Efficient synthesis of (−)-(R)- and (+)-(S)-rolipram

A novel, efficient and protecting group free enantioselective synthetic approach of (?)-(R)-1 and (+)-(S)-rolipram 2 is described employing the organocatalyzed asymmetric Michael addition, Henry condensation, Wittig olefination and reductive lactamization reactions as key steps.     

Enantioselective synthesis of (S)- and (R)-α-methylserines: application to the synthesis of (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals

This report describes the synthesis of enantiomerically pure (S)- and (R)-α-methylserines on a multigram scale, starting from the Weinreb amide of 2-methyl-2-propenoic acid and using a stereodivergent synthetic route that involves a Sharpless asymmetric dihydroxylation reaction. As a synthetic application of these quaternary α-amino acids, they were used as starting materials in the synthesis of the well-known valuable homochiral (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinal building blocks.     

A simple synthesis of (−)-(R)-ipsdienol and (−)-(S)-ipsenol

A short and efficient synthesis of the unnatural enantiomer of (+)-(S)-ipsdienol 1 and (−)-(S)-ipsenol 2 is presented via an asymmetric allylboration. The synthesis was achieved by using a one-pot reduction–methylenation of an exo-methylene lactone intermediate.     

Efficient synthesis of (S)-(−)- and (R)-(+)-enantiomers of 15-deoxyspergualin (15-DSG)

An efficient synthesis of the (S)-(−)- and (R)-(+)-enantiomers of 15-deoxyspergualin (15-DSG) is reported. The synthesis involves preparative HPLC separation and subsequent hydrogenolysis of two diastereoisomers 10a and 10b of fully protected 15-DSG penultimates. Alternatively, diastereomerically pure amide 10b (97% de) was also prepared from acid 8b (97% de), which was obtained via crystallization of a 1:1 diastereomeric mixture of 8a and 8b.     

The synthesis of (R)- and (S)-α-trifluoromethyl-α-hydroxycarboxylic acids via enzymatic resolutions

Kinetic resolution of 1,1,1-trifluoro-2-alkanone cyanohydrin acyl derivatives with Candida rugosa lipase afforded the remaining (R)-enantiomer in high selectivity (E from 30 to >200). Candida rugosa lipases from several suppliers were compared and found to differ remarkably in their selectivity. The (R)-enantiomer was hydrolyzed in one step to yield optically pure (R)-α-trifluoromethyl-α-hydroxycarboxylic acids in excellent yield. The (S)-acids were obtained in good e.e. by subtilisin-catalyzed resolution of the corresponding racemic esters followed by chemical hydrolysis of the remaining (S)-esters.     

Highly efficient synthesis of (R)- and (S)-piperazic acids using proline-catalyzed asymmetric α-hydrazination

The highly efficient synthesis of (R)- and (S)-piperazic acids, components of naturally occurring antibiotic cyclodepsipeptides, was achieved in 80% overall yield by the use of a proline-catalyzed asymmetric α-hydrazination as the key step.     

An improved synthesis of (S)-(+)- and (R)-(−)-4-ethenyl[2.2]paracyclophane

The resolution of the 4-acetyl[2.2]paracyclophane by the SAMP-hydrazone method is described. A new, short, high yield synthesis of both enantiomers (S)-(+)- and (R)-(−)-4-ethenyl[2.2]paracyclophane is reported.     

Asymmetric synthesis of (−)-(R)-sitagliptin

The asymmetric synthesis of (?)-(R)-sitagliptin was achieved in seven steps from commercially available starting materials using the highly diastereoselective conjugate additions of either lithium (R)-N-benzyl-N-(α-methylbenzyl)amide or lithium (R)-N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl 4-(2′,4′,5′-trifluorophenyl)but-2-enoate to install the correct stereochemistry. Subsequent sequential acid-catalysed hydrolysis of the resultant β-amino esters, HOBt/EDC mediated coupling with the triazolopyrazine fragment, and hydrogenolysis gave (?)-(R)-sitagliptin in 43% and 42% overall yields, respectively.     

Lipase catalyzed regio- and stereospecific hydrolysis: chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid

Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)-butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α-thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both (S)- and (R)-enantiomers of α-lipoic acid and their analogues.     

An improved synthesis of (S)-(+)- and (R)-(−)-[2.2]paracyclophane-4-carboxylic acid

Treatment of 4-bromo[2.2]paracyclophane with n-butyllithium followed by CO₂ produced [2.2]paracyclophane-4-carboxylic acid, 1. Both enantiomeric forms [63% of (+)-(S)-1 and 48% of (−)-(R)-1] were obtained by resolution via the corresponding diastereomeric α-(p-nitrophenylethylammonium salts.     

A practical stereoselective synthesis of (S)-( - )-ofloxacin

A very efficient and practical procedure for preparation of ( S)-( - )-ofloxacin has been developed (10 steps, overall yield ≥ 45 % ) . The key step of this approach is the regioselective nucleophilic substitution of 2-position fluorine atom of 2,3,4-tirfluoronitrobenzene by (S)-glycerol acetonide.     

Asymmetric synthesis of (?)-(R)-massoia lactone, (R)-δ-decalactone, and (+)-(3R,5R)-3-hydroxydecano-5-lactone. Formal synthesis of verbalactone

A simple and efficient procedure for the asymmetric synthesis of (?)-(R)-massoia lactone, (R)-??-decalactone, and (+)-(3R,5R)-3-hydroxy-1,5-decanolide is described. Verbalactone was synthesized using Heck allylation at the key stage of construction of the carbon skeleton.     

Diastereoselective α-iminoamine rearrangement: asymmetric synthesis of (R)-(−)- and (S)-(+)-2-benzyl-2-hydroxycyclohexanone

A convenient asymmetric synthesis of both (R)-(−)- and (S)-(+)-2-benzyl-2-hydroxycyclohexanones starting from racemic 2-benzyloxycyclohexanone and the chiral auxiliary 1-phenylethylamine is reported. The route involves a [1,3]-sigmatropic shift and a new diastereoselective α-iminoamine rearrangement of a 2-benzyl-2-iminocyclohexanamine substrate.     

An efficient synthesis of (R)-(−)-baclofen

In this report we describe an efficient synthesis of (R)-(−)-baclofen, a selective GABA_B agonist used as an antispastic agent. Our strategy is based on an enantioselective deprotonation of a cyclobutanone easily obtained by [2+2] cycloaddition of 4-chlorostyrene and dichloroketene.     

Preparative asymmetric synthesis of (R)- and (S)-α-methylserine Ni(II) complex with a Schiff base of α-alanine and (S)-2-[(N-benzylprolyl)amino]benzophenone

The kinetic and thermodynamic diastereoselectivity of the hydroxymethylation of the alanine fragment in the Ni(II) complex of the Schiff base of alanine and (S)-2-[(N-benzylprolyl)amino]benzophenone (BBP) was studied. Optically pure (R)- and (S)--methylserines were synthesized.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1175–1180, May, 1991.     

Asymmetric synthesis of heteroorganic analogs of natural products 5. Synthesis of pure diastereomers and enantiomers of fluoro-substituted (2S,3R)- and (2R,3R)-β-phenylserines

A convenient method is proposed for the preparative synthesis of pure diastereomers and enantiomers of fluoro-substituted (2S,3R)- and (2R,3R)--phenylserines by the hydroxyalkylation of the Ni(II) — complex of the Schiff base of glycine with (S)-2-N-(N¹-benzylpropyl)aminobenzophenone using the corresponding fluoro-substituted benzaldehydes.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya. No. 8, pp. 1906–1913, August, 1991.     

Chemoenzymatic synthesis of (4S,5R)-5-hydroxy-γ-decalactone

Reduction of ethyl 2-hydroxy-3-oxooctanoate with immobilised baker's yeast at pH 4.0 yields anti-2R,3R-dihydroxy ester with high diastereoselectivity and enantioselectivity (de 70%, ee 80%) which is conveniently converted to (4S,5R)-5-hydroxy-γ-decalactone.     

Interconversion of (R) and (S)-α-hydroxy esters: precursors of (S) and (R)-o-benzyl-α-hydroxylamino acid esters of high optical purity

(R)- and (S)-α-hydroxy esters 5 are interconverted via their triflates 6 in high chemical as well as optical yields by reaction with dimethylformamide. The same triflates are efficiently converted into N-hydroxy-α-amino acid derivatives 7 of high optical purity.     

Asymmetric synthesis of (S)-(−)-acromelobinic acid

A total synthesis of (S)-(−)-acromelobinic acid 2, which was isolated from clitocybe acromelalga, was achieved via an asymmetric hydrogenation protocol. Dehydroamino acid derivative 12 was prepared from 2,5-lutidine 5 and subjected to asymmetric hydrogenation using (S,S)-[Rh(Et-DuPHOS)(COD)]BF₄ to give the (S)-(+)-pyridylalanine derivative 13 in 93% yield and >96% e.e. Removal of the protecting groups in (S)-(+)-13 afforded (S)-(−)-acromelobinic acid 2.     

Asymmetric synthesis of (S)- and (R)-α-methylserine based on the chiral recyclable reagent (S)-N-(2-benzoyl-phenyl)-1-benzylpyrrolidine-2-carboxamide

Both enantiomers of -methylserine were synthesized with the use of Ni^II complexes based on the chiral recyclable reagent (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide. Intermediate diastereomeric complexes were separated by crystallization of their O-acetyl derivatives.