Biocatalytic, Enantioenriched Primary Amination of Tertiary C-H Bonds.

Intermolecular functionalization of tertiary C-H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, state-of-the-art catalysts struggle to introduce chirality to racemic tertiary s -carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C-H bonds to provide chiral -tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.

Biocatalytic Construction of Chiral Pyrrolidines and Indolines via Intramolecular C(sp)-H Amination.

Nature harnesses exquisite enzymatic cascades to construct -heterocycles and further uses these building blocks to assemble the molecules of life. Here we report an enzymatic platform to construct important chiral -heterocyclic products, pyrrolidines and indolines, via abiological intramolecular C(sp)-H amination of organic azides. Directed evolution of cytochrome P411 (a P450 enzyme with serine as the heme-ligating residue) yielded variant , capable of catalyzing the insertion of alkyl nitrene into C(sp)-H bonds to build pyrrolidine derivatives with good enantioselectivity and catalytic efficiency.

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp)-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging.

Enantioselective Copper-Catalyzed Remote C(sp)-H Alkynylation of Linear Primary Sulfonamides.

The highly efficient copper-catalyzed enantioselective alkynylation of the remote C(sp)-H bond on linear primary sulfonamides is presented here using a radical relay strategy. The chiral box-copper complex, which is used to recapture the -generated alkyl radical via a 1,5-HAT strategy, is the key to success, affording the chiral alkynes after a following reductive elimination. A general substrate scope, mild conditions, and excellent regio- and enantioselective control are demonstrated in this method.

Enantioselective Copper-Catalyzed Cyanation of Remote C(sp)-H Bonds Enabled by 1,5-Hydrogen Atom Transfer.

The direct functionalization of C(sp)-H bonds has led to the development of methods to access molecules or intermediates from basic chemicals in an atom- and step-economic fashion. Nevertheless, achieving high levels of chemo-, regio-, and enantioselectivity in these reactions remains challenging due to the ubiquity and low reactivity of C(sp)-H bonds. Herein, we report an unprecedented protocol for enantioselective cyanation of remote C(sp)-H bonds.

Novel and facile synthesis of 1-benzazepines via copper-catalyzed oxidative C(sp)-H/C(sp)-H cross-coupling.

A novel and facile synthetic strategy for the construction of 1-benzazepines has been developed via copper-catalyzed oxidative C(sp)-H/C(sp)-H cross-coupling directly from two inert C-H bonds. This transformation represents an atom- and step-economical way to synthesize biologically important seven-membered benzo-heterocycles compared with the known methods.