Joseph S. Amato

Acylimidazolides as Versatile Synthetic Intermediates for the Preparation of Sterically Congested Amides and Ketones: A Practical Synthesis of Proscar®

Abstract Acylimidazolides react with magnesium amides to produce car-boxamides in excellent yields, whereas Fe(III) catalyzed cross coupling between acylimidazolide and Grignard reagents produce ketones in high yields. These methods were utilized to prepare the α-reductase inhibitor Proscar® as well as various 17β-amide and ketone analogs of Δ1-4-aza-5α-androsten-3-one.

Annelation of aromatic oxo compounds

Abstract The silyl enol ether of α-diazoacetoacetate is used for the annelation of aromatic oxo compounds. The method involves condensation with the oxo compound in the presence of TiCl4 followed by rhodium octanoate-catalyzed ring closure to afford furan derivatives by direct carbene isertion and β-naphthol esters by a Wolff rearrangement pathway.

Cyclization of electrochemically generated nitrogen radicals. : A novel synthesis of 11-substituted dibenzo[a,d]cycloheptenimine derivatives

Abstract A novel and convenient synthesis of 11-substituted dibenzo[a,d]cyclo-heptimines 10 via annelatlon of electrochemically generated aminium radicals derived from substituted 5-hydroxylamino-5-methyl-5H-dibenzo[a,d]cycloheptenes 14 is described. The scope and limitations of the reaction as well as the effects of reactor design, current density and electrode material on the yield of 10 and the carbocation rearrangement by-product 28 are discussed.

Process development for the production of the (S)-acid precursor of a novel elastase inhibitor (L-694,458) through the lipase-catalyzed kinetic resolution of a β-lactam benzyl ester

Abstract A limited screen of several commercially-available and internally-produced lipases and esterases identified the lipase PS-800 as a suitable biocatalyst for the resolution of a racemic β-lactam benzyl ester to the ( S )-acid. This β-lactam is a precursor to the elastase inhibitor L-694,458, an experimental drug targeted for the treatment of cystic fibrosis. Key to the development of a scalable process was the optimization of β-lactam and surfactant (Triton X-100) charges. These optimization studies yielded a 21-fold increase in the volumetric production of the ( S )-acid (from 0.38 g/ l to 8.0 g/ l ) and a 10-fold improvement in the initial bioconversion rate (from 17 mg/( l ·h) to 170 mg/( l ·h)). Additionally, these studies achieved the control of the ( S )-acid enantiomeric excess (e.e.) which was improved from less than 65% to greater than 90%. Keys to an economical and high yielding process, both the recycling of the lipase (at levels of 90%) and the use of re-racemized unreacted ( R )-benzyl ester in multiple reaction cycles were successfully demonstrated. This process was scaled up in 2.0- l reactors and afforded gram quantities of greater than 90% e.e ( S )-acid, which upon purification was successfully used to synthesize the elastase inhibitor L-694,458.

1,2,5-thiadiazole-1-oxides, IV, ring transformation to 1,2,3,5-thiatriazole- and 1,2,4,6-thiatriazene-1-oxide

Abstract 2-Alkyl-1,2,5-thiadiazole-3-one-1-oxides were converted to 1,2,3,5-thiatriazole-1-oxides and 1,2,4,6-thiatriazene-1-oxides. The postulated intermediate of these rearrangements, a sulfinylamine, was isolated.

Enzymes and practical asymmetric synthesis

A practical, chemoenzymatic, four-step synthesis of the LTD4 antagonist MK-0679 is described. The key steps are enzymatic hydrolysis of the prochiral diester to the ester-acid in 99% enantiomeric excess followed by aluminum mediated amidation of the methyl ester to afford MK-0679 in high overall yield. This synthesis is superior to the synthesis of the racemate MK-0571.

High temperature reactions of benzene

Abstract High temperature reactions of benzene with olefins and acetylenes are described, and interpreted as Diels-Alder, retrodiene and related steps. The results are discussed in terms of both concerted and diradical mechanisms.