An efficient synthesis of the constrained peptidomimetic 2-oxo-3-(N-9-fluorenyloxycarbonylamino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid from pyroglutamic acid.
[reaction: see text] Azabicyclo[X.Y.0]alkane amino acids are rigid dipeptide mimetics that are useful tools for structure-activity studies in peptide-based drug discovery. Herein, we report an efficient synthesis of three diastereomers of 9-tert-butoxycarbonyl-2-oxo-3-(N-tert-butoxycarbonylamino)-1-azabicyclo[4.3.0]nonane (3S,6S,9S, 3S,6R,9R, and 3S,6R,9S). Methyl N-Boc-pyroglutamate is cleaved with vinylmagnesium bromide to produce an acyclic gamma-vinyl ketone. Michael addition of N-diphenylmethyleneglycine tert-butyl ester produces the N-Boc-delta-oxo-alpha,omega-diaminoazelate intermediate, which, on hydrogenloysis, gives the fused ring system. Acidolytic deprotection followed by Fmoc-protection provided building blocks suitable for solid-phase synthesis.
Mandal
Pijus Kumar
PK
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Box 316, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Kaluarachchi
Kumar K
KK
Ogrin
Douglas
D
Bott
Simon G
SG
McMurray
John S
JS
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D013237:Stereoisomerism
C511506:2-oxo-3-(N-9-fluorenyloxycarbonylamino)-1-azabicyclo(4.3.0)nonane-9-carboxylic acid; D000473:Alkanes; D001643:Bridged Bicyclo Compounds; D011761:Pyrrolidonecarboxylic Acid