Alkynes as allylmetal equivalents in redox-triggered C-C couplings to primary alcohols: (Z)-homoallylic alcohols via ruthenium-catalyzed propargyl C-H oxidative addition.

The cationic ruthenium catalyst generated upon the acid-base reaction of H2Ru(CO)(PPh3)3 and 2,4,6-(2-Pr)3PhSO3H promotes the redox-triggered C-C coupling of 2-alkynes and primary alcohols to form (Z)-homoallylic alcohols with good to complete control of olefin geometry. Deuterium labeling studies, which reveal roughly equal isotopic compositions at the allylic and distal vinylic positions, along with other data, corroborate a catalytic mechanism involving ruthenium(0)-mediated allene-aldehyde oxidative coupling to form a transient oxaruthenacycle, an event that ultimately defines (Z)-olefin stereochemistry.

Diastereo- and enantioselective three-component coupling approach to highly substituted pyrrolidines.

The enantioselective synthesis of substituted pyrrolidines through a mild Lewis-acid catalyzed three-component coupling reaction between picolinaldehyde, amino acids, and activated olefins is reported. The reaction uses low catalyst loadings of commercially available chiral diamines and copper triflate proposed to self-assemble in conjunction with the chelating aldehydes, 4-substituted-2-picolinaldehydes or 4-methylthiazole-2-carboxaldehyde, to generate a catalyst complex. A model is provided to explain how this complex directs enantioselectivity. This work represents a significant advance in the ease, scope, and cost of producing highly substituted, enantioenriched pyrrolidines.

Catalytic α-allylation of unprotected amino acid esters.

Catalytic α-allylation of unprotected amino acid esters to produce α-quaternary α-allyl amino acid esters is reported. Catalytic loadings of picolinaldehyde and Ni(II) salts induce preferential reactivity at the enolizable α-carbon of amino acid esters over the free nitrogen with electrophilic palladium π-allyl complexes. Fourteen examples are given. Additionally, the use of chiral ligands to access enantioenriched α-quaternary amino acid esters from racemic precursors is demonstrated by the enantioselective synthesis of α-allyl phenylalanine methyl ester from racemic phenylalanine methyl ester.

A diastereoselective three-component coupling approach to highly substituted pyrrolidines.

Building on the observation that metal complexation facilitates azomethine ylide formation, we report that chelating aldehydes participate in metal-templated, one-pot reactions with unprotected amino acid esters and activated olefins to provide highly substituted pyrrolidines. The high yields, broad substrate scope, excellent diastereoselectivities, functional group tolerance, and incorporation of commercially available materials in this reaction simplifies access to medicinally relevant proline derivatives.

Cooperativity of regiochemistry control strategies in reductive couplings of propargyl alcohols and aldehydes.

The nickel-catalyzed reductive coupling of propargyl alcohols and alkynes proceeds with excellent regiochemical control with an underlying electronic preference that can be supplemented by ligand size effects. The products obtained may be readily converted to substructures that are not directly available by an aldehyde-alkyne reductive coupling. A simple model for how steric and electronic factors are both important in governing regiochemistry in couplings of this type is presented, along with examples of how the effects can combine in either a constructive or destructive manner.

Selective oxidation of carbolide C-H bonds by an engineered macrolide P450 mono-oxygenase.

Regio- and stereoselective oxidation of an unactivated C-H bond remains a central challenge in organic chemistry. Considerable effort has been devoted to identifying transition metal complexes, biological catalysts, or simplified mimics, but limited success has been achieved. Cytochrome P450 mono-oxygenases are involved in diverse types of regio- and stereoselective oxidations, and represent a promising biocatalyst to address this challenge. The application of this class of enzymes is particularly significant if their substrate spectra can be broadened, selectivity controlled, and reactions catalyzed in the absence of expensive heterologous redox partners. In this study, we engineered a macrolide biosynthetic P450 mono-oxygenase PikC (PikC(D50N)-RhFRED) with remarkable substrate flexibility, significantly increased activity compared to wild-type enzyme, and self-sufficiency. By harnessing its unique desosamine-anchoring functionality via a heretofore under-explored "substrate engineering" strategy, we demonstrated the ability of PikC to hydroxylate a series of carbocyclic rings linked to the desosamine glycoside via an acetal linkage (referred to as "carbolides") in a regioselective manner. Complementary analysis of a number of high-resolution enzyme-substrate cocrystal structures provided significant insights into the function of the aminosugar-derived anchoring group for control of reaction site selectivity. Moreover, unexpected biological activity of a select number of these carbolide systems revealed their potential as a previously unrecorded class of antibiotics.

Direct vinylation of alcohols or aldehydes employing alkynes as vinyl donors: a ruthenium catalyzed C-C bond-forming transfer hydrogenation.

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to benzylic and aliphatic alcohols 1a-1l to furnish allylic alcohols 2a-2l, constituting a direct C-H vinylation of alcohols employing alkynes as vinyl donors. Under related transfer hydrogenation conditions employing formic acid as terminal reductant, 2-butyne couples to aldehydes 4a, 4b, and 4e to furnish identical products of carbonyl vinylation 2a, 2b, and 2e. Thus, carbonyl vinylation is achieved from the alcohol or the aldehyde oxidation level in the absence of any stoichiometric metallic reagents. Nonsymmetric alkynes 6a-6c couple efficiently to aldehyde 4b to provide allylic alcohols 2m-2o as single regioisomers. Acetylenic aldehyde 7a engages in efficient intramolecular coupling to deliver cyclic allylic alcohol 8a.

Functional analysis of MycCI and MycG, cytochrome P450 enzymes involved in biosynthesis of mycinamicin macrolide antibiotics.

Macrolides are a class of valuable antibiotics that include a macrolactone ring, at least one appended sugar unit, and, in most cases, additional hydroxyl or epoxide groups installed by cytochrome P450 enzymes. These functional groups contribute to structural diversification and serve to improve the bioactivity profiles of natural products. Here, we have characterized in vitro two P450 enzymes from the mycinamicin biosynthetic pathway of Micromonospora griseorubida. First, MycCI was characterized as the C21 methyl hydroxylase of mycinamicin VIII, the earliest macrolide form in the postpolyketide synthase tailoring pathway. Moreover, we established that optimal activity of MycCI depends on the native ferredoxin MycCII. Second, MycG P450 catalyzes consecutive hydroxylation and epoxidation reactions with mycinamicin IV as initial substrate. These reactions require prior dimethylation of 6-deoxyallose to mycinose for effective conversion by the dual function MycG enzyme.