Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation.

A kinase-cGAS cascade to synthesize a therapeutic STING activator.

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents.

Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp)-H Oxidative Addition Results in -to-Fluorine Selectivity.

The mechanism of C(sp)-H borylation of fluorinated arenes with BPin (Pin = pinacolato) catalyzed by bis(phosphino)pyridine (PNP) cobalt complexes was studied to understand the origins of the uniquely high -to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp)-H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)-aryl complex that was generated with the same high -to-fluorine regioselectivity associated with the overall catalytic transformation.

Earth-Abundant Transition Metal Catalysts for Alkene Hydrosilylation and Hydroboration: Opportunities and Assessments.

The addition of a silicon-hydrogen or a boron-hydrogen bond across a carbon-carbon multiple bonds is a well-established method for the introduction of versatile silane and borane functional groups to base hydrocarbon feedstocks. Transition metal catalysis, historically with precious second- and third- row transition metals, has been used to broaden the scope of the hydrofunctionalization reaction, improve reaction rate and enhance selectivity. The anti-Markovnikov selectivity of platinum-catalyzed hydrosilylation of alkenes, for example, is an enabling synthetic technology in the multibillion-dollar silicones industry.

Cobalt Pincer Complexes in Catalytic C-H Borylation: The Pincer Ligand Flips Rather Than Dearomatizes.

The mechanism for the borylation of an aromatic substrate by a cobalt pincer complex was investigated by density functional theory calculations. Experimental observations identified -(PNP)CoH(BPin) as the resting state in the borylation of five-membered heteroarenes, and 4-BPin-(PNP)Co(N)BPin as the resting state in the catalytic borylation of arene substrates. The active species, 4-R-(PNP)CoBPin (R=H, BPin), were generated by reductive elimination of H in the former, through Berry pseudorotation to the isomer, and N loss in the latter.

Mechanistic Studies of Cobalt-Catalyzed C(sp)-H Borylation of Five-Membered Heteroarenes with Pinacolborane.

Studies into the mechanism of cobalt-catalyzed C(sp)-H borylation of five-membered heteroarenes with pinacolborane (HBPin) as the boron source established the catalyst resting state as the -cobalt(III) dihydride boryl, (PNP = 2,6-(PrPCH)(CHN)), at both low and high substrate conversions. The overall first-order rate law and observation of a normal deuterium kinetic isotope effect on the borylation of benzofuran versus benzofuran-2- support H reductive elimination from the cobalt(III) dihydride boryl as the turnover-limiting step. These findings stand in contrast to that established previously for the borylation of 2,6-lutidine with the same cobalt precatalyst, where borylation of the 4-position of the pincer occurred faster than the substrate turnover and arene C-H activation by a cobalt(I) boryl is turnover-limiting.

Insights into Activation of Cobalt Pre-Catalysts for C()-H Functionalization.

The activation of readily prepared, air-stable cobalt (II) bis(carboxylate) pre-catalysts for the functionalization of C()-H bonds has been systematically studied. With the pyridine bis(phosphine) chelate, PNP, treatment of with either BPin or HBPin generated cobalt boryl products. With the former, reduction to (PNP)CoBPin was observed while with the latter, oxidation to the cobalt(III) dihydride boryl, -(PNP)Co(H)BPin occurred.

C(sp)-H Borylation of Fluorinated Arenes Using an Air-Stable Cobalt Precatalyst: Electronically Enhanced Site Selectivity Enables Synthetic Opportunities.

Cobalt catalysts with electronically enhanced site selectivity have been developed, as evidenced by the high ortho-to-fluorine selectivity observed in the C(sp)-H borylation of fluorinated arenes. Both the air-sensitive cobalt(III) dihydride boryl 4-Me-(PNP)Co(H)BPin (1) and the air-stable cobalt(II) bis(pivalate) 4-Me-(PNP)Co(OCBu) (2) compounds were effective and exhibited broad functional group tolerance across a wide range of fluoroarenes containing electronically diverse functional groups, regardless of the substitution pattern on the arene. The electronically enhanced ortho-to-fluorine selectivity observed with the cobalt catalysts was maintained in the presence of a benzylic dimethylamine and hydrosilanes, overriding the established directing-group effects observed with precious-metal catalysts.

Cobalt-Catalyzed C(sp(2))-H Borylation: Mechanistic Insights Inspire Catalyst Design.

A comprehensive study into the mechanism of bis(phosphino)pyridine (PNP) cobalt-catalyzed C-H borylation of 2,6-lutidine using B2Pin2 (Pin = pinacolate) has been conducted. The experimentally observed rate law, deuterium kinetic isotope effects, and identification of the catalyst resting state support turnover limiting C-H activation from a fully characterized cobalt(I) boryl intermediate. Monitoring the catalytic reaction as a function of time revealed that borylation of the 4-position of the pincer in the cobalt catalyst was faster than arene borylation.

Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation and Functionalization of Remote, Unactivated C(sp(3))-H Bonds.

Cobalt dialkyl and bis(carboxylate) complexes bearing α-diimine ligands have been synthesized and demonstrated as active for the C(sp(3))-H borylation of a range of substituted alkyl arenes using B2Pin2 (Pin = pinacolate) as the boron source. At longer reaction times, rare examples of polyborylation were observed, and in the case of toluene, all three benzylic C-H positions were functionalized. Coupling benzylic C-H activation with alkyl isomerization enabled a base-metal-catalyzed method for the borylation of remote, unactivated C(sp(3))-H bonds.

Cobalt catalyzed z-selective hydroboration of terminal alkynes and elucidation of the origin of selectivity.

A bis(imino)pyridine cobalt-catalyzed hydroboration of terminal alkynes with HBPin (Pin = pinacolate) with high yield and (Z)-selectivity for synthetically valuable vinylboronate esters is described. Deuterium labeling studies, stoichiometric experiments, and isolation of catalytically relevant intermediates support a mechanism involving selective insertion of an alkynylboronate ester into a Co-H bond, a pathway distinct from known precious metal catalysts where metal vinylidene intermediates have been proposed to account for the observed (Z) selectivity. The identity of the imine substituents dictates the relative rates of activation of the cobalt precatalyst with HBPin or the terminal alkyne and, as a consequence, is responsible for the stereochemical outcome of the catalytic reaction.

Cobalt-catalyzed C-H borylation.

A family of pincer-ligated cobalt complexes has been synthesized and are active for the catalytic C-H borylation of heterocycles and arenes. The cobalt catalysts operate with high activity and under mild conditions and do not require excess borane reagents. Up to 5000 turnovers for methyl furan-2-carboxylate have been observed at ambient temperature with 0.

Bis(imino)pyridine cobalt-catalyzed alkene isomerization-hydroboration: a strategy for remote hydrofunctionalization with terminal selectivity.

Bis(imino)pyridine cobalt methyl complexes are active for the catalytic hydroboration of terminal, geminal, disubstituted internal, tri- and tetrasubstituted alkenes using pinacolborane (HBPin). The most active cobalt catalyst was obtained by introducing a pyrrolidinyl substituent into the 4-position of the bis(imino)pyridine chelate, enabling the facile hydroboration of sterically hindered substrates such as 1-methylcyclohexene, α-pinene, and 2,3-dimethyl-2-butene. Notably, these hydroboration reactions proceed with high activity and anti-Markovnikov selectivity in neat substrates at 23 °C.

Highly selective bis(imino)pyridine iron-catalyzed alkene hydroboration.

Bis(imino)pyridine iron dinitrogen complexes have been shown to promote the anti-Markovnikov catalytic hydroboration of terminal, internal, and geminal alkenes with high activity and selectivity. The isolated iron dinitrogen compounds offer distinct advantages in substrate scope and overall performance over known precious metal catalysts and previously reported in situ generated iron species.