Desmethylamino formal 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. 

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). 

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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