The Importance of Hydrogen Bonding to Stereoselectivity and Catalyst Turnover in Gold-Catalyzed Cyclization of Monoallylic Diols

Abstract

Density functional calculations and experiment were used to examine the mechanism, reactivity, and origin of chirality transfer in monophosphine Au-catalyzed monoallylic diol cyclization reactions. The lowest energy pathway for cyclization involves a two-step sequence that begins with intramolecular C-O bond formation by anti-addition of the non-allylic hydroxyl group to the Au-coordinated alkene followed by concerted hydrogen transfer/anti-elimination to liberate water. Concerted S(N)2'-type transition states were found to be significantly higher in energy. The two-step cyclization pathway is extremely facile due to hydrogen bonding between diol groups that induces nucleophilic attack on the alkene and then proton transfer between diol groups after C-O bond formation. Importantly, intramolecular proton transfer and elimination provides an extremely efficient avenue for catalyst regeneration from the Au-C σ-bond intermediate, in contrast to other Au-catalyzed cyclization reactions where this intermediate severely restricts catalyst turnover. The origin of chirality transfer and the ensuing alkene stereochemistry is also the result of strong hydrogen-bonding interactions between diol groups. In the C-O bond-forming step, requisite hydrogen bonding biases the tethered nucleophilic moiety to adopt a chair-like conformation with substituents in either axial or equatorial positions, dictating the stereochemical outcome of the reaction. Since this hydrogen bonding is maintained throughout the course of the reaction, establishment of the resultant olefin geometry is also attributed to this templating effect. These computational conclusions are supported by experimental evidence employing bicyclic systems to probe the facial selectivity.

Nitrogen Nucleophiles in Au‐Catalyzed Dehydrative Cyclization Reactions

“…This result was somewhat contrary to the high chirality transfer observed in the formation of tetrahydropyrans 3d,g. It is possible that carbamate‐protected nitrogen nucleophiles function differently than hydroxyl groups and basic amines, which have been shown to transfer the allylic alcohol chirality 3d,g,4e,k. At the outset, it was expected that they would behave similarly and that amine nucleophiles would access a pathway analogous to our previously reported transfer of chirality for monoallylic diols 3g.…”

“…Surprisingly, upon treatment of substrate 13 with the optimized conditions, the product 14 was formed in only one hour, but in an unanticipated 30 % ee (Scheme ). This result was somewhat contrary to the high chirality transfer observed in the formation of tetrahydropyrans 3d,g. It is possible that carbamate‐protected nitrogen nucleophiles function differently than hydroxyl groups and basic amines, which have been shown to transfer the allylic alcohol chirality 3d,g,4e,k.…”

“…Treatment of alkyne 9 under the standard Carreira alkynylation conditions with 4‐bromobenzaldehyde gave the desired propargyl alcohol, 12 , in high yield, with 97 % ee. Reduction of the alkyne, followed by partial deprotection of the bis‐carbamate, occurred with only minor epimerization of the desired substrate 13 and provided a substrate for our chirality transfer studies 3d,g. Surprisingly, upon treatment of substrate 13 with the optimized conditions, the product 14 was formed in only one hour, but in an unanticipated 30 % ee (Scheme ).…”

New developments in gold-catalyzed manipulation of inactivated alkenes

“…Very recently Ess and Aponick reported a detailed mechanistic study on the intramolecular hydroalkoxylation of hydroxy allylic alcohols 94 , pointing out the key role of intramolecular hydrogen bond (H-bond) interactions for both reactivity and stereoselectivity [65]. Theoretical calculations and experimental evidences ruled out the S N 1 reaction mechanism via allylic carbocation.…”

“…Experiments with configurationally defined hydroxy allylic alcohols 105b , c demonstrated the stereospecificity of the process. Due to the complexity of the substrates, the stereochemical model proposed by Aponick [65] could only partially account for the stereochemical outcome of the reaction, since the importance of the configuration of the carbon bearing the nucleophilic OH group was not considered.…”