Synthesis of (S)-(−)-β-cuparenone and (S)-(−)-cuparene

A short and efficient synthesis of the title compounds is described. (S)-(−)-β-Cuparenone was prepared in 31% yield from p-tolualdehyde and mesityl oxide in eight steps. Absolute stereochemistry was established by means of a diastereoselective cyclopropanation using (R,R)-hydrobenzoin as a recoverable auxiliary.     

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.     

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.     

Total Synthesis of (R)-(−)-β-Cuparenone

Abstract

(R)-(?)-β-Cuparenone has been synthesized from (S)-(+)-acid-2 obtained via resolution of the racemic acid. Two of the noteworthy steps are (a) repeated methylation of ester (+)-8 with LDA/MeI to furnish (+)-10 and (b) the reaction of 12, having two neopentyl units with NaCN.     

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.     

Asymmetric synthesis of (S)-(−)-tetrahydropalmatine and (S)-(−)-canadine via a sulfinyl-directed Pictet–Spengler cyclization

(S)-(?)-Tetrahydropalmatine 2 and (S)-(?)-canadine 4 were synthesized in three steps from (S)-6, in 33% and 34% overall yield, respectively. Thus, condensation of the (S)-(E)-sulfinylimines 10 and 11 with the carbanion derived from (S)-6 gave the tetrahydroisoquinolines 12 and 13, respectively, which upon TFA induced N-desulfinylation, and subsequent microwave assisted Pictet–Spengler cyclization effected both cyclization and C-desulfinylation producing (S)-(?)-tetrahydropalmatine 2 and (S)-(?)-canadine 4 in optically pure form.     

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.     

A concise synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine

A convergent synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine (CPA) 1, a non-proteinogenic amino acid is described starting from a commercially available dimethyl l-aspartate 2 in good overall yield.     

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.     

Deracemization of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH): practical synthesis of (−)-(S)-HPPH

In the presence of 10% NaOH in boiling MeOH enantiomerically enriched HPPH is racemized. This permits the deracemization of HPPH in the presence of brucine, giving enantiomerically pure (−)-(S)-HPPH [(−)-(S)-5-(4-hydroxyphenyl)-5-phenylhydandoin].     

Enantiogenic synthesis of (R)-(−)-3-hydroxy-1-penten-4-one

Condensation of pyruvate and acrolein with whole cells of baker's yeast resulted in a mixture of 3-hydroxy-1-penten-4-one 1 and 4-hydroxy-1-penten-3-one 2. The absolute configuration (R) and the enantiomeric excess (ee 72%) of the compound 1 were determined.     

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.     

Enantioselective synthesis of (R)-(−)-mevalonolactone via cyclic sulfate methodology

An asymmetric synthesis of (R)-(−)-mevalonolactone is described using the Sharpless asymmetric dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfate as key steps.     

Scaleable processes for the synthesis of (−)-β-d-2,6-diaminopurine dioxolane (Amdoxovir,DAPD) and (−)-β-d-2-aminopurine dioxolane (APD)

An efficient and scalable synthesis of (?)-DAPD and (?)-APD has been developed. We discovered that t-butyl cyanoacetate can be used as a new additive for the sugar nucleoside base coupling step en route to DAPD with improved β-selectivity and an isolated yield four-fold greater than the original process scale method. Using this new process, (?)-DAPD has been prepared on greater than 20 g scale. In the synthesis of (?)-APD, a key enzyme-catalyzed hydrolysis reaction afforded the water soluble deprotected α-anomer while leaving the β-anomer completely untouched.     

Asymmetric synthesis of (−)-(1R,7aS)-absouline

The most efficient and concise asymmetric synthesis of (?)-(1R,7aS)-absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)-amide to an enantiopure α,β-unsaturated ester derived from l-proline was employed as the key step. Subsequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant β-amino ester produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (?)-(1R,7aS)-absouline.     

Asymmetric synthesis of (R)-(−)-chlozolinate through a chemoenzymatic procedure

A new asymmetric synthesis of (R)-chlozolinate 1, an important antifungal agent, based on the enzymatic asymmetrization of diethyl 2-benzyloxy-2-methylmalonate, is reported.     

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.     

Stereospecific Synthesis of (−)-β-Turmerone and (−)-Bisacurol

The structure of (+)-β-turmerone ((+)- 1a ), a constituent of the rhizomes of Curcuma longa Linn. , and Curcuma xanthorriza, is established as (1′R,6S)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-one by synthesis of its enantiomer (−)- 1a , and of the corresponding (1′S,6S)-diastereoisomer (+)- 1b as well. In a stereospecific seventeen-step procedure, the monoterpene diols 2a and 2b of well-established configuration are converted into the target compounds (−)- 1a and (+)- 1b , respectively. Moreover, (−)-bisacurol (−)- 3a (II), the enantiomer of another bisabolane sesquiterpene derived from Curcuma xanthorriza, is obtained as a single stereoisomer and shown to be (1′S,6R)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-ol, the relative configuration at the remaining OH-substituted chiral center C(4) still being unknown.     

Expedient syntheses of indolizidines (−)-167B and (−)-209D

Indolizidine alkaloids (−)-167B and (−)-209D were synthesized via an expedient route using hydroacylation and amination.