Total synthesis of uridine diphosphate-N-acetylmuramoyl-l-alanine

The first total synthesis of uridine diphosphate N-acetylmuramoyl-l-alanine in 13% overall yield is presented. The 11-step synthetic route is based on the synthetic strategy used for the synthesis of uridine diphosphate N-acetylmuramic acid, the MurC ligase substrate. However, an unexpected amide bond cleavage under basic conditions demanded crucial modifications of the final synthetic steps. The total chemical synthesis of MurD ligase substrate provides an excellent alternative to chemoenzymatic synthesis.

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(S)-Methyl 2-(2-(R)-(2-acetamido-1-O-benzyl-4,6-O-benzylidene-2-deoxy-3-α-d-glucopyranosyloxy)propanamido)propanoateC29H36N2O9Ee = 100%[α]D20=+44.6 (c 0.21, DMF)Source of chirality: N-acetyl-d-glucosamine, asymmetric synthesisAbsolute configuration: (S,R)

(S)-Methyl 2-(2-(R)-(2-acetamido-4,6-di-O-acetyl-1-O-benzyl-2-deoxy-3-α-d-glucopyranosyloxy)propanamido)propanoateC26H36N2O11Ee = 100%[α]D20=+77.2 (c 0.18, DMF)Source of chirality: N-acetyl-d-glucosamine, asymmetric synthesisAbsolute configuration: (S,R)

(S)-Methyl 2-(2-(R)-(2-acetamido-2-deoxy-4,6-di-O-acetyl-1-O-diphenoxyphosphoryl-3-α-d-glucopyranosyloxy)propanamido)propanoateC31H39N2O14PEe = 100%[α]D20=+61.4 (c 0.22, DMF)Source of chirality: N-acetyl-d-glucosamine, asymmetric synthesisAbsolute configuration: (S,R)

Triethylammonium salt of (S)-methyl 2-(2-(R)-(2-acetamido-2-deoxy-4,6-di-O-acetyl-1-O-phosphoryl-3-α-d-glucopyranosyloxy)propanamido)propanoateC19H31N2O14PEe = 100%[α]D20=+39.0 (c 0.09, MeOH)Source of chirality: N-acetyl-d-glucosamine, asymmetric synthesisAbsolute configuration: (S,R)

4-Morpholino-N,N′-dicyclohexylcarboxamidine salt of (S)-methyl 2-(2-(R)-(2-acetamido-2-deoxy-4,6-di-O-acetyl-1-O-(uridine-5′-diphosphoryl)-3-α-d-glucopyranosyloxy)propanamido)propanoateC28H42N4O22P2 × C17H31N3OEe = 100%[α]D20=+105.3 (c 0.08, DMF)Source of chirality: N-acetyl-d-glucosamine, d-uridine, asymmetric synthesisAbsolute configuration: (S,R)

Trisodium (S)-2-(2-(R)-(2-acetamido-2-deoxy-1-O-(uridine-5′-diphosphoryl)-3-α-d-glucopyranosyloxy)propanamido)propanoateC23H33N4O20P2Na3Ee = 100%[α]D20=+40.7 (c 0.04, MeOH)Source of chirality: N-acetyl-d-glucosamine, d-uridine, asymmetric synthesisAbsolute configuration: (S,R)