Synthesis of enantiomerically pure 4-substituted pyrrolidin-3-ols via asymmetric 1,3-dipolar cycloaddition

Asymmetric 1,3-dipolar cycloadditions of chiral azomethine ylides to 3-benzyloxy-substituted alkenoylcamphorsultams are described. trans-3,4-Disubstituted pyrrolidines containing a protected hydroxyl group at C(4) of the pyrrolidine ring are obtained in high diastereomeric ratios. Such compounds can serve as chiral building blocks for the syntheses of enantiopure bioactive pyrrolidines. This is exemplified by a short synthetic route to a known glycosidase inhibitor, (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol and its enantiomer.     

Synthesis of enantiomerically pure cis- and trans-cyclopentane analogues of phenylalanine

For the first time, all stereoisomers of 1-amino-2-phenylcyclopentanecarboxylic acid—c₅Phe—have been synthesised. A Strecker reaction on 2-phenylcyclopentanone and further transformations of each amino nitrile into the amino acid provides cis-c₅Phe and trans-c₅Phe with high efficiency. A divergent synthetic route was then developed to obtain the target compounds cis- and trans-c₅Phe in their racemic form. The preparation of the final enantiomerically pure amino acids and their corresponding N-protected derivatives was also achieved by HPLC resolution of one of the intermediates using a cellulose-derived chiral stationary phase. The relative stereochemistry of each amino acid and its precursors have been unambiguously assigned.     

Synthesis of enantiomerically pure cyclohex-2-en-1-ols: development of novel multicomponent reactions

Multicomponent reactions of aldehydes, dienophiles, and alcohols or carboxylic acid anhydrides have been developed for the first time. In situ generation of 1-acyloxy- and 1-alkoxy-1,3-butadiene derivatives in toluene in the presence of electron-deficient dienophiles provides selective and efficient access to functionalized cyclohex-2-ene-1-ols in good yields. Subsequent enzyme-catalyzed kinetic resolution gave the corresponding enantiomers with high enantioselectivity.     

Asymmetric synthesis of enantiomerically pure 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromen-2-ones

Four stereoisomers of 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromenon-2-one have been obtained for the first time. The key step of the synthesis involves asymmetric Michael addition of chiral enamines derived from dihydrocarvone to acrylate 1. Absolute configurations were established by X-ray analysis.     

Asymmetric synthesis of an enantiomerically pure rivastigmine intermediate using ketoreductase

A novel chemo-enzymatic synthesis of (S)-rivastigmine using ketoreductases with NADH/NADPH as the proton donor has been demonstrated. An exclusive enzymatic process has been developed by exploring the possible ketoreductases by screening to identify enzymes useful for the preparation of the (S)-isomer intermediate, and scaling up of the enzymatic process for the production of an adequate, enantiomerically pure precursor of rivastigmine and for the total synthesis of (S)-rivastigmine.     

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids (beta-ACCs) is described. Starting from pyrrole, (rac)-4 is readily obtained, which was kinetically resolved by enzymatic hydrolysis. Subsequent oxidation of (-)-4 and deformylation gives rise to the cis-beta-ACC derivative (ent)-9, while (+)-10 was converted to the trans-beta-ACC derivative 8. Both 8 and (ent)-9 and their benzyl esters 13 and 16, being conformationally restricted beta-alanine or gamma-aminobutyric acid (GABA) derivatives, represent useful building blocks for peptides containing unnatural amino acids.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.     

Synthesis of enantiomerically pure 3-aminochroman derivatives

Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from l-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from d-serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.     

Synthesis of enantiomerically pure 2-amino alcohols from amino acids mediated by sulfoxides

Enantiomerically pure (R₁,S₂)- and (S₁,S₂)-2-amino alcohols can be easily synthesized by stereodivergent reduction of α′-(N-Boc)amino β-keto sulfoxides (easily synthesized from readily available N-Boc amino ester hydrochlorides) with DIBAH (de 82–92%) and DIBAH/ZnBr₂ (de 80%), followed by hydrogenolysis of the C–S bond of the resulting hydroxy sulfoxides and final hydrolysis of the N-Boc protecting group.     

Synthesis of cis-4-trifluoromethyl- and cis-4-difluoromethyl-l-pyroglutamic acids

Efforts to synthesize 4-trifluoromethyl- and 4-difluoromethyl-l-pyroglutamic acids are described. After many arduous efforts, we successfully synthesized our target molecules cis-4-trifluoromethyl-l-pyroglutamic acid 25 and cis-4-difluoromethyl-l-pyroglutamic acid 26 from trans-4-hydroxy-l-proline through oxidation of fluorinated prolinates with RuO(4).     

Practical synthesis of enantiomerically pure beta2-amino acids via proline-catalyzed diastereoselective aminomethylation of aldehydes

Proline-catalyzed diastereoselective aminomethylation of aldehydes using a chiral iminium ion, generated from a readily prepared precursor, provides alpha-substituted-beta-amino aldehydes with 85:15 to 90:10 dr. The alpha-substituted-beta-amino aldehydes can be reduced to beta-substituted-gamma-amino alcohols, the major diastereomer of which can be isolated via crystallization or column chromatography. The amino alcohols are efficiently transformed to protected beta2-amino acids, which are valuable building blocks for beta-peptides, natural products, and other interesting molecules. Because conditions for the aminomethylation and subsequent reactions are mild, beta2-amino acid derivatives with protected functional groups in the side chain, such as beta2-homoglutamic acid, beta2-homotyrosine, and beta2-homolysine, can be prepared in this way. The synthetic route is short, and purifications are simple; therefore, this method enables the preparation of protected beta2-amino acids in useful quantities.     

A convenient synthesis of activated enantiomerically pure 2-ethynylaziridines

2,3-cis- and 2,3-trans-N-Arylsulfonyl-2-ethynylaziridines with high enantiomeric purity have been synthesized. N-Protected amino aldehydes synthesized from natural α-amino acids were successively treated with Ph₃PC(Br)CO₂Me, DIBAL, MsCl–Et₃N, NaH in DMSO, and tert-BuOK in THF to yield 2-ethynylaziridines in good to high yields.     

Synthesis of enantiomerically pure (3R,4R,5R)-4-hydroxy isoleucine lactone

A short four-step synthesis of (3R,4R,5R)-4-hydroxyisoleucine lactone with total control of stereochemistry is reported, the key intermediate being the didehydroamino acid derivative arising from an aldol dehydration reaction between a glycine anion equivalent and butan-2,3-dione.     

A simple and efficient synthesis of optically pure 4-alkylisoxazolidin-4-ols

The reaction between N-hydroxyphthalimide and optically pure epichlorohydrin followed by addition of methanol represents a straightforward procedure for the synthesis of isoxazolidin-4-ols in high enantiomeric purity. Under the same conditions, the reaction of glycidyl arenesulfonates can lead to different products depending on the nature of the sulfonate. This property allowed the synthesis of both enantiomers of 4-methylisoxazolidin-4-ol from the same chiral epoxide starting material.     

Resolution of racemic 3-aryloxy-1-nitrooxypropan-2-ols by lipase-catalyzed enantioselective acetylation

Both (R)- and (S)-enantiomers of 3-aryloxy-1-nitrooxypropan-2-ols (R)-(−)-1, (S)-(+)-2 were prepared in high enantiomeric excess by lipase from Pseudomonas cepacia (Amano PS) or Pseudomonas fluorescens (Amano AK)-catalyzed acetylation of racemic alcohols 1a–g with vinyl acetate in n-hexane at 4 or 22°C. The enantioselectivity of this transformation was dependent on the substitution pattern of the aryl ring with E-values ranging from 31 to 111.     

Efficient synthesis of enantiomerically pure 2-acylaziridines: Facile syntheses of N-Boc-safingol, N-Boc-D-erythro-sphinganine, and N-Boc-spisulosine from a common intermediate

Various enantiomerically pure 2-acylaziridines were prepared efficiently from the corresponding aziridine-2-carboxylate via Weinreb's amide and the subsequent treatment of organometallic compounds. The carbonyl group of those 2-acylaziridines was stereoselectively reduced by NaBH4in the presence of ZnCl2 to give erythro-1,2-amino alcohols with high diastereoselectivities and chemical yields. Using this methodology, we prepared (1R,2S)-N-Boc-norephedrine 5, N-Boc-safingol 8, N-Boc-D-erythro-sphinganine 9, and N-Boc-spisulosine 10 in high yields.     

A new biocatalyst for the preparation of enantiomerically pure 2-arylpropanoic acids

A new biocatalyst, a strain of Pseudomonas fluorescens MTCCB0015, is described, which produces ibuprofen, ketoprofen and flurbiprofen as enantiomerically pure (S)-2-arylpropanoic acids from their corresponding racemic esters. 2-Arylpropanoic acids are an important class of non-steroidal anti-inflammatory compounds, whose anti-inflammatory activity is mainly due to the (S)-enantiomer.     

Stereochemistry in enzyme inhibition: synthesis and evaluation of enantiomerically pure 2-benzyl-3-formylpropanoic acids as inhibitors of carboxypeptidase A

Both enantiomers of 2-benzyl-3-formylpropanoic acid were synthesized in five steps starting with hydrocinnamic acid and each enantiomer assayed for inhibitory activity against carboxypeptidase A to find that the (R)-form is 674-fold more potent than its enantiomer. The finding that the (R)-form which belongs to the l-series is mostly responsible for the inhibitory activity accords with the explanation that the present inhibitor is a transition state analog inhibitor because, as such, its stereochemistry should belong to the same series as that of the substrate, i.e., the l-series. The gem-diol form of the inhibitor generated in situ mimics the transition state in the catalytic process.     

Synthesis of enantiomerically pure C2-branched-2-deoxy-heptitols

2,3; 4,5-Di-O-isopropylidene-al- -(+)-arabinose 1a reacts with di-l-menthylmalonate to give the hepturonates 2a and 3a in a manno-glaco 7.8:2.2 ratio. The C-2 branched 2-Deoxy-2-hydroxy-methyl- -manno-heptitol 6 and 2-Deoxy-2-hydroxy-methyl- -gluco-heptitol 7 were obtained by submitting 2a and 3a to routine procedures. When the same reaction was performed with di-d-menthylmalonate a 3.5:6.5 mixture of 2b and 3b was obtained. A 8.2:1.8 anti-diastereosetectivity was also observed by reacting 2,3,4,5-O-tetraacetyl-al- -(−)-arabinose 1b with di-d-menthylmalonate. The absolute stereochemistry of the major hepturonate 10 obtained in this reaction was secured by a single crystal X-ray analysis.     

Sequential enzymatic procedure for the preparation of enantiomerically pure 2-heteroaryl-2-hydroxyacetic acids

Starting from the racemic 2-benzofuranyl- and 2-benzo[b]thiophenyl-2-hydroxyacetic acid ethyl esters as substrates, a general method was developed for the efficient synthesis of the corresponding highly enantiomerically enriched (ee up to 99%) (R)- and (S)-2-heteroaryl-2-hydroxyacetic acids.