Enantioselective ortho-C-H cross-coupling of diarylmethylamines with organoborons.

The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the CH activation of amines for the first time. An enantioselective ortho-CH cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono-N-protected amino acid (MPAA) ligands as a promoter.

Unlocking nature's C-H bonds.

In an idealistic setting, it can be imagined that if every CH bond on an organic molecule could be selectively functionalized, the fields of chemical synthesis and drug discovery would be forever revolutionized. With the purpose of investigating the practicality of this idealistic scenario, our group has endeavored to unlock the potential of nature's CH bonds by developing palladium-catalyzed, site selective CH insertions that can be incorporated into both known and new catalytic cycles. To this end, we have developed a number of catalytic transformations that not only provide rapid diversification of simple starting materials and natural products through CH functionalization, but streamline the synthesis of a variety of natural products with biological activity and expand upon methods to access highly valuable enantiopure materials.

Exceedingly fast copper(II)-promoted ortho C-H trifluoromethylation of arenes using TMSCF3.

The direct ortho-trifluoromethylation of arenes, including heteroarenes, with TMSCF3 has been accomplished by a copper(II)-promoted C-H activation reaction which completes within 30 minutes. Mechanistic investigations are consistent with the involvement of C-H activation, rather than a simple electrophilic aromatic substitution (SE Ar), as the key step.

Enantioselective total synthesis of (-)-minovincine in nine chemical steps: an approach to ketone activation in cascade catalysis.

Dressed to the nines: The first enantioselective total synthesis of (-)-minovincine has been accomplished in nine chemical steps and 13 % overall yield. A novel, one-step Diels-Alder/ß-elimination/conjugate addition organocascade sequence allowed rapid access to the central tetracyclic core in an asymmetric manner. Boc=tert-butoxycarbonyl, LG=leaving group, PMB=para-methoxybenzyl.

Enantioselective alpha-arylation of aldehydes via organo-SOMO catalysis. An ortho-selective arylation reaction based on an open-shell pathway.

The intramolecular alpha-arylation of aldehydes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Selective oxidation of chiral enamines (formed by the condensation of an aldehyde and a secondary amine catalyst) leads to the formation of a 3pi-electron radical species. These chiral SOMO-activated radical cations undergo enantioselective reaction with an array of pendent electron-rich aromatics and heterocycles thus efficiently providing cyclic alpha-aryl aldehyde products (10 examples: > or = 70% yield and > or = 90% ee). In accordance with our radical mechanism, when there is a choice between arylation at the ortho or para position of anisole substrates, we find that arylation proceeds selectively at the ortho position.

One-pot synthesis of imidazolinium salts via the ring opening of tetrahydrofuran.

A new one-pot synthesis of C2-hydroxypropyl-substituted imidazolinium salts via the ring opening of tetrahydrofuran (THF) with N,N'-disubstituted diamines has been developed. Preliminary studies of the reaction mechanism suggest the CO2-promoted oxidative ring opening of THF followed by Hg(ii)-mediated oxidation of an imidazolidine intermediate. These novel C2-substituted imidazolinium salts have shown to be active catalysts for the aza-Diels-Alder reactions.

Cu(II)-catalyzed coupling of aromatic C-H bonds with malonates.

A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp(2))-H activation and malonate coupling, followed by intramolecular oxidative N-C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction.

Ligand-enabled cross-coupling of C(sp3)-H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis.

There have been numerous developments in C-H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C-H bonds, chemists have discovered reaction conditions that enable reactions of C(sp(2))-H and C(sp(3))-H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp(3))-H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp(3))-H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids.

Ligand-controlled C(sp³)-H arylation and olefination in synthesis of unnatural chiral α-amino acids.

The use of ligands to tune the reactivity and selectivity of transition metal catalysts for C(sp(3))-H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst-controlled C(sp(3))-H arylation using pyridine and quinoline derivatives: The former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of ß-Ar-ß-Ar'-α-amino acids with excellent levels of diastereoselectivity (diastereomeric ratio > 20:1). Both configurations of the ß-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp(3))-H olefination of a protected alanine.

Synthesis of indolines via Pd(II)-catalyzed amination of C-H bonds using PhI(OAc)2 as the bystanding oxidant.

The Pd(II)-catalyzed intramolecular C-H amination of 2-pyridinesulfonyl-protected phenethylamine derivatives has been achieved using PhI(OAc)2 as a bystanding oxidant, providing access to a variety of substituted indoline derivatives in good yields. The use of the 2-pyridinesulfonyl protecting group allows for facile deprotection following C-H functionalization.