Formal Alkyne Aza-Prins Cyclization: Gold(l)-Catalyzed Cycloisomerization of Mixed N,O-Acetals Generated from Homopropargylic Amines to Highly Substituted Piperidines

摘要

Highly substituted piperidines are found in numerous bioactive alkaloid natural products and pharmaceuticals. Thus, considerable attention has been paid to the synthesis of this moiety. We envisioned that cycloisomerizution of mixed N,O-acetaI A generated from homoproparygylic amines to 4-methoxy-1,2,3,6-tetrahydro-pyridine B (Scheme Ⅰ) would be highly useful in accessing piperidine frameworks, because the enol ether could be easily transformed into other functional groups.rnBased on the well-established chemistry of iminium ions, we initially considered using an oxophilic metal-catalyzed method depicted in pathway 1. In this scenario, the key step involves the endocyclization of iminium ion C onto alkynes (alkyne aza-Prins reaction). Apparently simple reactions of this type have been surprisingly rare, due to the slow cyclization of C to form unstable vinyl cation D and the rapidly competing aza-Cope rearrangement of C (eq 1). In fact, this type of alkyne aza-Prins reaction reported in the literature has been limited to the 4-amino-1 -butyne substrates possessing no branch alkyl groups.