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A large-scale synthesis of denagliptin tosylate has been developed. The efficiency of the synthesis has been improved from the initially scaled route by changing the order of steps (performing a dehydration at a late stage). The key step of the synthesis is a single-step peptide coupling/dehydration, mediated by n-propanephosphonic acid cyclic anhydride. The challenges of developing this synthesis into a robust and practical manufacturing route are described.

4-Fluoro-β-(4-fluorophenyl)-l-phenylalanine 1 was synthesized by the asymmetric phase-transfer catalyzed alkylation of tert-butyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6. Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to add the catalyst or base last. From these studies, insight into the stability of the catalyst 6 under the reaction conditions was gained.

An efficient regioselective method for the direct arylation of 2-furaldehyde to provide a range of pi-diverse 5-aryl-2-formylfuran derivatives is described. The method employs functionalized aryl halides and a catalytic amount of palladium(II) chloride under relatively mild conditions.

α-Diazo carbonyl compounds containing an imino group in the γ-position have been found to undergo a rhodium(II) acetate induced cyclization reaction to generate cyclic azomethine ylides. The reactive dipole un- dergoes a subsequent 1,3-dipolar cycloaddition with added dipolarophi- les. The imino/oxime nitrogen lone pair of electrons must be properly oriented so as to interact with the rhodium carbenoid. Thus, acyclic oxide ethers which exist in the proper E-configuration readily undergo the tandem cyclization-cycloaddition reaction. In sharp contrast, the isomeric Z-oximino diazo carbonyl system does not cyclize to an azome- thine ylide but rather intramolecularly inserts into the oximino C-H bond

A series of alkenyl-substituted imides were prepared by treating the appropriate amide with 2,2,6-trimethyl-4H-1,3-dioxen-4-one in xylene at 140 o C to give the N-acetoacylated imides. Exposure of these imides to standard diazo transfer conditions gave the desired diazoimides. The carbenoid intermediate derived by treatment of the diazoimide with rho- dium(II) acetate undergoes ready cyclization onto the neighboring amide carbonyl oxygen atom to generate an isomunchnone intermediate. Subse- quent 1,3-dipolar cycloaddition across the pendant olefin affords the cycloadduct in high yield. The stereochemical assignment of several of the cycloadducts was deduced by X-ray crystallography. The stereochemi- cal outcome of the reaction is the consequence of an endo cycloaddition of the neighboring π-bond across the transient isomunchnone dipole. Mo- lecular mechanics calculations were used to model energy differences between the endo and exo diastereoisomers. The calculations reveal that the endo diastereomers are significantly (8-12 kcal/mol) lower in energy than the correspnding exo isomers thereby providing a rationale for the preferred endo cycloaddition

This review describes the methods of preparation and use of isomunchnones and thioisomunchnones to synthesize furans, 2-pyridones, functionalized lactams and other heterocyclic ring systems. Some promising intramolecular dipolar cycloadditions of these mesoionic compounds, and their potential for natural product syntheses, are presented

The intramolecular cycloaddition of isomunchnone dipoles containing alkenyl π-bonds produces oxabicyclic amides. These cycloadducts were employed as masked N-acyliminium ions for cationic π-cyclizations as an approach to B-ring homologues of erythrinane alkaloids

A unique buffering effect of various bases, i-Pr(2)NEt and CaCO(3) in particular, was observed for the acid-catalyzed chloro displacement of 2-chloro-5-ethylpyrimidine with a 2-methyl-2-phenylpropanamine. The use of the carefully chosen bases was essential for the progression of the chloro displacement as well as the stability of the product in the presence of HCl formed. Research work leading to an efficient synthesis of PPARpan agonist GW693085 is described, featuring highly selective sequential N- and O-alkylations.

The intramolecular cycloaddition of isomunchnone dipoles containing alkenyl π-bonds produces oxabicyclic amides. These cycloadducts were employed as masked N-acyliminium ions for cationic π-cyclizations as an approach to B-ring homologues of erythrinane alkaloids

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment for osteoporosis, arthritis, and other inflammatory diseases. A series of thienyl, furyl, and pyrrolyl ureas has been identified as potent p38 inhibitors, displaying in vitro activity in the nanomolar range.