Assymetric synthesis of (2S,3R)- and (2S,3S)-[2-C;3-H] glutamic acid

We have developed a synthetic route for (2S,3R)- and (2S,3S)-[2-¹³C;3-²H] glutamic acids with high enantioselectivity. The key reactions in this synthesis are the asymmetric reduction of the 2,3-didehydroornithine derivative using the (S,S)-Et-DuPHOS-Rh catalyst and the oxidation of the δ-position by ruthenium catalysis.     

An efficient stereoselective synthesis of (2S,3S)-3-hydroxypipecolic acid using chlorosulfonyl isocyanate

An efficient stereoselective syntheses of (2S,3S)-3-hydroxypipecolic acid and (2R,3S)-2-hydroxymethylpiperidin-3-ol were achieved from p-anisaldehyde via the regioselective and diastereoselective introduction of an N-protected amine group using chlorosulfonyl isocyanate, ring-closing methathesis, and oxidation of p-methoxyphenyl group as the key steps.     

Analogues of the Quararibea metabolite chiral enolic-γ-lactone from (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids

Reaction of dialkyl (2S,3S)- or (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates with POCl₃ in pyridine followed by diazomethane resulted in the isolation of dialkyl 2S-4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarboxylates, which are analogues of the Quararibea metabolite chiral enolic-γ-lactone (3-hydroxy-4,5-(R)-dimethyl-2(5H)-furanone). An unusual α-hydroxylation of γ-butyrolactone takes place involving POCl₃ in pyridine. When the dehydration was facilitated with methanesulfonyl chloride in triethylamine, instead of POCl₃, aromatic dialkyl 5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates were obtained.     

Synthesis of (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratrane. Amplification of enantiomeric purity in the reacti

The synthesis is described of the two enantiomerically pure isomers (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratr The structures were determined by ¹H- and ¹³C-NMR spectroscopy. A method for increasing the enantiomeric purity by trimerization reactions of partially-resolved (S) propylene oxide is proposed. The reaction was studied from the kinetic viewpoint and interpreted according to a binomial probability scheme. The experimental findings point to a rapid growth in enantiomeric purity for the (SSS) trimer compared with the starting material, whilst no increase was found for the (SSR) trimer.     

An efficient stereoselective synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine

A concise enantioselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1 is described starting from l-phenyl-glycine and using a Grignard reaction as a key step.     

An asymmetric dihydroxylation route to (2S,3S)-3-hydroxypipecolic acid

A concise enantioselective synthesis of (2S,3S)-3-hydroxypipecolic acid 1 starting from 1,4-butanediol using Sharpless asymmetric dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfate as the key steps is described.     

Synthesis of (2S,3R)- and (2S,3S)-[3-H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

A straightforward synthesis of (2S)-[3,3-²H₂]-proline 1c and (2S,3R)- and (2S,3S)-[3-²H₁]-proline, 1b and 1a, respectively, has been devised. The key step of the route to the latter compounds involves highly stereoselective hydrolysis of the silyl enol ethers 3 and 3a, respectively, with protonation (deuteriation) from the re-face of the silyl enol ether.     

Chemoenzymatic synthesis of (3S,4S)- and (3R,4R)-3-methoxy-4-methylaminopyrrolidine

Facile chemoenzymatic enantioselective synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, a key intermediate for a new quinolone antitumor compound AG-7352 has been described. This methodology illustrates the preparation of 3-azido-1-benzyloxycarbonyl-4-hydroxypyrrolidine starting from diallylamine via 1-benzyloxycarbonyl-3-pyrroline obtained by ring-closing metathesis (RCM) employing Grubbs’ catalyst. Enzymatic transesterification employing PS-C lipase gave (3S,4S)-3-azido-1-benzyloxycarbonyl-4-hydroxypyrrolidine in >99% ee, which upon methylation of the hydroxyl group followed by sequential reactions gave the desired intermediates, (3S,4S)-1-tert-butoxycarbonyl-3-tert-butoxycarbonylamino-4-methoxypyrrolidine.     

Synthesis and absolute configuration of two diastereoisomeric (1R,2S,3R)-and (1S,2S,3R)-2-amino-1-(2-furyl)-1,3-butandiols

The synthesis of (1R, 2S, 3R) and (1S, 2S, 3R)-2-(N-benzoylamino)-1-(2-furyl)-1, 3-butandiols (15) and (16) from D-threonine is described. The assignment of absolute configuration of the newly formed asymmetric center at C-1 was based on the ¹H-NMR spectra of O-isopropylidene derivatives 17 and 18.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

An efficient synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenyl piperidine and N-Boc-safingol

An efficient strategy has been developed for the stereo selective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenyl piperidine and N-Boc-safingol from benzaldehyde and N-Boc-imine.     

Stereoselective synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

A stereoselective synthesis of the pentaketide lactone (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone has been achieved.     

Studies on the aza-Claisen rearrangement of 4,5-dihydroxylated allylic trichloroacetimidates: the stereoselective synthesis of (2R,3S)- and (2S,3S)-2-amino-3,4-dihydroxybutyric acids

Two new synthetic approaches, involving substrate directed aza-Claisen rearrangements and aza-Claisen rearrangements mediated by chiral Pd(II) catalysts, have been developed for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, a dihydroxylated α-amino acid from the edible mushroom, Lyophyllum ulmarium and its (2S,3S)-unnatural diastereomer.     

A tethered aminohydroxylation route to l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C18-phytosphingosines

A concise and highly efficient synthesis of l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C₁₈-phytosphingosines has been achieved. The synthetic strategy features the Sharpless kinetic resolution and tethered aminohydroxylation as the key steps.     

Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.     

The first asymmetric synthesis of (2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxypyrrolidine

The novel (2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxypyrrolidine 5 has been produced in an efficient synthesis from trans-4-hydroxy-l-proline 8. The key step involves a tethered aminohydroxylation of the alkene 7 to introduce regio- and stereoselectively the amino alcohol functionality in the resulting products 6 and 13. Subsequent deprotection steps furnish the target molecule 5 as well as several differentially protected analogues.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate and propionate, the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (2) and propionate (3) was accomplished by utilizing the cheap and easily available chiron (R)-4-methyl-δ-valerolactone (4). The key steps were chelation-controlled addition of Gilmann reagent to chiral β-alkoxy aldehyde 12 and the Cu(I)-catalyzed coupling of Grignard reagent with bromoester 5 in the presence of NMP.     

A short, simple and general approach for the synthesis of (3S,4S)-3-methoxy-4-methylamino pyrrolidine and (3S,4R)-3-methoxy-4-methylamino pyrrolidine

A general and efficient stereoselective approach for the synthesis of (3S,4S) and (3S,4R)-3-methoxy-4-methylamino pyrrolidines, a part of the structure of AG-7352, a naphthyridine antitumor agent and quinoline antibacterial compounds has been described.     

An asymmetric synthesis of (2S,3S)-safingol

Two efficient asymmetric syntheses of (2S,3S)-safingol have been developed starting from easily available (R)-cyclohexylideneglyceraldehyde. The key steps in the syntheses were a diastereoselective addition of a suitable alkylmagnesium or lithium reagent, and simple organic transformations. Compared to earlier syntheses, the route involving alkyllithium addition is more viable practically due to its excellent diastereoselectivity, use of inexpensive materials/reagents and operational simplicity.     

An expeditious synthesis of a (3S,4S,5R)-trihydroxyazepane

A practical approach for the synthesis of the (2S,3S,4R)-trihydroxyazepane 1d has been reported. Starting from α-d-xylo-pentodialdose, readily available from d-glucose, the sequence involves Wittig olefination and reductive amination as key steps.