WO2006094770A2 - Apparatus and method for the final processing of a forming tool for a sheet-metal body part - Google Patents

Abstract

The present invention is directed to a process for the preparation of (4S)- or (4R)-2,2-dimethyl-4-(2-hydroxethyl)oxazolidine-3-carboxylic acid alkyl esters. The invention is further directed to an intermediate product from which those alkyl esters may be obtained.

Description

IMPROVED PROCEDURE FOR THE PREPARATION OF

(4S) OR (4R) -2,2-DIMETHYL-4- (2-HYDROXYETHYL) OXAZOLIDINE-S-CARBOXYLIC ACID ALKYL ESTERS

The present invention is directed to a process for the preparation of (4S)- or (4R)-2,2- dimethyl-4-(2-hydroxethyl)oxazolidine-3-carboxylic acid alkyl esters. The invention is further directed to an intermediate product from which those alkyl esters may be obtained.

4-Hydroxyornithine is a rare amino acid found in lentils¹ (e.g. Lens culinaris Medik.) and some members of the genus Vicia² (e.g. V. unijuga A. Br.). The structure of (2S,4R)-4- hydroxyornithine is given in Figure 1 below. Moreover it is a key constituent of the β-lactam antibiotic clavalanine³ and the cyclopeptide antibiotics biphenomycin A and B I⁴ (see Scheme 1). The latter have received considerable attention in recent years due to their high in vitro and in vivo antibacterial activity against multiresistant gram-positive pathogens.

Scheme 1: Structures of 4-hydroxyornithine and biphenomycin A and B

The inventors sought, as part of their program directed towards a convergent total synthesis of these antibiotics⁶ and analogues thereof with modified biaryl moiety, for an efficient access to an appropriate TV⁰^iV⁸, unprotected (25,4i?)-4-hydroxyornithine building block. While a number of synthetic pathways including stereoselective approaches have been developed for the synthesis of 4-hydroxyornithine⁷, only two approaches dealt with the synthesis of a derivative bearing N^a,Λ'^δ,O^γ-protection suitable for peptide synthesis.

Schmidt et al. reported a 13 step synthesis starting from (/?)-isopropylidene glyceraldehyde to form the Λζ,O-acetal 2 (see Scheme 2) albeit in low overall yield.⁸ More recently Rudolph et al. described a very concise access to the TBDMS protected 4-hydroxyornithine 3 starting from (S)-N-BoC aspartic acid tert-buty\ ester. This approach which is based on an initial homologization of the acid side chain to form an α-nitroketone and its subsequent diastereo- selective reduction to the corresponding β-nitro alcohol, however, also suffers from a low overall yield.⁵'⁹

--V⁰ NHBoc TBDMSO NHBoc

2 3

Scheme 2: Protected forms of 4-hydroxyornithine

In this application, a short and efficient stereoselective approach to both orthogonally

(2S,4R)- and (25^I,46)-4-hydroxyornithine based on an asymmetric nitroaldol (Henry) reaction of nitromethane with the homoserine derived aldehyde 6¹⁰ (Scheme 3) ' is disclosed. A retrosynthetic analysis of the nitroaldol reaction is given in Scheme 3 below.

reaction

5

Scheme 3: Retrosynthetic Analysis

A simple two-step preparation of building block 6 starting from readily available N-Boc- protected (S)-2-amino-l,4-butandiol 7¹² was previously reported by Ksander and co- workers.¹³'¹⁴ This commonly used approach, however, suffers from a low regioselectivity in the formation of the five-membered cyclic N,O-acetal 9 (Scheme 4). Thus, this crucial step was reported to proceed in only 42-48% yield by reacting 7 with excess 2,2-dimeth- oxypropane (DMP) (10 equiv., CH₂Cl₂, rt) in the presence of a catalytic amount of p-toluene sulfonic acid (TsOH), due to concurrent formation of the corresponding six-membered cyclic JV,O-acetal 10.¹³'¹⁵ Therefore, it is an object of the present invention to provide a new process for the preparation of compound (I) indicated below in high yield:

(I)

which can be used as a starting material to obtain hydroxyornithine. It is a further object to provide an intermediate product for the above given process.

These objects are solved by the subject-matter of the independent claims. Preferred embodiments are set forth in the dependent claims.

The present inventors based their improved process for obtaining the compound of formula (I) on the following considerations:

DMP Ii MeOH

Scheme 4: Acid Catalyzed N,OAcetal Formation of N-Boc-Protected (S)-2 -Amino- 1,4- butandiol 7 with DMP (it is noted that in scheme 4, compound 9 corresponds to the above compound (I) and compound 11 corresponds to the compound which is also termed "compound (V)" in the following). The inventors surprisingly found out in the course of their studies that the structure of this byproduct 10 (outlined above) was revised on the basis of ¹H-¹³C HMBC and ¹H-¹⁵N HMQC NMR experiments to be the corresponding seven-membered cyclic 0,0-acetal 8. Indeed, this isomer was shown to be the product of kinetic control, which slowly equilibrates with 9 under the reported reaction conditions. No evidence has been found for the occurrence of the six- membered cyclic N,(9-acetal 10.¹⁶ Furthermore N,0-acetal 9 was shown to exist also in an equilibrium with its 1 -methyl- 1 -methoxyethyl (MIP) ether derivative 11, a fact not mentioned in the previous papers.¹⁷ In the end, trapping 9 to form 11 allows the overall equilibrium to be shifted to the desired five-membered ring system.

The NMR spectra recorded to analyse compounds 5 and 8 are given as Figures.

The inventors of the present invention have found, that the trapping of liberated reaction product, i.e. methanol in this embodiment, could shift the equilibrium of 9 and 11 to the side of the derivative 11 (compound (V)). The trapping of the reaction side product, i.e. the liberated alcohol of the diester, shifts the equilibrium towards derivative 11. The desired product 9 (compound (I)) can easily be obtained from 11. Since product 9 is withdrawn from the equilibrium between the isomers 8, 9 and 10, this equilibrium is shifted towards the desired product 9.

Taking scheme 4 as an example, the liberated alcohol (MeOH) can be trapped by 2- methoxypropene to produce 2,2-dimethoxypropane. Thus, no further product which has to be removed from the resulting reaction mixture is generated while trapping the alcohol. In this example, the reaction conditions are modified in such a way that 2,2-dimethoxypropane is used as the solvent and 2-methoxypropene (3.0 equiv.) is added to trap liberated methanol. The desired product 9 can be obtained in high overall yield (92%) after mild hydrolysis (wet silica gel, CH₂Cl₂, rt) of the intermediate MIP ether 11. Of course, it is within the average knowledge of someone having ordinary skills in the art that any appropriate 2,2- dialkoxypropane of formula (III) can be used, 2,2-dimethoxypropane is provided as an example only. The present invention thus according to a first aspect provides a process for the preparation of a compound of formula (I) or its enantiomer

(I) wherein:

R¹ is methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, tert-butyl, 1-adamantyl, allyl, 9-fluorenylmethyl, benzyl or a substituted benzyl group;

which comprises reacting a compound of formula (II) or its enantiomer:

where R¹ is as defined above, with an appropriate 2,2-dialkoxypropane of formula (III)

H-C CH,

<o^Xo-^{R 2}

(III) wherein: R² is methyl or ethyl and with an appropriate 2-alkoxypropene of formula (IV)

(IV) wherein:

R² is methyl or ethyl, in the presence of an acid to give a compound of formula (V) or its enantiomer

wherein:

R¹ and R² are as defined above, which is hydrolyzed to give a compound of formula (I).

In formula (III):

H-C CH-

<o^Xo'^{R 2}

(III)

R² can be methyl or ethyl, with methyl being preferred.

Further, 2-alkoxypropene according to formula (IV) is used according to the invention.

(IV)

Here, R" is defined as above. Preferably, R is identical in both the 2,2-dialkoxypropane of formula (III) and the 2-alkoxypropene according to formula (IV). It is important to note that both compounds (III) and (IV) have to be present in the process of the invention in order to achieve the object of the invention, i.e. to obtain compound (V) and, finally, compound (I) in a high yield.

In order to catalyse the equilibrium reactions, an acid is added according to the invention. This acid preferably is soluble in the solvent used. A preferred acid is p-toluenesulfonic acid. However, also other acids may be used, for example camphorsulfonic acid.

As a solvent, 2,2-dialkoxypropane can be used according to the invention. In this embodiment, the solvent further acts as a reagent to form the desired product 9. However, also further solvents may be used in the process of the invention. As preferred examples, dichloromethane and acetone should be named. Any solvent may be used as long as it is compatible with strong acids and as long as it is possible to remove water therefrom.

As starting material, any protected (S)- or (R)-2-amino-l ,4-butandiol corresponding to formula (II) below may be used.

Here, R¹ is methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, tert-butyl, 1-adamantyl, allyl, 9-fluorenylmethyl, benzyl or a substituted benzyl group, with tert-butyl being preferred.

The above described process can thus be used to prepare a compound of the formula (I)

(I) wherein R¹ is methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, tert-butyl, 1- adamantyl, allyl, 9-fluorenylmethyl, benzyl or a substituted benzyl group, preferably tert- butyl.

Finally Swern oxidation of 9 provides the desired aldehyde 6 in 97% yield (Scheme 5).¹⁴

^{3 ste}Pl

(COCI)₂, DMSO, NEt₃, _H

CH₂CI₂, -60 ⁰C ^"Tf Y o >- O BocN-^—

97% ₆ /

Scheme 5: Improved Synthesis of Aldehyde 6

In a second aspect, the present invention provides the compound of formula (V) or its enantiomer, wherein R and R are as defined above. Compound (V) turned out to be a very useful intermediate, since its production and isolation by the present process shifts the equilibrium of the reaction (see scheme 4) in order to result in compound (V) in high yield. Second, it may be easily converted to the desired compound (I) by simple hydrolysis.

According to an embodiment, in this compound, R¹ is tert-buty\ and/or R² is methyl.

With key building block 6 in hand, its nitroaldol (Henry) reaction with nitromethane was examined (Table 1). LiAlH₄ ¹⁸- TBAF¹⁹- as well as t-BuOK²⁰-catalyzed Henry reactions led to nitro alcohols 12 and 13 with low diastereoselectivity, reflecting that the existing stereogenic center is too far away from the newly created one to exert appreciable asymmetric induction (Table 1, entries 1-3).²¹ An obvious way of resolving this problem was the introduction of additional chiral information, i.e. application of a chiral catalyst. In fact double stereodifferentiation using Shibasaki's well established heterobimetallic (,S)-BINOL catalyst 14²² (5 mol%, THF, -40 °C, 3 d) led to 12 with high diastereoselectivity albeit in low yield (Table 1, entry 4).

Recently, other highly efficient chiral catalysts for asymmetric Henry reactions have been developed. Thus, Corey²³ and Maruoka²⁴ have utilized chiral quaternary ammonium fluorides as catalysts while Trost²⁵ has presented a dinuclear zinc catalyst. Salen-cobalt(II) complexes have been used by Yamada whereas Jørgensen and Evans have introduced bis(oxazoline)-copρer(II) complexes. The latter seemed to be the catalysts of choice, at least for aliphatic aldehydes, with respect to attainable yields and degree of stereoselectivity. Table 1. Diastereoselective Henry Reaction of Aldehyde 6 with Nitromethane

yield ratio⁰ entry catalyst conditions

(%)^a 12:13

1 LiAlH₄ THF, rt 53 56:44

2 TBAF THF, rt 33 43:57

3 r-BuOK t- 72 23:77

BuOH/THF,0

⁰C

4 14 THF, -40 °C 45 98:2

5 {Cu[(+> EtOH, rt 87 92:8

15]} (OAc)₂

6 (CuK-)- EtOH, rt 85 9:91

15]}(OAc)₂

7 {Cu[(+> EtOH, rt 94 97:3

16]}(OAc)₂

8 (Cu[(-)- EtOH, rt 91 8:92

16I)(OAc)₂

^a isolated yield ^b determined by HPLC analysis of crude reaction mixtures Indeed application of Evans' bis(oxazoline) copper(II) acetate-based catalysts {Cu[(+)- 15]}(OAc)₂ and in particular {Cu[(+)-16]}(OAc)₂ (5 mol%, EtOH, rt, 5 d) gave the desired nitro alcohol 12 both with high diastereoselectivity and in high yield (Table 1 , entries 5 and 7). Finally, to obtain selectively diastereomer 13, aldehyde 6 was reacted with nitromethane in the presence of the enantiomeric catalysts {Cu[(-)-15]}(OAc)₂ and {Cu[(-)-16]} (OAc)₂ respectively. In these cases slightly lower stereoselectivities and yields were observed reflecting a mismatched pairing (Table 1, entries 6 and 8).

17

1. (CH₂OH)₂ , CSA (cat.), THF, 50 ⁰C

2. TEMPO (cat.), NaOCI (cat.), NaCIO₂, MeCN, buffer pH 6.7 ZHN^ ^C0*^H TIPSO NHBoc

53% (80%)a 4

¹ based on recovered starting material

Scheme 6: Synthesis of Orthogonally Protected (25',4i?)-4-Hydroxyornithine 4

The inventors next turned their attention to the transformation of β-nitro alcohol 12 into the desired amino acid building block 4 (Scheme 6).²⁹ Protection of the hydroxyl group as a TIPS ether proceeded smoothly under standard conditions (TIPSOTf/2,6-lutidine). Reduction of the nitro group was accomplished using ammonium formate as a hydrogen source, and palladium on carbon as the catalyst to afford the corresponding amine which was transformed (Z-OSu/NEt₃) to the Λ^-Z-protected 4-hydroxyornithine derivative 17 in 84% overall yield (three steps). Selective hydrolysis of the N,0-acetal using several methods (e.g. pyridinium tosylat, MeOH, 60 °C; I₂, MeOH, rt or CeCl₃"7H₂O/oxalic acid, rt) proved to be difficult due to concomitant partial cleavage of the TIPS ether. Fortunately, the inventors were able to effect this transformation cleanly and in good yield (64%, 96% based on recovered starting material) using ethylene glycol/CSA (THF₅ 50 °C, 2d).³⁰ The final oxidation of the amino alcohol was best accomplished with TEMPO/ΝaOCl/ΝaClθ₂ ³¹ to give the desired carboxylic acid 4 {mp 45-47 ⁰C₅ [oc]²² _D +67.6 (c 1.64, CH₂Cl₂)) in 83% yield without epimerization. The absolute configuration of product 4 was established to be 2S,4R by subsequent transformation into the known γ-lactone 18³² {mp 148-149 ⁰C lit. 143-145 °C; [α]_D ²³ -25.2 (c 0.85, CHCl₃) lit. [α]_D ²³ -22.4 (c 0.5, CHCl₃)).

0C\

According to this reaction sequence, 13 was converted to 5 {mp 53-55 ⁰C, [α] D -28.5 (c 1.00, CH₂Cl₂)) in 57% overall yield {66% based on recovered starting materials) in five steps.

In conclusion the inventors have developed a short and highly efficient approach to orthogonally protected (2S,4R)- and (25',45)-4-hydroxyornithine building blocks 4 and 5 respectively based on bis(oxazoline) copper(II) complex catalyzed diastereoselctive Henry reactions of nitromethane with aldehyde 6. In addition, a greatly improved procedure for a multigram synthesis of this valuable chiral building block and its precursor 9 has been developed.

The present invention is now illustrated in greater detail by the enclosed Figures and Examples. It is noted that the Examples are provided for illustrative purposes only and that the invention is not limited thereto.

In the Figures, the following is shown:

Fig. 1 is an ¹H NMR spectrum (500 MHz, CD₂Cl₂) of compound 8;

Fig. 2 is an ¹³C NMR spectrum (125 MHz, CD₂Cl₂) of compound 8;

Fig..3 is an ¹H-¹³C HMQC spectrum (CD₂Cl₂) of compound 8;

Fig. 4 is an ¹H-¹³C HMBC spectrum (CD₂Cl₂) of compound 8;

Fig. 5 is an ¹H-¹⁵N HMQC spectrum (CD₂Cl₂) of compound 8; and

Fig. 6 is an ¹H NMR spectrum (500 MHz, C₂D₂Cl₄, 80 ⁰C) of compound 5.

Examples:

General information. All reactions were carried out in oven-dried glassware under a nitrogen atmosphere unless stated otherwise. THF and NEt₃ were distilled from sodium, EtOH from sodium/ethyl phthalate, MeOH from magnesium and CH₂Cl₂ from calcium hydride immediately before use. Standard syringe techniques were applied for transferring anhydrous solvents. Indabox ligands (+)-16 and (-)-16 were prepared using literature procedures.³³ All other solvents and reagents were used as supplied. Analytical thin layer chromatography was performed on Merck 0.25 mm silica gel 60-F₂₅₄ plates. Visualization was accomplished with UV light and either eerie ammonium nitrate or permanganat stain, followed by heating. Purification of reaction products was carried out by flash chromatography using Merck silica gel 60 (40-63 μm). Melting points were obtained on a melting point apparatus Bϋchi No. 510 (Dr. Tottoli) and are uncorrected. Optical rotations were measured on a Perkin Elmer Model 241 polarimeter at 589 nm and are reported as follows: [α]^{τ °C} _D (c = g/100 mL, solvent). Infrared spectra were recorded on a Perkin Elmer FT-IR Spectrometer Paragon 1000. ¹H NMR spectra were recorded on a Jeol JNMR-GX400 (400 MHz) or on a Jeol JNMR-GX500 (500 MHz) spectrometer. Chemical shifts are reported in ppm using TMS as internal standard. Chemical shifts of high temperature ¹H NMR spectra are reported in ppm using solvent as an internal standard (C₂D₂Cl₄ at 5.99 ppm). Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad; coupling constant(s) in Hz; integration. Proton-decoupled ¹³C NMR spectra were recorded on a Jeol JNMR-GX400 (100 MHz) or on a Jeol JNMR-GX500 (125 MHz) spectrometer. Chemical shifts are reported in ppm using TMS as internal standard. Chemical shifts of high temperature ^]3C NMR spectra are reported in ppm using solvent as an internal standard (C₂D₂Cl₄ at 73.99 ppm). Mass spectra were obtained on a Hewlett Packard 5989A mass spectrometer with 59980B Particle Beam LC/MS Interface. High resolution mass spectra were obtained on a Jeol MStation 700. Combustion elemental analyses were measured on a Heraeus CHN Rapid.

The N-Boc-protected (5)-2-amino-l,4-butandiol 7 was prepared from aspartic acid in 3 steps in 95% overall yield using previously reported methods, shown in Scheme 7 below.

Scheme 7: Synthesis of iV-Boc-protected (S)-2-amino-l,4-butandiol 7

Synthesis of iV,0-acetal 9 according to literature (comparative example):³ 2,2-

Dimethoxypropane (1.2 mL, 10 mmol) and /?-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) were added to a stirred solution of diol 7 (205 mg, 1.0 mmol) in CH₂Cl₂ (4.5 mL). After stirring for 36 h at room temperature the reaction mixture was poured into saturated aqueous NaHCO₃ (5 mL) and extracted with EtOAc (5 x 5 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo to give a colorless oil. The ratio of 8:9:11 was determined by ¹H NMR (500 MHz) to be 30:45:25. The residue was purified by flash chromatography on silica gel («-hexane/EtOAc 80:20 + 0.5% iV-ethyldimethylamine) to afford N,O-acetal 9 (110 mg, 45%) as a colorless solid along with 0,<9-acetal 8 (47 mg, 19%) as a colorless oil and MIP derivative 11 (50 mg, 16%) as a colorless oil, which is prone to hydrolysis.

Example 1: A solution of 7 (13.36 g, 65.1 mmol) and j7-toluenesulfonic acid monohydrate (632 mg, 3.32 mmol) in 2,2-dimethoxyproρane (650 mL) was stirred at room temperature for 2 h. 2-Methoxypropene (20 mL, 209 mmol) was added and the reaction mixture was stirred for additional 67 h at room temperature. The solution then was poured into cold saturated aqueous NaHCO₃ (900 mL) and extracted with EtOAc (5 x 300 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo to give 11 as a colorless oil which was used without further purification. A solution of the crude product 11 in CH₂Cl₂ (400 mL) was treated with silica gel (166 g) and H₂O (1O mL) and stirred at room temperature for 72 h. After filtration through a pad of sand the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (π-hexane/EtOAc 80:20 + 0.5% ethyldimethylamine) to afford N,O-acetal 9 as a colorless solid (14.64 g, 92%) along with 0,0-acetal 8 (0.35 g, 2%) as a colorless oil.

Example 2: 2,2-Dimethoxypropane (2.53 mL, 20 mmol) and DL-camphor-10-sulfonic acid (23.7 mg, 0.1 mmol) were added to a stirred solution of diol 7 (410 mg, 2.0 mmol) in CH₂Cl₂ (5 mL). After stirring for 6 h at room temperature 2-methoxypropene (670 μl, 7 mmol) was added. After stirring for further 20 h the reaction mixture was poured into saturated aqueous NaHCO₃ (10 mL) and extracted with CH₂Cl₂ (5 x 30 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo to give 11 as a colorless oil (665 mg) which was used without further purification. A solution of the crude product 11 in CH₂Cl₂ (12 mL) was treated with silica gel (5 g) and H₂O (0.3 mL) and stirred at room temperature for 96 h. After filtration through a pad of sand the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (π-hexane/EtOAc 80:20 + 0.5% ethyldimethylamine) to afford N,O-aceta\ 9 as a colorless solid (469 g, 96%).

Example 3: 2,2-Dimethoxypropane (2.53 mL, 20 mmol) and DL-camphor-10-sulfonic acid (23.7 mg, 0.1 mmol) were added to a stirred solution of diol 7 (410 mg, 2.0 mmol) in acetone (5 mL). After stirring for 6 h at room temperature 2-methoxypropene (670 μl, 7 mmol) was added. After stirring for further 20 h the reaction mixture was poured into saturated aqueous NaHCO₃ (10 mL) and extracted with CH₂Cl₂ (5 x 30 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo to give 11 as a colorless oil (646 mg) which was used without further purification. A solution of the crude product 11 in CH₂Cl₂ (12 mL) was treated with silica gel (5 g) and H₂O (0.3 mL) and stirred at room temperature for 96 h. After filtration through a pad of sand the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel («-hexane/EtOAc 80:20 + 0.5% ethyldimethylamine) to afford N,O-acetal 9 as a colorless solid (442 g, 90%).

(45)-2,2-Dimethyl-4-(2-hydroxyethyl)-oxazolidine-3-carboxylic acid tert-bntyl ester (9): tnp 75-76°C; [α]¹⁹ _D -12.3 (c 1.53, CHCl₃) lit.³⁵ [α]_D

+12.1 (c 1.5, CHCl₃) [(Λ)-isomer]; ¹H ΝMR (500 MHz, CDCl₃): δ 1.50 (s, 9 H), 1.51 (s, 3 H), 1.55 (s, 3 H), 1.68-1.77 (m, 1 H), 1.78-1.89 (m, 1 H), 3.50-3.60 (m, 1 H), 3.60-3.77 (m, 2 H), 4.01 (m, 1 H), 4.23 (m, 1 H); ¹³C ΝMR (100 MHz, CDCl₃): δ 24.4 (CH₃), 27.8 (CH₃), 28.3 (CH₃), 37.8 (CH₂), 53.9 (CH), 58.7 (CH₂), 68.3 (CH₂), 81.0 (C), 93.7 (C), 153.9 (C). The spectroscopic data were consistent with those reported.²

(5S)-2,2-Dimethyl-l,3-dioxepane-5-carbaminic acid tert-butyl ester (8): [(X]²³D +0.16 (c 1.25, CH₂Cl₂); IR (film): 3452 cm^"1, 1713; ¹H NMR

(⁵⁰° ^MHz' CDCl₃): δ 1.32 (s, 3 H), 1.34 (s, 3 H), 1.45 (s, 9 H), 1.70 (bd, J

= 14.3 Hz, IH), 1.77 (ddt, J= 3.7, 10.5, 14.3 Hz, 1 H), 3.53 (ddd, J = 1.8, 4.3, 12.0 Hz, 1 H), 3.59 (dt, J= 3.9, 12.7 Hz, 1 H), 3.73 (bt, J= 1 1.6 Hz, 1 H), 3.74-3.85 (m, 2 H), 5.16 (bd, J= 6.6 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ 24.7 (CH₃), 24.9 (CH₃), 28.4 (CH₃), 35.8 (CH₂), 48.5 (CH), 58.0 (CH₂), 64.0 (CH₂), 79.3 (C), 101.4 (C), 155.2 (C); ¹H NMR (500 MHz, CD₂Cl₂): δ 1.29 (s, 3 H), 1.30 (s, 3 H), 1.42 (s, 9 H), 1.63 (dtt, J= 1.8, 4.6, 14.3 Hz, 1 H), 1.74 (dddd, J= 3.3, 4.1, 10.1, 14.3 Hz, 1 H), 3.49 (ddd, J= 1.7, 4.7, 12.0 Hz, 1 H), 3.55 (dddd, J= 0.4, 3.3, 4.6, 12.7 Hz, 1 H), 3.64-3.73 (m, 2 H), 3.75 (bd, J= 12.0 Hz, 1 H), 5.17 (bs, 1 H, NH); ¹³C-NMR (125 MHz, CD₂Cl₂): δ 24.6 (CH₃), 24.7 (CH₃), 28.2 (CH₃), 35.9 (CH₂), 48.9 (CH), 58.0 (CH₂), 64.1 (CH₂), 78.9 (C), 101.3 (C), 155.1 (C); MS (CI) m/z (rel. intensity): 246 (4) [M+H]⁺, 172 (100), 146 (9); Anal. Calcd for C₁₂H₂₃NO₄: C, 58.75; H, 9.45; N, 5.71. Found: C, 58.69; H, 9.59; N, 5.74.

¹H NMR (500 MHz, CDCl₃) and ¹³C NMR (125 MHz, CDCl₃) data match those reported for the six-membered cyclic N.O-acetal 10.^2a The structure of 10 was revised on the basis of ¹H- ¹³C HMBC [HMBC cross peaks between δ (H-4) = 3.49, δ (H-7) = 3.55, δ (H-7) ~ 3.70, δ (H- 4) ~ 3.75 and δ (C-2) = 101.6] and ¹H-¹⁵N HMQC [¹H-¹⁵N-HMQC cross peak between δ (¹H) = 5.17 and δ (¹⁵N) = -285 (nitrogen chemical shifts are reported in ppm using nitrobenzene as an external standard)] experiments to be 8, as shown below. For ¹H NMR, ¹³C NMR, ¹H- ¹³C HMQC, ¹H-¹³C HMBC and ¹H-¹⁵N HMQC spectra of compound 8 (see Figures).

ethyl]- 2,2- dimethyl- ester (11): H NMR

(500 MHz, CDCl₃): δ 1.34 (s, 6 H), 1.50 (bs, 12 H), 1.56-1.67 (m,

3 H), 1.71-1.87 (m, 1 H), 1.90-2.16 (m, 1 H), 3.19 (s, 3 H), 3.37-3.63 (m, 2 H), 3.81-4.09 (m, 3 H); ¹³C-NMR (125 MHz, CDCl₃): δ = 24.36 (CH₃), 24.39 (CH₃), 28.4 (CH₃), 28.5 (CH₃), 34.1 (CH₂), 48.4 (CH₃), 55.9 (CH), 58.2 (CH₂), 67.4 (CH₂), 79.4 (C), 93.7 (C), 99.9 (C), 151.8 (C); HRMS (FAB) calcd for C]₆H₃₁NO₅ [M+H]⁺: 318.2280, Found: 318.2280.

(4S)- 2,2- Dimethyl-4- (2-oxoethyI)- oxazolidine-3- carboxylic acid tert- butyl ester (6): A solution of DMSO (5.3 mL, 74.5 mmol) in CH₂Cl₂

(23 mL) was added dropwise to a cooled solution (-60 °C) of oxalyl chloride (3.44 mL, 40.0 mmol) in CH₂Cl₂ (83 mL). The solution was stirred for 15 min at -60 °C, before a solution of alcohol 9 (7.017 g, 28.6 mmol) in CH₂Cl₂ (36 mL, including rinses) was added slowly. After stirring at -60 ⁰C for 30 min, Et₃N (19.9 mL, 142.8 mmol) was added. After 30 min, the cold bath was removed and the reaction was stirred an additional hour at room temperature. The mixture was poured into H₂O (360 mL) and extracted with CH₂Cl₂ (5 x 100 mL). The combined organic layers were washed with H₂O (180 mL), dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel («-hexane/Et₂O 1 :1) to afford 6 (6.72O g, 97%) as a colorless solid: mp 34-38 °C lit.⁴ < 40 °C; [α]²² _D +35.1 (c l .03, CHCl₃) lit.³⁶ [α]²² _D +34.0 (c l.O, CHCl₃); ¹H NMR (400 MHz, C₂D₂Cl₄, 120 ⁰C): δ 1.47 (s, 9 H), 1.49 (s, 3 H), 1.56 (s, 3 H), 2.63 (dd, J- 7.7, 16.6 Hz, 1 H), 2.88 (dd, J = 4.0, 16.6 Hz, 1 H), 3.70 (bd, J= 9.2 Hz, 1 H), 4.05 (dd, J= 6.0, 9.2 Hz, 1 H), 4.24-4.33 (m, 1 H), 9.77 (bs, 1 H); ¹³C NMR (100 MHz, C₂D₂Cl₄, 120 ⁰C): δ 24.3 (CH₃), 27.1 (CH₃), 28.5 (CH₃), 48.0 (CH₂), 52.8 (CH), 67.8 (CH₂), 80.4 (C), 93.9 (C), 151.8 (C), 199.9 (CH).

(4S)- 4- [(2R)- 2- Hydroxy- 3- nitroρropyl]-2,2- dimethyloxazolidine- 3-carboxylic acid tert-butyl ester (12): A

solution of indabox ligand (+)-16 (493 mg, 1.375 mmol) and Cu(OAc)₂-H₂O (250 mg, 1.25 mmol) in EtOH (37.5 mL) was stirred for I h at room temperature. Nitromethane (13.6 mL, 250.0 mmol) and the aldehyde 6 (6.08 g, 25.0 mmol) were subsequently added to the resulting clear blue solution. After stirring for 5 d at room temperature the solvent was removed in vacuo. The diastereomeric ratio 12:13 was determined by HPLC analysis (n-heptane/i-PrOH 99:1; LiChrospher^® 250x4, Si 60, 5 μm; 1.5 mL/min; 215 nm; 13: t_r = 33.8 min; 12: t_r = 42.4 min) of the crude reaction mixture to be 97:3. The crude product was purified by flash chromatography on silica gel (/?-hexane:EtOAc 3:1) to give 12 (6.87 g, 94%) as a 97:3 mixture of diastereomers. For analytical purposes a small quantity of the diastereomers was separated by preparative HPLC (π-heptane/z-PrOH 99:1; Hibar^® 250x25, Si 60, 5 μm, 15 mL/min; 215 nm) to afford 12 as a colorless solid: mp 61-62 °C; [α]²² _D +28.9 (c O.56, CH₂Cl₂); IR (KBr): 3483 cm^"1, 1697, 1558, 1394; ¹H NMR (500 MHz, C₂D₂Cl₄, 100 ⁰C): δ 1.50 (s, 9 H), 1.51 (s, 3 H), 1.60 (s, 3 H), 1.82-1.94 (m, 2 H), 3.48 (bs, 1 H), 3.79 (dd, J= 1.2, 9.1 Hz, 1 H), 4.02 (dd, J= 6.1, 9.1 Hz, 1 H), 4.06-4.14 (m, 1 H), 4.35-4.42 (m, 1 H), 4.42-4.50 (m, 2 H); ¹³C NMR (100 MHz, C₂D₂Cl₄, 100 ⁰C): δ 24.2 (CH₃), 27.3 (CH₃), 28.5 (CH₃), 38.8 (CH₂), 54.7 (CH), 66.8 (CH), 68.1 (CH₂), 80.7 (CH₂), 80.9 (C), 94.1 (C), 152.6 (C); MS (CI) m/z (rel. intensity): 305 (1) [M+H]⁺, 188 (100); Anal. Calcd for C₁₃H₂₄N₂O₆: C, 51.31 ; H, 7.95; N, 9.20. Found: C, 51.31; H, 7.93; N, 9.04.

(45)-2,2- Dimethyl- 4- [(2R)-2-triisopropylsilanyloxy-3- o TlPSO BocN-/ — nitropropyl]-oxazoIidine-3-carboxylic acid tert-huty\ ester (19):

TIPSOTf (1.5 mL, 5.25 mmol) was added dropwise to a cooled solution (0 ⁰C) of alcohol 12 (1.52 g, 5.0 mmol, 97:3 mixture of diastereomers) and 2,6-Lutidine (680 μl, 5.75 mmol) in CH₂Cl₂ (1O mL). The reaction mixture was stirred for 90 min at 0 ⁰C and for 15 h at room temperature before it was quenched with saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was extracted with diethyl ether (5 x 20 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel («-hexane:EtOAc 85:15) to afford TIPS-ether 19 (2.252 g, 98%) as a 97:3 mixture of diastereomers: IR (film): 1688 cm^"1, 1556, 1388; ¹H NMR (500 MHz, CD₂Cl₂): δ 1.05 (bs, 21 H), 1.46 (s, 9 H), 1.47 (s, 3 H), 1.56 (s, 3 H), 1.80-1.87 (m, 1 H), 2.06 (m, 1 H), 3.69 (bd, J= 8.4 Hz, 1 H), 3.80-4.02 (m, 2 H), 4.44-4.60 (m, 1 H), 4.65 (dd, J= 6.3, 11.8 Hz, 1 H), 4.87 (bd, J= 11.8 Hz, 1 H); ¹³C NMR (125 MHz, CD₂Cl₂): δ 13.0 (CH), 18.2 (CH₃), 24.5 (CH₃), 28.2 (CH₃), 28.5 (CH₃), 42.0 (CH₂), 54.4 (CH), 68.4 (CH), 68.7 (CH₂), 80.72 (CH₂), 80.75 (C), 94.3 (C), 153.5 (C); HRMS (FAB) calcd for C₂₂H₄₅N₂O₆Si [M+H]⁺: 461.3047. Found: 461.3051.

(45)- 4- [(2/?)-3-BenzyIoxycarbonylamino-2-triisopropylsiIanyl- oxy-propyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-bntyλ

ester (17): Ammonium formate (3.083 g, 48.9 mmol) and palladium on carbon (10% Merck, 593 mg) were subsequently added to a cold (0 ⁰C) stirred solution of the nitro derivative 19 (2.23O g, 4.84 mmol, 97:3 mixture of diastereomers) in MeOH (26 mL). After stirring the reaction mixture for 24 h at room temperature, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL) and washed with saturated aqueous NaHCO₃ (20 mL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo to give the crude amine [2.038 g, ¹H NMR (400 MHz, CDCl₃): δ 1.05 (bs, 21 H), 1.46 (bs, 12 H), 1.54 (s, 0.6 x 3 H), 1.59 (s, 0.4 x 3 H), 1.68-1.90 (m, 1 H), 1.90- 2.10 (m, 1 H), 2.67-2.87 (m, 1 H), 2.93 (dd, J= 7.1 Hz, 12.6 Hz, 1 H), 3.80-3.92 (m, 3 H), 3.99-4.08 (m, 1 H)] which was used without further purification in the next step. N-(Benzyloxy-carbonyloxy)succinimide (1.24 g, 4.88 mmol) was added to a solution of the crude amine and Et₃N (850 μl, 6.04 mmol) in CH₂Cl₂ (15 mL). After stirring for 70 h at room temperature the reaction mixture was diluted with EtOAc (50 mL) and washed with phosphate buffer pH 5.5 (30 mL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel («-hexane:EtOAc 85:15) to afford 17 (2.252 g, 82%), which was judged to be diastereomerically pure by ¹H NMR (500 MHz), as a colorless oil: [α]²⁴ _D +31.2 (c O.49, CH₂Cl₂); IR (film): 3339 cm^"1, 1728, 1698, 1672, 1513; ¹H NMR (500 MHz, CH₂Cl₂): δ 1.07 (bs, 21 H), 1.44 (bs, 3 H), 1.46 (bs, 9 H), 1.52 (bs, 3 H), 1.77-1.96 (m, 2 H), 3.02- 3.22 (m, 1 H), 3.47-3.82 (m, 2 H), 3.83-4.16 (m, 3 H), 5.07 (bs, 2 H), 6.14 (bs, 1 H), 7.25-7.44 (m, 5 H); ¹³C NMR (125 MHz, CH₂Cl₂): δ 12.5 (CH), 18.0 (CH₃), 24.2 (CH₃), 27.6 (CH₃), 28.2 (CH₃), 38.4 (CH₂), 44.3 (CH₂), 53.4 (CH), 66.2 (CH₂), 68.9 (CH), 69.0 (CH₂), 80.3 (C), 93.1 (C), 127.6 (CH), 127.8 (CH), 128.4 (CH), 137.5 (C), 152.7 (C), 156.6 (C); HRMS (FAB) calcd for C₃₀H₅₃N₂O₆Si [M+H]⁺: 565.3673. Found: 565.3688.

_/«_s >v _/s (25,4R)-l-Hydroxy-4-triisopropyIsilanyIoxy-5-benzyloxycarbonyl-

ZHN jj jf OH

TiPSO NHBoc aminopent-2-ylaniinocarboxylic acid tert-butyl ester (20): A solution of oxazolidine 17 (565 mg, 1.0 mmol) in THF (12 mL) was treated with anhydrous ethylene glycol (558 μl, 10.0 mmol) and (±)-camphorsulfonic acid (17.0 mg, 0.05 mmol) and was stirred at 50 ⁰C for 48 h. The reaction mixture was cooled to 0 °C, quenched by the addition of saturated aqueous NaHCO₃ (10 mL) and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel («-hexane:EtOAc 75:25) to afford 20 (336 mg, 64%) as a colorless oil along with recovered starting material 17 (187 mg, 33%): [α] D +15.5 (c 2.46, CH₂Cl₂); IR (film): 3445 cm^"1, 3348, 1710, 1696, 1514; ¹H NMR (500 MHz, CHCl₃): δ 1.06 (bs, 21 H), 1.43 (bs, 9 H), 1.60-1.70 (m, 1 H), 1.71-1.83 (m, 1 H), 2.78 (bs, 1 H), 3.20 (dt, J = 4.8, 14.0 Hz, 1 H), 3.38-3.68 (m, 3 H), 3.73 (m, 1 H), 3.96-4.09 (m, 1 H), 4.91 (bs, 1 H), 5.07 (d, J= 12.2 Hz, 1 H), 5.12 (d, J= 12.2 Hz, 1 H), 5.41 (bs, 1 H), 7.27-7.40 (m, 5 H); ¹³C NMR (125 MHz, CHCl₃): δ 12.4 (CH), 18.1 (CH₃), 28.3 (CH₃), 36.7 (CH₂), 45.1 (CH₂), 49.7 (CH), 65.9 (CH₂), 66.7 (CH₂), 69.3 (CH), 79.6 (C), 128.0 (CH), 128.1 (CH), 128.5 (CH), 136.6 (C), 156.1 (C), 156.9 (C); HRMS (FAB) calcd for C₂₇H₄₉N₂O₆Si [M+H]⁺: 525.3360. Found: 525.3356.

/_\ >^\ .CO₂H (2S,4R)- 5-BenzyloxycarbonyIamino-2- fert-butoxycarbonyl- TIPSO NHBoc amino-4-triisopropylsilanyloxy-pentanoic acid (4): A catalytic amount of TEMPO (17.8 mg, 0.112 mmol) was added to a solution of alcohol 20 (839.6 mg, 1.6 mmol) in MeCN (8 mL) and sodium phosphate buffer pH 6.7 (6 mL). The mixture was heated to 35 ⁰C, and 2.0 M NaClO₂ (1.3 mL) and diluted bleach (730 μl, 0.034 mmol free chlorine) were added simultaneously over 1 h (Caution! Do not mix bleach and NaClO₂ before being added to the reaction mixture).³⁷ The reaction mixture was stirred at 35 ⁰C for another 4.5 h and then cooled to room temperature. H₂O (28 mL) was added and the pH was adjusted to 8-9 with 4 M NaOH. Then the mixture was poured into cold (0 ⁰C) 0.5 M Na₂SO₃ (60 mL). After 30 min the mixture was extracted with EtOAc (6 x 80 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n- hexane/EtOAc 6:4 + 0.5% HOAc) to afford 4 (719 mg, 83%) as a colorless solid: mp 45-47 °C; [α]²² _D +67.6 (c 1.64, CH₂Cl₂); IR (KBr): 3369 cm-¹, 1716, 1514; ¹H NMR (400 MHz, C₂D₂Cl₄, 80 ⁰C): δ 1.08 (s, 21 H), 1.45 (s, 9 H), 1.86 (m, 1 H), 2.03-2.14 (m, 1 H), 3.22 (dt, J= 5.3, 14.3 Hz, 1 H), 3.71 (m, 1 H), 4.15 (m, 1 H), 4.39 (m, 1 H), 5.11 (d, J= 12.6 Hz, 1 H), 5.15 (d, J= 12.6 Hz, 1 H), 5.45 (bd, J = 4.9 Hz, 1 H), 5.52 (bs, 1 H), 7.26-7.40 (m, 5 H); ¹³C NMR (100 MHz, C₂D₂Cl₄, 80 ⁰C): δ 12.5 (CH), 18.1 (CH₃), 28.4 (CH₃), 37.3 (CH₂), 44.8 (CH₂), 50.7 (CH), 67.2 (CH₂), 69.4 (CH), 80.7 (C), 127.9 (CH), 128.2 (CH), 128.6 (CH), 136.4 (C), 155.9 (C), 157.6 (C), 172.9 (C); MS (ESI) m/z (rel. intensity): 539.5 (23) [M+H]⁺, 561 (100) [M+Na]⁺; Anal. Calcd for C₂₇H₄₆N₂O₇Si: C, 60.19; H, 8.61; N, 5.20. Found: C, 60.39; H, 8.81; N, 5.19. O (3S,5Λ)-I5-(Benzyloxycarbonylaminomethyl)-2-oxotetrahydro-

*if o furan-3-yI]carbamic acid tert-buty\ ester (18): A solution of the

*-NHZ carboxylic acid 4 (51 mg, 0.095 mmol) in a mixture of THF (0.4 mL), H₂O (0.4 mL) and AcOH (1.2 mL) was stirred at 60 ⁰C for 3 d. The reaction mixture was cooled to room temperature, diluted with H₂O (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (n- hexane/EtOAc 1 :1) to afford 18 (18 mg, 51%) as a colorless solid: mp 148-149 ⁰C lit.³⁸ 143- 145 ⁰C; [Ct]²³ _D -25.2 (c 0.85, CHCl₃) lit. [α]²² _D -22.4 (c 0.5, CHCl₃); ¹H NMR (500 MHz, CHCl₃): δ 1.46 (bs, 9 H), 2.27-2.41 (m, 1 H), 2.43-2.57 (m, 1 H), 3.37 (dt, J= 6.4, 14.7 Hz, 1 H), 3.48-3.60 (m, 1 H), 4.18-4.31 (m, 1 H), 4.64-4.83 (m, 1 H), 4.99-5.19 (m, 3 H), 5.22 (bs, 1 H), 7.31-7.41 (m, 5 H); ¹³C NMR (125 MHz, CHCl₃): δ 28.3 (CH₃), 31.6 (CH₂), 44.7 (CH₂), 49.6 (CH), 67.2 (CH₂), 77.1 (CH), 80.9 (C), 128.2 (CH), 128.3 (CH), 128.6 (CH), 136.2 (C), 155.3 (C), 156.6 (C), 174.9 (C). The spectroscopic data were consistent with those reported.⁶

(4S)- 4-[(2S)-2- hydroxy-3-nitropropyl]- 2,2-dimethyloxazolidine- 3-carboxylic acid tert-hutyl ester (13): Nitroaldol adduct 13 was

prepared from aldehyde 6 (243 mg, 1.0 mmol) and nitromethane (0.55 mL, 10.0 mmol) in the presence of indabox ligand (-)-16 (19.7 mg, 0.055 mmol) and Cu(OAc)₂-H₂O (10.0 mg, 0.05 mmol) as described for diastereomer 12. The diastereomeric ratio 13:12 was determined by HPLC analysis (n-heptane//-PrOH 99:1; LiChrospher^® 250x4, Si 60, 5 μm; 1.5 mL/min; 215 nm; 13: t,- = 33.8 min; 12: t_r = 42.4 min) of the crude reaction mixture to be 92 : 8. The crude product was purified by flash chromatography on silica gel (/j-hexane:EtOAc 3:1) to give 13 (211 mg, 91%) as a 92:8 mixture of diastereomers. For analytical purposes a small quantity of the diastereomers was separated by preparative HPLC (/ι-heptane/ϊ-PrOH 99:1; Hibar^® 250x25, Si 60, 5 μm, 15 mL/min; 215 nm) to afford 13 as a colorless solid: mp 58-60 ⁰C; [α]²² _D -31.6 (c 1.08, CH₂Cl₂); IR (KBr): 3408 cm^"1, 1661, 1554, 1407; ¹H NMR (500 MHz, CDCl₃): δ 1.50 (s, 9 H), 1.51 (s, 3 H)₅ 1.56 (s, 3 H), 1.57-1.64 (m, 1 H), 1.77 (ddd, J= 2.0, 11.3, 13.4 Hz, 1 H), 3.67 (d, J- 8.9 Hz, 1 H), 4.03 (dd, J= 5.5, 8.9 Hz, 1 H), 4.22-4.31 (m, 2 H), 4.33 (dd, J= 4.0, 12.4 Hz, 1 H), 4.46 (dd, J= 8.6, 12.4 Hz, 1 H), 5.13 (bd, J= 3.8 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ 24.3 (CH₃), 28.0 (CH₃), 28.3 (CH₃), 39.9 (CH₂), 53.7 (CH), 65.5 (CH), 68.1 (CH₂), 80.1 (CH₂), 81.8 (C), 94.1 (C), 154.5 (C); MS (CI) m/z (rel. intensity): 305 (2) [M+H]⁺, 188 (100); Anal. Calcd for Ci₃H₂₄N₂O₆: C, 51.31; H, 7.95; N, 9.20. Found: C, 51.39; H, 7.94; N, 9.14. (45)-2,2-Dimethyl-4-{(2S)-2-triisopropylsilanyIoxy-3-nitropropyl]-

O TlPSO BocN-/ — oxazolidine-3-carboxylic acid tert-butyl ester (21): Silylether 21 was prepared from nitroaldol adduct 13 (1.035g, 3.4 mmol) as described for diastereomer 19. Flash chromatography on silica gel (w-hexane/EtOAc 90:10) of the crude product afforded 21 (1.517 g, 97%) as a 92:8 mixture of diastereomers: IR (film): 1699 cm^"1, 1558, 1389; ¹H NMR (400 MHz, CD₂Cl₂): δ 1.07 (bs, 21 H), 1.48 (bs, 12 H), 1.56 (s, 3 H), 1.79-2.01 (m, 2 H), 3.58-3.91 (m, 2 H), 3.91-4.04 (m, 1 H), 4.33-4.38 (m, 1 H), 4.48- 4.80 (m, 2 H); ¹³C NMR (100 MHz, CD₂Cl₂): δ 13.0 (CH), 18.2 (CH₃), 24.4 (CH₃), 27.7 (CH₃), 28.5 (CH₃), 40.4 (CH₂), 55.1 (CH), 67.9 (CH₂), 69.1 (CH), 80.6 (C), 81.6 (CH₂), 94.0 (C), 152.4 (C); HRMS (FAB) calcd for C₂₂H₄₅N₂O₆Si [M+H]⁺: 461.3047. Found: 461.3053.

(4S)-4-[(2S)-3-Benzyloxycarbonylamino-2-triisopropylsilanyloxy-propyl]-2,2- dimethyloxazolidine-3-carboxyIic acid tert-butyl ester (22): Z- protected amine 22 was prepared from nitro derivative 21 (1.473 g, 3.2 mmol, 92:8 mixture of diastereomers) as described for diastereomer 17. The crude product was purified by flash chromatography on silica gel (n-hexane/EtOAc 85:15) to afford 21 (1.445 g, 80%), which was judged to be diastereomerically pure by ¹H NMR (500 MHz), as a colorless oil: [α]^2I _D +13.7 (c = 0.90, CH₂Cl₂); IR (film): 3358 cm^"1, 1726, 1698; ¹H NMR (400 MHz, C₂D₂Cl₄, 120 ⁰C): δ 1.12 (bs, 21 H), 1.53 (bs, 9 H), 1.55. (bs, 3 H), 1.60 (bs, 3 H), 1.80-1.92 (m, 1 H), 1.97-2.11 (m, 1 H), 3.26-3.37 (m, 1 H), 3.38-3.49 (m, 1 H), 3.70-3.88 (m, 1 H), 3.88-4.00 (m, 2 H), 4.00-4.07 (m, 1 H), 5.06 (bs, 1 H), 5.16 (bs, 2 H), 7.31-7.42 (m, 5 H); ¹³C NMR (100 MHz, C₂D₂Cl₄, 12O ⁰C): δ = 12.8 (CH), 18.1 (CH₃), 24.3 (CH₃), 27.2 (CH₃), 28.6 (CH₃), 39.8 (CH₂), 47.1 (CH₂), 55.4 (CH), 66.6 (CH₂), 67.7 (CH₂), 70.1 (CH), 79.9 (C), 93.4 (C), 127.7 (CH), 127.9 (CH), 128.4 (CH), 137.1 (C), 151.8 (C), 156.4 (C); HRMS (FAB) calcd for C₃₀H₅₃N₂O₆Si [M+H]⁺: 565.3673. Found: 565.3676.

_/\_/\^^ (25,4S)-l-Hydroxy-4-triisopropylsilanyloxy-5-benzyloxycarbo-

ZHN ;[ jf OH

TlPSO NHBoc nyl-aminopent-2-ylaminocarboxylic acid tert-butyl ester (23): A solution of 22 (1.412 g, 2.5 mmol) and pyridinium /7-toluene sulfonate (377 mg, 1.5 mmol) in dry MeOH (20O mL) was stirred at 60 ⁰C for 4.5 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in EtOAc (300 mL) and washed with saturated aqueous NaHCO₃. The organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel («-hexane:EtOAc 75:25) to afford 23 (994 mg, 76%) as a colorless oil along with recovered starting material 22 (300 mg, 21%): [α]²³ _D -16.0 (c 0.75, CH₂Cl₂); IR (film): 3345 cm^"1, 1710, 1700; ¹H NMR (500 MHz, CHCl₃): δ 1.07 (bs, 21 H), 1.43 (s, 9 H), 1.65 (ddd, J = 5.0, 9.9, 14.6 Hz, 1 H), 1.74 (dt, J = 4.7, 14.6 Hz, 1 H), 3.13 (bs, 1 H), 3.22 (dt, J = 4.9, 14.0 Hz, 1 H), 3.42 (m, 1 H), 3.48-3.66 (m, 2 H), 3.77 (bs, 1 H), 4.09 (bs, 1 H), 5.08 (d, J = 12.5 Hz, 1 H), 5.12 (d, J = 12.5 Hz, 1 H), 5.12-5.18 (m, 1 H), 5.43 (bs, 1 H), 7.29-7.40 (m, 5 H); ¹³C-NMR (125 MHz, CDCl₃): δ 12.5 (CH), 18.1 (CH₃), 28.3 (CH₃), 35.3 (CH₂), 46.2 (CH₂), 50.4 (CH), 66.9 (CH₂), 67.0 (CH₂), 69.4 (CH), 79.7 (C), 128.1 (CH), 128.2 (CH), 128.5 (CH), 136.5 (C), 156.7 (C), 156.8 (C); HRMS (FAB) calcd for C₂₇H₄₉N₂O₆Si [M+H]⁺: 525.3360. Found: 525.3401.

,CO₂H (2S,4S)-5-Benzyloxycarbonylamino-2-fer/-butoxycarbonylainino-

ZHN

TIPSO NHBoc 4-triisopropyIsπanyloxy-pentanoic acid (5): Carboxylic acid 5 was prepared from alcohol 23 (787 mg, 1.5 mmol) by oxidation with

NaClO₂ in the presence of catalytic TEMPO and NaOCl as described for diastereomer 4. The crude reaction product was purified by flash chromatography on silica gel (π-hexane/EtOAc 60:40 + 0.5 % HOAc) to afford 5 (719 mg, 89%) as a colorless solid: mp 53-55 ⁰C; [α]²⁰ _D - 28.5 (c l .00, CH₂Cl₂); IR (KBr): 3350 cm^'1, 1719, 1517; ¹H NMR (500 MHz, C₂D₂Cl₄, 80 ⁰C): δ 1.10 (s, 21 H), 1.47 (s, 9 H), 1.92 (m, 1 H), 2.10 (m, 1 H), 3.27 (m, 1 H), 3.43 (m, 1 H), 4.16 (bs, 1 H), 4.34 (bs, 1 H), 5.07-5.18 (m, 3 H), 5.42 (bs, 1 H), 1.29-1 Al (m, 5 H); ¹³C NMR (125 MHz, C₂D₂Cl₄, 80 ⁰C): δ 12.7 (CH), 18.1 (CH₃), 28.4 (CH₃), 36.2 (CH₂), 46.4 (CH₂), 51.3 (CH), 67.0 (CH₂), 69.1 (CH), 80.9 (C), 128.0 (CH), 128.2 (CH), 128.6 (CH), 136.6 (C), 156.3 (C), 156.7 (C), 174.0 (C); HRMS (FAB) calcd for C₂₇H₄₇N₂O₇Si [M+H]⁺: 539.3153. Found: 539.3154. For ¹H NMR see Figures.

¹ (a) Sulser, H.; Stute, R. Experientia 1976, 32, 422-423. (b) Rozan, P.; Kuo, Y.-H.; Lambein, F. Phytochemistry 2001, 58, 281-289.

² (a) Bell, E. A.; Tirimanna, A. S. L. Biochem. J. 1964, 356-358. (b) Hatanaka, S.; Kaneko, S.; Saito, K.; Ishida, Y. Phytochemistry (Elsevier) 1981, 20, 2291-2292.

³ Pruess, D. L.; Kellett, M. J. Antibiotics 1983, 36, 208-212.

⁴ (a) Martin, J. H.; Mitscher, L. A.; Shu, P.; Porter, J. N.; Bohonos, N.; DeVoe, S. E.; Patterson, E. L. Antimicrob. Agents Chemother. -1967 1968, 422-425. (b) Ezaki, M.; Iwami, M.; Yamashita, M.; Hashimoto, S.; Komori, T.; Umehara, K.; Mine, Y.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiotics 1985, 38, 1453-1461. (c) Chang, C. C; Morton, G. O.; James, J. C; Siegel, M. M.; Kuck, N. A.; Testa, R. T.; Borders, D. B. J. Antibiotics 1991, 44, 674-677.

⁵ (a) Lampe, T.; Adelt, I.; Beyer, D.; Brunner, N.; Endermann, R.; Ehlert, K.; Kroll, H.-P.; von Nussbaum, F.; Raddatz, S.; Rudolph, J.; Schiffer, G.; Schumacher, A.; Cancho-Grande, Y.; Michels, M.; Weigand, S. WO 2003106480, 2003; Chem. Abstr. 2004, 140, 59934. (b) Lampe, T.; Adelt, I.; Beyer, D.; Brunner, N.; Endermann, R.; Ehlert, K.; Kroll, H.-P.; von Nussbaum, F.; Raddatz, S.; Rudolph, J.; Schiffer, G.; Schumacher, A. VVO 2004012816, 2004; Chem. Abstr. 2004, 140, 164239.

⁶ Paintner, F. F.; Gorier, K.; Voelter, W. Synlett 2003, 522-526.

⁷ (a) Hammarsten, E. Compt. Rend. Trav. Lab. Carlsberg, 1916, 11, 223-262. (b) Talbot, G.; Gaudry, R.; Berlinguet, L. Can. J. Chem. 1956, 34, 911-914. (c) Mizusaki, K.; Makisumi, S. Bull. Chem. Soc. Jpn. 1981, 54, 470-472. (d) Jackson, R. F. W.; Wood, A.; Wythes, M. J. Synlett 1990, 735-736. (e) Hausler, J. Liebigs Ann. Chem. 1992, 1231-1237. (f) Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J. J. Chem. Soc, Perkin Trans. 1 1994, 1719-1726. (g) Girard, A.; Greek, C; Genet, J. P. Tetrahedron Lett. 1998, 39, 4259-4260. (h) Mues, H.; Kazmaier, U. Synthesis 2001, 487-498. (i) Lepine, R.; Carbonnelle, A.-C; Zhu, J. Synlett 2003, 1455-1458.

⁸ Schmidt, U.; Meyer, R.; Leitenberger, V.; Stabler, F.; Lieberknecht, A. Synthesis 1991, 409-413.

⁹ Rudolph, J.; Hanning, F.; Theis, H.; Wischnat, R.; Org. Lett. 2001, 3, 3153-3155.

¹⁰ For recent use of this versatile chiral building block see: (a) Dondoni, A.; Massi, A.; Minghini, E.; Sabbatini, S.; Bertolasi, V. J. Org. Chem. 2003, 68, 6172-6183. (b) Catalano, J. G.; Deaton, D. N.; Furfine, E. S.; Hassell, A. M.; McFayden, R. B.; Miller, A. B-.; Miller, L. R.; Shewchuk, L. M.; Willard, D. H.; Whright, L. L. Bioorg.Med. Chem. Lett. 2004, 14, 275-278. (c) Dondoni, A.; Catozzi, N.; Marra, A. J. Org. Chem. 2004, 69, 5023-5036. (d) Dondoni, A.; Giovanni, P. P.; Massi, A.; Org. Lett. 2004, 6, 2929-2932.

¹¹ An analogous Henry reaction based strategy for the synthesis of 4-hydroxyornithine was previously reported by Rudolph et al. (ref. 9). This approach, however, suffers both from an unfavorable stereoselectivity and from a very low yield in the key nitroaldol reaction step and therefore was not pursued further.

¹² Although Λ/-Boc-protected (S)-2-amino-1 ,4-butandiol 7 is commercially available (Aldrich), its relatively high price leads to recommend its preparation on a multigram scale from inexpensive L- aspartic acid (see Supporting Information).

¹³ Ksander, G.; de Jesus, R.; Yuan, A.; Ghai, R. D.; Trapani, A.; McMartin, C; Bohacek, R. J. Med. Chem. 1997, 40, 495-505.

¹⁴ For an alternative approach to 6 starting from /V-terf-butoxy-carbonyl-L-aspartic acid γ-benzyl ester see: Ouerfelli, O.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Synlett 1993, 409-410.

¹⁵ Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001, 66, 206-215.

¹⁶ Ab initio MO calculations (DFT/B3LYP/6-311 G+) showed an energy difference of about 7.8 kcal/mol between 9 and the six-membered cyclic Λ/,O-acetal 10 indicating that only traces of this regioisomer are to be expected.

¹⁷ Products 8, 9 and 11 were obtained in a ratio of 30:45:25 (as determined by ¹H NMR analysis of the crude reaction product) by treatment of 7 with DMP (10 equiv.) and TsOH (0.1 equiv., CH₂CI₂, rt, 36h) according to lit. 15.

¹⁸ Youn, S. W.; Kim, Y. H. Synlett 2000, 880-882.

¹⁹ Ohrlein, R.; Jager, V. Tetrahedron Lett. 1988, 29, 6083-6086.

²⁰ Hanessian, S.; Brassard, M. Tetrahedron 2004, 60, 7621-7628.

²¹ Low stereoselectivity in nitroaldol reactions with aldehydes bearing a stereogenic center at the β- position has been observed previously. See: ref. 9 and references cited therein.

²² (a) Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418-4420. (b) Sasai, H.; Watanabe, S.; Suzuki, T.; Shibasaki, M. Org. Synth. 2002, 78, 14-22.

²³ Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931-1934.

²⁴ Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054-2055. ²⁵ (a) Trost, B. M.; Yeh, V. S. C; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621-2623. (b) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861-863.

²⁶ (a) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.; Ikeno, T.; Yamada, T. Chem. Lett. 2004, 33, 614-615. (b) Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis 2004, 1947-1950.

²⁷ (a) Christenseπ, C; Juhl, C; Jørgensen, K. A. Chem. Commun. 2001, 2222-2223. (b) Risgaard, T.; Gothelf, K. V.; Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 153-156.

²⁸ Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692-12693.

²⁹ Since β-nitro alcohols 12 and 13 were difficult to separate, 12 was used as a mixture of diastereomers (97 : 3). The minor diastereomer could be easily removed by flash chromatography on silica gel at the stage of the Λ/^s-Z-protected β-amino alcohol 17.

³⁰ Since β-nitro alcohols 12 and 13 were difficult to separate, 12 was used as a mixture of diastereomers (97 : 3). The minor diastereomer could be easily removed by flash chromatography on silica gel at the stage of the Λ/*-Z-protected β-amino alcohol 17.

³¹ Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J. ; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566.

³² Estiarte, M. A.; Diez, A.; Rubiralta, M.; Jackson, R. F. W. Tetrahedron 2001, 57, 157-161.

³³ (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824-5825. (b) Kuroso, M.; Porter, J. R.; Foley, M. A. Tetrahedron Lett. 2004, 45, 145-148.

³⁴ (a) Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001, 66, 206-215. (b) Ksander, G. M.; de Jesus, R.; Yuan, A.; Ghai, R. D.; Trapani, A.; McMartin, C; Bohacek, R. J. Med. Chem. 1997, 40, 495-505.

³⁵ Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Richard, Taylor J. K. J. Org. Chem. 2002, 67, 1802-1815.

³⁶ Dondoni, A.; Catozzi, N.; Marra, A. J. Org. Chem. 2004, 69, 5023-5036.

³⁷ Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566.

³⁸ Estiarte, M. A.; Diez, A.; Rubiralta, M.; Jackson, R. F. W. Tetrahedron 2001, 57, 157-161.

Claims

We claim:

1. A process for the preparation of a compound of formula (I) or its enantiomer

(I) wherein:

R¹ is methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, tert-bxtXyl, 1-adamantyl, allyl, 9-fluorenylmethyI, benzyl or a substituted benzyl group;

which comprises reacting a compound of formula (II) or its enantiomer:

where R is as defined above, with an appropriate 2,2-dialkoxypropane of formula (III)

(III) wherein: R is methyl or ethyl and with an appropriate 2-alkoxypropene of formula (IV)

(IV) wherein:

R² is methyl or ethyl, in the presence of an acid to give a compound of formula (V) or its enantiomer

wherein:

R¹ and R² are as defined above, which is hydro lyzed to give a compound of formula (I).

2. Process according to claim 1, wherein the acid is p-toluene sulfonic acid.

3. Process according to any of the preceding claims, wherein R¹ is tert-butyl.

4. Process according to any of the preceding claims, wherein R² is methyl.

5. Process according to any of the preceding claims, wherein the compound of formula (III) is used as the only solvent.

6. The compound of formula (V) or its enantiomer: wherein R and R" are as defined in claim 1.

7. Compound according to claim 6, wherein R¹ is tert-butyl.

8. Compound according to any of claims 6 or 7, wherein R is methyl.