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.

Experimental and computational studies illuminating the factors that guide metal-centered stereogenicity and, therefrom, selectivity in transfer hydrogenative carbonyl additions of alcohol proelectrophiles catalyzed by chiral-at-metal-and-ligand octahedral d6 metal ions, iridium(III) and ruthenium(II), are described. To augment or invert regio-, diastereo-, and enantioselectivity, predominantly one from among as many as 15 diastereomeric-at-metal complexes is required. For iridium(III) catalysts, cyclometalation assists in defining the metal stereocenter, and for ruthenium(II) catalysts, iodide counterions play a key role. Whereas classical strategies to promote selectivity in metal catalysis aim for high-symmetry transition states, well-defined low-symmetry transition states can unlock selectivities that are otherwise difficult to achieve or inaccessible.

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

O-Acetyl 1,3-propanediol serves as an acrolein proelectrophile in π-allyliridium-C,O-benzoate-catalyzed carbonyl allylations mediated by racemic α-substituted allylic acetates. Using the iridium catalyst modified by (R)-SEGPHOS, a variety of 3-hydroxy-1,5-hexadienes are formed with uniformly high levels of regio-, anti-diastereo-, and enantioselectivity.

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

The first systematic study of catalytic enantioselective 1,2-additions to acrolein is described. Specifically, using allyl alcohol as a tractable, inexpensive acrolein proelectrophile, iridium-catalyzed acrolein allylation is achieved with high levels of regio-, anti-diastereo-, and enantioselectivity. This process delivers 3-hydroxy-1,5-hexadienes, a useful compound class that is otherwise challenging to access via enantioselective catalysis. Two-fold use of this method unlocks concise total syntheses of amphidinolide R (9 vs 23 steps, LLS) and amphidinolide J (9 vs 23 or 26 steps, LLS), which are prepared in fewer than half the steps previously possible, and the first total synthesis of amphidinolide S (10 steps, LLS).

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

In this Perspective, the use of methanol and ethanol as C1 and C2 feedstocks in metal-catalyzed C-C couplings to π-unsaturated 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.

Enantioselective Iridium-Catalyzed Reductive Coupling of Dienes with Oxetanones and N-Acyl-Azetidinones Mediated by 2-Propanol.

Cyclometallated iridium-PhanePhos complexes generated in situ from [Ir(cod)Cl]2 and (R)-PhanePhos catalyze 2-propanol-mediated reductive couplings of 2-substituted dienes with oxetanone and N-acyl-azetidinones to form branched homoallylic oxetanols and azetidinols with excellent control of regio- and enantioselectivity without C-C cleavage of the strained ring via enantiotopic π-facial selection of transient allyliridium nucleophiles. This work represents the first systematic study of enantioselective additions to symmetric ketones.

Ethanol: Unlocking an Abundant Renewable C2 -Feedstock for Catalytic Enantioselective C-C Coupling.

With annual production at >85 million tons/year, ethanol is the world's largest-volume renewable small molecule carbon source, yet its use as a C2 -feedstock in enantioselective C-C coupling is unknown. Here, the first catalytic enantioselective C-C couplings of ethanol are demonstrated in reactions with structurally complex, nitrogen-rich allylic acetates incorporating the top 10 N-heterocycles found in FDA-approved drugs.

Catalytic Reductive Aldol and Mannich Reactions of Enone, Acrylate, and Vinyl Heteroaromatic Pronucleophiles.

Catalytic reductive coupling of enone, acrylate, or vinyl heteroaromatic pronucleophiles with carbonyl or imine partners offers an alternative to base-mediated enolization in aldol- and Mannich-type reactions. In this review, direct catalytic reductive aldol and Mannich reactions are exhaustively catalogued on the basis of metal or organocatalyst. Stepwise processes involving enone conjugate reduction to form discrete enol or (metallo)enolate derivatives followed by introduction of carbonyl or imine electrophiles and aldol reactions initiated via enone conjugate addition are not covered.

Inversion of Enantioselectivity in Allene Gas versus Allyl Acetate Reductive Aldehyde Allylation Guided by Metal-Centered Stereogenicity: An Experimental and Computational Study.

The use of gaseous allene as an allyl pronucleophile in enantioselective aldehyde reductive coupling is described. Notably, using the same antipode of chiral ligand, (S)-tol-BINAP, an inversion of enantioselectivity is observed for allene vs allyl acetate pronucleophiles. Experimental and computational studies corroborate intervention of diastereomeric π-allyliridium-C,O-benzoate complexes, which arise via allene hydrometalation (from a pentacoordinate iridium hydride) vs allyl acetate ionization (from a square planar iridium species).

Feedstock Reagents in Metal-Catalyzed Carbonyl Reductive Coupling: Minimizing Preactivation for Efficiency in Target-Oriented Synthesis.

Use of abundant feedstock pronucleophiles in catalytic carbonyl reductive coupling enhances efficiency in target-oriented synthesis. For such reactions, equally inexpensive reductants are desired or, ideally, corresponding hydrogen autotransfer processes may be enacted wherein alcohols serve dually as reductant and carbonyl proelectrophile. As described in this Minireview, these concepts allow reactions that traditionally require preformed organometallic reagents to be conducted catalytically in a byproduct-free manner from inexpensive π-unsaturated precursors.