2. An Olefination Entry for the Synthesis of Enantiopure alpha,omega-Diaminodicarboxylates and Azabicyclo[X.Y.0]alkane Amino Acids
Francis Gosselin, William D. Lubell J Org Chem. 1998 Oct 16;63(21):7463-7471. doi: 10.1021/jo9814602.
A new approach for synthesizing alpha,omega-diaminodicarboxylates of various chain lengths has opened the way for making a series of azabicyclo[X.Y.0]alkane amino acids of different ring sizes. beta-Keto phosphonates 21-23 were synthesized in 71-90% yield by the addition of the lithium anion of dimethyl methyl phosphonate to the omega-methyl ester of alpha-tert-butyl N-(PhF)aspartate 3, glutamate 9, and aminoadipate 12 (PhF = 9-phenylfluoren-9-yl). alpha,omega-Diaminodicarboxylates 24-26 of nine to eleven carbon chain lengths were prepared in 78-87% yield from the Horner-Wadsworth-Emmons olefination of alpha-tert-butyl N-(PhF)aspartate beta-aldehyde (5) with aminodicarboxylate-derived beta-keto phosphonates 21-23. The power of this approach for making azabicyclo[X.Y.0]alkane amino acid was then illustrated by the first synthesis of enantiopure indolizidin-9-one amino acid 2 in nine steps and >25% overall yield from inexpensive aspartic acid as chiral educt. Hydrogenation of (2S,8S)-di-tert-butyl 4-oxo-2,8-bis[N-(PhF)amino]non-4-enedioate (24) in 9:1 EtOH:AcOH furnished a 9:1 diastereomeric mixture of 6-alkylpipecolate 28 that was subsequently transformed into azabicyclo[4.3.0]alkane amino acid 2 via lactam cyclization and protecting group manipulations. Because alpha,omega-diaminodicarboxylates 25 and 26 may be similarly converted to heterocycles of larger ring sizes and because alkylation of similar ketones can be used to attach side-chains at different points on the heterocycle, this olefination strategy greatly expands our methodology for synthesizing azabicyclo[X.Y.0]alkane amino acids for the exploration of conformation-activity relationships of various biologically active peptides.
