (d, J= 10 Hz, IH), 3.79 (t, J= 9.1 Hz, IH), 3.69 (s, 3H), 2.80-2.58 (m, 2H), 1.99 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H); ¹³C-NMR (75 MHz): δ 169.7, 169.0, 168.1, 167.0, 154.0, 153.8, 143.1, 143.0, 142.9, 142.8, 141.2, 141.1, 137.4, 128.2, 127.8, 127.7, 127.6, 127.4, 127.3, 127.0, 125.0, 124.9, 119.9, 83.8, 80.6, 80.5, 77.2, 76.3, 75.6, 75.0, 74.5, 73.7, 71.5, 70.5, 70.4, 70.3, 70.0, 52.8, 52.7, 46.7, 24.9, 24.0, 20.9, 20.8, 14.9, 14.8; ESI-MS (m/z): 624.0 [M+NH₄]⁺, 629.2 [M+Na]⁺; HRMS m/z calcd for C₃₈H₃₈O₈SNa⁺: 629.1816, obsd: 629.1805.

Methyl (ethyl 2-0-acetyl-3-0-benzyl-4-0-fluoren-9-ylmethyIoxycarbonyl-l- thio-α/β-L-idopyranoside)uronate (25). Di(ethylthio)acetal 23 (0.10 mmol, 56 mg) was subjected to the general procedure for the Fmoc protection and cyclization of example 2 to give ethyl thioglycoside 25 (46 mg, 76 μmol, 76%). α_D ²⁰ = 12 (c = 1); IR (CHCl₃): 3010, 2954, 2944, 2858, 1731, 1602, 1369, 1261, 1097, 1010, 907, 818 cm⁴; α-anomer: 7.77-7.74 (m, 2H), 7.56-7.59 (m, 2H), 7.42-7.26 (m, 9H), 5.45 (bs, IH), 5.30 (d, J= 2.2 Hz, IH), 5.08-5.10 (m, IH), 4.96-4.98 (m, IH), 4.67-4.79 (m, 2H), 4.46 (dd, J= 7.4, 10.3 Hz, IH), 4.33 (dd, J= 7.3, 10.3 Hz, IH), 4.21 (bt, J= 7.8 Hz, IH), 3.86 (dt, J= 0.9, 6.0 Hz, IH), 3.78 (s, 3H), 2.79 (q, J = 7.5 Hz, 2H), 2.00 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H); β-anomer; 7.77-7.74 (m, 2H), 7.56-7.59 (m, 2H), 7.42-7.26 (m, 9H), 5.08-5.10 (m, IH), 5.04 (d, J=

1.6 Hz, IH), 4.96-4.98 (m, IH), 4.67-4.79 (m, 2H), 4.62 (d, J= 1.6 Hz, IH), 4.46 (dd, J= 7.4, 10.3 Hz, IH), 4.32 (dd, J= 7.3, 10.3 Hz, IH), 4.21 (bt, J= 7.8 Hz, IH), 3.97 (t, J= 2.7 Hz, IH), 3.77 (s, 3H), 2.67 (q, J = 7.5 Hz, 2H), 2.01 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H); ¹³C- NMR (75 MHz): δ 170.2, 169.7, 168.6, 167.6, 154.2, 154.1, 143.0, 142.9, 141.1, 141.0, 141.2, 136.8, 136.7, 128.5, 128.3, 128.1, 127.8, 127.7, 127.5, 127.1, 127.0, 125.0, 124.9, 120.0, 82.6, 81.3, 77.7, 77.2, 76.3, 74.3, 73.0, 72.7, 72.2, 71.9, 71.2, 70.1, 68.7, 68.5, 66.6, 52.6, 46.7, 29.8, 29.7, 26.8, 25.9, 21.0, 20.7, 15.1, 14.9; ESI-MS (m/z): ESI-MS (m/z): 624.0 [M+NH₄f, 629.2 [M+Naf; HRMS m/z calcd for C₃₈H₃₈O₈SNa⁺: 629.1816, obsd: 629.1807.

Example 4 — Synthesis of an Exemplary Cs Fragment

I — 30 R¹ = H I — 33 R¹ = Tr, R² = H 36 L-* 31 R¹ = Piv }=£ 34 R¹ = Tr, R² = Lev

C 35 R¹ = H, R² = Lev l,2-O-IsopropyIidene-5-O-triphenyImethyl-D-xylofuranose (27). To a solution of diol 26 (18.61 g, 97.9 mmol) in pyridine (150 mL) at 0 ⁰C was added triphenylmethyl chloride (30 g, 107.69 mmol). The mixture was stirred at room temperature for 12 h and the solvent was removed in vacuo. The residue was purified by flash chromatography (hexanes/ethyl acetate, 2:1) to give 27 (44.7 g, quant.) as a white foam. [OC]_D ²⁰ = 54.4 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3458, 3008, 1491, 1448, 1263, 1074, 908 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 7.57-7.19 (m, 15H), 6.04 (d, / = 3.7 Hz, IH), 4.55 (d, / = 3.7 Hz, IH), 4.38-4.23 (m, 2H), 3.63-3.53 (m, 2H), 3.30 (bs, IH), 1.55 (s, 3H), 1.36 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 143.2, 128.4, 128.0, 127.2, 111.5, 104.9, 87.5, 85.1, 78.6, 76.2, 61.9, 27.0, 26.3; MALDI-HRMS m/z calcd for C₂₇H₂₈O₅Na⁺: 455.1829, obsd: 455.1834 [M+Na]⁺.

3-O-Benzyl-l,2-O-isopropylidene-5-O-triphenylmethyl-D-xylofuranose (28).

Alcohol 27 (14.8 g, 34.2 mmol) was dissolved in DMF (100 mL) and cooled to 0 °C. Sodium hydride (1.5 g, 60 % in oil, 37.62 mmol), benzyl bromide (4.5 mL, 37.62 mmol) and TBAI (cat.) were added and the mixture was allowed to stir at room temperature for 12 h. The reaction was quenched with sat. aq. NH₄Cl and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water and brine, dried over MgSO₄ and concentrated in vacuo. The resulting residue was purified by flash chromatography (hexanes/ethyl acetate, 20:1 to 10:1) to give 28 (18.5 g, quant.) as a pale yellow oil. [α]o = -26.8 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3007, 1731, 1448, 1346, 1163, 1077, 1010, 899, 859 cm⁴; ¹H NMR (300 MHz, CDCl₃): δ 7.56-7.11 (m, 20H), 5.97 (d, / = 3.8 Hz, IH), 4.68-4.59 (m, 2H), 4.53-4.43 (m, 2H), 4.07 (d, J = 3.1 Hz, IH), 3.63 (dd, J = 9.3, 5.8 Hz, IH), 3.38 (dd, J = 9.3, 6.8 Hz, IH), 1.59 (s, 3H), 1.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 143.8, 137.4, 128.7, 128.3, 127.7, 127.6, 127.5, 126.9, 111.6, 86.9, 82.5, 79.5, 72.0, 61.4, 27.0, 26.4; MALDI-HRMS m/z calcd for C₃₄H₃₄O₅Na⁺: 545.2298, obsd: 545.2293 [M+Na]⁺.

3-O-Benzyl-D-xylose di(ethylthio)acetal (29). Acetonide 28 (14.7 g, 28.15 mmol) was dissolved in CH₂Cl₂ (80 mL) and cooled to 0 °C. Ethane thiol (12.5 mL, 168.9 mmol) and BF₃ ^»OEt₂ (6.9 mL, 56.3 mmol) were added dropwise and the mixture was allowed to stir at 0 ⁰C for 40 min. The reaction was quenched by adding 7 mL NEt₃ and stirred for an additional 10 min. The resulting mixture was adsorbed on silica gel and purified by flash chromatography (hexanes/ethyl acetate, 3:1 to 1:9) to give 29 (7.9 g, 81 %) as a colorless oil. [α]_D ²⁰ = 27.3 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3451, 3007, 2930, 1454, 1391, 1264, 1091, 1052, 876 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 1 '.40-7..27 (m, 5H), 4.79 (d, J - 11.3 Hz, IH), 4.72 (d, J = 11.3 Hz, IH), 4.07 (dd, J = 4.8, 2.5 Hz, IH), 4.04 (d, J = 7.7 Hz, IH), 3.95-3.77 (m, 3H), 3.72-3.59 (m, IH), 3.39 (d, / = 4.8 Hz, IH), 2.90 (d, / = 5.8 Hz, IH), 2.83 (dd, J = 8.3, 4.5 Hz, IH), 2.77-2.55 (m, 4H), 1.26 (d, J = 7.4, 3H), 1.25 (d, J = 7.4, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 131.9, 128.4, 128.1, 127.8, 78.4, 74.5, 71.9, 70.9, 62.9, 55.4, 25.2, 24.4, 14.6, 14.5; MALDI-HRMS m/z calcd for C₁₆H₂₆O₄S₂Na⁺: 369.1165, obsd: 369.1161 [M+Na]⁺.

3-0-Benzyl-4,5-0-isopropylidene-D-xylose di(ethylthio)acetal (30). To a solution of triol 29 (5.12 g, 14.78 mmol) in acetone (100 mL) was added pTsOH (422 mg). The mixture was stirred at room temperature for 12 h and the reaction was quenched with sat. aq. NaHCO₃. The suspension was filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes/ethyl acetate, 10:1) to give 30 (5.31 g, 93 %) as a colorless oil. [α]_D ²⁰ = 49.3 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3007, 2930, 1454, 1381, 1248, 1075, 852 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 7.44-7.19 (m, 5H), 4.94 (d, J = 11.3 Hz, IH), 4.72 (d, J = 11.3 Hz, IH), 4.52-4.41 (m, IH), 4.06 (dd, / = 8.1, 6.4 Hz, IH), 3.99 (d, J = 8.2 Hz, IH), 3.94 (dd, J = 7.0, 2.0 Hz, IH), 3.75 (d, J = 7.9 Hz, IH), 3.47 (ddd, J = 7.9, 5.6, 2.1 Hz, IH), 3.14 (d, J = 5.6 Hz, IH), 2.72-2.54 (m, 4H), 1.45 (s, 3H), 1.37 (s, 3H), 1.27-1.18 (m, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 138.3, 128.2, 128.1, 127.6, 109.3, 78.7, 77.7, 74.1, 72.3, 66.0, 55.5, 26.8, 25.7, 25.1, 24.2, 14.7, 14.5; MALDI-HRMS m/z calcd for C₁₉H₃₀O₄S₂Na⁺: 409.1478, obsd: 409.1473 [M+Na]⁺.

3-O-Benzyl-4,5-O-isopropyIidene-2-O-pivaIoyl-D-xylose di(ethylthio)acetal (31). Alcohol 30 (20 g, 51.74 mmol) was dissolved in CH₂Cl₂ (250 mL) and cooled to 0 °C. Pivaloyl chloride (8.5 mL, 69 mmol) was added dropwise, followed by portion wise addition of 4-dimethylaminopyridine (4-DMAP) (12.8 g, 103.46 mmol). After stinting at 0 ⁰C for 60 min, sat. aq. NH₄Cl (50 mL) was added and the phases were separated. The aqueous layer was extracted with CH₂Cl₂, and the combined organic layers were washed with brine and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate, 5:1) to give 31 (26.2 g, quant.) as a colorless oil. [α]_D ²⁰ = -15.4 (c = 1, CHCl₃); IR (thin film on NaCl): v = 2976, 1723, 1479, 1372, 1278, 1155, 1067, 854 cm^'1; ¹H NMR (300 MHz, CDCl₃): δ 139-120 (m, 5H), 5.13 (dd, / = 7.3, 3.6 Hz, IH), 4.90 (d, / = 11.7 Hz, IH), 4.72 (d, J = 11.7 Hz, IH), 4.23 (t, J = 7.2, IH), 4.16 (d, J = 7.3 Hz, IH), 4.05 (dd, J = 6.9, 3.6 Hz, IH), 3.97 (dd, / = 8.5, 6.4Hz, IH), 3.76 (dd, J = 8.5, 7.3 Hz, IH), 2.76-2.50 (m, 4H), 1.44 (s, 3H), 1.34 (s, 3H), 1.26-1.17 (m, 15H); ¹³C NMR (75 MHz, CDCl₃): δ 177.1, 138.5, 128.1, 127.4, 127.3, 109.3, 78.8, 77.2, 74.3, 72.7, 65.9, 51.9, 39.1, 27.4, 26.6, 25.5, 24.8, 24.5, 14.5, 14.2; MALDI-HRMS m/z calcd for C₂₄H₃₈O₅S₂Na⁺: 493.2053, obsd: 493.2046 [M+Na]⁺.

3-0-Benzyl-2-0-pivaloyl-D-xyIose di(ethylthio)acetal (32). Acetonide 31 (21.8 g, 46.3 mmol) was dissolved in 50 % AcOH in H₂O (500 mL). The mixture was allowed to stir at 50 °C for 3 h. The solvent was removed in vacuo and the residue was coevaporated with toluene twice. The resulting colorless oil 32 (19.9 g, quant.) was analytically pure and was used for the next step without further purification, [αfo²⁰ = -34.8 (c = 1, CHCI₃); IR (thin film on NaCl): v = 3559, 2973, 1726, 1479, 1278, 1151 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 7.38-7.22 (m, 5H), 5.49 (dd, / = 6.2, 4.5 Hz, IH), 4.77 (d, J = 11.4 Hz, IH), 4.60 (d, J = 11.4 Hz, IH), 4.09 (d, J = 4.5 Hz, IH), 4.02 (dd, / = 6.2, 3.7 Hz, IH), 3.79 (dd, J = 8.9, 5.0 Hz, IH), 3.65-3.53 (m, 2H), 2.81-2.58 (m, 4H), 1.30-1.19 (m, 15H); ¹³C NMR (75 MHz, CDCl₃): S 177.6, 137.6, 128.4, 127.8, 127.6, 79.0, 74.8, 73.8, 71.5, 63.7, 51.7, 39.2, 27.5, 25.6, 25.4, 14.5, 14.4; MALDI-HRMS m/z calcd for C₂₁H₃₄O₅S₂Na⁺: 453.1740, obsd: 453.1731 [M+Na]⁺.

S-O-Benzyl-l-O-pivaloyl-S-O-triphenylmethyl-D-xylose diCethylthioJacetaHSS).

To a solution of diol 32 (17.3 g, 40.2 mmol) in pyridine (200 mL) at 0 ⁰C was added portionwise triphenylmethyl chloride (16.7 g, 60 mmol). The mixture was stirred at room temperature for 24 h and the solvent was removed in vacuo. The residue was purified by flash chromatography (hexanes/ethyl acetate, 20: 1 to 6: 1) to give 33 (24.3 g, 90 %) as a pale yellow foam. [α]_D ²⁰ = -8.9 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3007, 1724, 1448, 1363, 1277, 1152, 1077, 632 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 7.70-7.11 (m, 20H), 5.70 (dd, J = 7.0, 4.0 Hz, IH), 4.76 (d, 7 = 11.1 Hz, IH), 4.51-4.42 (m, 2H), 4.27 (d, J = 4.0 Hz, IH), 4.25-4.17 (m, 2H), 3.52 (dd, J = 8.9, 5.5 Hz, IH), 3.22 (d, J = 8.4 Hz, IH), 3.02-2.82 (m, 2H), 2.80-2.71 (m, 2H), 1.50-1.32 (m, 15H); ¹³C NMR (75 MHz, CDCl₃): δ 177.4, 143.7, 137.8, 128.6, 128.2, 127.8, 127.6, 127.4, 127.2, 86.9, 82.1, 78.4, 75.1, 74.0, 70.5, 64.1, 39.2, 27.6, 26.0, 25.6, 14.8, 14.6; MALDI-HRMS m/z calcd for C₄₀H₄₈O₅S₂Na⁺: 695.2835, obsd: 695.2828 [M+Na]⁺.

3-O-Benzyl-4-O-levuIinoyl-2-O-pivaIoyl-5-O-triphenylmethyl-D-xylose di(ethylthio)acetal (34). Levulinic acid (6.79 g, 58.5 mmol) was dissolved in CH₂Cl₂ (500 mL), followed by the addition of 4-DMAP (7.15 g, 58.5 mmol). The mixture was cooled to 0 ⁰C and JV,ΛT-diisopropyl carbodiimide (DIC) (9.23 mL, 5.85 mmol) was added. After 10 min alcohol 33 (26.5 g, 39 mmol) in CH₂Cl₂ (40 mL) was added dropwise. The mixture was stirred at room temperature for 4 h. After dilution with CH₂Cl₂ (100 mL) the mixture was washed with sat. aq. NH₄Cl and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate, 4:1) to give 34 (2.96 g, quant.) as a white foam. [α]_D ²⁰ = -15.2 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3007, 1727, 1490, 1448, 1279, 1152, 1075, 1032, 899, 632 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 7.45-7.10 (m, 20H), 5.35-5.28 (m, IH), 5.23 (d, J = 5.6 Hz, IH), 4.70 (d, J = 11.5 Hz, IH), 4.57-4.49 (m, 2H), 4.06 (d, / = 5.4 Hz, IH), 3.25-3.21 (m, 2H), 2.81-2.47 (m, 8H), 2.13 (s, 3H), 1.28 (t, J = 7.4 Hz, 3H), 1.22-1.12 (m, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 205.8, 177.2, 172.1, 138.4, 128.1, 127.2, 127.0, 76.9, 75.0, 74.4, 72.4, 61.0, 52.0, 39.1, 37.8, 28.2, 27.5, 25.9, 25.1, 25.0, 18.2, 14.3; MALDI-HRMS m/z calcd for C₄₅H₅₄O₇S₂Na⁺: 793.3203, obsd: 793.3194 [M+Na]⁺.

3-O-Benzyl-4-O-levulinoyI-2-O-pivaloyI-D-xyIose di(ethylthio)acetal (35). Compound 34 (3.5 g, 4.54 mmol) was dissolved in CH₂Cl₂ (200 mL) and cooled to 0 ⁰C. Triethylsilane (14.5 mL, 91 mmol) was added, followed by dropwise addition of the trifluoroacetic acid (13.5 mL, 182 mmol). After 5 min the solution was adjusted to pH 5 by careful addition of sat. aq. NaHCO₃. The organic layer was separated, washed with brine and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate, 3:1 to 2:3) to give 35 (2.16 g, 90 %) as a colorless oil. [α]_D ²⁰ = -20.3 (c = 1, CHCl₃); IR (thin film on NaCl): v = 2973, 1722, 1479, 1367, 1152, 1152, 1048 cm ¹; ¹H NMR (300 MHz, CDCl₃): δ 136-1.20 (m, 5H), 5.33 (d, / = 5.5 Hz, IH), 5.10 (t, J = 4.7, 4.4 Hz, IH), 4.77 (d, / = 11.7 Hz, IH), 4.67 (d, J = 11.7 Hz, IH), 4.34 (d, J = 5.3 Hz, IH), 4.04 (d, / = 5.8 Hz, IH), 3.72-3.67 (m, 2H), 2.82-2.35 (m, 8H), 2.13 (s, 3H), 1.28-1.15 (m, 15H); ¹³C NMR (75 MHz, CDCl₃): δ 206.9, 177.4, 172.4, 138.0, 128.2, 127.5, 127.2, 77.0, 74.7, 74.6, 72.5, 61.4, 52.0, 39.1, 38.1, 28.3, 27.4, 25.1, 25.0, 14.5, 14.4; MALDI-HRMS m/z Ca^ fOr C₂₆H₄₀O₇S₂Na⁺: 551.2108, obsd: 551.2104 [M+Na]⁺.

3-0-Benzyl-2-0-levuIinoyl-2-0φivaIoyl-D-.*j/øφentodialdose l- di(ethylthio)acetal (36). To a solution of alcohol 35 (1.71 g, 3.24 mmol) in CH₂Cl₂ (32 mL) at 0 °C was added sulfur trioxide pyridine complex (2.07 g, 13 mmol), followed by the addition of N-diisopropylethylamine (3.9 mL, 22.7 mmol). The mixture was stirred for 5 min and dimethyl sulfoxide (3.2 mL, 4^'5.4 mmol) was added dropwise. After stirrring at 0 °C for 15 min the solution was diluted with CH₂Cl₂ (200 mL) and brine (50 mL) was added. The phases were separated and the organic layer was washed with brine and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexanes/ethyl acetate, 5:1) to give 36 (1.49 g, 88 %) as a yellow oil. [α]_D ²⁰ = 3.7 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3008, 1736, 1455, 1366, 1275, 1147 cm^"1; ¹H ΝMR (300 MHz, CDCl₃): δ 9.52 (s, IH), 7.38-7.24 (m, 5H), 5.41 (d, / = 5.5 Hz, IH), 5.28 (d, J = 4.6 Hz, IH), 4.75 (d, J = 11.3 Hz, IH), 4.66 (d, J = 11.1 Hz, IH), 4.61-4.57 (m, IH), 4.00 (d, / = 5.7 Hz, IH), 2.91-2.54 (m, 8H), 2.18 (s, 3H), 1.29-1.17 (m, 15H); ¹³C ΝMR (75 MHz, CDCl₃): δ 205.9, 195.9, 176.8, 171.7, 137.1, 128.3, 127.9, 127.6, 77.4, 76.3, 74.6, 72.0, 51.6, 39.1, 37.9, 29.8, 27.8, 27.4, 25.4, 25.2, 14.4, 14.3; MALDI-HRMS m/z calcd for C₂₆H₃₈O₇S₂Na⁺: 549.1951, obsd: 549.1946 [M+Na]⁺.

Example 5 — Synthesis of an Exemplary Carbohydrate Building Block

OLevOPiv OH OPiv O OH OPiv SEt _jΛ sEt __ Nc_γA₁A_rsEt __ _Me0A_IΛ_ϊΛ_rsEt __ yfigf

O OBn SEt OH ^* OBn SEt OH OBn SEt R¹O OPiv

36 37 38 I — 39 R¹ = H

>— 40 R¹ = Lev

3-0-Benzyl-2-0-pivaloyl-L-idurononitril di(ethylthio)acetal (37). Aldehyde 36 (1.49 g, 2.84 mmol) was dissolved in CH₂Cl₂ (28 mL) and cooled to 0 °C. MgBr₂-OEt₂ (2.93 g, 11.36 mmol) was added and the mixtute was stirred vigorously for 5 min. Trimethylsilyl cyanide (416 μL, 3.12 mmol) was added dropwise over 10 min. The mixture was stirred at 0 °C for 10 h before it was quenched with brine. The solution was diluted with CH₂Cl₂ (100 mL), washed with brine and dried over MgSO₄. After concentration the residue was filtered through silica gel (hexanes/ethyl acetate, 2:1) and concentrated again. The resulting yellow oil was dissolved in CH₂Cl₂ (28 mL). Hydrazine acetate (314 mg, 3.41 mmol) in MeOH (28 mL) was added dropwise and the mixture was stirred for 12 h. The solvent was removed in vacuo and the mixture of both nitriles was separated by silica gel chromatography (hexanes/ethyl acetate, 10:1 to 5:1) to give nitrile 37 (943 mg, 73 %, yellow solid). IR (thin film on NaCl): v = 3553, 2977, 1729, 1479, 1397, 1264, 1148 cm^"1; ¹H NMR (300 MHz, CDCl₃): δ 1 AQ-1.21 (m, 5H), 5.46 (dd, J = 5.9, 4.4 Hz, IH), 4.81 (d, J = 11.3 Hz, IH), 4.66 (d, J = 11.4 Hz, IH), 4.50 (d, / = 5.7 Hz, IH), 4.18 (dd, J = 5.9, 3.8 Hz, IH), 4.06 (d, / = 4.4 Hz, IH), 3.96 (dd, J = 5.7, 3.7 Hz, IH), 2.84-2.55 (m, 4H), 1.33- 1.17 (m, 15H); ¹³C NMR (75 MHz, CDCl₃): δ 178.1, 136.9, 128.6, 128.1, 127.8, 117.9, 77.2, 75.0, 73.8, 72.1, 62.3, 51.2, 39.1, 27.2, 25.4, 25.3, 14.2, 14.0; MALDI-HRMS m/z calcd for C₂₂H₃₃NO₅S₂Na⁺: 478.1692, obsd: 478.1682 [M+Na]⁺.

Methyl 3-O-benzyl-2-O-pivaloyI-L-iduronate di(ethylthio)acetal (38). To a solution of acetyl chloride (3.17 mL, 44.4 mmol) in Et₂O (20 mL) at 0 °C was added MeOH (3.5 mL, 88 mmol) dropwise and stirred for 2 min. Nitrile 37 (1.35 g, 2.9 mmol) in Et₂O (20 mL) was added dropwise over 10 min. The solution was stirred for 18 h at room temperature. Water (20 mL) was added dropwise and the mixture was stirred vigorously for 12 h. The phases were separated and the organic layer was washed with sat. aq. NaHCO₃ and brine and dried over over MgSO₄. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexanes/ethyl acetate, 1:1) to give ester 38 (1.19 g, 84 %) as a colorless oil. [α]_D ²⁰ = -29.7 (c = 1, CHCl₃); IR (thin film on NaCl): v = 3544, 2972, 1731, 1429, 1367, 1277, 1148 cm^"1; ¹H NMR (300 MHz, CDCl₃): S 7.44-7.27 (m, 5H), 5.43 (dd, J = 5.7, 4.9 Hz, IH), 4.84 (d, J = 11.3 Hz, IH), 4.71 (d, J = 11.3 Hz, IH), 4.30 (dd, J = 5.3, 2.8 Hz, IH), 4.25 (d, J = 5.1 Hz, IH), 4.14 (d, J = 6.1 Hz, IH), 4.07 (ddd, / = 8.1, 5.6, 2.8 Hz, IH), 3.66 (s, 3H), 3.10 (d, / = 5.4 Hz, IH), 2.80-2.57 (m, 4H), 1.31- 1.20 (m, 15H); ¹³C NMR (75 MHz, CDCl₃): δ 177.5, 173.1, 137.8, 128.3, 127.6, 127.5, 78.6, 74.8, 73.1, 72.4, 70.7, 52.8, 51.8, 39.2, 27.4, 25.1, 25.0, 14.4, 14.3; MALDI-HRMS m/z calcd for C₂₃H₃₆O₇S₂Na⁺: 511.1795, obsd: 511.1787 [M+Na]⁺.

Methyl (ethyl 3-0-benzyl-2-0-pivaloyl-l-thio-L-idopyranoside)uronate (39).

Diol 38 (420 mg, 0.72 mmol) was dissolved in CH₂Cl₂ (14 mL). TV-Iodosuccinimide (194 mg, 0.86 mmol) was added and stirred for 15 min. Sat. aq. sodium thiosulfate (10 ml) was added and stirred for 10 min. The mixture was diluted with CH₂Cl₂ (100 mL) and the phases were separated. The organic layer was washed with brine and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate, 20:1 to 8:1) to give 39 as 1:1 mixture (327 mg, 89 %, colorless oil). IR (thin film on NaCl): v = 3571, 2976, 1735, 1479, 1368, 1275, 1140, 1063, 908 cm^"1; ¹H NMR (300 MHz, CDCl₃, 1:1 mixture): δ 134 (m, 10H), 5.36 (s, IH), 5.22 (d, J = 1.6 Hz, IH), 5.11-5.06 (m, 2H), 5.04 (m, 2H), 4.85-4.51 (m, 4H), 4.02 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.71-3.64 (m, 2H), 2.81-2.57 (m, 8H), 1.35-1.19 (m, 24H); ¹³C NMR (75 MHz, CDCl₃, 1:1 mixture): δ 176.8, 176.5, 169.7, 168.7, 137.0, 128.5, 128.3, 128.1, 127.9, 127.7, 127.6, 127.5, 86.0, 83.4, 82.2, 81.4, 77.9, 77.8, 76.2, 74.5, 73.7, 72.8, 72.6, 72.2, 70.1, 69.5, 69.1, 68.4, 68.3, 67.6, 52.7, 52.4, 39.3, 39.0, 29.8, 27.4, 27.2, 26.0, 25.3, 25.0, 15.2, 15.1; HRMS m/z calcd for C₂₁H₃₀O₇SNa⁺: 449.1604, obsd: 449.1598 [M+Na]⁺.

Methyl (ethyl 3-0-benzyl-4-0-levulinoyl-2-0-pivaloyl-l-thio-L- idopyranoside)uronate (40). Levulinic acid (36 mg, 0.31 mmol) was dissolved in CH₂Cl₂ (3 mL), followed by the addition of 4-DMAP (38 mg, 0.31 mmol). The mixture was cooled to 0 °C and N,ΛT-diisopropyl carbodiimide (49 μL, 0.31 mmol) was added. After 10 min alcohol 39 (111 mg, 0.26 mmol) in CH₂Cl₂ (2 mL) was added dropwise. The mixture was stirred at room temperature for 4 h, then diluted with CH₂Cl₂ (50 mL), washed with sat. aq. NH₄Cl and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate, 1:1) to give 40 as a 1:1 mixture of anomers (136 mg, quant., colorless oil). IR (thin film on NaCl): v = 3586, 3032, 1740, 1602, 1364, 1150, 1071 cm^"1; ¹H NMR (300 MHz, CDCl₃, 1:1 mixture): δ 7.42-7.25 (m, 10H), 5.40 (s, IH), 5.27 (d, J = 2.3 Hz, IH), 5.24-5.19 (m, 2H), 5.01 (d, / = 2.0 Hz, IH), 5.00-4.97 (m, IH), 4.97-4.94 (m, IH), 4.81-4.75 (m, 2H), 4.72-4.65 (m, 2H), 4.55 (d, J = 1.8 Hz, IH), 3.79 (s, 3H), 3.78 (s, 3H, s), 3.73-3.71 (m, 2H), 2.84-2.47 (m, 8H), 2.18 (s, 3H), 2.17 (s, 3H), 1.34-1.19 (m, 12H); ¹³C NMR (75 MHz, CDCl₃, 1:1 DΛ-mixture): δ 205.8, 177.6, 177.2, 171.8, 171.6, 168.9, 167.8, 137.1, 136.9, 128.4, 128.3, 128.0, 127.7, 127.6, 127.4, 82.7, 82.1, 74.3, 73.5, 72.9, 72.7, 72.5, 68.3, 68.0, 66.9, 66.4, 52.3, 52.2, 38.6, 37.6, 29.6, 27.8, 27.7, 27.1, 27.0, 26.9, 26.5, 25.8, 14.8; MALDI-HRMS m/z calcd for C₂₆H₃₆O₉SNa⁺: 547.1972, obsd: 547.1965 [MH-Na]⁺.

Example 6 — Synthesis of an Exemplary Branched Building Block

41 42

44a 4S 43a 4S 44b 4R 43b 4R

2,3-O-Isopropylidine-D-arabinose diethyl dithio acetal (41). 2,2- Dimethoxypropane (40 mL, 325 mL, 2.25 equiv.) andp-toluenesulfonic acid (0.5 g, cat.) were added to a suspension of D-arabinose diethyl dithioacetal (36.8 g, 144 mmol) in acetone (500 mL). After obtaining a homogenous solution and stirring for an additional hour, the mixture was concentrated and the residue dissolved in a mixture of MeOH (500 mL) and H₂O (5 mL). The solution was stirred for 2 h at 50°C, sat. aq. NaHCO₃ (100 mL) was added and the mixture concentrated to 150 mL. The residue was extracted with ethyl acetate (3 x 100 mL), dried (MgSO₄) and concentrated. The resulting residue was triturated with dichloromethane and the solid D-arabinose diethyl dithioacetal (4.5 g; 17.6 mmol; 12%) collected by filtration. Concentration of the mother liquor and purification of the residue by column chromatography (hexanes -» ethyl acetate/hexanes, 1/3, v/v) gave homogeneous diol 41 (32 g, 108 mrnol, 75%) as a colorless oil. α_D ²⁰ = 59 (c 1.0, CHCl₃); IR (CHCl₃): 3606, 3421, 2991, 2931, 2873, 1602, 1455, 1385, 1374, 1248, 1161, 1052, 977, 881 cm^"1; ¹H-NMR (300 MHz, CDCl₃): δ 4.31 (dd, IH, J= 3.8 Hz, J = 6.9 Hz), 4.08 (dd, IH, J = 6.9, J = 7.0 Hz), 4.01 (d, IH, 7= 3.8 Hz), 3.81 (dd, IH, / = 2.8 Hz, J = 10.5 Hz), 3.73 (ddd, J = 2.8 Hz, J = 5.4 Bz, J = 7.0 Hz), 3.67 (dd, IH, / = 5.4 Hz, J = 10.5 Hz), 2.99 (bs, 2H), 2.77-2.65 (m, 4H), 1.43 (s, 3H), 1.36 (s, 3H), 1.25 (t, IH, /= 7.4 Hz), 1.24 (t, IH, J = 7.4 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 110.0, 83.2, 79.1, 73.0, 63.9, 53.1, 27.4, 27.1, 25.5, 25.2, 14.4; ESI-MS (m/z): 319.2 [M+Na]⁺, 615.2 [2M+Na]⁺, 341.0 [M+HC0₂]^'; HRMS(EI) m/z calcd for Ci₂H₂₂O₄S₂ ⁺: 296.1111, obsd: 296.1109.

Methyl 2,3-0-isopropyIidine-D-threuronate diethyl dithio acetal (42). A solution of NaIO₄ (6.34 g, 30 mmol, 1.4 equiv.) in H₂O (25 mL) was added dropwise to a cooled (0°C) and stirred solution of diol 41 (6.34 g, 21.4 mmol) in THF (75 mL). The ice bath was removed and the suspension stirred for 10 min before being quenched by the addition of cone. aq. sodium bicarbonate (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined extracts were washed with brine (200 mL), dried (MgSO₄), filtered and concentrated. The resulting aldehyde was dissolved in dioxane (100 mL) and the solution was added to a stirred suspension of AgO, freshly made by the addition of a solution of NaOH (2.56 g, 64.2 mmol, 3.0 equiv.) in H₂O (50 mL) to a vigorously stirred solution of AgNO₃ (7.28 g, 42.8 mmol, 2.0 equiv.) in H₂O (50 mL). After 5 min, the reaction mixture was filtered over celite and the filter washed with water. The aqueous solution was extracted with ether (2 x 100 mL), acidified with 1 M aq. HCl to pH 2, and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried (MgSO₄), filtered and concentrated. KOH (3.42 g, 56.1 mmol, 2.8 equiv.) was dissolved in a mixture of ether (15 mL), diethylene glycol monomethyl ether (30 mL) and H₂O (15 mL). This solution was placed in the distilling flask of a distillation setup equipped with a water bath at 70⁰C, a Claisen adapter, a dropping funnel, water cooled condensor and a vacuum adapter for pressure relief, all without sharp edges or ground-glass joints. The acid was dissolved in ether (90 mL) and placed in the receiving flask. An ethereal solution of diazomethane was distilled by the dropwise addition of a solution of N-methyl-N-(p-tolylsulfonyl)nitrosamide (11.9 g, 55.6 mmol, 2.6 equiv.) in ether (90 mL). After complete addition of the ethereal solution, two additional portions of ether (10 mL) were added slowly and the distillation continued until the distillate was colorless. After one hour, the reaction was quenched by the addition of acetic acid (2 x 1 mL) in both the receiving and distillation flasks. After stirring for an additional 16h, the reaction mixture was concentrated and the residue was purified by column chromatography (hexanes —> CH₂Cl₂/hexanes, 1/1, v/v) to yield homogeneous methyl ester 42 (5.16 g, 18 mmol, 82%) as a colorless oil. OC_D ²⁰ = 75 (c 1.0, CHCl₃); IR (CHCl₃): 2993, 2931, 1750, 1439, 1376, 1263, 1163, 1109, 876, 816 cm^"1; ¹H- NMR (300 MHz, CDCl₃): δ 4.64 (d, IH, J = 6.8 Hz), 4.56 (dd, IH, J = 4.4 Hz, J = 6.8 Hz), 3.98 (d, IH, J = 4.4 Hz), 3.79 (s, 3H), 2.77 (dq, 2H, J= 12.4 Hz, J= 7.4 Hz), 2.71 (dq, 2H, J= 12.3 Hz, J = 7.4 Hz), 1.50 (s, 3H), 1.42 (s, 3H), 1.27 (t, 3H, J = 7.4 Hz), 1.26 (t, 3H, J = 7.4 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 170.9, 112.1, 82.2, 77.6, 52.8, 52.6, 52.6, 26.9, 25.9, 25.4, 25.0, 14.5, 14.4, 14.3; ESI-MS (m/z): 312.3 [M+NHif, 317.3 [M+Na]⁺, 611.0 [2M+Na]⁺; HRMS(EI) m/z calcd for Cj₂H₂₂O₄S₂ ⁺: 294.0955, obsd: 294.0962.

S-Deoxy-S-C-methoxycarbonyl^S-O-isopropylidine-L-xylose diethyl dithio acetal (43a, major) and S-deoxy-S-C-methoxycarbonyl^jS-CMsopropylidine-D- arabinose diethyl dithio acetal (43b, minor): BuLi (10.1 mL 1.6 M in hexanes, 16.2 mmol, 2.0 equiv.) was added to a cooled (-50 C), stirred solution of tetramethyl piperidine (2.87 mL, 17.0 mmol, 2.1 equiv.) in THF (100 mL). After 30 min, the reaction mixture was cooled further (-78 C) and a solution of methyl ester 42 (2.38 g, 8.1 mmol) in THF (20 mL) was added dropwise. After another 30 min, acetaldehyde (2.26 mL, 40.4 mmol, 5.0 equiv.) was added and the reaction mixture stirred for two hours, allowing the temperature to rise to -20⁰C. The reaction was quenched by the addition of sat. aq. NH₄Cl (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried (MgSO₄), filtered and concentrated. Purification of the residue by column chromatography (hexanes -» 5% ethyl acetate in hexanes) gave first 43b (0.50 g, 1.5 mmol, 18 %) and then 43a (2.02 g, 6.0 mmol, 74 %). 43a: α_D ²⁰ = 70 (c 1.0, CHCl₃); IR (CHCl₃): 3578, 2988, 2931, 2873, 1750, 1720, 1455, 1435, 1382, 1259, 1143, 1101, 1034, 978, 894, 840 cm^"1; ¹H-NMR (300 MHz, CDCl₃): δ 4.76 (d, IH, J= 3.0 Hz), 4.13 (dq, IH, J= 9.9 Hz, J= 6.4 Hz), 4.03 (d, IH, J = 3.0 Hz), 3.74 (s, IH), 2.74 (dq, IH, J = 12.4 Hz, J= 7.5 Hz), 2.69 (dq, IH, J= 7.5 Hz, J = 12.4 Hz), 2.69 (dq, IH, J = 7.4 Hz, J = 11.8 Hz), 2.60 (dq, IH, J = 7.4 Hz, J = 11.8 Hz), 2.01 (d, IH, J = 9.9 Hz), 1.61 (d, 3H, J= 0.5 Hz), 1.43 (d, 3H, J= 0.5 Hz), 1.26 (t, 3H, J = 7.4 Hz), 1.21 (t, 3H, J = 7.5 Hz), 1.20 (d, 3H, J = 6.4 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 171.7, 110.7, 87.9, 83.0, 68.1, 52.4, 50.9, 26.9, 26.7, 25.9, 25.0, 18.9, 14.4, 13.7; ESI-MS (m/z): 699.0 [2M+Na]⁺; HRMS(EI) m/z calcd for C₁₄H₂₆O₅S₂ ⁺: 338.1217, obsd: 338.1217. 43b: α_D ²⁰ = 24 (c 1.0, CHCl₃); IR (CHCl₃): 3566, 2989, 2931, 2872, 1750, 1737, 1456, 1436, 1377, 1262, 1144, 1098, 1073, 970, 891, 835 cm⁴; ¹H-NMR (300 MHz, CDCl₃): δ 4.58 (d, IH, / = 6.5 Hz), 4.51 (qd, IH, J = 6.3 Hz, J = 7.5 Hz), 4.43 (d, IH, / = 6.5 Hz), 3.78 (s, 3H), 2.82 (dq, IH, / = 12.4 Hz, J = IA Hz), 2.82 (d, IH, J = 7.7 Hz), 2.77 (q, 2H, J = 7.4 Hz), 2.68 (dq, IH, / = 12.4 Hz, J= 7.4 Hz), 1.59 (bq, 3H, ⁴J= 0.6 Hz), 1.48 (bq, 3H, ⁴J = 0.6 Hz), 1.294 (t, IH, / = 7.4 Hz), 1.295 (t, IH, J = 7.4 Hz), 1.16 (d, 3H, J = 6.3 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 172.3, 110.1, 87.7, 84.7, 66.5, 52.5, 49.2, 26.8, 25.6, 24.8, 24.5, 18.8, 14.2; ESI-MS (m/z): 699.0 [2M+Na]⁺; HRMS(EI) m/z calcd for C₁₄H₂₆O₅S₂ ⁺: 338.1217, obsd: 338.1217. l-Deoxy-l-ethylthio-α,β-L-aceric acid methyl ester (44a). Acetonide 43a (100 mg, 0.30 mmol) was dissolved in a mixture of TFA (2.5 mL) and H₂O (2.5 mL). After stirring for 2h at room temperature the solvents were evaporated in vacuo and the residue was taken up in pure TFA and stirred for an additional hour. Concentration of the reaction mixture and purification of the residue by column chromatography (ethyl acetate) to give thioglycoside 44a (69 mg, 0.30 mmol, 99%) as a colorless oil. α_D ²⁰ = 4.7 (c 1.0, CHCl₃); IR (CHCl₃): 3520, 3007, 2931, 1732, 1602, 1439, 1380, 1264, 1147, 1063, 1012, 970, 909, 891 cm^"1, α-anomer: ¹H-NMR (300 MHz, CDCl₃): δ 5.55 (d, IH, 7= 5.0 Hz), 4.61 (q, IH, / = 6.3 Hz), 4.28 (dd, IH, J = 5.0 Hz, J = 6.3 Hz), 3.87 (s, 3H), 3.18 (bs, IH), 2.96 (bd, IH, / = 6.3 Hz), 2.77 (dq, IH, J= 12.7 Hz, J = 7.4 Hz), 2.71 (dq, IH, J= 12.7 Hz, /= 7.4 Hz), 1.32 (t, 3H, J = 7.4 Hz), 1.24 (d, 3H, /= 6.4 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 171.8, 89.8, 83.4, 81.7, 77.3, 53.4, 25.8, 15.4, 12.8; β-anomer: ¹H-NMR (300 MHz, CDCl₃): δ 4.94 (d, IH, J= 5.3 Hz), 4.42 (q, IH, /= 6.4 Hz), 4.12 (dd, IH, /= 5.2 Hz, J= 5.3 Hz), 3.88 (s, 3H), 3.35 (bs, IH), 2.90 (bd, IH, J= 5.2 Hz), 2.70 (q, 2H, / = 7.4 Hz), 1.32 (t, 3H, /= 7.4 Hz), 1.29 (d, 3H, J = 6.4 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 172.3, 87.3, 84.3, 83.2, 79.5, 53.4, 25.3, 15.1, 14.9; ESI-MS (m/z): 281.0 [M+HCO₂]^"; HRMS(ESI) m/z calcd for C₉H₁₆O₅SNa⁺: 259.0611, obsd: 259.0613. l-Deoxy-4-epi-l-ethylthio-L-aceric acid methyl ester (44b). Acetonide 44b (38 mg, 0.11 mmol) was dissolved in a mixture of TFA (2.5 mL) and H₂O (2.5 mL). After stirring for 2h at room temperature the solvents were evaporated in vacuo and the residue was taken up in pure TFA and stirred for an additional hour. Concentration of the reaction mixture and purification of the residue by column chromatography (ethyl acetate) to obtain thioglycoside 44b (25 mg, 0.11 mmol, 99%) as a colorless oil. α_D ²⁰ = 151 (c 0.5, CHCl₃); IR (CHCl₃): 3600, 3514, 3007, 2958, 2931, 2874, 1732, 1602, 1440, 1381, 1280, 1160, 1112, 1087, 970, 870 cm^"1; ¹H-NMR (300 MHz, CDCl₃): δ 5.22 (d, IH, J= 6.7 Hz), 4.26 (d, IH, J= 6.1 Hz), 4.23 (q, IH, J= 6.5 Hz), 3.93 (s, 3H), 2.77 (qd, IH, J= 7.4 Hz, J= 12.9 Hz), 2.71 (qd, IH, J= 7.4 Hz, J= 12.9 Hz), 1.33 (t, 3H, J= 7.4 Hz), 1.18 (d, 3H, J= 6.5 Hz); ¹³C-NMR (75 MHz, CDCl₃): δ 171.9, 87.7, 84.9, 84.1, 77.4, 77.2, 53.3, 25.8, 15.1, 14.2; ESI-MS (m/z): 281.0 [M+HCO₂]^"; HRMS(ESI) m/z calcd for C₉H₁₆O₅SNa⁺: 259.0611, obsd: 259.0613.

EQUIVALENTS & INCORPORATION BY REFERENCE

It is understood that the examples and embodiments described herein are provided for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. All U.S. patents and U.S. patent application publications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

We Claim:

1. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

^cyclization „

wherein

X₂, X₃, X₄ and X₅ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and N₃;

Y₁, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, -CR(XR), =C(XR)₂, and =C(R)_2;

X is independently for each occurrence selected from the group consisting of O,

NH, NR, S, and Se;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted inline, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, pliosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, X₄ or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

2. The method of claim 1, wherein said condensation is an aldol condensation.

3. The method of claim 1 , wherein said condensation comprises a Lewis acid.

4. The method of claim 1, wherein said condensation comprises BF₃OEt₂ or MgBr₂OEt.

5. The method of claim 1, wherein said condensation comprises MgBr₂OEt.

6. The method of claim 1, wherein said one or more steps comprises one or more reductions, protections or deprotections.

7. The method of claim 1, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

8. The method of claim 1, wherein said cyclization comprises N-iodosuccinimide (NIS).

9. The method of claim 1, wherein A is -SR¹; and R' is alkyl.

10. The method of claim 1, wherein A is -SEt.

11. The method of claim 1 , wherein X₂ is -O-.

12. The method of claim 1, wherein X₂ is -O- ; and B is H.

13. The method of claim 1 , wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

14. The method of claim 1, wherein X₃ is -O-.

15. The method of claim 1, wherein X₃ is -O-; and C is H.

16. The method of claim 1, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

17. The method of claim 1, wherein X₄ is -O-.

18. The method of claim 1 , wherein X₄ is -O-; and D is H.

19. The method of claim 1, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

20. The method of claim 1, wherein X₅ is -O-.

21. The method of claim 1, wherein X₅ is -O-; and E is H.

22. The method of claim 1, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

23. The method of claim 1 , wherein X₆ is -CH₂O-.

24. The method of claim 1 , wherein X₆ is -CH₂O-; and F is H.

25. The method of claim 1, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

26. The method of claim 1, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane- 1,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

27. The method of claim 1 , wherein Y₁ is -C(XR)₂H.

28. The method of claim 1 , wherein Y₁ is -C(SR)₂H; and R is alkyl.

29. The method of claim 1 , wherein Yi is -C(SEt)₂H.

30. The method of claim 1 , wherein Y₂ is -C(=O)H.

31. The method of claim 1 , wherein Y₃ is =C(XR)H.

32. The method of claim 1 , wherein Y₃ is =C(OR)H; and R is silyl.

33. The method of claim 1 , wherein Y₃ is =C(OTBDMS)H.

34. The method of claim 1 , wherein Y₄ is -C(X)XR.

35. The method of claim 1 , wherein Y₄ is -C(H)OR.

36. The method of claim 1, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

37. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

wherein

X₂, and X₃ are independently selected from the group consisting of H, -0-, -CN, -NH-, -NO₂, and -N₃;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine; substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂ or X₃ is H, -CN₃ -NO₂, or -N₃, the corresponding B, C or E is absent.

38. The method of claim 37, wherein said condensation is an aldol condensation.

39. The method of claim 37, wherein said condensation comprises a Lewis acid.

40. The method of claim 37, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

41. The method of claim 37, wherein said condensation comprises MgBr₂OEt.

42. The method of claim 37, wherein said one or more steps comprises one or more reductions, protections or deprotections.

43. The method of claim 37, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

44. The method of claim 37, wherein said cyclization comprises N-iodosuccinimide (NIS).

45. The method of claim 37, wherein A is -SR'; and R' is alkyl.

46. The method of claim 37, wherein A is -SEt.

47. The method of claim 37, wherein X₂ is -O-.

48. The method of claim 37, wherein X₂ is -O-; and B is H.

49. The method of claim 37, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

50. The method of claim 37, wherein X₃ is -O-.

51. The method of claim 37, wherein X₃ is -O-; and C is H.

52. The method of claim 37, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

53. The method of claim 37, wherein at B or C is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane- 1,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

54. The method of claim 37, wherein Y₁ is -C(XR)₂H.

55. The method of claim 37, wherein Y₁ is -C(SR)₂H; and R is alkyl.

56. The method of claim 37, wherein Y₁ is -C(SEt)₂H.

57. The method of claim 37, wherein Y₂ is -C(=0)H.

58. The method of claim 37, wherein Y₃ is =C(XR)H.

59. The method of claim 37, wherein Y₃ is =C(0R)H; and R is silyl.

60. The method of claim 37, wherein Y₃ is =C(OTBDMS)H.

61. The method of claim 37, wherein Y₄ is =C(XR)₂.

62. The method of claim 37, wherein Y₄ is =C(0R)₂; and R is alkyl or silyl

63. The method of claim 37, wherein Y₄ is =C(0Me)(0TMS).

64. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below: condensation _ur. _{γ D}

X Λ₂,BD f Toolnloowweedα ^HV T i p² ^γ4-_γ ¹ 3

Y2 r "YYii bbvy oonnee oorr mmoorree FX^β J ^*Yi steps X₃C

cyclization

wherein

A represents acetimidoyl, substituted acetimidoyl, halogen, trichloroacetimidoyl, thiocarbamoyl, sulfoxide, -OR', -SR', or -SeR'; R' is selected independently for each occurrence from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, and substituted aryl;

X₂ and X₃ are independently selected from the group consisting of H, -O-, -CN,

-NH-

-NO₂, and -N₃;

Y₁, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, - C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), ^C(XR)₂, and =C(R)_2;

X is independently for each occurrence selected from the group consisting of O,

NH, NR, S, and Se;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂ or X₃ is H, -CN, -NO₂, or -N₃, the corresponding B, C, or E is absent; and when any occurrence of X₆ is -CH₃, - CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

65. The method of claim 64, wherein said condensation is an aldol condensation.

66. The method of claim 64, wherein said condensation comprises a Lewis acid.

67. The method of claim 64, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

68. The method of claim 64, wherein said condensation comprises MgBr₂OEt.

69. The method of claim 64, wherein said one or more steps comprises one or more reductions, protections or deprotections.

70. The method of claim 64, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

71. The method of claim 64, wherein said cyclization comprises N-iodosuccinimide (NIS).

72. The method of claim 64, wherein A is -SR'; and R' is alkyl.

73. The method of claim 64, wherein A is -SEt.

74. The method of claim 64, wherein X₂ is -O-.

75. The method of claim 64, wherein X₂ is -O-; and B is H.

76. The method of claim 64, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

77. The method of claim 64, wherein X₃ is -O-.

78. The method of claim 64, wherein X₃ is -O-; and C is H.

79. The method of claim 64, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

80. The method of claim 64, wherein X₆ is -CH₂O-.

81. The method of claim 64, wherein X₆ is -CH₂O-; and F is H.

82. The method of claim 64, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

83. The method of claim 64, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane- 1,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

84. The method of claim 64, wherein Y₁ is -C(XR)₂H.

85. The method of claim 64, wherein Y₁ is -C(SR)₂H; and R is alkyl.

86. The method of claim 64, wherein Y₁ is -C(SEt)₂H.

87. The method of claim 64, wherein Y₂ is -C(=O)H.

88. The method of claim 64, wherein Y₃ is =C(XR)H.

89. The method of claim 64, wherein Y₃ is =C(OR)H; and R is silyl.

90. The method of claim 64, wherein Y₃ is =C(OTBDMS)H.

91. The method of claim 64, wherein Y₄ is -C(X)XR.

92. The method of claim 64, wherein Y₄ is -C(H)OR.

93. The method of claim 64, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

94. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below: condensation _ur. _{γ n}

EX₅ followed ^MV J²**

Y₄^Y₃ ^{+ Yi} by one or more ^Fχe" ηf Yⁱ steps X3C

cyclization

wherein

X₂, X₃, and X₅ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and -N₃; X₆ represents independently for each occurrence, -CH₂O-, -CH₂NH-, -CH₃, -CH₂NO₂, -CH₂N₃, -COO-, -CONH-, -CN or -COS-;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted allcyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, or E is absent; and when any occurrence of X₆ is -CH₃, - CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

95. The method of claim 94, wherein said condensation is an aldol condensation.

96. The method of claim 94, wherein said condensation comprises a Lewis acid.

97. The method of claim 94, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

98. The method of claim 94, wherein said condensation comprises MgBr₂OEt.

99. The method of claim 94, wherein said one or more steps comprises one or more reductions, protections or deprotections.

100. The method of claim 94, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

101. The method of claim 94, wherein said cyclization comprises N-iodosuccinimide (NIS).

102. The method of claim 94, wherein A is -SR'; and R' is alkyl.

103. The method of claim 94, wherein A is -SEt.

104. The method of claim 94, wherein X₂ is -O-.

105. The method of claim 94, wherein X₂ is -O-; and B is H.

106. The method of claim 94, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

107. The method of claim 94, wherein X₃ is -O-.

108. The method of claim 94, wherein X₃ is -O-; and C is H.

109. The method of claim 94, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

110. The method of claim 94, wherein X₅ is -O-.

111. The method of claim 94, wherein X₅ is -O-; and E is H.

112. The method of claim 94, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

113. The method of claim 94, wherein X₆ is -CH₂O-.

114. The method of claim 94, wherein X₆ is -CH₂O-; and F is H.

115. The method of claim 94, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

116. The method of claim 94, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

117. The method of claim 94, wherein Y₁ is -C(XR)₂H.

118. The method of claim 94, wherein Y₁ is -C(SR)₂H; and R is alkyl.

119. The method of claim 94, wherein Y₁ is -C(SEt)₂H.

120. The method of claim 94, wherein Y₂ is -C(=O)H.

121. The method of claim 94, wherein Y₃ is =C(XR)H.

122. The method of claim 94, wherein Y₃ is =C(OR)H; and R is silyl.

123. The method of claim 94, wherein Y₃ is =C(OTBDMS)H.

124. The method of claim 94, wherein Y₄ is -C(X)XR.

125. The method of claim 94, wherein Y₄ is -C(H)OR.

126. The method of claim 94, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

127. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

wherein

X₂, X₃, and X₅ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and -N₃; X₆ represents independently for each occurrence, -CH₂O-, -CH₂NB-, -CH₃, -CH₂NO₂, -CH₂N₃, -COO-, -CONH-, -CN or -COS-;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁, Y₂, Y₃ and Y₄ have the appropriate bond order; provided that when any occurrence of X₂, X₃, or X₅ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, - CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

128. The method of claim 127, wherein said condensation is an aldol condensation.

129. The method of claim 127, wherein said condensation comprises a Lewis acid.

130. The method of claim 127, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

131. The method of claim 127, wherein said condensation comprises MgBr₂-OEt.

132. The method of claim 127, wherein said one or more steps comprises one or more reductions, protections or deprotections.

133. The method of claim 127, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

134. The method of claim 127, wherein said cyclization comprises N-iodosuccinimide (NIS).

135. The method of claim 127, wherein A is -SR¹; and R' is alkyl.

136. The method of claim 127, wherein A is -SEt.

137. The method of claim 127, wherein X₂ is -O-.

138. The method of claim 127, wherein X₂ is -O-; and B is H.

139. The method of claim 127, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

140. The method of claim 127, wherein X₃ is -O-.

141. The method of claim 127, wherein X₃ is -O-; and C is H.

142. The method of claim 127, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

143. The method of claim 127, wherein X₅ is -O-.

144. The method of claim 127, wherein X₅ is -O-; and E is H.

145. The method of claim 127, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev. <

146. The method of claim 127, wherein X₆ is -CH₂O-.

147. The method of claim 127, wherein X₆ is -CH₂O-; and F is H.

148. The method of claim 127, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

149. The method of claim 127, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

150. The method of claim 127, wherein Y₁ is -C(XR)₂H.

151. The method of claim 127, wherein Y₁ is -C(SR)₂H; and R is alkyl.

152. The method of claim 127, wherein Y₁ is -C(SEt)₂H.

153. The method of claim 127, wherein Y₂ is -CO=O)H.

154. The method of claim 127, wherein Y₃ is =C(XR)H.

155. The method of claim 127, wherein Y₃ is =€(0R)H; and R is silyl.

156. The method of claim 127, wherein Y₃ is ^C(OTBDMS)H.

157. The method of claim 127, wherein Y₄ is -C(X)XR.

158. The method of claim 127, wherein Y₄ is -C(H)OR.

159. The method of claim 127, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

160. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

cyclization

wherein

R' is selected independently for each occurrence from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;

X₂, X₃, X₄ and X₅ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, or -N₃; X₆ represents independently for each occurrence, -CH₂O-, -CH₂NH-, -CH₃, -CH₂NO₂, -CH₂N₃, -COO-, -CONH-, -CN, or -COS-;

161. The method of claim 160, wherein said condensation is an aldol condensation.

162. The method of claim 160, wherein said condensation comprises a Lewis acid.

163. The method of claim 160, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

164. The method of claim 160, wherein said condensation comprises MgBr₂OEt.

165. The method of claim 160, wherein said one or more steps comprises one or more reductions, protections or deprotections.

166. The method of claim 160, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

167. The method of claim 160, wherein said cyclization comprises N-iodosuccinimide (NIS).

168. The method of claim 160, wherein A is -SR'; and R' is alkyl.

169. The method of claim 160, wherein A is -SEt.

170. The method of claim 160, wherein X₂ is -O-.

171. The method of claim 160, wherein X₂ is -O-; and B is H.

172. The method of claim 160, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

173. The method of claim 160, wherein X₃ is -O-.

174. The method of claim 160, wherein X₃ is -O-; and C is H.

175. The method of claim 160, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

176. The method of claim 160, wherein X₄ is -O-.

177. The method of claim 160, wherein X₄ is -O-; and D is H.

178. The method of claim 160, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

179. The method of claim 160, wherein X₅ is -O-.

180. The method of claim 160, wherein X₅ is -O-; and E is H.

181. The method of claim 160, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

182. The method of claim 160, wherein X₆ is -CH₂O-.

183. The method of claim 160, wherein X₆ is -CH₂O-; and F is H.

184. The method of claim 160, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

185. The method of claim 160, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-diliydroxypropanone, gulose, idose, lyxose, mannosamine, mamiose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

186. The method of claim 160, wherein Y₁ is -C(XR)₂H.

187. The method of claim 160, wherein Y₁ is -C(SR)₂H; and R is alkyl.

188. The method of claim 160, wherein Y₁ is -C(SEt)₂H.

189. The method of claim 160, wherein Y₂ is -C(=O)H.

190. The method of claim 160, wherein Y₃ is =C(XR)H.

191. The method of claim 160, wherein Y₃ is =C(OR)H; and R is silyl.

192. The method of claim 160, wherein Y₃ is -C(OTBDMS)H.

193. The method of claim 160, wherein Y₄ is -C(X)XR.

194. The method of claim 160, wherein Y₄ is -C(H)OR.

195. The method of claim 160, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

196. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

wherein

Yi, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, - C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, or =C(R)_2;

197. The method of claim 196, wherein said condensation is an aldol condensation.

198. The method of claim 196, wherein said condensation comprises a Lewis acid.

199. The method of claim 196, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

200. The method of claim 196, wherein said condensation comprises MgBr₂OEt.

201. The method of claim 196, wherein said one or more steps comprises one or more reductions, protections or deprotections.

202. The method of claim 196, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

203. The method of claim 196, wherein said cyclization comprises N-iodosuccinimide (NIS).

204. The method of claim 196, wherein A is -SR'; and R' is alkyl.

205. The method of claim 196, wherein A is -SEt.

206. The method of claim 196, wherein X₂ is -O-.

207. The method of claim 196, wherein X₂ is -O-; and B is H.

208. The method of claim 196, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

209. The method of claim 196, wherein X₃ is -O-.

210. The method of claim 196, wherein X₃ is -O-; and C is H.

211. The method of claim 196, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

212. The method of claim 196, wherein X₄ is -O-.

213. The method of claim 196, wherein X₄ is -O-; and D is H.

214. The method of claim 196, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

215. The method of claim 196, wherein X₆ is -CH₂O-.

216. The method of claim 196, wherein X₆ is -CH₂O-; and F is H.

217. The method of claim 196, wherein X₆ is -CH₂O-; and F is Ac, Bn₃ TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

218. The method of claim 196, wherein B, C₃ D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

219. The method of claim 196, wherein Y₁ is -C(XR)₂H.

220. The method of claim 196, wherein Y₁ is -C(SR)₂H; and R is alkyl.

221. The method of claim 196, wherein Y₁ is -C(SEt)₂H.

222. The method of claim 196, wherein Y₂ is -C(=O)H.

223. The method of claim 196, wherein Y₃ is =C(XR)H.

224. The method of claim 196, wherein Y₃ is =C(OR)H; and R is silyl.

225. The method of claim 196, wherein Y₃ is =C(OTBDMS)H.

226. The method of claim 196, wherein Y₄ is -C(X)XR.

227. The method of claim 196, wherein Y₄ is -C(H)OR.

228. The method of claim 196, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

229. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

wherein

-CN, -NH-, -NO₂, orN₃;

230. The method of claim 229, wherein said condensation is an aldol condensation.

231. The method of claim 229, wherein said condensation comprises a Lewis acid.

232. The method of claim 229, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

233. The method of claim 229, wherein said condensation comprises MgBr₂OEt.

234. The method of claim 229, wherein said one or more steps comprises one or more reductions, protections or deprotections.

235. The method of claim 229, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

236. The method of claim 229, wherein said cyclization comprises N-iodosuccinimide (NIS).

237. The method of claim 229, wherein A is -SR¹; and R' is alkyl.

238. The method of claim 229, wherein A is -SEt.

239. The method of claim 229, wherein X₂ is -O-.

240. The method of claim 229, wherein X₂ is -O-; and B is H.

241. The method of claim 229, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

242. The method of claim 229, wherein X₃ is -O-.

243. The method of claim 229, wherein X₃ is -O-; and C is H.

244. The method of claim 229, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

245. The method of claim 229, wherein X₄ is -O-.

246. The method of claim 229, wherein X₄ is -O-; and D is H.

247. The method of claim 229, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

248. The method of claim 229, wherein X₅ is -O-.

249. The method of claim 229, wherein X₅ is -O-; and E is H.

250. The method of claim 229, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

251. The method of claim 229, wherein X₆ is -CH₂O-.

252. The method of claim 229, wherein X₆ is -CH₂O-; and F is H.

253. The method of claim 229, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

254. The method of claim 229, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane-l,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosarnine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

255. The method of claim 229, wherein Y₁ is -C(XR)₂H.

256. The method of claim 229, wherein Y₁ is -C(SR)₂H; and R is alkyl.

257. The method of claim 229, wherein Y₁ is -C(SEt)₂H.

258. The method of claim 229, wherein Y₂ is -C(=0)H.

259. The method of claim 229, wherein Y₃ is =C(XR)H.

260. The method of claim 229, wherein Y₃ is =C(OR)H; and R is silyl.

261. The method of claim 229, wherein Y₃ is =C(OTBDMS)H.

262. The method of claim 229, wherein Y₄ is -C(X)XR.

263. The method of claim 229, wherein Y₄ is -C(H)OR.

264. The method of claim 229, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

265. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

cyclization

wherein

X₂, X₃, and X₄ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, orN₃;

Y₁, and Y₂ are independently for each occurrence selected from the group consisting Of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, -CR(XR), =C(XR)₂, and =€(R)_2;

R is independently for each occurrence selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxide, substituted alkoxide, carbonyl, substituted carbonyl, carboxide, substituted carboxide, orthoester, substituted orthoester, amine, substituted amine amide, substituted amide, imine, substituted imine, carbamate, substituted carbamate, sulfide, substituted sulfide, sulfoxide, substituted sulfoxide, sulfonate, substituted sulfonate, sulfate, substituted sulfate, silyl, substituted silyl, borane, substituted borane, phosphane, substituted phosphane, halogen, metal, and substituted metal; and the connecting carbon atoms to Y₁ and Y₂ have the appropriate bond order; provided that when any occurrence of X₂, X₃, or X₄ is H, -CN, -NO₂, or -N₃, the corresponding B, C, D or E is absent; and when any occurrence of X₆ is -CH₃, -CH₂NO₂, -CN or -CH₂N₃, the corresponding F is absent.

266. The method of claim 265, wherein said condensation is an aldol condensation.

267. The method of claim 265, wherein said condensation comprises a Lewis acid.

268. The method of claim 265, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

269. The method of claim 265, wherein said condensation comprises MgBr₂OEt.

270. The method of claim 265, wherein said one or more steps comprises one or more reductions, protections or deprotections.

271. The method of claim 265 , wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, iodine, or pyridinium tribromide.

272. The method of claim 265, wherein said cyclization comprises N-iodosuccinimide (NIS).

273. The method of claim 265 , wherein A is -SR'; and R' is alkyl.

274. The method of claim 265 , wherein A is -SEt.

275. The method of claim 265, wherein X₂ is -O-.

276. The method of claim 265, wherein X₂ is -O-; and B is H.

277. The method of claim 265, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

278. The method of claim 265, wherein X₃ is -O-.

279. The method of claim 265, wherein X₃ is -O-; and C is H.

280. The method of claim 265, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

281. The method of claim 265 , wherein X₄ is -O-.

282. The method of claim 265 , wherein X₄ is -O-; and D is H.

283. The method of claim 265, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

284. The method of claim 265, wherein X₆ is -CH₂O-.

285. The method of claim 265, wherein X₆ is -CH₂O-; and F is H.

286. The method of claim 265, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

287. The method of claim 265, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane- 1,2,3 -trio 1, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

288. The method of claim 265, wherein Y₁ is -C(XR)₂H.

289. The method of claim 265, wherein Y₁ is -C(SR)₂H; and R is alkyl.

290. The method of claim 265, wherein Y₁ is -C(SEt)₂H.

291. The method of claim 265 , wherein Y₂ is -C(=O)H.

292. The method of claim 265, wherein Y₃ is RCN.

293. The method of claim 265, wherein Y₃ is RCN; and R is silyl.

294. The method of claim 265, wherein Y₃ is TMSCN.

295. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

cyclization

wherein A represents acetimidoyl, substituted acetimidoyl, halogen, trichloroacetimidoyl, thiocarbamoyl, sulfoxide, -OR', -SR', or -SeR';

Y₃ and Y₄ are independently for each occurrence selected from the group consisting Of-C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, =CR(XR), =C(XR)₂, or -C(R)_2;

Y₁ is selected from the group consisting of C(X)R₂, C(X)(XR)₂, C(R)₄, C(R)₃(XR), CR₂(XR)₂, C(XR)₄, C(R)₃N₃, RCN, or C(R)₃NO₂;

X is independently for each occurrence selected from the group consisting of O,

NH, NR, S, and Se;

296. The method of claim 295, wherein said condensation is an aldol condensation.

297. The method of claim 295, wherein said condensation comprises a Lewis acid.

298. The method of claim 295, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

299. The method of claim 295, wherein said condensation comprises MgBr₂OEt.

300. The method of claim 295, wherein said one or more steps comprises one or more reductions, protections or deprotections.

301. The method of clainr295, wherein said cyclization comprises N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NTS), bromine, iodine, or pyridinium tribromide.

302. The method of claim 295, wherein said cyclization comprises N-iodosuccinimide (NIS).

303. The method of claim 295, wherein A is -SR¹; and R' is alkyl.

304. The method of claim 295, wherein A is -SEt.

305. The method of claim 295, wherein X₂ is -O-.

306. The method of claim 295, wherein X₂ is -O-; and B is H.

307. The method of claim 295, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

308. The method of claim 295, wherein X₃ is -O-.

309. The method of claim 295, wherein X₃ is -O-; and C is H.

310. The method of claim 295, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

311. The method of claim 295 , wherein X₄ is -O-.

312. The method of claim 295, wherein X₄ is -O-; and D is H.

313. The method of claim 295, wherein X₄ is -O-; and D is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

314. The method of claim 295, wherein X₅ is -O-.

315. The method of claim 295 , wherein X₅ is -O-; and E is H.

316. The method of claim 295, wherein X₅ is -O-; and E is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr₃ or Lev.

317. The method of claim 295, wherein X₆ is -CH₂O-.

318. The method of claim 295, wherein X₆ is -CH₂O-; and F is H.

319. The method of claim 295, wherein X₆ is -CH₂O-; and F is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

320. The method of claim 295, wherein B, C, D, or F is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane- 1, 2,3 -triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/threaric acid, threose, xylose, or xylulose.

321. The method of claim 295, wherein Y₁ is C(X)R₂.

322. The method of claim 295, wherein Y₃ is =C(XR)H.

323. The method of claim 295, wherein Y₃ is =C(OR)H; and R is silyl.

324. The method of claim 295 , wherein Y₃ is =C(OTBDMS)H.

325. The method of claim 295 , wherein Y₄ is -C(X)XR.

326. The method of claim 295, wherein Y₄ is -C(H)OR.

327. The method of claim 295, wherein Y₄ is -C(H)OR; and R is silyl, carbonyl or alkyl.

328. A method of preparing a carbohydrate building block, comprising the steps depicted in the reaction schemes below:

X₂, and X₃ are independently selected from the group consisting of H, -O-, -CN, -NH-, -NO₂, and N₃;

Y₁, Y₂, Y₃ and Y₄ are independently for each occurrence selected from the group consisting of -C(X)R, -C(X)XR, -C(R)₃, -C(R)₂(XR), -CR(XR)₂, -C(XR)₃, -C(R)₂N₃, -CN, -C(R)₂NO₂, -CR(XR), =C(XR)₂, or =C(R)_2;

329. The method of claim 328, wherein said condensation is an aldol condensation.

330. The method of claim 328, wherein said condensation comprises a Lewis acid.

331. The method of claim 328, wherein said condensation comprises BF₃OEt₂ or MgBr₂-OEt.

332. The method of claim 328, wherein said condensation comprises MgBr₂OEt.

333. The method of claim 328, wherein said cyclization comprises acid.

334. The method of claim 328, wherein said cyclization comprises trifluoroacetic acid (TFA).

335. The method of claim 328, wherein A is -SR¹; and R¹ is alkyl.

336. The method of claim 328, wherein A is -SEt.

337. The method of claim 328, wherein X₂ is -O-.

338. The method of claim 328, wherein X₂ is -O-; and B is H.

339. The method of claim 328, wherein X₂ is -O-; and B is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

340. The method of claim 328, wherein X₃ is -O-.

341. The method of claim 328, wherein X₃ is -O-; and C is H.

342. The method of claim 328, wherein X₃ is -O-; and C is Ac, Bn, TBDMS, TMS, Fmoc, Piv, Tr, or Lev.

343. The method of claim 328, wherein B or C is allose, altrose, arabinose, erythrose, erythrulose, fructose, fucosamine, fucose, galactosamine, galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde, 2,3-dihydroxypropanal, glycerol, propane- 1,2,3-triol, glycerone, 1,3-dihydroxypropanone, gulose, idose, lyxose, mannosamine, mannose, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sialic acid, sorbose, tagatose, talose, tartaric acid, erythraric/tlirearic acid, threose, xylose, or xylulose.

344. The method of claim 328, wherein Y₁ is -C(XR)₂H.

345. The method of claim 328, wherein Y₁ is -C(SR)₂H; and R is alkyl.

346. The method of claim 328, wherein Y₁ is -C(SEt)₂H.

347. The method of claim 328, wherein Y₂ is -C(=O)OR; and R is alkyl.

348. The method of claim 328, wherein Y₂ is -C(=O)OMe.

349. The method of claim 328, wherein Y₃ is -C(=O)H.

350. The method of claim 328, wherein Y₄ is -CR₃; and R is hydrogen or alkyl.

351. The method of claim 328, wherein Y₄ is -CH₃.