Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by chiral sulfinyl auxiliary

Aminophosphonic acids have become increasingly important in different fields of chemistry, medicine and agriculture. This account outlines the results obtained in the author’s laboratory on the asymmetric synthesis of acyclic and cyclic aminophosphonic acids mediated by chiral sulfinyl auxiliary. A key reaction in the synthesis of enantiopure α- and β-aminoalkanephosphonic acids involving a highly diastereoselective addition of phosphite anions or α-phosphonate carbanions to enantiopure sulfinimines is discussed. The asymmetric cyclopropanation of enantiopure α-phosphorylvinyl sulfoxides with sulfur ylides is presented as a platform for developing a new approach to optically active β-aminocyclopropanephosphonic acids. It is exemplified by the total synthesis of enantiopure β-amino-γ-phenylcyclopropanephosphonic acid - a constrained analogue of the GABA_B antagonist phaclofen.     

Asymmetric synthesis of quaternary α-amino acids using d-ribonolactone acetonide as chiral auxiliary

We describe a new simple methodology to prepare enantiopure α,α-dialkylglycines based on the use of commercially available d-ribonolactone as a chiral auxiliary. Enantiopure α-methyl and α-butyl series are prepared through diastereoselective alkylation and subsequent Schmidt rearrangement of α,α-dialkylacetoacetates of d-ribonolactone acetonide. Absolute configuration was assigned through preparation of enantiopure 4,4-disubstituted 3-methyl-2-pyrazolin-5-ones.     

Asymmetric synthesis of α,α-difluoro-β-amino phosphonic acids using sulfinimines

Addition of diethyl lithiodifluoromethylphosphonate to enantiopure sulfinimines afforded the corresponding N-sulfinyl α,α-difluoro-β-amino phosphonates with good diastereoselectivity. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl α,α-difluoro-β-amino phosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl afforded enantiopure α,α-difluoro-β-amino phosphonic acids.     

The first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis with enantiopure cyclopropylmagnesium carbenoids

The reaction of lithium α-sulfinyl carbanion of enantiopure dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave optically active 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group with high asymmetric induction from the sulfur chiral center. Reduction of the carbonyl group followed by treatment with Grignard reagent, the 1-chlorocyclopropyl p-tolyl sulfoxides resulted in the formation of enantiopure allenic alcohols via the Doering-LaFlamme-type rearrangement of enantiopure cyclopropylmagnesium carbenoid intermediates. This is the first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis.     

Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of β-oligopeptides by chemoselective amide ligation

The design and general synthesis of enantiopure isoxazolidinone monomers as precursors for the preparation of enantiopure N-terminal hydroxylamine-β³-oligopeptides, which may be used as reaction partners with α-ketoacids in the decarboxylative amide ligation reaction, is described.     

Enantiopure 1,4-diols and 1,4-aminoalcohols via stereoselective acyclic sulfoxide-sulfenate rearrangement

Treatment of acyclic α-hydroxy and α-tosylamino sulfinyl dienes with amines affords enantiopure 1,4-diol or 1,4-hydroxysulfonamide derivatives in good yields and diastereoselectivities. This one-pot procedure entails a conjugate addition that triggers a diastereoselective sulfoxide-sulfenate [2,3]-sigmatropic rearrangement.     

Asymmetric total synthesis of enantiopure (−)-methyl jasmonate via catalytic asymmetric intramolecular cyclopropanation of α-diazo-β-keto sulfone

A new asymmetric total synthesis of enantiopure (−)-methyl jasmonate is described. This synthesis was accomplished starting from the new enantiopure building block prepared via the catalytic asymmetric intramolecular cyclopropanation (IMCP) of the α-diazo-β-keto 1-naphthyl sulfone, which was devised to give good selectivity both in the IMCP reaction and in the C-alkynylation of the intermediate required for the total synthesis of enantiopure (−)-methyl jasmonate.     

Enantioselective synthesis of α-fluoro-β(3)-amino esters: synthesis of enantiopure, orthogonally protected α-fluoro-β(3)-lysine

The scope of a tandem conjugate addition-fluorination sequence performed on α,β-unsaturated esters using the enantiopure lithium amide derived from (S)-N-benzyl-N-(α-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide has been investigated. Using this method, α-fluoro-β(3)-amino esters can be obtained in up to quantitative yield and 80:20 to >99:1 dr. This simple methodology does not rely on the use of α-amino acids from the chiral pool and thus provides the potential for the preparation of enantiopure α-fluoro-β(3)-amino acids with a wide variety of side chains. Its utility was demonstrated through the synthesis of orthogonally protected (2S,3S)-α-fluoro-β(3)-lysine.     

Asymmetric synthesis of ethoxydienamines in superbasic medium mediated by chiral sulfinyl group

The direct addition of metalated alkoxydiene 2, obtained from α,β-unsaturated acetal 1 through a LIC-KOR-promoted conjugated elimination reaction, to enantiopure sulfinimines 3 (both R and SN-sulfinyl imines) afforded N-sulfinyl alkoxydienyl amines 4 with high diastereoselectivity. Functionalized enantiopure alkoxydienyl amines 5 were then easily obtained upon the selective removal of the chiral auxiliary under mild conditions. Moreover, the further hydrolysis of the alkoxydienyl moiety gave access to protected enantiopure β-keto amines 7.     

Synthesis of Enantiopure Dehydropiperidinones from α-Amino Acids and Alkynes via Azetidin-3-ones

Chiral dehydropiperidinones were synthesized in enantiopure form from α-amino acids and alkynes via azetidin-3-ones.     

Rapid access to enantiopure bupropion and its major metabolite by stereospecific nucleophilic substitution on an α-ketotriflate

A stereospecific method for the synthesis of enantiopure α-aminoketone from its corresponding α-hydroxy-ketone via the triflate intermediate is discussed. This strategy provides a rapid and efficient route for the preparation of either enantiomer of bupropion and its biologically active hydroxylated metabolite.     

Asymmetric synthesis of β-trifluoromethylated β-amino aldehyde as well as carboxylic acid derivatives using enantiopure α-trifluoromethylated homoallylamine

Asymmetric synthesis of β-trifluoromethylated β-amino aldehyde and acid derivatives via the oxidation of enantiopure α-trifluoromethylated homoallylamine as a new trifluoromethylated chiral building block is described.     

Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

The -CHF₂ moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of difluoromethylated compounds. However, the more challenging enantioselective introduction of the difluoromethyl group has been scarcely described yet. We recently developed a new strategy, based on the use of an enantiopure difluoromethyl sulfoxide used as chiral and traceless auxiliary, for the synthesis of highly enantioenriched α-difluoromethyl alcohols. The first method developed in our laboratory aims to access highly stereoenriched α,α-difluoro-β-hydroxysulfoxides through the condensation of the enantiopure difluoromethyl sulfoxide on carbonyl derivatives. It is noteworthy that highly diastereo- and enantioenriched α,α-difluoro-β-hydroxysulfoxides can also be accessed after the diastereoselective reduction of highly enantioenriched α,α-difluoro-β-ketosulfoxides. Finally, the expected difluoromethyl-substituted alcohols can be obtained after removal of the chiral auxiliary with complete retention of stereoenrichment at carbon.     

Chiral Sulfinimines in Asymmetric Synthesis of Enantiomeric Aminophosphonic Acids

Abstract

Aminophosphonic acids have become important in different fields of chemistry, medicine and agriculture. In this review article, we highlight a new strategy developed in the author's laboratory of asymmetric synthesis of enantiomeric aminophosphonic acid that users chiral sulfinimines as reagents. A key reaction in the synthesis of enantiopure α-, β- and γ-aminophosphonic acids is a highly or fully diastereoselective addition of trivalent phosphorus nucleophiles and α-phosphonate carbanions to enantiopure sulfinimines. The steric course of these addition reactions is rationalized. The usefulness of the sulfinimine methodology is demonstrated by the synthesis of biologically active enantiopure 2-amino-3-phosphonopropanoic acid (AP3), 2-amino-4-phosphonobutanoic acid (AP4) and phosphoemeriamine.     

Double asymmetric induction as a mechanistic probe: the doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure α,β-unsaturated esters and enantiopure α,β-unsaturated hydroxamates

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure α,β-unsaturated esters [derived from Corey’s 8-phenylmenthol chiral auxiliary] and enantiopure α,β-unsaturated hydroxamates [derived from our ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine] has been used as a mechanistic probe to determine the reactive conformations of these acceptors.     

Access to β,γ-diamino acids. Application to the synthesis of 3-deoxyaminostatine

The synthesis of orthogonally protected diastereo- and enantiopure β,γ-diamino acids starting from natural α-amino acids is described, as well as its application to the synthesis of fully protected 3-deoxyaminostatine.     

One-pot reactions: enantiomerically pure bicyclo[5.3.1]undecanes; synthesis of a taxoid compound

Reaction of C-2 substituted cyclohexenone with an enantiomerically pure α-bromopentenoate leads to enantiopure tricyclooctane, which can be transformed into a taxoid like compound having the typical bicyclo[5.3.1]undecane skeleton.     

Enzymatic and chiral HPLC resolution of α-azido acids and amides

For the first time, enzymatic resolution of α-azido acid amides has been successfully demonstrated with high yields and enantiomeric excess. In one case dynamic kinetic resolution was achieved leading to more than 50% yield of the enantiomerically pure azido acid. Chiral HPLC was also used to separate racemic α-azido acids and the separation process was automated. Two routes to enantiopure α-azido acid building blocks for solid-phase peptide synthesis have, therefore, been established.     

Facile synthesis of 1,4-benzodiazepin-3-ones from o-bromobenzylamines and amino acids via a cascade coupling/condensation process

CuI-catalyzed coupling of 2-bromobenzylamines and α-amino acids and subsequent condensative cyclization (directly or mediated with DPPA) provides 1,4-benzodiazepin-3-ones in moderate yields. Using l-proline and l-valine as the starting materials enantiopure products are obtained although partial racemization occurs for other amino acids.     

Approaches to the synthesis of enantiopure α-hydroxy-β-lactams with functionalized side chains

We report a synthesis of pharmaceutically important α-hydroxy (or t-butyldimethylsilyl protected α-hydroxy)-β-lactams with functionalized chains in position 4 of the azetidinone ring. A convenient and high-yielding route to these compounds was developed and optimized. Preparation and characterization of several new enantiopure title compounds with various functional groups are discussed.