A robust, cost effective and high yielding manufacturing process for enantiomerically enriched (S)-allylic amine 3, a key intermediate for fully synthetic tetracyclines have been developed.Two novel and scalable asymmetric vinylations resulting in high to excellent stereoselectivity have been developed for the key step. The final product is purified by an efficient crystallization of a L-tartaric salt. The process described has been used to manufacture ~350 kg of the tartaric salt of 3 with 99.0% ee in 8 steps (35% overall yield) from cheap and readily available dimethyl maleate.

Malonic acid derivatives undergo unusually mild decarboxylation when treated with N,N'-carbonyldiimidazole (CDI) at room temperature to generate the carbonyl imidazole moiety in high yield, which can be reacted further with a variety of nucleophiles in an efficient one-pot process.

Two new routes have been developed to generate manganese-chelated amides from imine and carbon monoxide building blocks. The reaction of (CO) 5 MnR (R ) CH 3 , Ph) with (ptolyl)(R 1 )dNR 2 (R 1 ) H, t Bu; R 2 ) alkyl, H) results in the generation of the cyclometalated imine complexes (CO) 4 Mn[η 2 -4-CH 3 -2-(C(R 1 )dNR 2 )-C 6 H 3 ] in 50-84% isolated yield. However, when the reaction of (p-tolyl)(H)CdNCH 3 with (CO) 5 MnCH 3 is performed in the presence of AlCl 3 , the product of sequential carbon monoxide and imine insertion is generated in 35% yield: (CO) 4 Mn[η 2 -C(H)(p-tolyl)N(CH 3 )COCH 3 ]. The addition of PPh 3 to the latter complex results in replacement of a carbonyl ligand and formation of the isolable fac-(CO) 3 (PPh 3 )-Mn[η 2 -C(H)(p-tolyl)N(CH 3 )COCH 3 ]. In an alternative route to metal-bound amides, the oxidative addition of the N-acyl iminium salt (p-tolyl(H)CdN(CH 3 )COPh + Clto (CO) 5 Mn -Na + has been found to lead to the generation of the product of subsequent CO insertion, (CO) 4 Mn-[η 2 -COC(H)(p-tolyl)N(CH 3 )COPh]. The latter represents the first example of a acyl-bound transition-metal-chelated R-amino acid complex and has been characterized by X-ray crystallography. Preliminary reactivity studies demonstrate that (CO) 4 Mn[η 2 -COC(H)(ptolyl)N(CH 3 )COPh] reacts with PPh 3 to generate the unchelated cis-(CO) 4 (PPh 3 )Mn[COC-(H)(p-tolyl)N(CH 3 )COPh], while reaction with NaBH 4 leads to the liberation of the amide (p-tolyl)CH 2 N(CH 3 )COPh, rather than the amino acid residue.

A new synthetic route to a dipeptidyl peptidase-4 (DPP4) inhibitor was developed and demonstrated on a multigram scale. This approach takes advantage of the cheap and readily available Boc-trans-4-hydroxy-l-proline methyl ester as starting material which was derivatized through an SN2 reaction. Several leaving groups were studied, and the nosylate group showed superiority over other derivatives. Formation of an amide using the most costly starting material, 3,3-difluoropyrrolidine, was performed late in the synthesis to minimize its economical impact on the overall cost of the API.

A novel iodide-catalyzed reduction method using hypophosphorous and/or phosphorus acids was developed to reduce both diaryl ketones and nitroarenes chemoselectively in the presence of chloro and bromo substituents in high yield. This efficient and practical method has been successfully applied to a large scale production of a potential anticancer agent.