A Flexible Synthesis of Polypropionates via Diastereodivergent Reductive Ring-Opening of Trisubstituted Secondary Glycidols.

Polypropionates, characterized by their alternating sequence of stereocenters bearing methyl- and hydroxy-groups, are structurally diverse natural products of utmost importance.[1] Herein, we introduce a novel concept approach towards polypropionate synthesis featuring a diastereodivergent reductive epoxide-opening as a key step. Readily available and stereochemically uniform trisubstituted sec-glycidols serve as branching points for the highly selective synthesis of all isomers of polypropionate building blocks with three or more consecutive stereocenters. Stereodiversification is accomplished by an unprecedented mechanism-control over the stereochemically complementary modification of the epoxide's tertiary C-atom with excellent control of regio- and stereoselectivity. Since our method is not only suited for the preparation of specific targets but also for compound libraries, it will have a great impact on polypropionate synthesis.

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.