Gold(I)/Copper(II)‐Cocatalyzed Tandem Cyclization/Semipinacol Reaction: Construction of 6‐Aza/Oxa‐Spiro[4.5]decane Skeletons and Formal Synthesis of (±)‐Halichlorine

Abstract

A simple and efficient strategy for the construction of 6-aza/oxa-spiro[4.5]decane skeletons under the cocatalysis of gold(I)/copper(II) was developed, and its potential utility was demonstrated by a formal synthesis of the biologically active marine alkaloid (AE)-halichlorine.

Total Synthesis of Natural Products using Gold Catalysis

“…(2015) communicated an Au(I)/Cu(II) cocatalyst, which enabled them to synthesize the 6‐aza/oxa‐spiro[4.5]decane framework. The synthetic application of the strategy is the formal total synthesis of (±)‐halichlorine [63] . (±)‐halichlorine has been established as a biologically active marine alkaloid that effectively represses the expression of vascular cell adhesion molecule‐1 (VCAM‐1) [62,64,65] .…”

“…(±)‐halichlorine has been established as a biologically active marine alkaloid that effectively represses the expression of vascular cell adhesion molecule‐1 (VCAM‐1) [62,64,65] . The installation of aza/oxa‐spirocyclic is a very complicated task, however, its biological utilities are crucial for drug discovery applications [63] . The authors initiated the synthesis from an alkyne 1 via tandem or semi‐pinacol strategy.…”

“…The synthetic application of the strategy is the formal total synthesis of (�)-halichlorine. [63] (�)-halichlorine has been established as a biologically active marine alkaloid that effectively represses the expression of vascular cell adhesion molecule-1 (VCAM-1). [62,64,65] The installation of aza/oxa-spirocyclic is a very complicated task, however, its biological utilities are crucial for drug discovery applications.…”

[1, 2]‐Migration Reactions Catalyzed by Gold Complexes and their Applications in Total Synthesis

“…In the formal total synthesis of halichlorine, an inhibitor of VCAM‐1 expression, alkyne 71 underwent gold‐catalyzed heterocyclization followed by ring‐expansion of the cyclobutanol moiety (Scheme ) . This reaction was catalyzed by a bimetallic system using [BINAP(AuCl) 2 ] activated with AgBF 4 , and Cu(OTf) 2 was added as Lewis‐acid.…”

Coinage-Metal-Catalyzed Reactions of Propargylic Alcohols

“…Recently, Tu, Wang and co-workers developed an efficient route to 6-aza-or 6-oxaspiro[4.5]decane derivatives 210 from compounds 209 through a tandem cyclization and semipinacol reaction with the aid of gold(I), copper(II) and silver(I) catalysts (Scheme 93). 110 Using this methodology, natural compounds, such as (±)-halichlorine (211), were successfully obtained. From the results of control experiments, copper(II) triflate was determined to play a vital role in the rearrangement step, most likely owing to its activation of the carbonyl group in the intermediate 210-1.…”