Simultaneous enzymatic synthesis of (S)-3-fluoroalanine and (R)-3-fluorolactic acid

A coupled enzymatic system for the simultaneous synthesis of (S)-3-fluoroalanine (1a) and (R)-3-fluorolactic acid (3) with l-alanine dehydrogenase (l-AlaDH) from Bacillus subtilis and rabbit muscle l-lactate dehydrogenase (l-LDH) using rac-1 and NAD⁺ is described. Analysis of isolated products of the laboratory preparative scale process revealed 1a in 60% yield and 88% ee and 3 in 80% yield and over 99% ee. The compounds 1a and 3 represent chiral building blocks for the synthesis of several products with pharmacological activity.     

Sesquiterpene lactones : A total synthesis of (±)-vernolepin

A novel synthesis of (± )-Vernolepin (1) is described. A suitably substituted cis-fused 2-oxa-3-decalone precursor (29) has been constructed starting from 2,5-cyclohexadiene carboxylic acid via an intramolecular cyclopropanation reaction (23 to 18). The route culminated in the synthesis of Grieco's lactone (53) which has previously been converted to (± )-vernolepin (1) and (± )-vernomenin (2).     

Synthesis of (R)-(+)-methyl 3-amino-3-(5-hydroxy-2-pyridinyl)propanoate,an analog of l-azatyrosine

A concise asymmetric synthesis of (R)-(+)-methyl 3-amino-3-(5-hydroxy-2-pyridinyl)propanoate 2, a β-amino acid analog of l-azatyrosine 1 starting from the commercially available (−)-Andersen reagent (−)-3 in good overall yield is described.     

Synthetic studies on macrolactin A by using a (diene)Fe(CO)3 complex

The stereoselective synthesis of the two segments 3 and 4 of macrolactin A 1 is described. Macrolactin A is a 24-membered polyene macrolide antibiotic, which is of interest due to a strong activity against B16-F10 murine tumor cell and HIV-1 virus. The key step of the synthesis is the 1,2-migration reaction of a (diene)Fe(CO)₃ complex with a introduction of the thiol group to construct the unstable (E,Z)-conjugated dienic moiety (C8-C11).     

Boron trifluoride etherate-assisted ring opening of ethylene oxide by a chiral organolithium: enantioselective synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine

A practical synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine in high enantiomeric purity is described. The synthesis involves BF₃·Et₂O-assisted ring opening of ethylene oxide by a homochiral carbanion (R)-3, which is derived from sparteine-mediated asymmetric deprotonative lithiation of 1-Boc-pyrrolidine.     

Synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one as a key intermediate of sphingosine 1-phosphate-1 receptor agonists

Herein we report the asymmetric synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one (S)-3 as a practical chiral synthon for a wide range of pharmaceutical and/or natural products, using Lipshutz’s asymmetric copper-catalyzed conjugate reduction. This method makes it feasible to prepare a conformationally constrained cyclopentane analogue 12, which is one of the key intermediates for the synthesis of novel sphingosine 1-phosphate-1 receptor agonists.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Studies on the Synthesis of Reidispongiolide A: Stereoselective Synthesis of the C(22)-C(36) Fragment

A highly stereoselective synthesis of the C(22)-C(36) fragment 2 of reidispongiolide A is described. This synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 dr. Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was elaborated by three steps into the targeted reidispongiolide fragment 2.     

Pheromone synthesis. Part 249: Syntheses of methyl (R,E)-2,4,5-tetradecatrienoate and methyl (2E,4Z)-2,4-decadienoate,the pheromone components of the male dried bean beetle,Acanthoscelides obtectus (Say)

The enantiomers of methyl (E)-2,4,5-tetradecatrienoate (1), a component of the male pheromone of Acanthoscelides obtectus, were synthesized from the enantiomers of 1-undecyn-3-ol (6), which were obtained via asymmetric acetylation of (±)-1-trimethylsilyl-1-undecyn-3-ol (4) with vinyl acetate as catalyzed by lipase PS (Amano). The ortho ester Claisen rearrangement of 6 with triethyl orthoacetate was the key-step to generate the chiral allenic system. A new synthesis of (±)-1 was also executed starting from (±)-6. Three different syntheses of methyl (2E,4Z)-2,4-decadienoate (2), another component of the male pheromone of A. obtectus, were achieved by means of either palladium-catalyzed Heck reaction or a Claisen and an Al₂O₃ catalyzed thermal rearrangements.     

Synthesis of (2S)-2-amino-3-(1H-4-indolyl)propanoic acid,a novel tryptophan analog for structural modification of bioactive peptides

A convenient, multigram synthesis of a novel α-amino acid (2S)-2-amino-3-(1H-4-indolyl)propanoic acid (1a), is reported. An Fmoc–t-Boc derivative of this novel regioisomer of the natural aromatic amino acid tryptophan could be readily incorporated into bioactive synthetic peptides using standard solid phase synthesis. The synthesis featured the use of Schöllkopf chiral auxiliary reagents for chirality induction during a key step.     

Stereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one

A short, efficient, and highly diastereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one (1) is described. Use of phthalic anhydride as thiolate scavenger effectively preserves the chiral integrity of the α-aminoketone 4 product obtained from the reaction of organozincate 3 with thioester 2.     

Stereoselective synthesis of tacalcitol via (R)-MeCBS catalyzed borane reduction

A novel and efficient approach for the synthesis of 1α, 24(R)-dihydroxyvitamin D₃ (tacalcitol) starting from readily available enone 1 has been achieved with high stereoselectivity. The key step involved in the synthesis of tacalcitol was the stereoselective reduction of enone 1 using borane as the reducing agent, and the effects of the critical reaction parameters such as temperature, various borane complexes have been examined. Finally, tacalcitol was obtained in five steps from enone 1 with an overall yield of 32% and a ratio of 24-R/S = 95/5.     

Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives

Efficient procedures for the synthesis of (R)-N-benzyl-2-amino-3-methoxypropionamide ((R)-3), 2-acetamido-3-methoxypropionic acid (4), and O-methylserine (5) are described beginning from (R)-Cbz-serine ((R)-7). The reactions proceeded with little or no racemization and permitted the synthesis of the potent anticonvulsant (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2). The anticonvulsant activities of 2–4 were determined revealing the surprising activity of (R)-2.     

Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2-phenylethyl)oxirane

A short and efficient enantioselective synthesis of the HIV protease inhibitor amprenavir 1 (99% ee) as well as a formal synthesis of saquinavir 3 have been achieved in high enantiomeric purity starting from commercially available materials. Our strategy mainly comprises a Co-catalyzed two-stereocentred hydrolytic kinetic resolution (HKR) of racemic 2-(1-azido-2-phenylethyl)oxirane as the chirality inducing step. Also presented is a concise synthesis of (S)-3-hydroxytetrahydrofuran 4, the key structural feature, in high enantiomeric purity (98% ee).     

Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epoxypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j were synthesised from diethyl (R)- and (S)-2,3-epoxypropylphosphonates in a reaction sequence including azidolysis followed by 1,3-dipolar cycloaddition with selected alkynes.     

Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.     

Biomimetically inspired total synthesis of (12S)-12-hydroxymonocerin and (12R)-12-hydroxymonocerin

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).     

Asymmetric synthesis of tert-butyl ((1R,4aR,8R,8aR)-1-hydroxyoctahydro-1H-isochromen-8-yl)carbamate

The asymmetric synthesis of methyl (E)-4-((1R,2S,3R)-3-amino-2-((E)-2-methoxycarbonyl-eten-1-yl)cyclohexyl)but-2-enoate 14 has been achieved from dimethyl (2E,7E)-nona-2,7-dienedioate 2. A key step is the asymmetric synthesis of 1-hydroxyoctahydro-1H-isochromene derivative 5 whose X-ray analysis corroborated the stereochemistry of the new stereocenters. The asymmetric synthesis of the isochromenyl acetate derivative 11 shows the potential of this methodology for fused cyclohexanic system heterocyclic synthesis.     

An enantioselective approach to 3-substituted pyrrolidines: Asymmetric synthesis for pyrrolidine core of serotonin norepinephrine reuptake inhibitors (SNRIs)

A novel and efficient synthetic approach to enantiopure 3-substituted pyrrolidine skeleton from readily available (S)-PMB glycidyl ether as a starting material and its application to the asymmetric synthesis of pyrrolidine core 1 of serotonin norepinephrine reuptake inhibitors (SNRIs) 2 and 3 are described. The synthesis utilizes the organocatalyzed asymmetric Michael addition reaction as key step.     

An asymmetric synthesis of the novel H3 agonist (+)-(3R,4R)-3-(4-imidazolyl)-4-methylpyrrolidine dihydrochloride (Sch 50971)

A short, high yielding, enantioselective synthesis of the novel H₃ agonist Sch 50971 1 is described. The key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin.