Suresh R. Kapadia

Large-Scale Asymmetric Synthesis of a Cathepsin S Inhibitor

A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.

Enantioselective synthesis of the (syn,anti)-1-amino-2,3-diol subunit of renin inhibitors by reaction of β-Lactams with a Grignard reagent

A new approach to the BOC-protected amino diol 1a via the opening of 3,4-cis-disubstituted β-lactam 3 with isobutylmagnesium chloride is described. Nonracemic β-lactam 3 could be obtained by enzymatic resolution of the 3-acetoxy-β-lactam 4 or from a chiral precursor, methyl (R)-(−)-mandelate.

Isoquinolinone synthesis by SNAr reaction: a versatile route to imidazo[4,5-h]isoquinolin-9-ones

Abstract Reaction of 2-chlorobenzonitriles with β-ketoesters in an S N Ar reaction, followed by cyclization in acid provides a versatile route to isoquinolones. Starting from 2,6-dichloro-3-nitrobenzonitrile 7 , sequential displacement of the chlorines by an amine and a β-ketoester leads to imidazo[4,5- h ]isoquinolin-9-ones 1 , a new class of kinase inhibitor.

High-performance liquid chromatography and photoaffinity crosslinking to explore the binding environment of nevirapine to reverse transcriptase of human immunodeficiency virus type-1

Nevirapine (BI-RG-587) is a potent inhibitor of the polymerase activity of reverse transcriptase of human immunodeficiency virus type-1. Nevirapine, as well as several other non-nucleoside compounds of various structural classes, bind strongly at a site which includes tyrosines 181 and 188 of the p66 subunit of reverse transcriptase. The chromatography which was utilized to explore this binding site is described. BI-RH-448 and BI-RJ-70, two tritiated photoaffinity azido analogues of nevirapine, are each crosslinked to reverse transcriptase. The use of several HPLC-based techniques employing different modes of detection makes it possible to demonstrate a dramatic difference between the two azido analogues in crosslinking behavior. In particular, by comparing HPLC tryptic peptide maps of the photoadducts formed between reverse transcriptase and each azido analogue, it can be shown that crosslinking with BI-RJ-70 but not with BI-RH-448 is more localized, stable, and hence exploitable for the identification of the specifically bonded amino acid residue(s). In addition, comparison of the tryptic maps also makes it feasible to assess which rings of the nevirapine structure are proximal or distal to amino acid side chains of reverse transcriptase. Finally, another feature of the HPLC peptide maps is the application of on-line detection by second order derivative UV absorbance spectroscopy to identify the crosslinked amino acid residue.