Gold-Catalyzed Synthesis of Oxygen- and Nitrogen-Containing Heterocycles from Alkynyl Ethers:  Application to the Total Synthesis of Andrachcinidine

Abstract

In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones. Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration, alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran and piperidine formation are very good to excellent. This method has been applied to an efficient total synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the scope of products that can be accessed through this protocol.

Catalysis

“…Gold catalysis was required in the last step of the synthesis, as shown in Scheme 8.22 [119]. Gold catalysis was required in the last step of the synthesis, as shown in Scheme 8.22 [119].…”

Efficient gold(I)/silver(I)-cocatalyzed cascade intermolecular N-Michael addition/intramolecular hydroalkylation of unactivated alkenes with α-ketones

“…The increasing demand for environmentally benign and economical synthetic processes calls for the development of cascade reactions for the efficient construction of cyclic compounds from simple starting materials [41]. We initially envisioned that the gold(I)-catalyzed cascade process could be established starting from the intermolecular N-Michael reaction of α,β-unsaturated ketone 1 and substituted allylamine 2 to furnish an α-ketone intermediate I [42–44] (for gold-catalyzed intramolecular N-Michael reaction see [42–43]), which further undergoes a subsequent gold(I)-catalyzed hydroalkylation to give pyrrolidine compounds 3 (Scheme 1); these compounds are versatile synthetic building blocks for organic synthesis and are important structural elements of many therapeutic drug molecules. Disappointingly, no conversion was observed when ( t -Bu) 2 ( o -diphenyl)PAuOTf only was used as the catalyst.…”

2,6-Disubstituted Tetrahydropyrans by Domino Meyer-Schuster Rearrangement-Hetero-Michael Addition of 6-Alkyne-1,5-diols

“…19 Another interesting route to hydroxy enones, which are substrates for the intramolecular Michael addition, relies on the gold-mediated hydration of homopropargylic ethers followed by elimination of methanol. 20,21 In case of tetrahydropyran formation, selective formation of the 2,6-cis-diastereomer was observed.…”