Studies toward the Synthesis of Lepadiformine A

Abstract

Herein is described an original approach to access a tricyclic framework of the lepadiformine-type alkaloids. A Grignard/N-acylpyridinium salt reaction of a 4-methoxytetrahydroquinoline is the key carbon–carbon bond-forming step that was used to establish the desired absolute stereochemistry at the C2 position of the target alkaloid. The synthesis features an allylation reaction with an N-acyliminium ion to set the C10 quaternary stereocenter, a mild dissolving-metal cleavage of hindered phenyl carbamates, and an aminoiodocyclization to form the pyrrolidine ring. While this route does not provide the correct C10 stereochemistry, it showcases an efficient method to build analogues with the ring system of this class of alkaloids in 11 steps overall.

Accessing spiropiperidines from dihydropyridones through tandem triflation–allylation and ring-closing metathesis (RCM)

“…Using this new protecting group, we were able to obtain the desired compound ( 2b ), however, in a low yield (Table 1, entry 2). These first results led us to reconsider the nature of the nucleophile and to replace allyltrimethylsilane with allyltributyltin, which was demonstrated in the studies of Trauner 33 and Comins 36,37 to exhibit appropriate properties. Notably, good conversion to the desired addition product 2b was observed within 3 h under these novel conditions (Table 1, entry 3).…”

Stereoselective Domino Semipinacol‐Schmidt Reaction: Diastereoselective Synthesis of 7 a‐epi‐(+)‐Lepadiformine C and Formal Synthesis of 7 a‐epi‐(−)‐Lepadiformine A

“…Although lepadiformines A and C exhibit moderate anticancer activity against various cancer cell lines, [2,3] synthesis of analogous compounds of the natural products, may result in the increased efficacy with respect to the natural one. The synthesis of double‐epimer analogues of lepadiformine A was reported by Pearson [5a,b] utilizing aza‐allyl anion 1,3‐dipolar cycloaddition reaction, whereas Comins [5c] reported the synthesis of double‐epimer analogue of lepadiformine A using alkylation of N ‐acylpyridinium ion chemistry. We envisaged the construction of angularly fused azatricyclic core of lepadiformine scaffold using a common strategy in a single transformation based on a sequence of semipinacol followed by an intramolecular Schmidt cyclization.…”

Direct Deoxygenation of α-Hydroxy and α,β-Dihydroxy Ketones Using a Silyl Lithium Reagent

“…To achieve direct deoxygenation from acyloin without prior functionalization, we considered using various additives in the reaction to get the desired product 4b . Accordingly, a freshly prepared PhMe 2 SiLi , reagent was added to compound 4a at −78 °C, which resulted in the exclusive formation of product 4c (Table , entry 1). Further, a few activating additives such as few coordinating metal salts or Lewis acids such as LiClO 4 , Ag­(OTf), CuCl 2 , or MgCl 2 were used, which failed to give the product 4b (Table , entries 2–5, respectively); instead, the 1,2-addition product 4c was observed in all the cases.…”