Charles Jackson Barnett

1,3-Dipolar cycloaddition reactions of pyrazolidinium ylides with vinyl sulfones. A regioselective synthesis of bicyclic pyrazolidinone antibacterial agents

Abstract The 1, 3-dipolar cycloaddition reaction of pyrazolidinium ylide 1 with substituted vinyl sulfones 5 was studied. Elimination of benzenesulfinic acid from the resulting cycloadducts gave rise to bicyclic pyrazolidinones 3 . The (E)-olefin isomers were found to undergo cycloaddition in a highly regioselective fashion. These pyrazolidinones 3 represent the nuclei of an exciting new class of potent antibacterial agents that mimic β-lactams.

Asymmetric synthesis of dideazafolate antitumor agents via amidomethylation of nonracemic oxazolidinone imidates. Synthesis of LY309887, a cytotoxic dideazafolate analog related to lometrexol

Abstract The asymmetric synthesis of LY309887, a cytotoxic dideazatetrahydrofolate analog related to lometrexol, has been accomplished via an application of diastereoselective amidomethylation of a chiral titanium (IV) acyloxazolidinone enolate.

Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF)

Abstract Lipase-catalyzed enantioselective esterification of 2-substituted 1,3-diols has been utilized in the asymmetric synthesis and consequent configurational assignments of the title compounds.

Synthesis of LY288601, a 5.6-Dihydropyprrolo[2,3-d]pytrimidine Based Antifolate Compunds Related to LY231514

An expeditious synthesis of LY288601 (2), the 5,6-dihydro analog of the pyrrolo[2,3-d]pyrimidine-based antifolate compound LY231514 (1a), is described. The synthesis proceeds in eight steps from tert-butyl 4-iodobenzoate and involves the elaboration of a 2-amino-4-hydroxypyrmidine ring onto an activated 3-carboalkoxy-2-pyrrolidinone via reaction with guanidine as a key step

Synthesis of pyrrolo[2,3-d]pyrimidines via cyclocondensation of β-alkoxy- and β-amino-α-bromoaldehydes

Abstract A series of β-alkoxy- and β-amino-α-bromoaldehydes was synthesized. The cyclocondensation of these intermediates with 2,4-diamino-6-hydroxypyrimidine yielded a series of pyrrolo[2,3- d ]pyrimidines containing heteroatoms in the side chain. Choice of protecting group proved critical to the success of the bromination and cyclocondensation reactions. A number of oxygen and nitrogen protecting groups were examined and the results are described herein.

Synthesis and Antitumor Activity of LY288601, the 5,6-Dihydro Analog of LY231514

The series of deaza analogs of folic acid has been a rich source of compounds of interest as potential antitumor drugs.1 The mode of action of these compounds is, however, related to structure in ways not yet fully understood. For example, DDATHF2 is a specific inhibitor of glycinamide ribonucleotide formyl transferase (GARFT)3 while the related pyrrolo[2,3-d]pyrimidine-based analog, LY231514, has been found to inhibit thymidylate synthase (TS) 4 Both (6R)-DDATHF (lometrexol)5 and LY2315146 have shown promising in vivo antitumor activity against a variety of murine and human tumor cell lines and are currently undergoing clinical evaluation. LY288601 may be viewed as a hybrid structure which possesses both the ring saturation of DDATHF and the 6,5-heterocyclic ring system of the pyrrolo[2,3-d]pyrimidine-based LY231514. LY288601 was first described by Akimoto and coworkers7 (as Takeda T-41440) but only limited cytotoxicity data has been reported.8 We report here a convenient alternate synthesis of LY288601, the results of cell culture cytotoxicity and reversal experiments, and in vivo antitumor evaluation of this compound in comparison with DDATHF and LY231514.