Pyranocyclopropanyl sugar amino acids, a new class of constrained (di)peptide isosteres

The design, synthesis and application of oxabicyclo[4.1.0]heptane amino acids as conformationally restricted sugar amino acid dipeptide isosteres are reported.

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(1S,3R,4S,5R,6S,7S)-Ethyl 4,5-bis(benzyloxy)-3-hydroxymethyl)-2-oxabicyclo[4.1.0]heptane-7-carboxylateC24H28O6Ee = 100%[α]D20=+20 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-Ethyl 3-(azidomethyl)-4,5 bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxylateC24H27N3O5Ee = 100%[α]D20=+43.4 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-3-(Azidomethyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxylic acidC22H23N3O5Ee = 100%[α]D20=+54.8 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-Ethyl 4,5-bis(benzyloxy)-3-((tert-butyldimethylsilyloxy)methyl)-2-oxabicyclo[4.1.0]heptane-7-carboxylateC30H42O6SiEe = 100%[α]D20=+25.4 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-3-((tert-butyldimethylsilyloxy) methyl)-2-oxabicyclo[4.1.0]heptane-7-carboxylic acidC28H38O6SiEe = 100%[α]D20=+21.8 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

tert-Butyl(1S,3R,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-3-((tert-butyldimethylsilyloxy)methyl)-2-oxabicyclo[4.1.0]heptane-7-ylcarbamateC32H47NO6SiEe = 100%[α]D20=+39 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-7-((tert-butyloxycarbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carboxylic acidC26H31NO7Ee = 100%[α]D20=+43 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-Methyl-4,5-bis(benzyloxy)-7-((tert-butyloxycarbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carboxylateC27H33NO7Ee = 100%[α]D20=+73.4 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S)

(1S,3R,4S,5R,6S,7S)-Methyl 4,5-bis(benzyloxy)-7-((1S,3R,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-(tert butoxy-carbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carboxamido)-2-oxabicyclo[4.1.0]heptane-7-carboxylateC48H54N2O11Ee = 100%[α]D20=+36 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S) for each unit

(1S,3S,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-7 ((1S,3S,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-(tert-butoxy-carbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carbox-amido)-2-oxabicyclo[4.1.0]heptane-3-carboxylic acidC47H52N2O11Ee = 100%[α]D20=+46 (c 0.1, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S) for each unit

(1S,3S,4S,5R,6S,7S)-Methyl 4,5-bis(benzyloxy)-7-(1S,3S,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-((1S,3S,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-((1S,3S,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-(tert-butoxy-carbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carbox-amido)-2-oxabicyclo[4.1.0]heptane-3-carboxamido)-2-oxabicyclo[4.1.0]heptane-3-carboxamido)-2-oxabicyclo[4.1.0]heptane-3-carboxylateC90H96N4O19Ee = 100%[α]D20=+24 (c 0.1, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S) for each unit

(1S,3R,4S,5R,6S,7S)-Ethyl 3-(((1S,3R,4S,5R,6S,7S)-3-(azidomethyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxamido)-methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxylateC46H50N4O9Ee = 100%[α]D20=+18 (c 1.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S) for each unit

(1S,3R,4S,5R,6S,7S)-3-(((1S,3R,4S,5R,6S,7S)-3-(Azidomethyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxylic acidC44H46N4O9Ee = 100%[α]D20=+41 (c 2.0, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S) for each unit

(1S,3R,4S,5R,6S,7S)-Ethyl 3-(((1S,3R,4S,5R,6S,7S)-3-(((1S,3R,4S,5R,6S,7S)-3-(((1S,3R,4S,5R,6S,7S)-3-(azidomethyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carboxylateC90H96N6O17Ee = 100%[α]D20=+36 (c 0.1, CHCl3)Source of chirality: d-glucalAbsolute configuration: (1S,3R,4S,5R,6S,7S) for each unit