Synthetic route towards (5R,2′S,5′S,6′S)-ribosyl-diazepanone,an analogue core of the liposidomycins

The synthesis of (5R,2′S,5′S,6′S)-ribosyl-diazepanone, an analogue core of liposidomycins is described. The core ribosyl seven-membered heterocycle of nucleoside antibiotic liposidomycins was formed by reductive amination of an α-ribosylamino ester derived from d-ribose, and an amino aldehyde derived from methyl 4-triisopropylsilyloxy-3-oxobutanoate, followed by a peptidic coupling reaction.     

Reduced collagen cross links: the first synthesis of all the possible (2S,2′S)-stereoisomers of 5-hydroxylysinonorleucine and of 5,5′-dihydroxylysinonorleucine in enantiomerically pure form

The paper reports the first enantioselective synthesis of all the possible collagen reduced cross links as described: (2S,2′S,5R)- and (2S,2′S,5S)-5-hydroxylysinonorleucine 3a and 3b, (2S,2′S,5R,5′R)-5,5′-dihydroxylysinonorleucine 4a, (2S,2′S,5R,5′S)-5,5′-dihydroxylysinonorleucine 4b and (2S,2′S,5S,5′S)-5,5′-dihydroxylysinonorleucine 4c. The Williams’ glycine template methodology was used both for the introduction of a stereogenic at the α-position and for an easy protection of the amino acidic functionalities during the synthesis of the dimeric amino acids.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol and its propionate,the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol (diprionol) and its propionate, the sex pheromones of pine sawflies (Neodiprion sp. and other), in high enantiomeric purity was achieved from (1R,3S)-2,2-dichloro-3-methylcyclopropanecarboxylic acid. The carbon skeleton of diprionol was formed via copper-catalyzed cross-coupling reactions and diastereoselective methylation of the intermediate chiral α-methylbranched aldehyde with MeTi(Oi-Pr)₃ in the presence of [(R,R)-TADDOL]Ti(Oi-Pr)₂. The latter transformation leads to a syn-adduct with high stereoselectivity, which depends on the presence and configuration of the α-stereogenic center in the aldehyde. The diastereomeric purity of (2S,3S,7S)-diprionol can be substantially increased via crystallization of its 3,5-dinitrobenzoate.     

A new asymmetric synthesis of (2S,3R,4R,5S)-trihydroxypipecolic acid

A novel four step synthesis of enantiomerically pure (2S,3R,4R,5S)-trihydroxypipecolic acid, starting from readily available materials, that is, condensation products of (R)-(−)-phenylglycinol with a mesotrihydroxylated glutaraldehyde, is described. The scope and limitations of the reaction have also been investigated.     

Efficient access to N-protected derivatives of (R,R,R)- and (S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution

The preparation of the proline analogue (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic) and its enantiomer, (2R,3aR,7aR)-Oic, is described. A racemic precursor has been synthesized in good yield and subjected to HPLC resolution on a chiral column. The high efficiency of both the synthetic and chromatographic procedures has allowed the isolation of multigram quantities of each amino acid in enantiomerically pure form and suitably protected for use in peptide synthesis.     

A flexible organocatalytic enantioselective synthesis of heptadeca-1-ene-4,6-diyne-3S,8R,9S,10S-tetrol and its congeners

A unified enantioselective route is developed for the synthesis of heptadeca-1-ene-4,6-diyne-3S,8R,9S,10S-tetrol and its synthetic congeners. A proline-catalyzed aminoxylation, cross-metathesis, Wittig reaction, and catalytic dihydroxylation are key steps of this synthesis. This new approach is envisioned to facilitate the synthesis of every representative member of the family with skeletal and stereochemical variation.     

A chiron approach to (1R,2R,5S,7S)-2-hydroxy-exo-brevicomin: a component of the volatiles produced by the male mountain pine beetle,Dendroctonus ponderosae

A chiron approach for the synthesis of (1R,2R,5S,7S)-2-hydroxy-exo-brevicomin 1, a component of the volatiles obtained from male mountain pine beetles, Dendroctonus ponderosae has been achieved. Our synthesis started with commercially available d-ribose and involves a Wittig olefination, an acid catalyzed one pot hydrogenation and the internal acetalization as key steps.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Chiron approach for the synthesis of (1S,2R,5R,7S)-2-hydroxy-exo-brevicomin

(1S,2R,5R,7S)-2-Hydroxy-exo-brevicomin ent-1 was synthesized from 1,2;5,6-di-O-isopropylidene-d-glucose in seven steps. The key reaction in our synthesis is the formation of bicyclic ketal 7 under acid mediated acetal exchange of a 1,2-acetonide of d-glucose derivative 6.     

Stereoselective synthesis of conformationally constrained (2S,3S)-3-hydroxyornithine

A convenient and efficient route is described for the highly stereoselective synthesis of δ-amino protected and conformationally restricted (2S,3S)-3-hydroxyornithine through the N-benzylnitrone adduct to the α,β-unsaturated bicyclic lactam 2 derived from (S)-pyroglutaminol.     

Enantioselective synthesis of (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-exo-carboxylic acid

A scalable enantioselective access to (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-exo-carboxylic acid 7, a key precursor in the synthesis of A2a receptor antagonist 1 by means of an enzymatic resolution of the respective butyl ester with lipase A from Candida antarctica, is described.     

Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine

Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine, an important intermediate for a novel quinolone antitumor agent AG-7352 is presented. Starting from either d- or l-tartaric acid, a stereospecific synthesis of the chiral pyrrolidine was achieved via two S_N2 displacement reactions. From the results of this synthetic study, the absolute structure of AG-7352 was chemically determined.     

Stereoselective synthesis,solution structure and metal complexes of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids

The highly stereoselective synthesis of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids was achieved by addition of dimethyl phosphite to N-protected aminoaldehydes. Relative configuration and solution conformations of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids (in D₂O) and their dimethyl esters (in CDCl₃ and CD₃OD) were established by means of NMR basing on the dependence between observed values of coupling constants (³J_HH, ³J_PC, ³J_HP) and corresponding dihedral angles. Potentiometric and spectroscopic methods were used for the evaluation of the structure of the complexes of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids with Zn(II) and Cu(II) ions in aqueous solutions.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

A convenient synthesis of (1S,2R)-1,2-indene oxide and trans-(1S,2S)-2-bromo-1-indanol via oxazaborolidine-catalyzed borane reduction

A facile synthesis of (1S,2R)-indene oxide with >99% e.e. and (1S,2S)-trans-2-bromo-1-indanol with 87% e.e. has been established by employing CBS-oxazaborolidine-catalyzed asymmetric borane reduction of 2-p-toluenesulfonyloxy-1-indanone using N-ethyl-N-isopropylaniline–borane complex as the borane carrier.     

Stereospecific synthesis of differentially protected (2S,4S)-2,4-diaminoglutaric acid suitable for incorporation into peptides

The first synthesis of differentially protected (2S,4S)-2,4-diaminoglutaric acids 2 and 3 suitable for incorporation into peptides has been accomplished in a completely stereospecific manner in seven steps (overall yield 25–28%) from tert-butyl (2S,4S)-4-azido-N-tert-butoxycarbonylprolinate 5.     

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. IV: Synthesis of enantiopure methyl (1S,2R,3R,4R,5S)-5-benzyloxycarbonylamino-2,3-isopropylidenedioxy-4-methoxycyclopentanecarboxylate

The first total synthesis of a new enantiopure polyhydroxylated cyclopentyl β-amino acid [methyl (1S,2R,3S,4R,5S)-2-benzyloxy-5-benzyloxycarbonylamino-3-hydroxy-4-methoxycyclopentanecarboxylate] was achieved according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines. This approach is based on an intramolecular cyclization leading to 2-oxabicyclo[2.2.1]heptane derivatives. Epimerization of this amino acid derivative to methyl (1S,2R,3R,4R,5S)-2-benzyloxy-5-benzyloxycarbonylamino-3-hydroxy-4-methoxycyclopentanecarboxylate constitutes the first example of the preparation of one of the members of this family of amino acids with a stereochemistry that is not compatible with the above key cyclization step.     

Synthesis of optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one

Bicyclo[2.2.2]octanone is an important building block for the synthesis of bioactive compounds and natural products. Herein, we present a new synthetic route for the formation of (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one derivatives via a catalytic asymmetric Michael reaction in high stereoselectivity and yields.     

A simple and efficient enantioselective route to 2,6-disubstituted piperidines: synthesis of (2R,6S)-isosolenopsin A and (2S,6R)-isosolenopsin

The enantioselective synthesis of 2,6-cis-disubstituted piperidine alkaloids, (2R,6S)-isosolenopsin A 2 and (2S,6R)-isosolenopsin 5 from fire ant venom is described. Starting from the dodecanal and decanal, the synthesis presents two key steps. The first step involves Keck allylation to afford the chiral homoallylalcohol with the required stereochemistry and the second key step consists of Grubbs olefin cross metathesis. The synthesis was achieved in five steps with 44% overall yield.     

Expedient asymmetric synthesis of (2S,3S)-Boc-phenylalanine epoxide,a key intermediate for the synthesis of biologically active compounds

The asymmetric synthesis of (2S,3S)-3-(tert-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane [(2S,3S)-Boc-phenylalanine epoxide] has been achieved in six steps and in 55% overall yield from the N-benzylimine derived from (R)-2,3-O-isopropylidene-glyceraldehyde. The required vic-aminodiol intermediate was obtained through a highly diastereoselective addition of benzylmagnesium chloride to the N-benzylimine in the presence of BF₃·OEt₂ as an imine precomplexing agent.