Oxazolidinone Chiral Auxiliary Research Articles

Synthesis of Natural Fragrant Molecules cis-3-Methyl-4-decanolide and Aerangis Lactone. General Enantioselective Routes to β,γ-cis-Disubstituted γ-Lactones and γ,δ-cis-Disubstituted δ-Lactones

General enantioselective routes to 3,4-cis-dialkyl substituted gamma-lactones and 4,5-cis-dialkyl substituted delta-lactones using TiCl(4)-mediated Evans asymmetric aldolization as the key step are reported. The syntheses are exemplified with two natural fragrant molecules, cis-3-methyl-4-decanolide (1) and aerangis lactone (2). The (R,R) steroegenic centers were established using (S)-phenylalanine-derived 2-oxazolidinone or thiazolidinethione as chiral auxiliary, whereas the (S,S) ones were constructed with auxiliary prepared from (R)-phenylglycine. NaBH(4)/CaCl(2)/THF in the presence of a small amount of EtOH was introduced as a new effective method for reductive cleavage of chiral oxazolidinone auxiliaries. Previously unknown, tricky concentration effects were observed during the monotosylation of diol 7 and BOM protection of Evans aldol 23.

Metallations and Reactions with Electrophiles of 4-Isopropyl-5,5-diphenyloxazolidin-2-one (DIOZ) with N-Allyl and N-Propargyl Substituents: Chiral Homoenolate Reagents

N-Allyl, N-cinnamyl, and N-(3-trimethylsilyl)propargyl derivatives of 4-isopropyl-5,5-diphenyloxazolidin-2-one (DIOZ) are prepared by lithiation of the parent DIOZ (with BuLi in THF) and reaction with the corresponding bromides (Scheme 1). Lithiation in the same solvent, with deprotonation by BuLi on the allylic or propargylic CH2 group at dry-ice temperature, provides colorful solutions, which are either combined with aldehydes or ketones directly or after addition (with or without warming) of (Me2N)3TiCl or (i-PrO)3TiCl. Conditions have thus been elaborated under which all three types of conjugated lithium compounds react in the γ-position with respect to the oxazolidinone N-atom: carbamoyl derivatives of enamines and allenyl amines are formed in yields ranging from 60 to 80% and with diastereoselectivities up to 98% (Schemes 2–5). The C=C bond of the N-hydroxyalkenyl groups has (Z)-configuration (products 5 and 8), the allene chirality axis has (M)-configuration (products 9), and the addition to aldehydes and unsymmetrical ketones has taken place preferentially from the Si face. A mechanistic model is proposed that is compatible with the stereochemical outcome (assuming kinetic control and disregarding the presence of Li and Ti species in the reaction mixture; cf. L, M in Fig. 4). Hydrolysis of the enamine derivatives leads to lactols, oxidizable to γ-lactones, with recovery of the crystalline oxazolidinone, as demonstrated in three cases (Scheme 6). Thus, the application of chiral oxazolidinone auxiliaries (cf. Figs. 1 and 2) has been extended to the overall enantioselective preparation of homoaldols.

ChemInform Abstract: Synthesis of a New Chiral Oxazolidinone Auxiliary Based on D‐Xylose and Its Application to the Staudinger Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Metal ion-mediated diastereoface-selective 1,3-dipolar cycloaddition of nitrile oxides with dipolarophiles bearing an oxazolidinone chiral auxiliary

Magnesium ion-mediated cycloaddition reactions of nitrile oxides to chiral 3-acryloyl-2-oxazolidinones lead to highly diastereoselective formation of 2-isoxazolines. The magnesium ion serves to fix the α,β-unsaturated moiety through chelation to effect chiral shielding. These asymmetric reactions provide the first successful examples of Lewis acid-mediated stereocontrol of nitrile oxide cycloaddition reactions to electron-deficient dipolarophiles.

Synthesis of a new chiral oxazolidinone auxiliary based on d-xylose and its application to the Staudinger reaction

The synthesis of a new chiral oxazolidinone auxiliary based on d-xylose is described which is employed in diastereoselective Staudinger-type β-lactam syntheses. Using 2-chloro-1-methylpyridinium iodide as the dehydrating reagent, the reaction of auxiliary tethered acetic acid with acyclic or cyclic imines gave the desired β-lactams in good yields with excellent cis- or trans-selectivity depending on the geometry of the imine. X-Ray structure determination of one of the obtained compounds corroborated the absolute configuration for all cis products.

Free-Radical Polymerization and Copolymerization of Acrylimides: Homopolymers of Oxazolidinone Acrylimide and Control of 1,5-Stereochemistry in Copolymers Derived from Isobutylene and an Oxazolidinone Acrylimide

The polymerization and copolymerization of N-acryloyl imides was investigated. Thus, Lewis acids were used to control the free-radical copolymerization of N-acryloyl imides derived from oxazolidinones and isobutylene. Complexation of an appropriate Lewis acid (Sc(OTf)3) to acrylimides of achiral and chiral oxazolidinone auxiliaries allowed the preparation of alternating 1:1 copolymers as determined from integration of the copolymer 1H NMR spectra. Highly isotactic copolymers were made when chiral oxazolidinones were used as starting material if Lewis acid was present in the reaction. NMR analysis (1H and 13C) of the copolymers showed that the m/r dyad ratio was in excess of 95:5 for some of the chiral acrylimides. Homopolymerization of the parent achiral acrylamide was also carried out. NMR analysis of the homopolymer showed a temperature-dependent preference for the r dyad with a m/r dyad ratio as low as 0.25 in polymerizations carried out at −78 °C.

Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil ®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the ( S) configuration at C-3 of VCD was fixed by synthesizing ( S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2 RS,3 S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2 R,3 S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2 R,3 S)-VCD and (2 S,3 S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.

Solid phase aldol and conjugate addition reactions using Evans' oxazolidinone chiral auxiliary

Resin-supported Evans' chiral auxiliary is used in an aldol and a conjugate addition reaction on solid phase. The experiments show that solid-phase asymmetric reactions can reproduce the high enantiomeric excesses observed in solution phase reactions and also highlight specific problems associated with working on resin.

ChemInform Abstract: Simple and Efficient N‐Acylation Reactions of Chiral Oxazolidinone Auxiliaries.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total Synthesis of the Serine/Threonine-Specific Protein Phosphatase Inhibitor Tautomycin(1).

A convergent, asymmetric synthesis of the protein phosphatase inhibitor, tautomycin, is described. The natural product was constructed by joining two major fragments of comparable complexity at the C21-C22 bond. Absolute stereochemistry of the C1-C21 ketone originates from (S)-citronellene and (2R,3S)-geraniol epoxide. The anti stereochemical relationships at C6-C7 and C18-C19 were introduced with Duthaler's chiral titanium propionic enolate. Syn stereochemical relationships at C13-C14 and C23-C24 were established using an Evan's oxazolidinone chiral auxiliary. The spiroketal was efficiently constructed via a one-pot double-alkylation-spirocyclization sequence with acetone N,N-dimethylhydrazone serving as the central linchpin. Final coupling of the two halves using a chelation-controlled Mukaiyama aldol addition followed by deprotection yielded synthetic tautomycin that is identical to the natural product.

Enantioselective synthesis of 2-substituted 4-aminobutanoic acid (GABA) analogues via cyanomethylation of chiral enolates

Cyanomethylation by bromoacetonitrile of sodium or lithium enolates derived from (4S,5R)-3-acyl-4-methyl-5-phenyl-1,3-oxazolidin-2-ones usually shows good stereoselectivity; although the reaction of 3-(3-carboxypropanoyl)oxazolidinone 5d is exceptionally unselective, the 3-(pent-4-enoyl)- and 3-(3,4-dimethoxyhydrocinnamoyl)oxazolidinones 5e and 5f are found to be effective synthetic equivalents of 5d. The cyanomethylation products can be converted into 2-substituted derivatives of 4-aminobutanoic acid (γ-aminobutyric acid, GABA) by the alkaline hydrolysis of the oxazolidinone chiral auxiliary followed by hydrogenation of the cyano group.

(R)-(+)-3-Amino-2-phenylpropanoic acid: a revised absolute configuration based on an enantioselective synthesis and an X-ray crystal structure of the salt with (1S)-(+)-camphor-10-sulfonic acid

Amidoalkylation of the lithium enolate of (4S,5R)-4-methyl-5-phenyl-3-(phenylacetyl)oxazolidin-2-one 5 by 1-(N-benzyloxycarbonylaminomethyl)benzotriazole 2c, followed by cleavage of the oxazolidinone chiral auxiliary and of the N-benzyloxycarbonyl group, gave (R)-(+)-3-amino-2-phenylpropanoic acid 1, the absolute configuration of which was determined by X-ray crystallography on the salt 8 with (1S)-(+)-camphor-10-sulfonic acid.