Asymmetric synthesis of α-acetylenic epoxides

Chiral α-acetylenic oxiranes were easily synthesized from readily available propargylic esters by a four-step sequence involving the stereoselective reduction of α′-alkynyl β-keto sulfoxides with DIBAH (de 66–78%) and DIBAH/ZnBr₂ (de 78–88%), followed by further reduction of the resulting hydroxy sulfoxides into the corresponding sulfenyl derivatives and final epoxy ring closure via sulfonium salt.     

Asymmetric Strecker synthesis of α-arylglycines

A practically simple three-component Strecker reaction for the asymmetric synthesis of enantiopure α-arylglycines has been developed. Addition of a range of aryl-aldehydes to a solution of sodium cyanide and (S)-1-(4-methoxyphenyl)ethylamine affords highly crystalline (S,S)-α-aminonitriles that are easily obtained in diastereomerically pure form. Heating the resultant (S,S)-α-aminonitriles in 6 M aqueous HCl at reflux resulted in cleavage of their chiral auxiliary fragments and concomitant hydrolysis of their nitrile groups to afford enantiopure (S)-α-arylglycines. The enantiopurities of these (S)-α-arylglycines were determined via derivatization of their corresponding methyl esters with 2-formylphenylboronic acid and (S)-BINOL, followed by (1)H NMR spectroscopic analysis of the resultant mixtures of diastereomeric iminoboronate esters.     

α-Methylserinals as an access to α-methyl-β-hydroxyamino acids: application in the synthesis of all stereoisomers of α-methylthreonine

The asymmetric synthesis of all stereoisomers of α-methylthreonine using a stereodivergent synthetic route starting from (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals is reported. The key step involves the asymmetric addition of methylmagnesium bromide to these aldehydes with a high level of asymmetric induction being observed. This methodology represents a powerful tool for the synthesis of different β-substituted α-methylserines.     

Asymmetric synthesis of α-chloro-β-amino-N-sulfinyl imidates as chiral building blocks

New chiral α-chloro-β-amino-N-sulfinyl imidates were synthesized in high yield and excellent diastereomeric excess via highly anti-selective Mannich-type reactions of (R(S))-methyl N-tert-butanesulfinyl-2-chloroethanimidate with aromatic aldimines. The α-chloro-β-amino-N-sulfinylimidates proved to be excellent building blocks for the asymmetric synthesis of β-amino-α-chloro amides and esters, aziridine-2-carboxylic amides and esters, trans-2-aryl-3-chloroazetidines, and methyl 4-phenyloxazolidin-2-one-5-carboxylate. The obtained absolute anti-diastereoselectivity is the opposite of the stereochemical outcome observed for α-methyl-substituted imidates.     

Asymmetric synthesis of α,β-substituted β-aminoalkanamides and stereochemical determination

Highly enantiomerically enriched β-aminoalkanamides 12 and β-phenylaminoalkanamides 13 have been prepared by the addition reaction of α-lithiated 2-alkyl-2-oxazolines 9-Li, derived from optically active oxazolines 9, to N-cumyl nitrones 2. The relative stereochemistry of alkanamides 5 and 6 has been established by 1D-NOESY experiments carried out on the related pyrimidinones 7, whereas the absolute configuration of alkanamides 12 and 13 has been confirmed by an X-ray analysis.     

Asymmetric synthesis of differentially protected α-alkyl succinates

The alkylation of the chiral iron acyls [(η⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂R] (R = H, Me, n-Pr, n-Bu, i-Bu, n-C₅H₁₁) with t-butyl bromoacetate takes place highly stereoselectively to provide a series of novel iron succinoyl complexes, which on oxidative decomplexation lead directly to chiral α-alkyl succinates.     

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.     

Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach’s method. This synthetic method can be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P₁) receptor agonists, with significant improvements to the previously reported method with regard to the reaction temperature.     

Asymmetric synthesis of α-alkyl-α-hydroxy-γ-butyrolactones

A new enantioselective approach to α-alkyl-α-hydroxy-γ-butyrolactones employing (1R,2S)-ephedrine-derived chiral allyl morpholinones as starting materials is described.     

Asymmetric synthesis of erythro-β-hydroxyasparagine

erythro-Hydroxyasparagine (eHyAsn, 1) occurs in a number of naturally occurring peptides and proteins. Previous syntheses have relied on enzyme-catalyzed reactions to produce relevant, optically active intermediates. We report herein a completely chemical synthesis that intercepts Boger’s synthesis of the diastereomer (tHyAsn, 4), utilizing a Sharpless asymmetric aminohydroxylation reaction to introduce the two stereocenters. Boc-HyAsn(OTBS)-OH (10) was coupled effectively with phenylalanine methyl ester using EDC/HOBt.     

Asymmetric synthesis of α-alkyl α-selenocarbonyl compounds catalyzed by bifunctional organocatalysts

A new organocatalytic approach for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of α-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented. This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with excellent ee's and dr's by using catalytic loadings of 3 mol%.     

Stereoselective synthesis of syn-α-methyl-β-hydroxy esters

Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2-syn/1,3-syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O-formylated syn-α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.     

Asymmetric synthesis of anti-β-hydroxy-α-amino acids

The stereoselective aldol addition reactions of chiral haloacetate enolates is reported. The conversion of these adducts to enantiomerically pure anti-β-hydroxy-α-amino acids is demonstrated (Eq 2).     

Asymmetric synthesis of α-amino acids by reduction of N-tert-butanesulfinyl ketimine esters

A highly regio- and diastereoselective reduction of various N-tert-butanesulfinyl ketimine esters with L-Selectride resulting in the formation of α-amino acids is reported. This method is quite general and also practical for the preparation of both enantiomers of aryl or aliphatic α-amino acids in high yields.     

Asymmetric synthesis of α-aryl amino acids; aryne-mediated diastereoselective arylation

An aryne-mediated α-arylation reaction of Scho?llkopf's bis-lactim ether is described. Arynes were generated via an ortho-lithiation approach, affording syn-arylated products in up to 94:6 dr with moderate to good yields and excellent regioselectivities. Hydrolysis provided a variety of substituted arylglycines containing a range of functional groups without racemization.     

Asymmetric synthesis of α-substituted alkylphosphonates based on symmetrical dialkyl phosphites

Chiral C₂-symmetrical dialkyl phosphites and C₃-symmetrical trialkyl phosphites, derived from (−)-borneol, (−)-menthol, and 1,2∶5,6-di-O-isopropylidene-α-d-glucofuranose, were studied as the starting reagents for the preparation of chiral organophosphorus compounds. The reactions of C₂-symmetrical dialkyl phosphites and C₃-symmetrical trialkyl phosphites with aldehydes and amines or aldehydes are accompanied by asymmetrical induction at the α-carbon atom to yield optically active α-aminoalkylphosphanates or α-hydroxyalkylphosphonates, respectively. The stereoselectivity of the reaction depends on the structure of the starting compounds and the reaction conditions. Translated fromIzvestiya Akademii, Nauk, Seriya Khimicheskaya, No. 8, pp. 1588–1593, August, 1999.     

A simple synthesis of α-methylene-β-hydroxyalkanones

Reaction of methyl vinyl ketone with a variety of aldehydes, catalyzed by 1,4-diazabicyclo (2.2.2)octane (DABCO) in tetrahydrofuran, conveniently provides the corresponding α-methylene-β-hydroxyalkanones in good yields.     

Improved enantioselective synthesis of anti α-methyl-β-hydroxyesters through TiCl4-PPh3 mediated aldol condensation

The complex between TiCl₄ and PPh effectively catalyses the aldol addition of silyl ketene acetals to aldehydes dramatically improving the anti-syn ratios.     

Asymmetric synthesis of α-fluoro-α-sulfenyl-β-ketoesters using DBFOX-Ph/Ni(II) complex

Enantioselective α-sulfenylation of α-fluoro-β-ketoesters 4 with phenylsulfenyl chloride catalyzed by DBFOX-Ph/Ni(II) complex afforded the corresponding α-fluoro-α-sulfenyl-β-ketoesters 2 in moderate to good yields with excellent enantiomeric excesses up to 93% ee. α-Fluoro-α-sulfenyl-β-ketoesters can be effectively converted to tri-fluorinated α-sulfenylcarboxylates by the use of DAST, which should be useful intermediates for the synthesis of non-racemized fluorinated isosteres of pharmaceutically attractive SM₃₂. The enantioselective α-phenylsulfenylation as well as α-pentafluoro-phenylsulfenylation of non-fluorinated β-ketoesters 5 were also carried out under the same catalyst conditions affording up to 95% ee of the products 6-8.