Dissecting the Stereocontrol Elements of a Catalytic Asymmetric Chlorolactonization: Syn Addition Obviates Bridging Chloronium

Abstract

We report absolute and relative stereochemistry of addition in enantioselective chlorolactonizations of 4-phenyl-4-pentenoic acid and its related t-butyl ester, catalyzed by (DHQD)2PHAL. Predominant syn addition of the chlorenium and the nucleophile across the olefin is observed. As shown by isotopic labeling, NMR spectroscopy, and derivative studies, the two new stereocenters formed by addition across the double bond are set independently and influenced by different factors. These findings suggest a stepwise process via an intermediate capable of lactone closure with either stereochemistry, in contradistinction to the more familiar scenario in which anti addition is dictated by a bridging chloronium ion intermediate.

Toward Catalytic, Enantioselective Chlorolactonization of 1,2-Disubstituted Styrenyl Carboxylic Acids

“…24 It was concluded that the reaction operates via an open tertiary carbocation intermediate which then undergoes ring closing under the stereocontrol of the catalyst. This mechanism of operation explains the lack of selectivity for 1,2-disubstituted olefinic acids in the chlorolactonization with cinchona-based catalysts; these substrates should form less stable secondary carbocations and would be more prone to be captured as chloriranium ions or tight ion pairs in an anti addition process.…”

Reversing the Regioselectivity of Halofunctionalization Reactions through Cooperative Photoredox and Copper Catalysis

“…[2] They have also provided evidence, in some cases, for a concerted mechanism in these reactions; while in other cases, formation of a carbocation intermediate was found to be favored. [2–4] …”

“…[2] They have also provided evidence,i ns ome cases,f or ac oncerted mechanism in these reactions;w hereas in other cases,the formation of acarbocation intermediate was found to be favored. [2][3][4] Numerous reports of enantioselective variants of traditional halofunctionalization reactions exploit this classic reaction manifold. [2,5,6] Ty pically,such enantioselective transformations proceed through activation of the electrophilic halogen source with achiral Lewis acid [7][8][9] or hydrogen-bond donor/acceptor, [10][11][12] or through the formation of ac hiral electrophilic halogenating reagent in situ.…”

Reversing the Regioselectivity of Halofunctionalization Reactions through Cooperative Photoredox and Copper Catalysis

“…Tr aditional halofunctionalization reactions proceed reliably through the formation of halonium ions,which form through nucleophilic attack at an electrophilic halogen by an alkene. [2][3][4] Numerous reports of enantioselective variants of traditional halofunctionalization reactions exploit this classic reaction manifold. Recent efforts by the Borhan research group have also suggested ar ole for the nucleophile in activating alkenes,s pecifically in chlorolactonization reactions.…”