Michael P. Trova

Practical, Large-Scale Synthesis of 2,2-Dimethyl-5-hydroxy-4-oxo-benzo-1,4-dioxin

Abstract Modification of a known procedure employing the interaction of thionyl chloride, acetone, and 2,6-dihydroxybenzoic acid was found, to provide the title compound in multikilogram quantities of acceptable yield and purity.

Heterobiaryl purine derivatives as potent antiproliferative agents: Inhibitors of cyclin dependent kinases. Part II

C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).

Synthesis of C2-symmetric compounds via double alkylation of (α,ω-dioxo-alkanediyl)bis-2-oxazolidinone derivatives

Abstract A series of chiral C 2 -symmetric compounds was prepared from readily available α,ω-diacyl chlorides and optically pure 2-oxazolidinone derivatives. Following preparation of the asymmetrically pure bis-oxazolidinone derivatives ( 6a–d , 11 , 13 , and 20 ), we prepared the dienolate of these compounds and quenched the reaction mixture with electrophiles such as iodomethane, allyl iodide, and benzyl bromide. Compounds 14a–e , and 15 were isolated with diastereomer ratios in excess of 9.8:1. If the chain length between the two carbonyl atoms was sufficiently small, dialkylation did not occur, but instead, provided cyclization products 18 , 19 , and 21 . Mono-alkylated products 22a–c were prepared from 6c or 6d in modest yield. Unsymmetrical dialkylated compound 23 was prepared in 50% yield from 22b .

Synthesis and biological evaluation of a series of HIV-1 protease inhibitors

Abstract A series of HIV-1 protease inhibitors was prepared and evaluated against the free enzyme for inhibition properties, and for their anti-viral properties in human T lymphoid cells infected with HIVIIIB. Compounds 12, and 19 are the most potent anti-viral agents prepared in this study and are compared to Ro 31-8959, a compound currently in clinical trials for the treatment of AIDS.

Asymmetric synthesis of cis- and trans-γ-lactones useful in HIV-1 protease inhibitor synthesis

Abstract Iodolactones 5 and 11 have been prepared in asymmetric form from a common precursor carboxylic acid 4 . These iodolactones were then transformed into lactones 7 and 12 , respectively. Lactones 7 and 12 were converted to potent HIV-1 protease inhibitors 1 and 2 , respectively, by a five-step sequence. Lactones 7 and 12 were also prepared in a 1:1 ratio from epoxide 14 .

Asymmetric synthesis of optically active decahydroisoquinolines useful in HIV-1 protease inhibitor synthesis

Abstract An efficient synthesis of amino acid ester 8 is described featuring an asymmetric aza-Diels-Alder reaction of diene 5 and chiral imine 6 which establishes the asymmetry at C-3. Hydrogenation of 7 provides 8 with the desired asymmetry at C-4a and C-8a.