Collagen cross-links: Synthesis of pyridinoline, deoxypyridinoline and their analogues

An efficient chiral synthesis of (S,S)-(-)-3g, a key intermediate for the preparation of collagen cross-links pyridinoline (Pyd, 1) and deoxypyridinoline (Dpd, 2) was achieved from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5- oxopentanoic acid (21b). Quaternization of (S,S)-(-)-3g with iodide (2S,5R)-(+)-4a followed by hydrolysis provided a first chiral synthesis of natural (+)-Pyd (1). 1-(2S)-(+)-Pyd (1) was also synthesized from (S,S)-(-)-3g and iodide (2S,5S)-(+)-4a. Similarly, quaternization of (S,S)-(-)-3g with iodide (2S)-(-)-4b, which was prepared from (2S)-(-)-6-amino-2-[(tert-butoxycarbonyl)amino]hexanoic acid (31) in three steps, followed by hydrolysis afforded natural (+)-Dpd (2) in 5.3% overall yield. Also, the synthesis of racemic Dpd [(+/-)-2] and a variety of its analogues is presented. (C) 1998 Elsevier Science Ltd. All rights reserved.