Iridium-, Ruthenium-, and Nickel-Catalyzed C–C Couplings of Methanol, Formaldehyde, and Ethanol with π-Unsaturated Pronucleophiles via Hydrogen Transfer

Abstract

In this Perspective, the use of methanol and ethanol as C1 and C2 feedstocks in metal-catalyzed C−C couplings to πunsaturated pronucleophiles via hydrogen auto-transfer is surveyed. In these processes, alcohol oxidation to form an aldehyde electrophile is balanced by reduction of an π-unsaturated hydrocarbon to form a transient organometallic nucleophile. Mechanistically related reductive couplings of paraformaldehyde mediated by alcohol reductants or formic acid also are described. These processes encompass the first catalytic enantioselective C−C couplings of methanol and ethanol and, more broadly, illustrate how the native reducing ability of alcohols enable the departure from premetalated reagents in carbonyl addition.

Allyl Alcohol as an Acrolein Equivalent in Enantioselective C–C Coupling: Total Synthesis of Amphidinolides R, J, and S

“…Two-fold application of this method enabled concise total syntheses of amphidinolide R (9 vs 23 steps, LLS) and amphidinolide J (9 vs 23 or 26 steps, LLS) and the first total synthesis of amphidinolide S (10 steps, LLS). This work and related studies from our laboratory demonstrate how catalytic C–C couplings of stable, tractable alcohols streamline chemical synthesis …”

“…Allyl alcohol, a reduced form of acrolein, is highly tractable, inexpensive, and broadly available (1 × 10 5 tons/year) . Given our recent development of methods for the catalytic enantioselective conversion of lower alcohols to higher alcohols, including hydrogen auto-transfer processes for the valorization of methanol (>95 million tons/year) and ethanol (>95 million tons/year), the use of allyl alcohol as a latent source of acrolein in catalytic enantioselective C–C coupling was explored using ortho -cyclometalated π-allyliridium- C , O -benzoate complexes developed in our laboratory . The feasibility of such processes was uncertain, due to the intrinsic instability of acrolein, and reports of rapid, exothermic iridium-catalyzed allyl alcohol-to-propanal redox isomerization .…”

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

“…Similarly, the macrolide antibiotic erythromycin A, 8 the first polyketide approved for use in human medicine, comprises recurring 3-carbon ‘propionate’ subunits. The challenge of preparing these structural motifs impelled advances in acyclic stereocontrol, especially stereospecific methods for diastereo- and enantioselective carbonyl addition such as the aldol reaction 9 and, as described in the present monograph, carbonyl allylation and crotylation. 4…”

O-Acetyl 1,3-Propanediol as an Acrolein Proelectrophile in Enantioselective Iridium-Catalyzed Carbonyl Allylation

“…Catalytic enantioselective 1,2-additions to acrolein are limited to a small number of isolated reports . Recently, in connection with longstanding studies on the use of alcohols as carbonyl proelectrophiles in catalytic enantioselective carbonyl addition, our laboratory described the use of allyl alcohol 1a as a tractable, inexpensive acrolein proelectrophile in asymmetric iridium-catalyzed carbonyl allylations mediated by allylic acetates 2 (Scheme ). Although these reactions were highly effective, delivering 3-hydroxy-1,5-hexadienes 3 with high levels of regio-, anti -diastereo-, and enantioselectivity, in certain cases it was not possible to completely suppress redox isomerization of allyl alcohol to form propanal, which resulted in contamination with inseparable propanal adducts 4 .…”

“…Unlike corresponding reactions in which allyl alcohol serves as an acrolein proelectrophile, the present method delivers 3-hydroxy-1,5-hexadienes free of propanal allylation adducts. This work adds to the lexicon of catalytic asymmetric methods that transform inexpensive commodity chemicals into value-added products via hydrogen autotransfer. ,, …”