Gold-catalyzed and IBr-Promoted Tandem Cyclization of 1,5-Enynes Leading to Highly Stereocontrolled Synthesis of Functionalized Cyclohexenes

Abstract

Our research interests are focusing on the novel reaction discovery based on gold-catalysts. The use of Au(I) and Au(III) complexes in the activation of -bonds such as alkyne, allene, and alkene has attracted considerable recent attention because of their merits such as strong chemoselective activation of -bonds, as well as easy handling and stability upon storage. Evaluation of the gold-complexes in catalysis has led us to the identification of a number of novel C-X (heteroatom) bond formations1-7 and tandem C-C and C-O bond formations.8 Various structures such as butenolides,1 cyclic carbonates,3 oxazines and oxazoles,4 spirofurans,5 oxazolidinones,6 and 2,5-dihydro-isoxazoles7 could be assembled efficiently. We also identified pentafluorophenyl- phosphine gold complex (Au[P(C6F5)3)]X) provides presumably the most potent activation of alkynes, as exemplified by the shortest reaction time in a number of cases.2,3 Gold complex also triggers addition of alkene onto the Au-activated alkyne. This mode of reactivity allows the formation of C-C bond as well as C-X bond in a single operation. Tandem reaction where multiple bonds are formed in a stereocontrolled fashion represents a highly desirable goal in light of the complexity and diversity of poly-functionalized natural products. However, to realize such tandem reaction concept, several conditions needs to be met: (1) Firstly, alkyne has to be activated chemoselectively in the presence of alkene by electrophilic reagent or catalyst, (2) Secondly, alkene nucleophile (vs. heteroatom nucleophile) should attack preferentially at the activated alkyne. Recently, we have developed Au(I)-catalyzed tandem C-C and C-O bond formation of 1,5-enynes leading to a densely functionalized cyclohexenes having three contiguous stereocenters including a quaternary carbon.8 Mechanistic analysis of this reaction mode indicates Au-carbenoid is the key intermediate in stabilizing the cationic intermediate and promoting the reaction. Similar to the gold-catalyzed cyclization, substrates having 4-O-Boc-1,5-enyne skeleton underwent a successful tandem cyclization upon treatment with 2 equiv. of IBr. While traditional iodocyclization such as iodolactonization has been amply successful in cyclic and acyclic stereocontrol, the exploitation of tandem reactivity in halonium-initiated cyclization has been demonstrated first time in the context of 1,5-enyne cyclization. Also synthetic applications of these novel cyclizations will be presented highlighting the utility of the current methods.