Chiral N-acyloxazolidinones Research Articles

Optimized Asymmetric Synthesis of Umuravumbolide.

Herein, the asymmetric synthesis of umuravumbolide (1) is described. The new approach features highly stereoselective transformations (dr ≥ 95:5) to install both stereocenters and the Z olefin, which involve a new radical alkylation, an Ando olefination, and a Krische allylation on a Z allylic alcohol, not reported before. The application of such successful reactions, together with the limited use of protecting groups and concession steps, makes it possible to complete the synthesis in 10 steps, resulting in a 39% overall yield from chiral N-acyl oxazolidinone 2.

Stereoselective Alkylation of Chiral Titanium(IV) Enolates with tert-Butyl Peresters.

Here, we present a new stereoselective alkylation of titanium(IV) enolates of chiral N-acyl oxazolidinones with tert-butyl peresters from Cα-branched aliphatic carboxylic acids, which proceeds through the decarboxylation of the peresters and the subsequent formation of alkyl radicals to produce the alkylated adducts with an excellent diastereoselectivity. Theoretical calculations account for the observed reactivity and the outstanding stereocontrol. Importantly, the resultant compounds can be easily converted into ligands for asymmetric and catalytic transformations.

Stereoselective Oxidation of Titanium(IV) Enolates with Oxygen

A novel approach to synthesize enantiomerically pure α-hydroxy carboxylic derivatives is reported. A highly stereoselective oxidation of titanium(IV) enolates from chiral N-acyloxazolidinones is performed with oxygen under simple experimental conditions that do not require any reducing steps. The success of this approach depends on the biradical character of titanium(IV) enolates.

The Synthesis of Both Diastereomers of 5′-Methylhomoaristeromycin

GRAPHICAL ABSTRACT

SmI 2-promoted intra- and intermolecular C–C bond formation with chiral N-acyl oxazolidinones

The suitability of chiral oxazolidinones in the SmI 2-mediated C–C bond generation between the imide functionality of an N-acyl oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon–carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5- exo- trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.

Modular Synthesis of Chiral N-Protected β-Seleno Amines and Amides via Cleavage of 2-Oxazolidinones and Application in Palladium-Catalyzed Asymmetric­ Allylic Alkylation

A set of chiral β-seleno amines have been efficiently synthesized via the ring-opening reaction of chiral N-acyl oxazolidin-ones by selenium nucleophiles. These compounds could be transformed into β-seleno amides by reaction with acid chlorides. The present method is applicable to the synthesis of β-chalcogeno amides containing selenium, sulfur and tellurium atoms in good yields. Additionally, these new compounds were evaluated as ligands in the palladium-catalyzed asymmetric allylic alkylation, giving the corresponding alkylated products in up to 98% ee.

Synthesis of a C-glycoside analogue of beta-D-galactosylthreonine.

A C-linked analogue of beta-D-galactosylthreonine has been prepared from 2,3,4,6-tetra-O-benzyl-D-galactopyranolactone (1) in 14 steps. Three stereogenic centers were created during the synthesis, with the anomeric center of the C-glycoside being generated first by addition of a Grignard reagent to 1 and subsequent reduction of the intermediate hemiacetal with triethylsilane. The two stereogenic centers in the threonine moiety were both established by alkylation of Evans' chiral N-acyloxazolidinone enolates.

Diastereoselective magnesium halide-catalyzed anti-aldol reactions of chiral N-acyloxazolidinones.

A chiral auxilliary-based direct aldol reaction is reported. The reactions are catalytic in magnesium salts and are facilitated by silylation with chlorotrimethylsilane. The adducts isolated are in high diastereoselectivity (up to 32:1 dr) and favor the anti-aldol diastereomer B. Reactions are operationally simple and can be run under ambient atmosphere without rigorous exclusion of water. Many of the adducts are highly crystalline and a single diastereomer can be isolated without chromatography.

A General Method for the Synthesis of Enantiomerically Pure β-Substituted, β-Amino Acids through α-Substituted Succinic Acid Derivatives

A general procedure for the synthesis of enantiopure β-substituted, β-amino acids is presented. Alkylation of the sodium enolates derived from chiral N-acyloxazolidinone imides 2 (R = Me, i-Pr, t-Bu, Ph, Bn) with tert-butyl bromoacetate afforded the 2-substituted succinate derivatives 3 in good yields (82−89%) and with high selectivity (≥93:7). Following hydrolysis, Curtius rearrangement of the resulting carboxylic acid provided the enantiopure benzyloxycarbonyl (Cbz)-protected β-amino esters 6 in good yields (74−79%).

フッ素化合物を中心とする光学活性化合物の不斉合成法の開発

The synthesis of chiral fluorinated molecules is important in the biological and medicinal chemistry fields in view of the influence of fluorine's unique properties on biological activity. In recent years, we have studied asymmetric synthesis focussing on such optically active compounds. This review describes 1) diastereoselective trifluoromethylation of chiral N-acyloxazolidinones, 2) catalytic enantioselective aldol reactions of fluorine-substituted ketene silyl acetals, and 3) catalytic enantioselective allylation of aldehydes mediated by chiral Lewis bases. The trifluoromethylation of lithium enolates of N-acyloxazolidinones with iodotrifluoromethane is mediated by triethylborane to give the corresponding trifluoromethylated products with up to 86% diastereomeric excess. The stereoselective reaction is considered to proceed through the attack of the trifluoromethyl radical on the less hindered face of the lithium imide. Difluoroketene and bromofluoroketene trimethylsilyl ethyl acetals react with various aldehydes in the presence of chiral Lewis acids to afford the corresponding desired aldols with up to 99% enantiomeric excess (ee). It is noteworthy that the aldol reactions of the fluorine-substituted acetals at -78 degrees C and at higher temperatures (-45 or -20 degrees C) provide the (+)- and (-)-aldols, respectively, with excellent-to-good enantioselectivity. Chiral phosphoramides newly prepared from (S)-proline were found to catalyze the allylation and crotylation of aromatic aldehydes with allylic trichlorosilanes in good enantioselective yields (up to 90% ee). (S,S)-Bis(alpha-methylbenzyl)formamide developed as an efficient catalyst for the allylation and crotylation of aliphatic aldehydes mediates the enantioselective addition with the assistance of hexamethylphosphoramide (HMPA) to afford the corresponding homoallylic alcohols in up to 98% ee.

Regio- and diastereoselective boron-mediated aldol reactions of chiral α,β,γ,δ-unsaturated N-acyloxazolidinones

Chiral N-acyloxazolidinones derived from conjugated dienoic acids undergo boron-mediated aldol condensation in good yield and with high regio- and diastereoselectivity to provide a convenient method for introducing a 1,3-diene subunit. The condensation of a homologous triene derivative is also described.

Ｎ−アシルオキサゾリジノンを用いる光学活性含フッ素化合物の合成

A variety of optically active fluorinated molecules have been prepared by diastereoselective reactions of chiral N-acyloxazolidinones. The trifluoromethyl radical generated from iodotrifluoromethane with a radical initiator, triethylborane, reacts on the si-face of the lithium enolates of the oxazolidinones with good diastereomeric excess. The perfluoroalkylation and ethoxycarbonyldifluoromethylation of the lithium enolates mediated by triethylborane also proceeds diastereoselectively via a radical mechanism. The bromodifluoromethylation of the lithium enolates proceeds not via a radical mechanism involving bromodifluoromethyl radical but via an ionic chain mechanism involving the insertion of difluorocarbene. The Evans aldol reaction of hexafluoroacetone and trifluoroacetaldehyde causes complete reversal of diastereofacial selectivity. The boron enolate derived from chiral N-acyloxazolidinones reacts with trifluoroacetaldehyde to give anti and “non-Evans” syn aldols with stereoselectivity in the range of 7 : 317 : 3. This unexpected and usual reversal of π-face selectivity was reproduced by semiempirical molecular orbital calculations.

Diastereoselective (Ethoxycarbonyl)difluoromethylation of Chiral Imide Enolates Mediated by Triethylborane.

Triethylborane-mediated reactions of lithium enolates derived from chiral N-acyloxazolidinones with ethyl difluoroiodoacetate allows easy access to α-(ethoxycarbonyl)difluoromethylated carboximides with good diastereomeric excess (86->98%de). The stereochemistry of the (ethyoxycarbonyl)difluoromethylated carboximides indicates that the (ethoxycarbonyl)difluoromethyl radical generated from ethyl difluoroiodoacetate and triethylborane reacts preferentially on the si face of the lithium enolates.

Diastereoselective perfluoroalkylation of chiral imide enolates with perfluoroalkyl iodides mediated by triethylborane

The perfluoroalkylation of lithium enolates of chiral N-acyloxazolidinones with perfluoroalkyl iodides mediated by triethylborane proceeds with good diastereomeric excess (55%–93% de).

Diastereoselective Palladium(0)-catalyzed Reactions of Lithium Enolates of Chiral N-Acyloxazolidinones. Asymmetric Synthesis of 2-Substituted (E)-4-Alkylidenepentanedioates

The palladium(0)-catalyzed reactions of lithium enolates 1 of N-acyloxazolidinones with 3-acetoxy-2-methylenealkanoates 2, easily prepared via DABCO-catalyzed coupling of corresponding aldehydes with acrylates, proceeded diastereoselectively and regioselectively to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones3, useful intermediates of metallopeptidase inhibitors.

Diastereoselective palladium(0)-catalyzed reactions of lithium enolates of chiral N-acyloxazolidinones. Asymmetric synthesis of 2-substituted ( E)-4-alkylidenepentanedioates

The palladium(0)-catalyzed reactions of lithium enolates 1 of N-acyloxazolidinones with 3-acetoxy-2-methylenealkanoates 2, easily prepared via DABCO-catalyzed coupling of corresponding aldehydes with acrylates, proceeded diastereoselectively and regioselectively to give chiral N-[( E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 3, useful intermediates of metallopeptidase inhibitors.

Diastereoselective addition-elimination reactions of lithium enolates of chiral N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates

Addition-elimination reactions of lithium enolates 2 of N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates 3 and 10 proceeded diastereoselectively and regiospecifically to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 4 and 12a, which are useful intermediates for the synthesis of enzyme inhibitors.

Diastereoselective bromodifluoromethylation of chiral imide enolates via insertion of difluorocarbene

The bromodifluoromethylation of lithium enolates of chiral N-acyloxazolidinones via the insertion of difluorocarbene proceeds with good diastereomeric excess (68–92% de).

Diastereoselective introduction of an EtO 2CCF 2-group into chiral imide enolates mediated by triethylborane

The introduction of an EtO 2CCF 2- group into lithium enolates of chiral N-acyloxazolidinones with ethyl difluoroiodoacetate mediated by triethylborane proceeds with good diastereomeric excess (86->98% de).

Diastereoselective trifluoromethylation of chiral imide enolates with iodotrifluoromethane mediated by triethylborane

The trifluoromethylation of lithium enotates of chiral N-acyloxazolidinones with iodotriftuoromcthane mediated by triethylborone proceeds with good diastereomeric excess.