Nicholas Marcopulos

Application of 5-lithiotetrazoles in organic synthesis

Abstract Lithiation of 1-benzyl and 1- p -methoxybenzyltetrazole at the 5-position with n -butyllithium followed by treatment with electrophiles gave functionalized 1-benzylic tetrazoles, which were converted into the 1-unsubstituted derivatives by debenzylation.

ENANTIOSELECTIVE SYNTHESIS OF 4-SUBSTITUTED PHENYLALANINES BY CROSS-COUPLING REACTIONS

The enantiomerically enriched BOC-protected (4-pinacolylborono)phenylalanine methyl ester (8) is produced via enzymatic resolution of the racemic material, or direct synthesis from the corresponding iodide (or triflate), and undergoes Suzuki-Miyaura coupling reactions with aromatic halides and triflates in the presence of catalytic amounts of PdCl2(dppf) to produce enantiomerically enriched 4-substituted phenylalanine derivatives.

Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity and Diabetes

Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).

Synthesis of tetrazole analogs of α-amino acids by alkylation of a Schiff base of α-aminomethyltetrazole

Abstract A benzophenone imine of N-1 protected α-aminomethyltetrazoles was found to undergo alkylation with organic halides in good yields. Deprotection afforded tetrazole analogs of α-amino acids.