Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.     

A practical asymmetric synthesis of homochiral α-arylglycines

Enantioselective reduction of a series of substituted aryl trichloromethyl ketones with the CBS-catecholborane reagent afforded homochiral aryl trichloromethyl carbinols which have been elaborated to give homochiral α-arylglycines in high e.e.     

Catalytic, asymmetric synthesis of α-acetoxy amides

Non-racemic cyanohydrin acetates are readily available from aldehydes and potassium cyanide/acetic anhydride by use of bimetallic titanium (salen) catalyst 1. Treatment of the cyanohydrin acetates with a platinum(II) phosphinito catalyst 3 under neutral conditions results in chemoselective hydrolysis to the corresponding α-acetoxy amides in a racemization free process.     

Absolute asymmetric synthesis of tertiary α-amino acids

Frozen: the spontaneous crystallization of an achiral compound in a chiral conformation is used as the unique source of chirality in an absolute asymmetric synthesis of tertiary amino acids. The dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the deprotonation/alkylation. α-Amino acid derivatives are synthesized in up to 96 % ee.     

One-pot asymmetric synthesis of α-trifluoromethylated amines from α-trifluoromethyl ketones

Diastereoselective reduction of (Rs)-N-tert-butanesulfinyl α-trifluoromethyl ketimines formed in situ from the corresponding α-trifluoromethyl ketones and N-tert-butanesulfinamide has been achieved, and either diastereomer of N-tert-butanesulfinyl α-trifluoromethyl amines was obtained in good yields with excellent diastereoselectivities (up to 99:1 dr) using NaBH₄ and L-Selectride as the reductants, respectively.     

Catalytic asymmetric one-pot synthesis of α-methylene-γ-lactams

An organocatalytic enantioselective synthesis of α-methylene-γ-lactams has been developed. The reaction between protected 2-aminomalonates and Morita–Baylis–Hillman carbonates is catalyzed by chiral Lewis bases to afford the corresponding lactams in excellent yields and moderate to good enantioselectivities, after work-up.     

Highly enantioselective synthesis of α-fluoro-α-nitro esters via organocatalyzed asymmetric Michael addition

Primary amines catalyzed the asymmetric Michael addition of ethyl 2-fluoro-2-nitroacetate to enones to provide chiral α-fluoro-α-nitro ester ketones with two contiguous stereogenic centers, one of which is a fluorinated quaternary chiral center, with excellent enantioselectivities and in moderate to good yields.     

Enantioselective synthesis of stimulus-responsive amino acid via asymmetric α-amination of aldehyde

Development of a methodology to control the function of peptides and proteins is an indispensable task in the field of chemical biology and drug delivery. Recently, we reported synthesis of racemic stimulus-responsive amino acids and their application for controlling peptidyl function. In this study, we report enantioselective synthesis of a key intermediate of stimulus-responsive amino acids via asymmetric α-amination reaction of an aldehyde. The obtained chiral intermediate was converted to an Fmoc protected UV-responsive amino acid with (S)-configuration, and it was successfully incorporated into a model peptide by Fmoc solid phase peptide synthesis.     

Practical asymmetric synthesis of α-methylserine derivatives under mild phase-transfer conditions

The enantioselective methylation reaction of phenyloxazoline tert-butyl ester 5 using (R)-4b as a catalyst under mild phase-transfer conditions provides optically active α-methylserine derivatives in moderate yields with high enantioselectivity. Other α-alkylated serine derivatives are also achievable in high yields with high enantioselectivity by using catalytic amount of (R)-4b.     

Copper(II)salen catalysed, asymmetric synthesis of α,α-disubstituted amino acids

Cu(salen) complex 1 was found to be a versatile catalyst for the asymmetric alkylation of a range of enolates derived from α-amino acids, leading to α,α-disubstituted amino acids. The enantioselectivity of the process decreases as the size of the amino acid sidechain increases, but functionalized amino acids such as allylglycine and aspartic acid are substrates for the process. Benzylic bromides are found to be more enantioselective alkylating agents than propargylic bromides. As an example of the utility of this chemistry, an α-propargylic allylglycine derivative is prepared and subjected to ene-yne metathesis using Grubbs' catalyst to give a non-racemic cyclopentenyl amino acid.     

The asymmetric synthesis of chiral cyclic α-hydroxy phosphonates and quaternary cyclic α-hydroxy phosphonates

A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the addition of silver carbonate. Particularly, significant improvement has been achieved on the asymmetric hydrophosphonylation of unactivated ketones, giving quaternary α-hydroxy phosphonates with excellent enantioselectivity (up to 99% ee).     

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.     

Direct asymmetric synthesis of α-deuterated α-amino acid derivatives from the parent α-amino acids via memory of chirality

A method for asymmeyric α-deuteration of α-amino acid derivatives has been developed by a memory of chirality (MOC) strategy. The α-deuterated α-amino acid derivatives with 88–93% D were obtained in 60–98% ee in retention of the configuration (7 examples). The characterisrtic feature of the present procedure is that asymmeric induction was achieved by employing the parent amino acid derivatives as a sole source of chirality without the use of any external chiral souces.     

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.     

BINOL-based azacrown ether catalyzed enantioselective Michael addition: asymmetric synthesis of α-aminophosphonates

Several novel 1,1′-bi-2-naphthyl-appended azacrown ethers with donor side-arms were synthesized and applied for the first time as chiral catalysts in the asymmetric Michael addition of an N-protected aminomethylenephosphonate onto acrylonitriles, resulting in high diastereoselectivity and enantioselectivity. The absolute configuration of the adduct was determined from its experimental and calculated CD spectra.     

Catalytic asymmetric synthesis of stereoisomers of 1-C-n-butyl-LABs for the SAR study of α-glucosidase inhibition

We achieved synthesis of seven stereoisomers of 1-C-n-butyl-L-iminofuranose derivatives using catalytic asymmetric alkylation and Negishi coupling as key reactions. The synthetic strategy based on these key reactions was quite useful, since both α- and β-iminofuranoses could be obtained by switching the chirality of the ligand employed for the AAA reaction. The common intermediates for α- and β-isomers were subjected to further manipulations to install a diol unit at C2 and C3 to give the desired stereoisomers of L-iminofuranose derivatives. We achieved the preparation of all stereoisomers of 1-C-n-butyl-L-iminofuranose derivatives, with the exception of β-lyxo type iminofuranose. It is noteworthy that a synthetic route for many stereoisomers of iminofuranose derivatives was developed. Unfortunately, none of the L-iminofuranoses obtained showed inhibitory activity against the α-glycosidases examined—e.g., maltase, sucrase, and isomaltase.     

New general synthesis of α-alkoxyketones via α'-alkylation, α-alkylation and α,α'-dialkylation of α-alkoxyketimines

α-Methoxy- and α-ethoxyketones, as important intermediates in organic synthesis and flavor compounds in food chemistry, were synthesized by deprotonation of N-(1-alkoxy-2-propylidene)isopropylamine, prepared by condensation of the corresponding α-alkoxyacetone with isopropylamine, and subsequent reaction of the corresponding 1-azaallylic anions with alkyl halides to afford α'-alkylated, α-alkylated and α,α'-dialkylated ketimines. Hydrolysis of the imino function led to the desired substituted α-alkoxyketones. The ratio of α-, α'-, and α,α'-(di)alkylated compounds depended on the amount of base used and on the nature of the alkylating reagent.     

A catalytic asymmetric ring-expansion reaction of isatins and α-alkyl-α-diazoesters: highly efficient synthesis of functionalized 2-quinolone derivatives

Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)(3) catalyst bearing an N,N'-dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl).     

Enantioselective synthesis of α,α-disubstituted amines from nitroalkenes

Disubstituted nitroalkenes were converted into enantiomerically enriched amines (isolated as their hydrochloride salts) with enantiomeric excesses of 88 to >95% in three steps: (a) highly stereoselective conjugate addition of the potassium salt of 4-phenyloxazolidin-2-one; (b) radical-mediated removal of the nitro group; (c) cleavage of the oxazolidinone.