Titanium(II)-Mediated Cyclizations of (Silyloxy)enynes:  A Total Synthesis of (−)-7-Demethylpiericidin A₁

Abstract

A concise total synthesis of 7-demethylpiericidin A1 has been completed. The synthesis features a titanium(II)-mediated cyclization of a (silyloxy)enyne as the key step and proceeds in nine steps from tiglic aldehyde.

Synthesis and Biological Activity of 10‐Aza‐narciclasine

“…Attempts to follow a procedure described for similar systems [10,11] did not lead to the desired product. Slow addition of the substrate to a solution of lithium tetramethylpiperidide (LTMP) at low temperature (between À90 8C and À80 8C) led to simple deprotonation at the a-position with no halogen dance, and at higher temperatures (between À75 8C and À70 8C) decomposition was observed.…”

“…[9] This approach has been applied several times to the synthesis of polyoxygenated pyridinecontaining natural products such as atpenins [10] and piericidin. [11] Halopyridine 11, which represents the core of the desired compound, was produced from furfural in two steps by a known procedure. [12] Despite the low yields of some of the steps in this sequence, its simplicity allowed the production of multigram quantities of intermediate 11.…”

Total Synthesis of Piericidin A1 and B1 and Key Analogues

“…14 Shortly following this preliminary disclosure, Phillips and Keaton reported a complementary total synthesis of (-)−7-demethylpiericidin A1, a natural product closely related to 1. 15 In earlier efforts directed at this family, a racemic synthesis of analogues incorporating the full side chain, but a substituted benzene in place of the substituted pyridine of 1 has been disclosed, and an asymmetric synthesis of the C6-C13 segment of the side chain bearing the most recent stereochemical assignment (9R,10R) has been reported. 16,17 In addition, the preparation of several analogues bearing simplified side chains have been disclosed.…”

Highly diastereoselective titanium(II)-mediated cyclizations of 1,7-(silyloxy)enynes

“…1 Excision of the silicon gives rise to homoallylic alcohols, and these building blocks were used as part of the syntheses of dictyostatin 2 and 7-demethylpericidin A 1 . 3 In conjunction with our interest in exploring the utility of these types of cyclization, we have examined the cyclization of 1,7-(silyloxy)enynes (see also Figure 1), and in this paper we report our preliminary studies. A variety of substrates that were cyclized and that provide some measure of the broad utility of the reaction are shown in Table 1.…”

“…We recently described the highly diastereoselective cyclization of 1,6-(silyloxy)enynes with ClTi(i-PrO) 3 and Grignard reagents to give 5-membered cyclic siloxanes ( Figure 1). 1 Excision of the silicon gives rise to homoallylic alcohols, and these building blocks were used as part of the syntheses of dictyostatin 2 and 7-demethylpericidin A 1 .…”