A simple, efficient access to functionalized pyrrolobenzazepines related to the ABC core of cephalotaxine

✍ Scribed by Eduardo R. de Oliveira; Françoise Dumas; Jean d'Angelo

• Book ID: 104257071
• Publisher: Elsevier Science
• Year: 1997
• Tongue: French
• Weight: 201 KB
• Volume: 38
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(97)00709-0

✦ Synopsis

Tetraeyclic nitrilc 19a and ester 19b

, exhibiting the ABC cam of eephalotaxine la, were prepared through KI-I-i~__,_.r__~_ cyelization o£ thioimides 14a and 14b, respectively. This new ring-closure methodology pt'oved to be particularly efficient: thus ~ 19a was obtained in only 7 steps with a 17 % overall yield from eommexcially available, inexpensive safiule 2. © 1997 Elsevier Science Ltd.

Cephalotaxine la, the major alkaloid encountered in several Cephalotaxus species, has become an interesting synthetic target, because of the potent antileukemic activity found for some of its derivative esters Oaarringtonine Ib, homoharringtonine le). 2 lb : R = COOMe HO CO-I

"°'H

Several swategies have been evolved for the synthesis of cephalotaxine la. 2 In this paper, we report on a simple, efficient methodology for the elaboration of the pyrrolobenzazepine-type core of la, based on the ring B closure of AC subunits, by creating the C4-C5 linkage.

Preparation of the AC subunits. 8b,9, I0, 14a, 14b, 15 and 16) were prepared and subjected to various cyclization conditions. The common intermediate in the synthesis of these precursors was bromide 43, prepared as follows. Ozonolyzis 4 of inexpensive safrole 2 (i: 03, CH2CI2 -EtOH, -78 °C; ii: NaBI-I4) furnished with a 78 % yield alcohol 3, which was then converted into bromide 4 (Ph3P, Br2, CH2C12, 30 rain at 20 °C, 83 % yield). <o:os <o:o o. <°o:C Br 2 3 4

In the "lactam series" (AC subunits 8a, 8b, 9, and I0), the starting material was lactam 5, prepared from 4 (pyrrolidone, Nail, benzene, 18 h at 20 °C, 58 % yield).