Synthesis of enantiopure 7-[3-azidopropyl]indolizidin-2-one amino acid. A constrained mimic of the peptide backbone geometry and heteroatomic side-chain functionality of the Ala-Lys dipeptide

Enantiopure N-(BOC)amino-7-[3-azidopropyl]indolizidin-2-one acid 1 has been synthesized by displacement of the methanesulfonate of its 7-hydroxypropyl counterpart 11 with sodium azide and subsequent ester hydrolysis. N-(BOC)A mino-7-[3-hydroxypropyl]indolizidin-2-one ester 11 was obtained from a sequ ence commencing with the alkylation of (2S,8S)-di-tert-butyl 5-oxo-2,8-di-[ N-(PhF)amino]azelate 5 (PhF = 9-(9-phenylfluorenyl)). Stereoselective allyl ation of 5, regioselective olefin hydroboration, selective primary alcohol protection as a silyl ether, and oxidation of the secondary alcohol gave (2 S,4R,8S)-di-tert-butyl 4-[3-tert-butyldimethylsiloxypropyl]-5-oxo-2,8-di-[N -(PhF)amino]azelate 9 as a pure diastereomer in 33% overall yield. Linear k etone 9 was then converted into the indolizidinone heterocycle by a route f eaturing reductive amination, lactam cyclization, and isolation by way of a silyl ether which provided the (6S,7R)-isomer of 11.