A concise enantioselective synthesis of (R)-selegiline, (S)-benzphetamine and formal synthesis of (R)-sitagliptin via electrophilic azidation of chiral imide enolates

A concise and high yielding enantioselective synthesis of (R)-selegiline, an anti-Parkinson’s drug, (S)-benzphetamine, an anti-obesity agent, and (S)-sitagliptin, an anti-diabetic drug has been described starting from commercially available starting materials employing Evans’ electrophilic azidation of chiral imide enolates as a key chiral inducing step, which proceeds in a highly diastereoselective manner (>99%).

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(S)-2-Azido-3-phenylpropan-1-olC9H11N3OEe 97% determined by chiral HPLC[α]D25 = −2.4 (c 1.0, CHCl3)Source of chirality: Evans’ electrophilic azidation of chiral imide enolates using a chiral auxiliary, followed by reductionAbsolute configuration: (S)

(R)-4-Benzyl-3-(3-(2,4,5-trifluorophenyl)propanoyl)oxazolidin-2-oneC19H16F3NO3[α]D25 = +62.9 (c 1.0, CHCl3)Source of chirality: attachment of chiral auxiliaryAbsolute configuration: (R)

(R)-3-((R)-2-Azido-3-(2,4,5-trifluorophenyl)propanoyl)-4-benzyloxazolidin-2-oneC19H16F3N4O3[α]D25 = +57.2 (c 1.0, CHCl3)Source of chirality: Evans’ electrophilic azidation of chiral imide enolatesAbsolute configuration: (R,R)

(R)-2-Azido-3-(2,4,5-trifluorophenyl)propan-1-olC9H8F3N3OEe 97% determined by chiral HPLC[α]D25 = +4.2 (c 1, CHCl3)Source of chirality: Evans’ electrophilic azidation of chiral imide enolates using a chiral auxiliaryAbsolute configuration: (R)

(R)-tert-Butyl-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl)carbamateC14H18F3NO3[α]D25 = +16.8 (c 1, CHCl3)Source of chirality: Evans’ electrophilic azidation of chiral imide enolates using a chiral auxiliaryAbsolute configuration: (R)

(R)-3-(tert-Butyl-1-cyano-(2,4,5-trifluorophenyl)propan-2yl)carbamateC15H17F3N2O2[α]D25 = +22.2 (c 0.6, CHCl3)Source of chirality: Evans’ electrophilic azidation of chiral imide enolates using a chiral auxiliaryAbsolute configuration: (R)