Catalytic Contra-Thermodynamic Isomerization–Asymmetric Hydroboration of Alkenyl Alcohols and Amines

Abstract

Catalytic isomerization of alkenes is a powerful tool for the construction of complex synthetically valuable molecules due to their redox-neutral, atom-and step-economical nature. However, traditional catalytic asymmetric isomerization of alkenes typically required the use of a heteroatomic group such as OH or NR 2 as the thermodynamic driving force (i.e., the C�C double bond isomerizes along the direction of heteroatomic groups). Here, we present a contra-thermodynamic isomerization/asymmetric hydroboration of alkenyl alcohols and amines, in which the C�C double bond isomerizes along the opposite direction of OR and NR 2 . Compared to the traditional thermal isomerizations, this reaction overcomes the unfavorable thermodynamic bias to form a contra-thermodynamic alkene intermediate, followed by an irreversible asymmetric terminal hydroboration to provide highly synthetically valuable chiral 1,n-boryl ethers and amines. This protocol shows a wide substrate scope, including allylic alcohols, homoallylic alcohols, alkenyl alcohols, protected alkenyl alcohols, and various free and protected alkenyl amines. The synthetic utilities and practicability of this method were demonstrated by gram-scale reactions, diverse product transformations, and its applications in the synthesis of bioactive molecules. Preliminary mechanistic studies show that this reaction involves dissociative alkene isomerization and an asymmetric hydroboration of 1,1-disubstituted alkene intermediates.

Remote Functionalization by Pd-Catalyzed Isomerization of Alkynyl Alcohols

“…In these relay reactions, two distant functional groups can be interconverted by exploiting the reactivity of one function to induce a reaction on the other via a dynamic transmission process, which occurs typically by alkene migration through a hydrocarbon linker (a process referred to as “chain-walking”). With a few exceptions, the current catalytic methods are based on the formation of the thermodynamically most stable product or the most stable organometallic intermediate, before it is intercepted by an appropriate reagent to install a novel functional group.…”

“…As the literature analysis presented above demonstrates, long-range yne-to-diene isomerizations (type C) are conspicuously absent from the current library of remote functionalization strategies. To address this challenge, we hypothesized that alkynes featuring a hydrocarbon chain terminated by an alcohol functionality may impart a sufficient thermodynamic driving force to ensure displacement of the two π components of the CC bond. , The choice of such substrates was equally dictated by the ubiquitous nature of the α,β-unsaturated aldehydes that would ultimately be obtained upon complete isomerization. Nevertheless, in addition to sustaining migration of the two π systems of an alkyne over several carbon atoms, we recognized that the ideal catalyst would have to overcome several challenges.…”

“…Moreover, the transient dienes and/or skipped dienes that are expected to be generated during the reaction are susceptible to act as catalyst poisons by chelation to the metal center or simply to be thermodynamically too stable to undergo further isomerization. Finally, because deconjugation of α,β-unsaturated carbonyls has been achieved using several metal hydride complexes, the ability of the product to act as an effective thermodynamic sink was initially unclear …”