Stereoconvergent Approach to the Enantioselective Construction of α-Quaternary Alcohols by Radical Epoxide Allylation.

We describe a highly stereoconvergent radical epoxide allylation towards diastereomerically and enantiomerically enriched α-quaternary alcohols in two steps from olefins. Our approach combines the stereospecifity and enantioselectivity of the Shi epoxidation with the unprecedented Ti(III)-promoted intramolecular radical group transfer allylation of epoxides. A directional isomerization step via configurationally labile radical intermediates enables the selective preparation of all-carbon quaternary stereocenters in a unique fashion.

Formal Anti-Markovnikov Addition of Water to Olefins by Titanocene-Catalyzed Epoxide Hydrosilylation: From Stoichiometric to Sustainable Catalytic Reactions.

Here, the evolution of the titanocene-catalyzed hydrosilylation of epoxides that yields the corresponding anti-Markovnikov alcohols is summarized. The study focuses on aspects of sustainability, efficient catalyst activation, and stereoselectivity. The latest variant of the reaction employs polymethylhydrosiloxane (PMHS), a waste product of the Müller-Rochow process as terminal reductant, features an efficient catalyst activation with benzylMgBr and the use of the bench stable Cp2TiCl2 as precatalyst. The combination of olefin epoxidation and epoxide hydrosilylation provides a uniquely efficient approach to the formal anti-Markovnikov addition of H2O to olefins.

Converging Stereodivergent Reactions: Highly Stereoselective Formal anti-Markovnikov Addition of H2 O to Mixtures of Olefins.

We describe a highly diastereo- and enantioselective two-step formal anti-Markovnikov addition of H2 O to diastereomeric mixtures of trisubstituted olefins. Our approach overcomes the limits of classical stereospecific addition reactions to olefins for the generation of adjacent stereocenters. In these stereospecific reactions, separation of olefin diastereomers is essential. Our method circumvents the need for such difficult separations by simultaneously employing both diastereomeric olefins in the organocatalytic, highly enantioselective, syn-specific Shi-epoxidation to yield diastereomeric oxiranes. The stereochemical model proposes the smallest substituent on the olefin to be stereodefining resulting in an identical enantiotopic approach for both olefin isomers on the less substituted carbon. By employing a stereoconverging epoxide hydrosilylation the identically configured center is retained, while the differing one is converted to a planar radical center that is reduced by a syn-selective intramolecular hydrogen atom transfer (HAT) from a Ti-H bond. The observed converging behavior can be attributed to a HAT-preceding directional isomerization step, that interconverts the obtained rotameric radicals which ultimately leads to high to excellent enantiomeric ratios of the final secondary alcohols.

Titanocene(III)-Catalyzed Precision Deuteration of Epoxides.

We describe a titanocene(III)-catalyzed deuterosilylation of epoxides that provides ß-deuterated anti-Markovnikov alcohols with excellent D-incorporation, in high yield, and often excellent diastereoselectivity after desilylation. The key to the success of the reaction is a novel activation method of Cp2 TiCl2 and (tBuC5 H4 )2 TiCl2 with BnMgBr and PhSiD3 to provide [(RC5 H4 )2 Ti(III)D] without isotope scrambling. It was developed after discovering an off-cycle scrambling with the previously described method. Our precision deuteration can be applied to the synthesis of drug precursors and highlights the power of combining radical chemistry with organometallic catalysis.