Stereoselective synthesis of N-benzyl (2S,3S,4S)-3-hydroxy-4-methylproline

The synthesis of (2S,3S,4S)-N-benzyl-3-hydroxy 4-methyl proline and its stereoisomer (2R,3R,4S)-N-benzyl-3-hydroxy 4-methyl proline has been achieved starting with the conjugate addition of methyl methacrolate and benzylamine. The other key reactions performed in our strategy include enzymatic separation of an α-methyl β-amino alcohol, Sharpless asymmetric dihydroxylation of an α,β-unsaturated δ-amino ester, and intramolecular cyclization of a sulfonate to a pyrrolidine ring system. Two stereoisomers were synthesized from the common α,β-unsaturated δ-amino ester intermediate. This protocol is simple, straightforward, efficient, highly stereoselective, and economically viable.

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(R)-tert-Butyl benzyl(3-hydroxy-2-methylpropyl)carbamateC16H25NO3[α]D25 = +16.6 (c 0.3 MeOH)Absolute configuration: (R)Source of chirality: enzymatic resolution

(S)-3-(Benzyl(tert-butoxycarbonyl)amino)-2-methylpropylacetateC18H27NO4[α]D25 = +6.6 (c 0.3 MeOH)Absolute configuration: (S)Source of chirality: enzymatic resolution

(S)-tert-Butyl benzyl(3-hydroxy-2-methylpropyl)carbamateC16H25NO3[α]D25 = −16.3 (c 0.3 MeOH)Absolute configuration: (S)Source of chirality: enzymatic resolution

(S)-tert-Butyl benzyl(2-methyl-3-oxopropyl)carbamateC16H23NO3[α]D25 = −10.3 (c 0.3 MeOH)Absolute configuration: (S)Source of chirality: enzymatic resolution

(R,E)-Ethyl 5-(benzyl(tert-butoxycarbonyl)amino)-4-methylpent-2-enoateC20H29NO4[α]D25 = +8.3 (c 0.3 MeOH)Absolute configuration: (R,E)Source of chirality: enzymatic resolution

(2S,3R,4S)-Ethyl 5-(benzyl(tert-butoxycarbonyl)amino)-2,3-dihydroxy-4-methylpentanoateC20H31NO6[α]D25 = −26.5 (c 0.3 MeOH)Absolute configuration: (2S,3R,4S)Source of chirality: asymmetric Sharpless dihydroxylation

(2S,3R,4S)-Ethyl-5-(benzyl(tert-butoxycarbonyl)amino)-2,3-dihydroxy-4-methylpentanoateC20H29NO7S[α]D25 = −9.7 (c 0.3 MeOH)Absolute configuration: (2S,3R,4S)Source of chirality: asymmetric Sharpless dihydroxylation

(2R,3S,4S)-Methyl 1-benzyl-3-hydroxy-4-methylpyrrolidine-2-carboxylateC13H17NO3[α]D25 = −12.2 (c 0.3 MeOH)Absolute configuration: (2R,3S,4S)Source of chirality: asymmetric Sharpless dihydroxylation

tert-Butyl-(2R,3S,4S)-4-(methoxycarbonyl)-3,4-dihydroxy-2-methylbutylbenzylcarbamateC20H31NO6[α]D25 = +16.5 (c 0.3 MeOH)Absolute configuration: (2R,3S,4S)Source of chirality: asymmetric Sharpless dihydroxylation

(2S,3R,4R)-Ethyl-5-(benzyl(tert-butoxycarbonyl)amino)-2,3-dihydroxy-4-methylpentanoateC20H29NO7S[α]D25 = +9.3 (c 0.3 MeOH)Absolute configuration: (2S,3R,4R)Source of chirality: asymmetric Sharpless dihydroxylation

(2R,3R,4S)-Ethyl 1-benzyl-3-hydroxy-4-methylpyrrolidine-2-carboxylateC15H21NO3[α]D25 = −9.2 (c 0.3 MeOH)Absolute configuration: (2R,3R,4S)Source of chirality: asymmetric Sharpless dihydroxylation