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WO1990006311A1 - Synthesis of (-)-swainsonine and intermediate compounds employed in such synthesis - Google Patents

Synthesis of (-)-swainsonine and intermediate compounds employed in such synthesis Download PDF

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Publication number
WO1990006311A1
WO1990006311A1 PCT/US1988/004253 US8804253W WO9006311A1 WO 1990006311 A1 WO1990006311 A1 WO 1990006311A1 US 8804253 W US8804253 W US 8804253W WO 9006311 A1 WO9006311 A1 WO 9006311A1
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Prior art keywords
swainsonine
imine
enamide
group
constituent
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French (fr)
Inventor
Jin Kun Cha
Richard Bernard Bennett, Iii
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Vanderbilt University
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Vanderbilt University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a method of synthesizing (-)-swainsonine and to unique intermediates used in such synthesis.
  • Swainsonine is a known compound which is a trihydroxy indolizidine alkaloid. It has been isolated from locoweed (Astragalus lentiginosus and swainsona canescens) . It has also been produced from fungus (Rhizoctonia leguminicola and Metarhizium anisopliae) . The alpha-mannosidase inhibitory and immuno- regulative properties of (-)-swainsonine have resulted in significant interest in biosynthetic and pharmacological studies of the compound.
  • Swainsonine also has been recognized as having potential for use in chemotherapy with cancer patients.
  • R is (C ⁇ Cg) alkyl
  • R ⁇ is a halide or sulfonate
  • R 2 is (a) cyclic acetal (ketal) or
  • R 2 is (a) (C j -Cg) cyclic acetal (ketal) or
  • the imine is hydrolized with an inorganic base to produce an acid which is subsequently heated at reflux, temperature in a suitable organic solvent to produce an enamide of the following structure
  • R 2 is (a) (C ⁇ -Cg) cyclic acetal (ketal) or
  • R an oxygen atom or a hydrogen atom, and treating the enamide with borane, followed by 20. removal of a protective group to produce swainsonine.
  • the imine and enamide intermediates have unique compositions.
  • the present invention contemplates construction of a bicyclic imine which may be employed to create the enamide of the invention with subsequent stereospecific hydroboration of the enamide being employed to synthesize swainsonine or its analogues.
  • a highly efficient method of synthesizing swainsonine involves protecting the 1,2-diol moiety of swainsonine as an isopropylidene group followed by removal thereof as by acidic hydrolysis.
  • Swainsonine (-) (lS,2R,8R,8aR)-l,2,8- trihydroxyoctahydroindolizine has the structure
  • R is (C ⁇ -Cg) alkyl
  • R 2 is (a) (C j -Cg) cyclic acetal (ketal) or ⁇ (b) (C ⁇ -Cg) alkoxymethyl or
  • arylmethyl (c) arylmethyl.
  • R methyl, ethyl, propyl and benzyl.
  • R- j _ are chloride, bromide, _p_-toluenesulfonate, benzene- sulfonate, or methanesulfonate.
  • R 2 Among the preferred materials for R 2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, or (b) methoxymethyl , 2- methoxyethoxymethyl, benzyloxymethyl, or (c) benzyl, JD- methoxybenzyl or _p_-nitrobenzyl.
  • alcohol 4 was prepared with a 50-65 percent yield by coupling 2,3,-isopropylidene-D- erythrose with the known Wittig reagent ( 4- carbethoxybutyl) triphenylphosphoniu bromide and
  • R is (C ⁇ -Cg) alkyl
  • R 2 is (a) (C j -Cg) cyclic acetal (ketal) or (b) (C j -Cg) alkoxymethyl or (c) arylmethyl.
  • R examples are methyl, ethyl, propyl, or benzyl.
  • R 2 Among the preferred materials for R 2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, or (b) methoxymethyl, 2- methoxyethoxy ethyl, benzyloxymethyl, or (c) benzyl, _p_- methoxybenzyl or ja-nitrobenzyl.
  • an acid 8 which may be a crystalline acid was prepared. In the conversion of the imino ester to the acid, the yield was 74 percent.
  • R 2 is (a) (C ⁇ -Cg) cyclic acetal (ketal) or
  • R is an oxygen atom or a hydrogen atom.
  • R 2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene; or (b) methoxymethyl, 2- methoxyethoxymethyl, benzyloxymethyl; or (c) benzyl, _p_- methoxybenzyl or j_-nitrobenzyl.
  • crystalline acid 8 undergoes internal cyclization to provide a spiro lactone which then suffers acyl group migration and subsequent dehydration.
  • the enamide was treated with diborane in a suitable solvent such as tetrahydrofuran (THF) (CH 2 ) 4 0, to produce swainsonine acetonide which has a melting point of about 101-103 degrees C.
  • THF tetrahydrofuran
  • the synthesis to swainsonine 12 was completed by acid hydrolysis with 6N hydrochloric acid in THF to yield swainsonine. The yield of swainsonine was 85 percent.
  • (+)-(4R,cis) (Z)- 2,2-Dimethyl-5-[4-carbethoxy-l-butenyl]-1,3-dioxolane- 4-methanol 4-1 will be provided.
  • 4- carbethoxybutyltriphenylphosphonium bromide (19.52 g, 42.7 mmol) in anhydrous THF (50ml) was added dropwise potassium bis(trimethylsilyl)amide [KN(SiMe 3 ) 2 ] (82 ml, 41.0 mmol) at 0 degree C over 10 min.
  • Example II As an example of the requisite sulfonate, the production of (+)-(4R,cis) (Z)-2,2-Dimethyl-5-[4- carbethoxy-l-butenyl]-l,3 dioxolane-4-methanol _p_- toluene-sulfonate 4-2 will be provided-
  • reaction mixture was washed with H 2 0 (2 x 40 ml) , saturated aqueous NaHC0 (2 x 40 ml) and brine solution (1 x 40 ml), dried over Na SO_ j , and concentrated in vacuo to a yellow oil.
  • Example III As an example of production of the imino ester, the production of (-)-(2S, 3R)-Dimethyl-8- [3- carbethoxy-1-propyl] -7-aza-2,4-dioxabicylco [3.3.0] oct- 7-ene 6 will be provided.
  • the imino ester (884 mg, 3.46 mmol) produced by Example III was dissolved in 33 ml of methanol and 10 ml of water. Potassium carbonate (1.20g, 8.75 mmol) was added. The mixture was stirr-ed at room temperature for 12h, and was concentrated in vacuo to remove
  • Example V As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-
  • Example VI The conversion of the enamide to swainsonine acetonide, i.e. , (-)-( IS,2R,8R,8aR)-l,2- isopropylidenedioxy-8-hydroxyindolizidine was achieved.
  • Example VII Swainsonine acetonide was then converted to swainsonine, i.e., (-)-(lS, 2R, 8R, 8aR)-l,2,8- trihydroxyoctahydroindolizine 12.
  • Example VIII Examples VIII-XIV illustrate the use of a benzyloxymethyl group to protect the 1,2-diol moiety of swainsonine.
  • R is (C ⁇ -C ) alkoxymethyl, (-)-2,3-dibenzyloxymethyl-D-erythronolactone, (-)-2,3- dibenzyloxymethyl-D-erythrose, and (6S, 7R) ethyl. (Z)- 6,7-dibenzyloxymethoxy-8-hydroxy-4-butenoate were produce .
  • Example VIII in dry CH 2 C1 2 at 0 degree C there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H 2 0, saturated aqueous NaHC0 3 and brine solution, dried over Na 2 S0 4 , and concentrated in vacuo to a yellow oil. Purification by Si0 2 column chromatography yielded the _p_-toluenesulfonate.
  • Example X
  • Example XI As an example of the production of the imino acid, the production of (3S, 4R)-3,4- dibenzyloxy- methoxy-2[3-carboxy-l-propyl]-pyrrolid-1-ene will be produced.
  • the imino ester produced by Example X was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HC1, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl acetate, and methylene chloride. The organic extracts were combined, dried over a 2 S0 4 , and concentrated in vacuo to give the acid.
  • Example XII As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-0- dibenzyloxymethoxy-2-oxo-l-azabicyclo[4.3.0]non-5-ene will be provided.
  • Example XIII A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si0 2 column chromatography to provide the enamide.
  • Example XIII A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si0 2 column chromatography to provide the enamide.
  • Example XIII A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si0 2 column chromatography to provide the enamide.
  • Example XIII A solution of the acid produced by Example XI in to
  • Example XII To a cold (0 degree C) THF solution of the enamide produced in Example XII was added 1.0M BH 3 THF solution- The reaction was brought to room temperature overnight. The solvent was removed in vacuo, and ethanol was then added. To this solution were added sodium hydroxide and 30% hydrogen peroxide. Additional ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, the ethanol removed in vacuo, and the residue dissolved in H 2 0- The aqueous solution was saturated with solid NaCl, then extracted five times each with ethyl acetate, and methylene chloride.
  • Example XIV The conversion of 1,2- dibenzyloxymethylswainsonine to swainsonine, i.e. , (-)- (is, 2R, 8R, 8aR)-l,2,8-Trihydroxyoctahydroindolizidine will be provided.
  • Example XV Examples XV-XXI illustrate the use of benzyl group to protect the 1,2 diol moiety of swainsonine. -17-
  • R 2 is (C j -Cg) arylmethyl, (-)- 2 , 3-dibenzyl-D-erythronolactone, (-)-2,3-dibenzyl-D- erythrose, and (6S, 7R) ethyl ( Z)-6 ,7-dibenzyloxy-8- hydroxy-4-butenoate were produced.
  • ** R 2 is (C j -Cg) arylmethyl, (-)- 2 , 3-dibenzyl-D-erythronolactone, (-)-2,3-dibenzyl-D- erythrose, and (6S, 7R) ethyl ( Z)-6 ,7-dibenzyloxy-8- hydroxy-4-butenoate
  • Example XVI As an example of the production of the corresponding sulfonate, (6S, 7R) ethyl (Z)-6,7- dibenzyloxy-8-_p-toluenesulfonyloxy-4-butenoate was produced.
  • Example XVII As an example of production of the imino ester, the production of (3S, 4R)-3,4-dibenzyloxy-2[3- carbethoxy-l-propyl]-pyrrolid-l-ene will be provided.
  • Example XVIII To a solution of the _p_-toluenesulfonate produced by Example XVI in DMF was added sodium azide- The mixture was heated at 80 degrees C for 2 days under the N 2 atmosphere. The mixture was then diluted with ethyl acetate, washed with H 2 0 and brine solution, dried over Na S0 4 and concentrated in vacuo. The product was purified by Si0 2 column chromatography to afford the imino ester.
  • Example XVIII To a solution of the _p_-toluenesulfonate produced by Example XVI in DMF was added sodium azide- The mixture was heated at 80 degrees C for 2 days under the N 2 atmosphere. The mixture was then diluted with ethyl acetate, washed with H 2 0 and brine solution, dried over Na S0 4 and concentrated in vacuo. The product was purified by Si0 2 column chromatography to afford the imino ester.
  • Example XIX The imino ester produced by Example XVII was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HCl, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl - ⁇ acetate, and methylene chloride. The organic extracts were combined, dried over Na 2 S0 4 , and concentrated in vacuo to give the acid.
  • Example XIX The imino ester produced by Example XVII was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then
  • Example XX The conversion of the enamide to 1,2- dibenzylswainsonine, i.e. , (-)-lS, 2R, 8R, 8aR)-l,2- dibenzyloxymethoxy-8-hydroxyindolizidine will be provided.
  • Example XIX To a cold (0 degree C) THF solution of the enamide produced in Example XIX was added 1.0M BH 3 - THF solution. The reaction was brought to room temperature overnight. The solvent was removed _in_ vacuo, and ethanol was then added. To this solution were added sodium hydroxide and 30% hydrogen peroxide. Additional ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, ethanol removed in vacuo, and the residue dissolved in H 2 0.
  • Example XX To a 5% acetic acid - methanol solution of the protected swainsonine produced by Example XX was added 10% Pd-C- The mixture was stirred under H 2 overnight, filtered through celite and concentrated in vacuo. The concentrate was then purified by ion exchange column chromatography to give swainsonine as a white solid.
  • the present invention provides an efficient means for the synthesis of swainsonine employing unique imino ester and enamide intermediates. All of this is accomplished in an efficient and economical manner which is reliable and rapid-

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Abstract

A method of synthesizing swainsonine and its analogues employing a unique intermediate imine and a unique intermediate enamide.

Description

SYNTHESIS OF (-)-S AINSONINE AND INTERMEDIATE COMPOUNDS EMPLOYED IN SUCH SYNTHESIS
The invention disclosed and claimed herein was made in the course of work under a grant from the United States Department of Health and Human Services and the United States Government has rights therein pursuant to Grant No. GM35956 awarded by the National
Institutes of Health.
BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention relates to a method of synthesizing (-)-swainsonine and to unique intermediates used in such synthesis. 2. Description of the Prior Art Swainsonine is a known compound which is a trihydroxy indolizidine alkaloid. It has been isolated from locoweed (Astragalus lentiginosus and swainsona canescens) . It has also been produced from fungus (Rhizoctonia leguminicola and Metarhizium anisopliae) . The alpha-mannosidase inhibitory and immuno- regulative properties of (-)-swainsonine have resulted in significant interest in biosynthetic and pharmacological studies of the compound. See, generally, Hino et al., Journal of Antibiotics Vol. 38, 926 (1985); Kino et al. , Journal of Antibiotics, Vol 38, 936 (1985); Humphries et al., Proceedings of the National Academy of Sciences (USA) 83 1752 (1986); Dennis, Cancer Research 46, 5131 (1986); Granato et al., Molecular Immunology 24, 849 (1987); White et al., Biochemical and Biophysical Research Communications
150, 615 (1988); and Humphries et al. , Cancer Research 48, 1410 (1988). Swainsonine also has been recognized as having potential for use in chemotherapy with cancer patients.
It has also been known to synthesize (-)- swainsonine- See, generally Fleet et al., Tetrahedron Letters 25, 1853 (1984); Ali et al. , Journal of Chemical Society, Chemical Communications 447 (1984); Carbohydrate Research 136, 225 (1985); Suami et al. , Carbohydrate Research 135, 67 (1985); Yasuda et al., Chemistry Letters 1201 (1984); Adams et al., Journal of Organic Chemistry 50, 420 (1985); Setoi et al., Journal of Organic Chemistry 50, 3948 (1985); and Ikota et al., Chemical and Pharmaceutical Bulletin 35, 2140 (1987). The known methods of synthesis, however, remain rather expensive and inefficient.
In spite of this prior knowledge, there remains a very real and substantial need for an efficient, reliable method of synthesizing swainsonine.
SUMMARY OF THE INVENTION The need for a method of synthesizing (-)- swainsonine as set forth herein has been met by the present invention wherein a unique method of synthesis is provided as are two unique intermediate compounds. In the preferred process of the present invention (-)-swainsonine or its analogues are synthesized by treating a material having the structure
Figure imgf000004_0001
wherein R is (C^Cg) alkyl;
R^ is a halide or sulfonate; and
R2 is (a)
Figure imgf000004_0002
cyclic acetal (ketal) or
(b) C-j^-Cg) alkoxymethyl or
(c) arylmethyl, to produce an imine structure
Figure imgf000005_0001
wherein R is (C^-Cg) alkyl; and
R2 is (a) (Cj-Cg) cyclic acetal (ketal) or
(b) (Cj-Cg) alkoxymethyl or
(c) arylmethyl.
The imine is hydrolized with an inorganic base to produce an acid which is subsequently heated at reflux, temperature in a suitable organic solvent to produce an enamide of the following structure
Figure imgf000005_0002
15 wherein R2 is (a) (C^-Cg) cyclic acetal (ketal) or
(b) (C -Cg) alkoxymethyl or
(c) arylmethyl.
R = an oxygen atom or a hydrogen atom, and treating the enamide with borane, followed by 20. removal of a protective group to produce swainsonine.
The imine and enamide intermediates have unique compositions.
It is an object of the present invention to provide a reliable means for synthesizing swainsonine 25 and its analogues.
It is a further object of the present invention to provide such a method which is highly efficient and economical to employ.
It is a further object of the invention to 30 provide a relatively simple enantioselective method of synthesizing (-)-swainsonine.
It is an object of the present invention to provide unique imine and enamide intermediates for use in such a process.
These and other objects of the invention will be more fully understood from the following description of the invention on reference to the illustrations appended hereto .
BRIEF DESCRIPTION OF THE DRAWING The Figure illustrates a preferred method of effecting the synthesis of the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENT in general, the present invention contemplates construction of a bicyclic imine which may be employed to create the enamide of the invention with subsequent stereospecific hydroboration of the enamide being employed to synthesize swainsonine or its analogues.
In the preferred practice of the invention a highly efficient method of synthesizing swainsonine involves protecting the 1,2-diol moiety of swainsonine as an isopropylidene group followed by removal thereof as by acidic hydrolysis.
Swainsonine (-) (lS,2R,8R,8aR)-l,2,8- trihydroxyoctahydroindolizine has the structure
Figure imgf000006_0001
Referring to the Figure, there is shown a compound identified by the reference number 2 which is 2,3-O-isopropylidine-D-erythrose (also known as acetonide) which is a suitably protected D-erythrose. This is converted to a material 4 having the structure
Figure imgf000006_0002
wherein R is (C^-Cg) alkyl; and
R is a halide or sulfonate. (The indication Rτ=OH in the Figure is for the alcohol).
R2 is (a) (Cj-Cg) cyclic acetal (ketal) or^ (b) (C^-Cg) alkoxymethyl or
(c) arylmethyl. Among the preferred materials for R are methyl, ethyl, propyl and benzyl.
Among the preferred materials for R-j_ are chloride, bromide, _p_-toluenesulfonate, benzene- sulfonate, or methanesulfonate.
Among the preferred materials for R2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, or (b) methoxymethyl , 2- methoxyethoxymethyl, benzyloxymethyl, or (c) benzyl, JD- methoxybenzyl or _p_-nitrobenzyl.
For example, alcohol 4 was prepared with a 50-65 percent yield by coupling 2,3,-isopropylidene-D- erythrose with the known Wittig reagent ( 4- carbethoxybutyl) triphenylphosphoniu bromide and
KN(SiMe3)2 in THF at -78 degrees C to 0 degrees C. The alcohol 4 was then treated with jD-toluenesulfonyl chloride to furnish the corresponding _p_- toluenesulfonate. This jo-toluenesulfonate was treated with sodium azide NaN3 in dimethyl formamide (DMF)
(CH3) NCHO at about 70 degrees C to 100 degrees C to produce the imino ester 6 having the structure
Figure imgf000007_0001
wherein R is (C^-Cg) alkyl;
R2 is (a) (Cj-Cg) cyclic acetal (ketal) or (b) (Cj-Cg) alkoxymethyl or (c) arylmethyl.
Examples of R are methyl, ethyl, propyl, or benzyl.
Among the preferred materials for R2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, or (b) methoxymethyl, 2- methoxyethoxy ethyl, benzyloxymethyl, or (c) benzyl, _p_- methoxybenzyl or ja-nitrobenzyl.
By hydrolizing the imino ester 6 with an inorganic base such as K2C03 in aqueous methyl alcohol at room temperature, an acid 8 which may be a crystalline acid was prepared. In the conversion of the imino ester to the acid, the yield was 74 percent.
When this acid was heated at reflux temperatures in a suitable solvent, such as toluene, there was created in
87 percent yield, the desired enamide 10 having the structure
Figure imgf000008_0001
wherein R2 is (a) (C^-Cg) cyclic acetal (ketal) or
(b) (C-j_-Cg) alkoxymethyl or (c) arylmethyl; and
R is an oxygen atom or a hydrogen atom. Examples of R2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene; or (b) methoxymethyl, 2- methoxyethoxymethyl, benzyloxymethyl; or (c) benzyl, _p_- methoxybenzyl or j_-nitrobenzyl.
It is believed that the crystalline acid 8 undergoes internal cyclization to provide a spiro lactone which then suffers acyl group migration and subsequent dehydration. The enamide was treated with diborane in a suitable solvent such as tetrahydrofuran (THF) (CH2)40, to produce swainsonine acetonide which has a melting point of about 101-103 degrees C. The synthesis to swainsonine 12 was completed by acid hydrolysis with 6N hydrochloric acid in THF to yield swainsonine. The yield of swainsonine was 85 percent. In order to reaffirm the effectiveness of the process of synthesis and the intermediate imine and enamide compounds, experiments were performed.
In summary, an example of a preferred method of synthesizing swainsonine in accordance with the
Figure is as follows. An enantioselective synthesis of (-)-swainsonine has been achieved in 7 steps from a suitably protected D-erythrose. The suitably protected D-erythrose was coupled with ( 4-alkoxybutyl)- triphenylphosphonium bromide in the presence of a strong base [i.e. , KN(SiMe )2] to give the corresponding alcohol. Treatment of the alcohol with _p-toluenesulfonyl chloride, followed by the displacement of the _p_-toluenesulfonyloxy group with sodium azide and the concomitant 1,3-dipolar cycloaddition gave an imino ester. Subsequent mild hydrolysis of the imino ester gave the corresponding acid. When the latter was heated in a suitable organic solvent, the enamide was obtained in good yield. The preparation of swainsonine was then completed by hydroboration with diborane in THF, followed by acid hydrolysis (6N HC1, THF).
The preferred synthesis of swainsonine of the present invention is set forth in Examples I through VII. Additional procedures and materials employable in the synthesis of swainsonine are provided in Examples VIII through XXI.
In the preferred practice of the invention the 1,2-diol moiety of swainsonine is protected by an isopropylidene group (acetonide group) which is subsequently removed by acidic hydrolysis. Example I
As an example of the production of the starting alcohol, the production of (+)-(4R,cis) (Z)- 2,2-Dimethyl-5-[4-carbethoxy-l-butenyl]-1,3-dioxolane- 4-methanol 4-1 will be provided. To a solution of 4- carbethoxybutyltriphenylphosphonium bromide (19.52 g, 42.7 mmol) in anhydrous THF (50ml) was added dropwise potassium bis(trimethylsilyl)amide [KN(SiMe3)2] (82 ml, 41.0 mmol) at 0 degree C over 10 min. The resulting red solution was stirred for an additional 30 min at 0 degree C and then cooled to -78 degrees C. A solution of 2,3-isoρropylidene-D-erythrose (2.74 g, 17.09 mmol) in THF (15ml) was added dropwise. The reaction mixture was brought to room temperature overnight, and then quenched with saturated aqueous NH Cl. The product was extracted with ether, washed with brine, dried over Na2SOj and concentrated in vacuo. Purification by Si02 chromatography yielded 2-55 g (58%) of 4-1, as a pale, yellow oil: [©c]D25 = +29-25° (c 3.33, CHC13); 1H NMR (CDC13, 300MHz) f l . 25 (t, 3H, J = 7-1 Hz), 1.40 (s,3H), 1.50 (s,3H), 1.95 (t, 1H, J = 5-8 Hz), 2.33- 2.50 (m,4H), 3-57 (t, 2H, J = 5-8 Hz), 4.13 (q, 2H, J = 7.1 Hz), 4.27 (m, 1H) , 5-05 (t, 1H, J = 7.4 Hz), 5.53 (dd, 1H, J = 7-4 & 11-0 Hz), 5-61 ( , 1H) ; HRMS(M-CH3) 243-1233 calcd for C13H2205(-CH3) , found 243.1226.
Example II As an example of the requisite sulfonate, the production of (+)-(4R,cis) (Z)-2,2-Dimethyl-5-[4- carbethoxy-l-butenyl]-l,3 dioxolane-4-methanol _p_- toluene-sulfonate 4-2 will be provided-
To a solution of the alcohol (1.958 g, 7-57 mmol) produced by Example I in dry CH C12 (28ml) at 0 degree C there were added triethylamine (1.6 ml, 11.47 mmol) r _£-toluenesulfonyl chloride (1.64 g, 8-60 mmol) and N,N-dimethyl-4-aminopyridine (89mg, 0-73 mmol). The mixture was stirred at room temperature for 20 h, and then diluted with ethyl acetate (200 ml). The reaction mixture was washed with H20 (2 x 40 ml) , saturated aqueous NaHC0 (2 x 40 ml) and brine solution (1 x 40 ml), dried over Na SO_j, and concentrated in vacuo to a yellow oil. Purification by Si02 column chromatography yielded 2-64 gm (85%) of tosylate 4-2, as a pale, yellow oil: [c<]D25 = +25-48° (c 2.41, CHC13); ^-H NMR (CDC13, 300 MHz) 1-26 (t, 3H, J = 7.2 Hz), 1.33 (s, 3H), 1.36 (s, 3H), 2.35-2.39 ( , 4H) , 2.44 (s, 3H), 3.88 (dd, IH, J = 6.8 & 10.2 Hz) , 4.01 (dd, IH, J = 4.6 & 10.2 Hz) , 4.12 (q, 2H, J = 7.2 Hz) , 4.32 (m, IH), 5.00 (dd, IH, J = 6.6 & 8.7 Hz), 5.35 (dd, IH, J = 8.7 & 10.4 Hz), 5.58 ( , IH), 7.34 (d, 2H, J = 8.2 Hz), 7.79 (d, 2H, J = 8.2 Hz).
Example III As an example of production of the imino ester, the production of (-)-(2S, 3R)-Dimethyl-8- [3- carbethoxy-1-propyl] -7-aza-2,4-dioxabicylco [3.3.0] oct- 7-ene 6 will be provided.
To a solution of the tosylate (122.4 mg , 0.30 mmol) produced by Example II in DMF (3ml) was added sodium azide (98.7 mg, 1.52 mmol). The mixture was heated at 80 degrees C for approximately 48 h under the N2 atmosphere. The mixture was then diluted with ethyl acetate (40ml), washed with H20 (3 x 5 ml) and brine solution (2 x 5 ml) , dried over Na2S0_j and concentrated in vacuo. The product was purified by Si02 column chromatography (eluted with 1:1 hexane:ethyl acetate, Rf = 0-21) to afford 61-2 mg (81%) of the imino ester 6, as a viscous, yellow oil: [ ]D25 - 34.25° (c 2.73, CHC13); IR (CHC13) 1635 (s), 1720 (s) cm"1; ^-H NMR (CDC13, 400MHz) <_T l.20 (t, 3H, J = 7.1 Hz), 1.30 (s, 3H) , 1.31 (s, 3H), 1.91-2.02 (m, 2H) , 2.31 -2.52 (m, 4H), 3.81 (br d, IH, A of AB q) , 3.94 (d, IH, B of AB q, J = 16.9 Hz), 4.07 (q, 2H, J = 7.1 Hz), 4.67 (m, 1H), 4.86 (d, IH, J = 5.7 Hz); 13C NMR (CDCI3, 100 MHz) g 14.13, 20.88, 25.60, 26.80, 29-91, 33.66, 60.20, 64.63, 77-64, 86-53, 111-77, 173.13, 175.84; HRMS(M+ -C2H5OH) 209.1052 calcd for C13H21N04(-C2H5OH) , found 209.1049.
Bxample IV As an example of the production of the imino acid, the production of (-)-(2S, 3R)-Dimethyl-8-[3- carboxy-l-propyl]-7-aza -2,4-dioxabicyclo[3.3.0]oct-7- ene 8 will be produced.
The imino ester (884 mg, 3.46 mmol) produced by Example III was dissolved in 33 ml of methanol and 10 ml of water. Potassium carbonate (1.20g, 8.75 mmol) was added. The mixture was stirr-ed at room temperature for 12h, and was concentrated in vacuo to remove
MeOH. The aqueous mixture was washed with ether (1 x 10 ml) , and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HC1, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl acetate, and methylene chloride. The organic extracts were combined, dried over Na SO_j, and concentrated in vacuo to give 579 mg (74% yield) of acid 8, as a yellow solid: mp 105-110 C, σ. ]D25 = 28.46° (c = 0-98, CHC13); IR (CHCI3) 3510 (br), 1720 (s), 1640 (s) cm-1; λE NMR (CDC13, 300 MHz) 1-34 (s, 6H) , 1.91 - 2-04 (m, 2H) , 2-33 -2.38 (m,2H) , 2.45 -2.64 (m, 2H) , 3-88 (br d, IH, A of ABq) , 3-98 (d, IH, B of ABq, J = 16-8 Hz), 4.72 (m, IH) , 4.95 (d, IH, J = 5.7 Hz), 9.47 -9.82 (br s, IH); 13C NMR (CDCI3, 100 MHz) 20.81, 25-53, 26-83, 29.74, 33.54, 63-53, 77-24, 86.32, 112.09, 176-31, 177.76.
Example V As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-
Isopropylidenedioxy-2-oxo-l -azabicyclo[4.3.0]non-5-ene 10 will be provided.
A solution of acid 8 (355 mg , 1.56 mmole) in toluene (35ml) was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by Si0 column chromatography ~ (eluted with 1:1 hexane:ethyl acetate, Rf = 0.5 in 10:1 CH2C12: MeOH) to provide 261 mg (80%) of enamide 10: [oc ]D25 = -86.70° (c = 1.82, CHC13); IR (CHC13) 1650 (s), 1680 (sh) cm-1; IH NMR (CDC13, 300MHz) £1.36 (s, 3H), 1.45 (s, 3H), 2.34-2.57 (m, 4H) , 3.70 (dd, IH, J = 5.5 & 13.1 Hz), 3.86 (d, IH, J = 13.1 Hz) , 4.73 (br t, IH), 5.03 (d, IH, J = 5.9 Hz), 5.24 (m, IH); 13C NMR (CDC13, 100MHz) £- 20.85, 25.69 , '27.44 , 30.44, 49.95, 75.88, 79.30, 101.59, 112.76, 139.95, 168.50; HRMS(M+) 209.1052 calcd for C11H15N03, found 209.1047.
Example VI The conversion of the enamide to swainsonine acetonide, i.e. , (-)-( IS,2R,8R,8aR)-l,2- isopropylidenedioxy-8-hydroxyindolizidine was achieved.
To a cold (0 degree C) solution of enamide 10
(261 mg , 1.29 mmol) in anhydrous THF (1.6 ml) was added
5.0 ml of 1.0JM BH3THF solution. The reaction was brought to room temperature overnight. The solvent was removed in vacuo, and ethanol (3 ml) was then added. To this solution were added sodium hydroxide (208 mg , 5-20 mmol) and 30% hydrogen peroxide (0.6 ml). Additional 2 ml of ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, the ethanol removed in vacuo, and the residue dissolved in 3 ml of H 0. The aqueous solution was saturated with solid NaCl, then extracted five times each with ethyl acetate, and methylene chloride. The combined organic extracts were dried over Na2S04, and concentrated in vacuo to give crude swainsonine acetonide as a colorless solid. Column (Si02) chromatography eluted with 25:1 CH2Cl2:MeOH afforded 209.1 mg (79%) of the pure product (visualized with I2) as a white crystal: mp 100-103 ; [eX}D25 = -72.16° (c 0.43, MeOH) ; 1H NMR (CDC13, 400MHz) ^1-18-1-24 (m, IH) , 1.33 (s, 3H) , 1.51 (s, 3H) , 1.61~1.70 (m, 4H) , l-85(m, IH) , 2-05 (m, IH) ,_• 2.13 (dd, J = 4-2 & 10.7 Hz, IH) , 2.98 (dt, J = 3.2 & 10-6 Hz, IH), 3-16 (d, J - 10-7 Hz, IH) , 3-81-3-87 (m, IH), 4-61 (dd, J = 4.2 & 6.2 Hz, IH) , 4.71 (dd, J = 4-6 & 6.2 Hz, IH) ; 13C NMR (CDC13, 100MHz) £24-08, 24-81, 25.96, 33-01, 51.60, 59-88, 67-53, 73-68, 78.26, 79.17, 111.37; HRMS(M+) 2-13.1365 calcd for 11HlgN03 found 213.1366.
Example VII Swainsonine acetonide was then converted to swainsonine, i.e., (-)-(lS, 2R, 8R, 8aR)-l,2,8- trihydroxyoctahydroindolizine 12.
To a solution of swainsonine acetonide (104 mg, 0.49 mmol) in THF (6-5 ml) was added 6.0 ml of 6_M HC1. The colorless solution was stirred overnight at room temperature. The solvent was removed in vacuo, leaving a colorless, viscous oil. The oil was then purified by an ion exchange chromatography (Dowex- 1X8). Fractions (visualized with iodine or ninhydrin) were collected and concentrated in vacuo to furnish 68.5 mg(81% yield) of swainsonine as a white solid: mp and mixed mp 140-142 C; [ ]D25 = -75.71 (c 2.33, MeOH); Rf = 0-36 in l-butanol:chloroforπ ethanol:- concentrated ammonium hydroxide (4:4:4:1); ^H NMR (D20, ref. DSS, 300MHz) 4.34 (m, IH, H-2), 4.24 (dd, Jlf8a = 3-7 Hz, Jlf2 = 6.1 Hz, IH, H-l) , 3.78 (ddd, J = 3-9, 9.3 & 10.7 Hz, IH, H-8), 2.89 (m, IH) , 2-86 (dd, J = 2-6 & 11.0 Hz, IH, H-3), 2-53 (dd, J = 7.8 & 11.0 Hz, IH, H-31), 2.04 (m, IH) , 1-96 (m, IH) , 1-89 (dd, Jga g = 9.3 Hz, Q.! = 3-7 Hz, H-8a) , 1.70 (m, IH) , 1.49 (m, IH) , 1-22 (m, IH) ; 13C NMR (D20, ref: _CH3CN, 100MHz) S 23.21, 32.51, 51.72, 60.65, 66.37, 69.08, 69.72, 72.87; HRMS(M+) 173.1052 calcd for CgH15N03, found 173.1041.
Example VIII Examples VIII-XIV illustrate the use of a benzyloxymethyl group to protect the 1,2-diol moiety of swainsonine.
As an example of the production of the starting material wherein the protecting group for the alcohol function, i.e. , R is (C^-C ) alkoxymethyl, (-)-2,3-dibenzyloxymethyl-D-erythronolactone, (-)-2,3- dibenzyloxymethyl-D-erythrose, and (6S, 7R) ethyl. (Z)- 6,7-dibenzyloxymethoxy-8-hydroxy-4-butenoate were produce .
To a solution of D-erythronolactone (1 equiv) in methylene chloride at 0 degree C were added diisopropylethylamine (6 equiv) and benzyl chloromethyl ether (3 equiv). The resulting mixture was stirred overnight at room temperature, and poured into ice water. The aqueous layer was extracted three times with methylene chloride. The organic extracts were washed with water, dried with sodium sulfate, and concentrated in vacuo. Purification by Si02 column chromatography gave pure 2,3-dibenzyloxymethyl-D- erythronolactone. To the methylene chloride solution of 2,3-dibenzyloxymethyl-D-erythronolactone (1 equiv) thus obtained was added slowly DIBAL-H (1.1 equiv) at -78βC. The reaction mixture was stirred for 4h at -78 degrees C, and cautiously decomposed by the dropwise addition of methanol. The mixture was poured into a mixture of ice water and ethyl acetate. The pH of the resulting mixture was adjusted to 3 with IN H S04. The aqueous layer was extracted four times with ethyl acetate. The organic extracts were washed with water, dried with sodium sulfate, and concentrated in vacuo. Purification by Si02 column chromatography gave 2,3- dibenzyloxymethyl-D-erythrose. To a solution of 4-carbethoxybutyltriphenyl- phosphonium bromide (3.5 equiv) in anhydrous THF was added dropwise potassium bis(tri ethylsilyl)amide [KN(SiMe3)2] (3.5 equiv) at 0 degree C over 10 min. The resulting red solution was stirred for an additional 30 min at 0 degree C and then cooled to -78 degrees C- A THF solution of 2,3-dibenzyloxymethyl-D- erythrose (1 equiv) thus obtained was added dropwise. The reaction mixture was brought to room temperature overnight, and then quenched with saturated aqueous NH4CI. The product was extracted with ether, washed with brine, dried over Na S04 and concentrated in vacuo. Purification by Si02 chromatography yielded ethyl (Z)-6,7-dibenzyloxymethoxy-8-hydroxy-4-butenoate- Example IX
As an example of the production of the corresponding sulfonate, (6S, 7R) ethyl (Z)-6,7- dibenzyloxymethoxy-8-P-toluenesulfonyloxy-4-butenoate was produced. To a solution of the alcohol produced in
Example VIII in dry CH2C12 at 0 degree C there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H20, saturated aqueous NaHC03 and brine solution, dried over Na2S04, and concentrated in vacuo to a yellow oil. Purification by Si02 column chromatography yielded the _p_-toluenesulfonate. Example X
As an example of production of the imino ester, the production of (3S, 4R)-3,4- dibenzyloxymethoxy-2-[3-carbethoxy-l-propyl]-pyrrolid- 1-ene will be provided- To a solution of the p-toluenesulfonate produced by Example IX in DMF was added sodium azide. The mixture was heated at 80 degrees C for 2 days under the N2 atmosphere. The mixture was then diluted with ethyl acetate, washed with H20 and brine solution, dried over Na2S04 and concentrated in vacuo. The product was purified by Si02 column chromatography to afford the imino ester.
Example XI As an example of the production of the imino acid, the production of (3S, 4R)-3,4- dibenzyloxy- methoxy-2[3-carboxy-l-propyl]-pyrrolid-1-ene will be produced.
The imino ester produced by Example X was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HC1, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl acetate, and methylene chloride. The organic extracts were combined, dried over a2S04 , and concentrated in vacuo to give the acid.
Example XII As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-0- dibenzyloxymethoxy-2-oxo-l-azabicyclo[4.3.0]non-5-ene will be provided.
A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si02 column chromatography to provide the enamide. Example XIII
The conversion of the enamide to 1,2- dibenzyloxymethylswainsonine, i.e. , (-)-(lS, 2R, 8R, 8aR)-l,2-dibenzyloxymethoxy-8-hydroxyindolizidine will be provided.
To a cold (0 degree C) THF solution of the enamide produced in Example XII was added 1.0M BH3 THF solution- The reaction was brought to room temperature overnight. The solvent was removed in vacuo, and ethanol was then added. To this solution were added sodium hydroxide and 30% hydrogen peroxide. Additional ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, the ethanol removed in vacuo, and the residue dissolved in H20- The aqueous solution was saturated with solid NaCl, then extracted five times each with ethyl acetate, and methylene chloride. The combined organic extracts were dried over Na2S04, and concentrated in vacuo to give crude 1,2- dibenzyloxymethylswainsonine- Column (Si0 ) chromatography afforded the pure product (visualized with I2) -
Example XIV The conversion of 1,2- dibenzyloxymethylswainsonine to swainsonine, i.e. , (-)- (is, 2R, 8R, 8aR)-l,2,8-Trihydroxyoctahydroindolizidine will be provided.
To a 5% acetic acid - methanol solution of the protected swainsonine produced by Example XIII was added 10% Pd-C. The mixture was stirred under H2 overnight, filtered through celite and concentrated in vacuo. The concentrate was then purified by ion exchange column chromatography to give swainsonine as a white solid-
Example XV Examples XV-XXI illustrate the use of benzyl group to protect the 1,2 diol moiety of swainsonine. -17-
As an example of the production of the starting material wherein the protecting group for the alcohol function, i.e. , R2 is (Cj-Cg) arylmethyl, (-)- 2 , 3-dibenzyl-D-erythronolactone, (-)-2,3-dibenzyl-D- erythrose, and (6S, 7R) ethyl ( Z)-6 ,7-dibenzyloxy-8- hydroxy-4-butenoate were produced. '**
To a solution of D-erythronolactone (1 equiv) in N,N-dimethylformamide at 0 degree C were added benzyl bromide (3 equiv) and silver oxide (3 equiv). The resulting mixture was stirred overnight at room temperature, and poured into saturated aqueous NH4C1. The aqueous layer was extracted three times with methylene chloride. The organic extracts were washed with water, dried with sodium sulfate, and concentrated in vacuo. Purification by Si0 column chromatography gave pure 2,3-dibenzyl-D-erythronolactone. To the methylene chloride solution of 2,3-dibenzyl-D- erythronolactone (1 equiv) thus obtained was added slowly DIBAL-H (1.1 equiv) at -78° C. The reaction mixture was stirred for 4h at -78 degrees C, and cautiously decomposed by the dropwise addition of methanol. The mixture was poured into a mixture of ice water and ethyl acetate. The pH of the resulting mixture was adjusted to 3 with IN H2S04- The aqueous layer was extracted four times with ethyl acetate. The organic extracts were washed with water, dried with sodium sulfate, and concentrated in vacuo. Purification by Si02 column chromatography gave 2,3- dibenzyl-D-erythrose. To a solution of 4-carbethoxybutyltriphenyl- phosphonium bromide (3.5 equiv) in anhydrous THF was added dropwise potassium bis( trimethylsilyl) amide [KN(SiMe3)2] (3.5 equiv) at 0 degree C over 10 min. The resulting red solution was stirred for an additional 30 min at 0 degree C and then cooled to -78 degrees C. A THF solution of 2,3-dibenzyl-D-erythrose (1 equiv) thus obtained was added dropwise- The reaction mixture was brought to room temperature overnight, and then quenched with saturated aqueous NH4C1. The product was extracted with ether, washed with brine, dried over Na2S04 and concentrated in ** vacuo. Purification by Si02 chromatography yielded ethyl (Z)-6,7-dibenzyloxy-8-hydroxy-4-butenoate-
Example XVI As an example of the production of the corresponding sulfonate, (6S, 7R) ethyl (Z)-6,7- dibenzyloxy-8-_p-toluenesulfonyloxy-4-butenoate was produced.
To a solution of the alcohol produced in Example XV in dry CH2C12 at 0 degree C there were added triethylamine, _p_-toluenesulfonyl chloride and N,N- dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate- The reaction mixture was washed with H20, saturated aqueous NaHC03 and brine solution, dried over Na2S04, and concentrated in vacuo to a yellow oil. Purification by Si02 column chromatography yielded the _p_-toluenesulfonate.
Example XVII As an example of production of the imino ester, the production of (3S, 4R)-3,4-dibenzyloxy-2[3- carbethoxy-l-propyl]-pyrrolid-l-ene will be provided.
To a solution of the _p_-toluenesulfonate produced by Example XVI in DMF was added sodium azide- The mixture was heated at 80 degrees C for 2 days under the N2 atmosphere. The mixture was then diluted with ethyl acetate, washed with H20 and brine solution, dried over Na S04 and concentrated in vacuo. The product was purified by Si02 column chromatography to afford the imino ester. Example XVIII
As an example of the production of the imino acid, the production of (3S, 4R)-3 ,4-dibenzyloxy-2 [3- carboxy-1-propyl] -pyrrolid-1-ene will be produced.
The imino ester produced by Example XVII was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HCl, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl - ■ acetate, and methylene chloride. The organic extracts were combined, dried over Na2S04, and concentrated in vacuo to give the acid. Example XIX
As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-0- dibenzyloxy-2-oxo-l-azabicyclo[4.3.0] non-5-ene will be provided. A solution of the acid produced by Example
XVIII in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si02 column chromatography to provide the enamide.
Example XX The conversion of the enamide to 1,2- dibenzylswainsonine, i.e. , (-)-lS, 2R, 8R, 8aR)-l,2- dibenzyloxymethoxy-8-hydroxyindolizidine will be provided.
To a cold (0 degree C) THF solution of the enamide produced in Example XIX was added 1.0M BH3 - THF solution. The reaction was brought to room temperature overnight. The solvent was removed _in_ vacuo, and ethanol was then added. To this solution were added sodium hydroxide and 30% hydrogen peroxide. Additional ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, ethanol removed in vacuo, and the residue dissolved in H20. The aqueous solution was saturated with solid NaCl, then extracted five times each with ethyl acetate, and methylene chloride- The combined organic extracts were dried over Na2S04, and concentrated in vacuo to give crude 1,2-dibenzylswainsonine- Column (Si02) chromatography afforded the pure product (visualized with I2)- Example XXI
The conversion of 1,2-dibenzylswainsonine to swainsonine, i.e. , (-)-(lS, 2R, 8R, 8aR)-l,2,8- Trihydroxyoctahydroindolizidine will be provided.
To a 5% acetic acid - methanol solution of the protected swainsonine produced by Example XX was added 10% Pd-C- The mixture was stirred under H2 overnight, filtered through celite and concentrated in vacuo. The concentrate was then purified by ion exchange column chromatography to give swainsonine as a white solid.
It will be appreciated therefore, that the present invention provides an efficient means for the synthesis of swainsonine employing unique imino ester and enamide intermediates. All of this is accomplished in an efficient and economical manner which is reliable and rapid-
Whereas particular embodiments of the invention have been described above for purposes of illustration, it will be appreciated by those skilled in the art that numerous variations of the details may be made without departing from the invention as described in the appended claims-

Claims

J_ ±L__.__.Ji__.
1. A process for producing swainsonine or its analogues comprising providing an imine having the structure
Figure imgf000023_0001
wherein R is alkyl and
R2 is (a) (C -Cg) cyclic acetal (ketal) or
(b) (Cj-Cg) alkoxymethyl or
(c) arylmethyl; and employing said imine to produce an enamide having the structure
Figure imgf000023_0002
wherein 2 is (a) (Cj_-Cg) cyclic acetal (ketal) or
(b) (C -Cg) alkoxymethyl or
(c) arylmethyl,
R3 is an oxygen atom or a hydrogen atom, and treating said enamide to produce swainsonine or an analogue thereof.
2. The method of claim 1 including hydrolizing said imine with an inorganic base to create an acid, and heating said acid at reflux temperature in a suitable organic solvent to produce said enamide.
3. The method of claim 2 including providing said imine by treating a starting material having the structure
Figure imgf000023_0003
wherein R is (C-j^-C ) alkyl; j is a halide or sulfonate; and R2 is (a) (Cj-Cg) cyclic acetal (ketal) or (b) (C^-Cg) alkoxymethyl or (c) arylmethyl.
4- The method of claim 3 including producing swainsonine from said enamide by treating said enamide with borane followed by removal of said R constituent.
5. The method of claim 4 including creating said acid as a crystalline acid.
6. The method of claim 1 including obtaining said starting material from a material having the structure
Figure imgf000024_0001
7- The method of claim 1 including effecting said imine hydrolysis employing an inorganic base selected from the group consisting of potassium carbonate and sodium carbonate, in aqueous alcohol.
8. The method of claim 1 including converting said enamide to swainsonine acetonide.
9. The method of claim 8 including converting said swainsonine acetonide to swainsonine by acid hydrolysis.
10. The method of claim 3 including employing an alcohol as said starting material.
11. The method of claim 1 including employing a tosylate as said starting material.
12. The method of claim 10 including employing an azide in producing said imine * from said alcohol-
13. The method of claim 1 including selecting said R constituent from the group consisting of methyl and ethyl.
14. The method of claim 13 including selecting said R^ constituent from the group consisting of ja-toluenesulfonate and bromide.
15. The method of claim 14 including selecting said R constituent from the group consisting of isopropylidene and benzyloxymethyl.
16. The method of claim 1 including providing said imine by treating a protected
D-erythrose.
17. The method of claim 16 including employing an isopropylidene as said protected
D-erythrose.
18. The method of claim 1 including employing a benzyl group to protect the 1,2- diol moiety of swainsonine.
19- The method of claim 1 including employing a benzyloxymethyl group to protect the 1,2-diol moiety of swainsonine.
20. An imine having the formula
Figure imgf000025_0001
wherein R is (C^-Cg) alkyl; and R is (a) (C^-Cg) cyclic acetal (ketal) or
(b) (C -Cg) alkoxymethyl or (c) arylmethyl.
21. The imine of claim 20 wherein said R constituent is selected from the group consisting of methyl and ethyl.
22- The imine of claim 21 wherein ^ said R-L constituent is selected from the group consisting of _p_-toluenesulfonate and bromide.
23. The imine of claim 22 wherein said constituent is selected from the group consisting of isopropylidene and benzyloxymethyl.
24. An enamide having the structure
wherein R2 is (a) (C^-Cg) cyclic acetal (ketal) or
(b) (C-j^-Cg) alkoxymethyl or
(c) arylmethyl, and R3 is an oxygen atom or a hydrogen atom.
25. The enamide of claim 21 wherein said R2 constituent is selected from the group consisting of isopropylidene and benzyloxymethyl.
PCT/US1988/004253 1988-11-29 1988-11-29 Synthesis of (-)-swainsonine and intermediate compounds employed in such synthesis Ceased WO1990006311A1 (en)

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PCT/US1988/004253 WO1990006311A1 (en) 1988-11-29 1988-11-29 Synthesis of (-)-swainsonine and intermediate compounds employed in such synthesis

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021858A1 (en) * 1997-10-24 1999-05-06 Glycodesign Inc. Synthesis of swainsonine salts
US5962467A (en) * 1995-06-07 1999-10-05 Glycodesign, Inc. Derivatives of swainsonine and their use as therapeutic agents
US6048870A (en) * 1996-10-01 2000-04-11 Glycodesign 3, 5, and/or 6 substituted analogues of swainsonine processes for their preparation and their use as therapeutic agents
US6395745B1 (en) 1997-04-15 2002-05-28 Glycodesign, Inc. Alkaloid halide salts of swainsonine and methods of use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"A short enantioselective synthesis of (-) swainsonine", R. BENNETT, J. AMERICAN: CHEMICAL SOCIETY 11 1(7), 2580 (1989). *
CHEMICAL ABSTRACTS, Volume 78, No. 21, issued 28 May 1973, (Columbus, Ohio, USA); H. HAJEK: "N-substituted 2-oxo-1 2,3,4 tetrahydropyridines and octahydroquinoline analogues", see page 366 the Abstract No. 136086a for Ger. Offen. 2,143,755. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962467A (en) * 1995-06-07 1999-10-05 Glycodesign, Inc. Derivatives of swainsonine and their use as therapeutic agents
US6048870A (en) * 1996-10-01 2000-04-11 Glycodesign 3, 5, and/or 6 substituted analogues of swainsonine processes for their preparation and their use as therapeutic agents
US6395745B1 (en) 1997-04-15 2002-05-28 Glycodesign, Inc. Alkaloid halide salts of swainsonine and methods of use
WO1999021858A1 (en) * 1997-10-24 1999-05-06 Glycodesign Inc. Synthesis of swainsonine salts
US6051711A (en) * 1997-10-24 2000-04-18 Glycodesign Inc. Synthesis of swainsonine salts
JP2001521036A (en) * 1997-10-24 2001-11-06 グリコデザイン インコーポレイテッド Synthesis of swainsonine salts

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