Asymmetric Ruthenium-Catalyzed Carbonyl Allylations by Gaseous Allene via Hydrogen Auto-Transfer: 1° versus 2° Alcohol Dehydrogenation for Streamlined Polyketide Construction

Abstract

Iodide-bound ruthenium−JOSIPHOS complexes catalyze the redox-neutral C−C coupling of primary alcohols 2a−2r with the gaseous allene (propadiene) 1a to form enantiomerically enriched homoallylic alcohols 3a−3r with complete atom efficiency. Using formic acid as the reductant, aldehydes dehydro-2a and dehydro-2c participate in reductive C−C coupling with allene to deliver adducts 3a and 3c with comparable levels of asymmetric induction. Deuterium labeling studies corroborate a mechanism in which alcohol dehydrogenation triggers allene hydroruthenation to form transient allylruthenium−aldehyde pairs that participate in carbonyl addition. Notably, due to a kinetic preference for primary alcohol dehydrogenation, chemoselective C−C coupling of 1°,2°-1,3-diols occurs in the absence of protecting groups. As illustrated by the synthesis of C7−C15 of spirastrellolide B and F (7 vs 17 steps), C3−C10 of cryptocarya diacetate (three vs seven or nine steps) and a fragment common to C8′−C14′ of mycolactone F (one vs four steps) and C22−C28 marinomycin A (one vs nine steps), this capability streamlines type I polyketide construction.

Carbonyl Allylation and Crotylation: Historical Perspective, Relevance to Polyketide Synthesis, and Evolution of Enantioselective Ruthenium-Catalyzed Hydrogen Auto-Transfer Processes

“…38 Using the iodide-bound ruthenium-JOSIPHOS­ catalyst, we very recently developed the first enantioselective allene-mediated carbonyl allylations via hydrogen auto-transfer from alcohol proelectrophiles (Scheme 5 ). 35b As shown, these reactions are efficient at catalyst loadings as low as 1.5 mol% and, like the closely related butadiene-mediated crotylations, primary alcohols are subject to allylation in the presence of unprotected secondary alcohols. This method was used to construct previously reported substructures of spirastrellolide B and F (C7–C15, 7 vs 17 steps), cryptocarya diacetate (C3–C10, 3 vs 7 or 9 steps), mycolactone F (C8′–C14′, 1 vs 4 steps), and marinomycin A (C22–C28, 1 vs 9 steps) in fewer steps than previously possible (not shown).…”

Leveraging the Stereochemical Complexity of Octahedral Diastereomeric-at-Metal Catalysts to Unlock Regio-, Diastereo-, and Enantioselectivity in Alcohol-Mediated C–C Couplings via Hydrogen Transfer

“…For the chloride and bromide complexes, mixtures of diastereomeric-at-metal complexes were evident, but for the iodide complex, a single diastereomer was observed (Figure 7). Additionally, for the iodide complex, QTAIM (Quantum Theory of Atoms-in-Molecules) analysis 26 implicated the presence of a formyl CH•••I hydrogen bond that stabilizes the preferred transition state for carbonyl addition. 27 The collective data are consistent with the indicated catalytic cycle where, from a plurality of stereoisomeric structures, predominantly one diastereomeric-at-metal complex intervenes in the enantiodetermining transition state for carbonyl addition because of the enhanced size and polarizability of iodide versus chloride or bromide.…”

Integrating MOF‐Based Catalysis with Nanocavity‐Confined Pd Catalysis over Multifunctional Pd‐MOF‐Fe for Acceptorless Dehydrogenation of Alcohols under Visible Light

“…[7][8][9][10] More importantly, the value-added carbonyl compounds can be synchronously formed during the ADAs process, thus improving the atomic efficiency. [11] Nowadays, ADAs employing homogeneous Ru, [12,13] Ir, [14][15][16] Au, [17,18] and Pt [19] catalysts have been reported as effective catalysts. [20,21] However, these developed systems encounter the drawbacks of difficulties in catalyst recyclability and requirement of acid or base additives.…”