Stereoselective synthesis of optically active cyclitol precursors via a chemoenzymatic method

Racemic α′-acetoxy α,β-unsaturated cyclohexanone has been converted to the corresponding enantiomerically enriched α′-hydroxylated and acetoxylated compounds with 97% ee via enzymatic resolution with PLE. OsO₄-Catalyzed dihydroxylation of enantiomerically enriched α′-acetoxylated compound afforded a single diastereomer in 85% chemical yield. The absolute configuration of 2,3,6-triacetoxycylohexanone was determined by X-ray diffraction analysis. Subsequent Luche reduction allowed us to obtain corresponding syn-type cyclitol precursors in a highly stereoselective manner as expected.     

Total synthesis of lycopene-5,6-diol and γ-carotene-5′,6′-diol stereoisomers and their HPLC separation

Lycopene-5,6-diol stereoisomers (1a,b) and (2a,b) and γ-carotene-5′,6′-diol stereoisomers (3a,b) and (4a,b) were synthesized by a stepwise C₁₅ + C₁₀ + C₁₅ double Wittig reaction strategy. The key compounds erythro(anti)-C₁₅-dihydroxy aldehydes 17a,b and their threo(syn)-stereoisomers 23a,b were prepared via Sharpless asymmetric epoxidation of geraniol and nerol followed by acidic hydrolysis of the epoxides in a stereospecific manner. The enantiomerically enriched anti-isomers were obtained by way of recrystallization of 2,3-epoxygeranyl 3,5-dinitrobenzoates 9a,b, whereas syn-isomers were obtained as enantiomerically pure forms via recrystallization of dihydroxyneryl 3,5-dinitrobenzoates 21a,b. In order to determine the absolute stereochemistry of natural products, HPLC separation methods for each enantiomers 1a,b–4a,b were established by using a column carrying a chiral stationary phase.     

Synthesis and separation of the atropisomers of 2-(5-benzo[b]fluorenyl)-2′-hydroxy-1,1′-binaphthyl and related compounds

Several syn and anti atropisomers of 2-(5-benzo[b]fluorenyl)-2′-hydroxy-1,1′-binaphthyl and related compounds were synthesized from 1,1′-binaphthyl-2,2′-diol (BINOL). It was possible to separate the syn and anti atropisomers by silica gel column chromatography. The syn atropisomers are potential hetero-bidentate ligands for complex formation with metals. By starting from enantiomerically pure (R)-(+)-BINOL and (S)-(−)-BINOL, four optically active syn atropisomers and two anti atropisomers with high enantiomeric purity were obtained. The structures of two syn atropisomers and one anti atropisomer were established by X-ray structure analyses.     

Asymmetric aldol addition of α-azido ketones to ethyl pyruvate mediated by a cinchona-based bifunctional urea catalyst

The first asymmetric synthesis of ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutanoates via a cinchona organocatalyst induced aldol addition of α-azido ketones to ethyl pyruvate has been developed. The coupling reaction under optimized conditions was carried out to furnish tetrafunctionalized synthons with enantioselectivities of up to 91:9 and enriched diastereoselectivities of up to 95:5 (syn:anti).     

Improved synthesis of structural analogues of (−)-epicatechin gallate for modulation of staphylococcal β-lactam resistance

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.     

Highly enantioselective synthesis of anti aryl β-hydroxy α-amino esters via DKR transfer hydrogenation

An efficient preparation of highly enantiomerically enriched aryl β-hydroxy α-amino esters via dynamic kinetic resolution (DKR), asymmetric transfer hydrogenation of α-amino β-keto esters is described. The anti β-hydroxyl α-amino esters were obtained both in high yields and high diasteroselectivity. The observed high anti selectivity is inconsistent with the previous results in literature. The absolute stereochemistry of the aryl β-hydroxy α-amino esters was unambiguously confirmed via chemical derivatization as well as Vibrational Circular Dichroism (VCD) techniques.     

Chiral enolates for highly stereoselective aldol reactions—Scope and limitations

Enantioselective approaches to the formation of α,β-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure β-substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel synthesis of functionalized β,γ-unsaturated acetals is also described.     

SmI2-coupling reaction of chiral non-racemic α-bromo-α′-sulfinyl ketones with imines: synthesis of enantiomerically pure 2-methyl-3-amino-1-ol moieties

Chiral non-racemic α-bromo-α′-sulfinyl ketones were shown to react with imines in the presence of SmI₂ to give the corresponding 1,3-aminoketo derivatives with good syn-diastereoselectivity. Further reduction of these adducts either with DIBAL-H only or with DIBAL-H in the presence of Yb(OTf)₃ afforded syn- and anti-2-methyl-3-amino-1-ol moieties, respectively, in good yields and diastereoselectivities.     

Stereoselective synthesis of β-amino alcohols: practical preparation of all four stereomers of N-PMB-protected sphingosine from l- and d-serine

Serine was efficiently converted to the N-p-methoxybenzyl (PMB) protected α′-amino enone derivative 6, which was reduced with Zn(BH₄)₂ to the corresponding anti-β-amino alcohol in >96% de. On the other hand, N-PMB-N-Boc-protected α′-amino enone derivative 8 was reduced by NaBH₄ to syn-product with a diastereoselectivity of ca. 90%.     

Synthesis of C18–C28 ketone fragment of micromonospolide B possessing 1,3-diene and 1,3-anti-diol functionalities

A highly stereocontrolled synthesis of the C18–C28 ketone fragment of the 16-membered plecomacrolide micromonospolide B has been accomplished. The C21–C23 syn–anti stereotriad is secured by the anti-selective aldol condensation of the ephedrine-derived chiral propionate with (E,E)-hexa-2,4-dienal and Sharpless asymmetric allylic epoxidation–regioselective reductive epoxide ring opening, respectively. The overall yield of this 14-step sequence is 18.4% and the target C18–C28 ketone was obtained in enantiomerically pure form.     

Concise and diastereoselective approach to syn- and anti-N-tosyl-α-hydroxy β-amino acid derivatives

The methyl diazoacetate and aryl (N-tosyl)imines can be transformed into syn or anti α-hydroxy β-amino esters with high diastereoselectivities in three steps: the base promoted nucleophilic condensation of the methyl diazoacetate and aryl (N-tosyl)imines to give β-(N-tosyl)amino α-diazoesters, followed by oxidation with Oxone^® to generate α-oxo esters, which were reduced with NaBH₄ to yield the anti-N-tosyl-α-hydroxy β-amino ester, or hydrogenated with Pd/C (10%) as the catalyst to yield corresponding syn isomer, both in high diastereoselectivity.     

First report of syn isomers in the diastereoselective synthesis of highly functionalized piperidines catalysed by wet picric acid: factors influencing the syn-anti ratios

This is the first report of the formation of a syn-diastereoisomer in the diastereoselective synthesis of highly functionalized piperidines catalysed by wet picric acid via a one-pot, step-economic condensation of aromatic aldehydes, 1,3-dicarbonyl compounds and aromatic amines. DFT calculation shows that anti isomers are more stable compared to the syn. The syn-anti ratio of the products depends on the temperature and the nature of substitution on both the aromatic aldehydes and aromatic amines. Conditions for getting pure anti and pure syn compounds have been studied.     

Equilibres conformationnels de glucides au niveau de liaisons σ sp2-sp3 C-C. III Dérivés d'oximes d'aldéhydo-sucres utilisation de tris-dipivaloylméthanato-europium

A series of sugar oximes and O-methyloximes of the general formula RCH?NOR′ (R′ ? H, CH₃) have been studied by PMR. spectroscopy. These compounds exist in solution as a mixture of the syn and anti isomers. The conformational equilibrium of the syn isomers seems to consist exclusively of the eclipsed rotamers, whereas for the anti isomers there appears to be a significant contribution from bisecting rotamers. Using tris-dipivaloylmethanato-europium it is found that the α proton of the anti oximes is much more deshielded than the corresponding proton of the syn isomers, which means that the downfield shift of a particular proton does not depend exclusively on its distance from the oxygen of the oxyimino group.     

An efficient and practical procedure for Strecker reaction: a highly diastereoselective synthesis of a key intermediate for (+)-biotin

Treatment of α-amino aldehyde 2, which was prepared through Moffatt oxidation of the corresponding β-amino alcohol 5, with aqueous sodium bisulfite allowed clean conversion to a water-soluble bisulfite adduct 6 [>99% conversion, 89% yield (two steps)]. The aqueous solution of 6 was treated with benzylamine followed by easy-handling NaCN to effect the Strecker reaction to afford α-amino nitrile 3 with high diastereoselectivity and in high yield (syn/anti = 11:1, 95% assay yield). Both the compounds syn-3 and anti-3 were converted to a key intermediate 4 for (+)-biotin through S,N-carbonyl migration in high yields.     

Cephalosporines a chaines amino-2 thiazolyl-4 acetyles: Influence de la presence et de la configuration d'un groupe oxyimino sur l'activite antibacterienne

The syntheses of 2-(2-amino-4-thiazolyl) 2-(hydroxy or alkoxy)-imino acetic acid derivatives, with the anti (E) and syn (Z) configurations, are described. By means of these compounds, the acylation of the amino-group of 7β-amino cephalosporanic acid (7-ACA) has been achieved. The two resulting series of cephalosporin derivatives-anti and syn-are markedly different with respect to their antibiotic activity. Some of the syn compounds possess an antibacterial activity which is the highest ever observed.     

Kinetic resolution of vic-diols by Bacillus stearothermophilus diacetyl reductase

The kinetic resolution of several racemic syn- and anti-1,2-diols by enzymatic oxidation with Bacillus stearothermophilus diacetyl reductase is described. The enantiomerically pure (R,R)- and (R,S)-diols are recovered in almost quantitative yield.     

Diastereoselective synthesis of γ-hydroxy α,β-epoxyesters and their conversion into β-hydroxy α-sulfenyl γ-butyrolactones

The diastereoselectivity of the nucleophilic epoxidation of γ-hydroxy-α,β-unsaturated esters has been studied. The γ-hydroxy-α,β-unsaturated esters were obtained through treatment of ethyl (E)-4-oxo-2-butenoate with the corresponding Grignard reagent and were used as a racemic mixture. The resulting γ-hydroxy α,β-epoxyesters were treated with thiophenol for transformation into α-phenylsulfanyl trisubstituted γ-butyrolactones. The syn,syn-lactones isomerize easily in basic media into the syn,anti structures. In order to explain this interconversion, a retroaldol-aldol sequence has been proposed and a sulfur-oxygen interaction has been invoked to explain the syn stereochemical preference of the α-sulfured aldols resulting from the intramolecular aldol reaction.     

(S)-Threonine/α,α-(S)-diphenylvalinol-derived chiral ionic liquid: an immobilized organocatalyst for asymmetric syn-aldol reactions

Chiral ionic liquids containing (S)- or (R)-threonine amide and α,α-(S)-diphenylvalinol units were synthesized In the presence of the (S)-threonine-derived catalyst reactions between ketones with secondary carbon atom(s) at the α-position with respect to the carbonyl group and aromatic (heteroaromatic) aldehydes afforded the corresponding syn-aldols in high yields (up to 99%) and with high diastereo-(syn/anti up to 97:3) and enantioselectivity (up to 99% ee), which was maintained over three reaction cycles.     

Formation and reaction of 2-metalated N-Boc-4,4-dimethyl-1,3-oxazolidines in the presence of (−)-sparteine: new chiral formyl anion equivalents

Lithiation of N-Boc-4,4-dimethyl-1,3-oxazolidine with s-BuLi and the following reaction with benzaldehyde was carried out in the presence of (−)-sparteine. The reaction was not diastereoselective (syn:anti=46:54), but each isomer of the adducts was obtained enantioselectively (syn: 90% ee, anti: 88% ee). Addition of MgBr₂ to the reaction mixture increased the diastereoselectivity to syn:anti=90:10.     

Addition of lactate-derived chiral allyltrichlorostannanes to chiral aldehydes

Chiral lactate-derived allyltrichlorostannanes reacted with chiral α-methyl β-alkoxy and syn and anti α-methyl-β-alkoxy aldehydes to give the corresponding homoallylic alcohols with moderate to high 1,4-syn-diastereoselectivities.