Desmethylamino synthesis

Four total syntheses of FR901483 have been reported so far the enantiocontrolled approaches of Snider [2], Sorensen [5], and Ciufolini [6], and Funk s synthesis in the racemic series [7]. Furthermore, Brummond has communicated a partial total synthesis [8] and Wardrop reported a formal synthesis of the desmethylamino analog, which had been described by Snider [9,10]. Additionally, Kibayashi and Bonjoch and co-workers have reported other synthetic entries to the azatricyclic core of FR901483, which has also been reported by Brummond in her initial studies [11-14], An overview of FR901483 synthetic studies is outlined in Table 1. 

Snider published the synthesis of desmethylamino FR901483 in 1998 [9] and one year later, the first total synthesis of natural (-)-FR901483 [2]. The disconnective analysis is outlined in Scheme 5. The key step in the retrosynthetic analysis is the disassembly of the azatricyclic structure of 1 by a retro-aldol process, which leads to aldehyde 6. In the forward sense, while this approach should provide efficient access to the ring system,... 

The synthesis of racemic desmethylamino FR901483 was reported by Snider in 1998 [9] (3.1.1). Three years later, using the A-alkoxy-A-acylnitrenium ion methodology for the azaspirocyclization step (3.2.1), Wardrop published a formal synthesis of desmethylamino FR901483 [10] having reached the advanced intermediate 15 previously reported in Snider s pioneering work (Scheme 8). 

Scheme 28. Wardrop proposal for the synthesis of ( )-desmethylamino FR901483...

In summary, Wardrop developed a synthetic route to azatricycle 15 (16 steps), which Snider had previously transformed to 19. Accordingly, a formal synthesis of racemic desmethylamino FR901483 was achieved, the key steps being (i) formation of the azaspirodecane ring by an N-methoxy-A-acylnitrenium ion-induced spirocyclization (ii) construction of the bridge framework by a 6-exo-trig radical cyclization, and (iii) installation of the C(6) p-methoxybenzyl side chain by Lewis acid-mediated alkylation of a silyl enol ether. 

Wardrop DJ, Zhang W. IV-methoxy-lV-acylnitreitium ions application to the formal synthesis of ( )-desmethylamino FR901483. Org. Lett. 2001 3(15) 2353-2356. 

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