Stereoselective Synthesis of the IDO Inhibitor Navoximod.

A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(Ot-Bu)3. Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.7% ee and high purity.

Magnesium Ethoxide Promoted Conversion of Nitriles to Amidines and Its Application in 5,6-Dihydroimidazobenzoxazepine Synthesis.

Magnesium ethoxide has been shown to be a mild, safe, and scalable alternative to trimethylaluminum for the direct addition of amines to aryl nitriles to access cyclic amidines. A variety of electronically diverse oxa-, thia-, and diazepine products were successfully synthesized in moderate to high yields. Further elaboration of these compounds to 5,6-dihydroimidazobenzoxazepines, a privileged class of pharmacologically active heterocycles, highlights the utility of this method.

The acid promoted Petasis reaction of organotrifluoroborates with imines and enamines.

The acid promoted addition of organotrifluoroborate salts to imine and enamine electrophiles is reported. Use of the pre-activated trifluoroboronate complex bypasses the need for α-hetero substitution on the electrophile component, greatly expanding the scope of the Petasis borono-Mannich reaction. A variety of vinyl, aromatic and heteroaromatic trifluoroborate salts undergo addition with good efficiency under mild reaction conditions. The reaction is amenable for use with a variety of carbamate protected imine and enamine electrophiles, achieving for the first time the effective coupling with aliphatic aldehydes.

Highly Diastereoselective α-Arylation of Cyclic Nitriles.

A highly diastereoselective α-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl•LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles.

Development of a general, enantioselective organocatalytic Mukaiyama-Michael reaction with α,ß-unsaturated aldehydes.

LUMO-lowering organocatalysis has been extended to promote the conjugate addition of S-alkyl and -pyrrolyl silylketene acetals to α,ß-unsaturated aldehydes, yielding both, syn and anti Mukaiyama-Michael products with high levels of enantioselectivity. This strategy allows for the generation of chemically useful 1,5-dicarbonyl systems and again highlights the utility of organocatalysis.

Enantioselective organocatalytic reductive amination.

The first enantioselective organocatalytic reductive amination reaction has been accomplished. The development of a new chiral phosphoric acid catalyst has provided a convenient strategy for the enantioselective construction of protected primary amines and provided a highly stereoselective method for the reductive amination of heterocyclic amines. A diverse spectrum of ketone and amine substrates can be accommodated in high yield and excellent enantioselectivity. This new protocol realizes a key benefit of reductive amination versus imine reduction, in that ketimines derived from alkyl-alkyl ketones are unstable to isolation, a fundamental limitation that is comprehensively bypassed using this direct organocatalytic reductive amination.