Carbohydrate-derived conformationally restricted bicyclic dipeptides as potential hetero foldamer building blocks

Starting from carbohydrate precursors, hetero foldamer building blocks featuring diverse amino acid side chains and stereochemistry have been accessed via a multi-step synthetic protocol. These conformationally restricted bicyclic dipeptide building blocks are characterized by a constrained β-lactam ring fused with a pyrrolidine ring carrying a hydroxyethylamine isostere (HEA) on the backbone. These building blocks offer the possibility of developing foldamers with interesting structural architectures, conspicuously different from those classically observed. Furthermore, such hetero-building blocks have the potential to augment the conformational space available for foldamer design with diverse backbone conformations and structural architectures.

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(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-1-yl)propanoateC12H18N4O5[α]D25=+160 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-1-yl)-3-methylbutanoateC14H22N4O5[α]D25=+118 (c 1.5, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-1-yl)-4-methylpentanoateC15H24N4O5[α]D25=+146 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(R)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-1-yl)-3-phenylpropanoateC18H22N4O5[α]D25=+170 (c 0.2, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (R,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-4-oxoazetidin-1-yl)propanoateC9H14N4O5[α]D25=+164 (c 0.2, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-4-oxoazetidin-1-yl)-3-methylbutanoateC11H18N4O5[α]D25=+100 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-4-oxoazetidin-1-yl)-4-methylpentanoateC12H20N4O5[α]D25=+150 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(R)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-4-oxoazetidin-1-yl)-3-phenylpropanoateC15H18N4O5[α]D25=+118 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (R,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyloxy)ethyl)-4-oxoazetidin-1-yl)propanoateC16H20N4O7S[α]D25=+154 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyloxy)ethyl)-4-oxoazetidin-1-yl)-3-methylbutanoateC18H24N4O7S[α]D25=+96 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyloxy)ethyl)-4-oxoazetidin-1-yl)-4-methylpentanoateC19H26N4O7S[α]D25=+112 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,S)

(R)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyloxy)ethyl)-4-oxoazetidin-1-yl)-3-phenylpropanoateC22H24N4O7S[α]D25=+124 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (R,R,R,S)

(1R,4R,5R)-tert-Butyl 4-hydroxy-6-((S)-1-methoxy-1-oxopropan-2-yl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylateC14H22N2O6[α]D25=+180 (c 0.7, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,R)

(1R,4R,5R)-tert-Butyl 4-hydroxy-6-((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylateC16H26N2O6[α]D25=+110 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,R)

(1R,4R,5R)-tert-Butyl 4-hydroxy-6-((S)-1-methoxy-4-methyl-1-oxopentan-2-yl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylateC17H28N2O6[α]D25=+125 (c 0.8, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (S,R,R,R)

(1R,4R,5R)-tert-Butyl 4-hydroxy-6-((R)-1-methoxy-1-oxo-3-phenylpropan-2-yl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylateC20H26N2O6[α]D25=+190 (c 1, CHCl3)Source of chirality: d-glyceraldehydeAbsolute configuration: (R,R,R,R)