Lisa DiMichele

The behavior of indene oxide in the ritter reaction: A simple route to cis-aminoindanol

Abstract A regio- and stereoselective synthesis of cis-1-aminoindan-2-ol via a Ritter reaction is described.

AN EFFICIENT ASYMMETRIC HYDROGENATION APPROACH TO THE SYNTHESIS OF THE CRIXIVAN PIPERAZINE INTERMEDIATE

Abstract The Crixivan ® HIV protease inhibitor piperazine intermediate 2 was prepared by a four step sequence using a chiral hydrogenation of the tetrahydropyrazine 9 to establish the absolute stereochemistry.

Highly efficient synthesis of α,β-acetylenic aldehydes from terminal alkynes using DMF as the formylating reagent

Abstract The formylation of lithium acetylides with DMF led to α,β-acetylenic aldehydes in excellent yields (>94%). A reverse quench into a phosphate buffer (10% aqueous KH 2 PO 4 ,4 equiv) proved to be the key for this high-yielding reaction.

Bioconversion of indene to cis (1S,2R) indandiol and trans (1R,2R) indandiol by Rhodococcus species

Abstract cis (1 S ,2 R ) indandiol or trans (1 R ,2 R ) indandiol are both potential precursors to (−)- cis (1 S ,2 R )-1-aminoindan-2-ol, a key chiral synthon for Crixivan ® (Indinavir), a leading HIV protease inhibitor. Enrichment and isolation studies yielded two Rhodococcus sp. strain B 264-1 (MB 5655) and strain I-24 (MA 7205) capable of biotransforming indene to cis (1 S ,2 R ) indandiol and trans (1 R ,2 R ) indandiol respectively. Isolate MB 5655 was found to have a toluene dioxygenase, while isolate MA 7205 was found to harbor both toluene and naphthalene dioxygenases as well as a naphthalene monooxygenase. When scaled up in a 14- l bioreactor, MB 5655 produced up to 2.0 g/ l of cis (1 S ,2 R ) indandiol with an enantiometric excess greater than 99%. MA 7205 cultivated under similar conditions produced up to 1.4 g/ l of trans (1 R ,2 R ) indandiol with an enantiomeric excess greater than 98%. Process development studies yielded titers greater that 4.0 g/ l of cis indandiol for MB 5655. Due to their resistance to indene toxicity and easy cultivation in bioreactors, both Rhodococcus sp. strains appeared as good candidates for future strain engineering and process development work.

Regio- and stereocontrolled syntheses of cyclic chiral cis-amino alcohols from 1,2-diols or epoxides

Abstract The behavior of 1,2-dioxygen derivatives of indane, tetralin, and benzosuberane in acetonitrile-strong acid media is exploited in the regio- and stereocontrolled syntheses of chiral cis-amino alcohols.

An efficient and versatile synthesis of piperazine-2-carboxamides

Abstract An efficient and versatile synthesis of piperazine-2-carboxamides 5 is described. The preparation consists of a one-pot, 4-component Ugi condensation between an N-alkylethylenediamine 1 , chloroacetaldehyde ( 2 ), an isonitrile 3 and a carboxylic acid 4 .

Effects of amino acid and trace element supplementation on pneumocandin production by Glarea lozoyensis: impact on titer, analogue levels, and the identification of new analogues of pneumocandin B0

Addition of the amino acids threonine, serine, proline, and arginine to fermentations of the fungus Glarea lozoyensis influenced both the pneumocandin titer and the spectrum of analogues produced. Addition of threonine or serine altered the levels of the “serine analogues” of pneumocandins B0 and B5 and allowed for their isolation and identification. Proline supplementation resulted in a dose-dependent increase in the levels of pneumocandins B0 and E0, whereas pneumocandins C0 and D0 decreased as a function of proline level. Moreover, proline supplementation resulted in an overall increase in the synthesis of both trans-3- and trans-4-hydroxyproline while maintaining a low trans-4-hydroxyproline to trans-3-hydroxyproline ratio compared to the unsupplemented culture. Pneumocandin production and the synthesis of hydroxyprolines was also affected by addition of the proline-related amino acid arginine but not by the addition of glutamine or ornithine. Zinc, cobalt, copper, and nickel, trace elements that are known to inhibit α-ketoglutarate-dependent dioxygenases, affected the pneumocandin B0 titer and altered the levels of pneumocandins B1, B2, B5, B6, and E0, analogues that possess altered proline, ornithine, and tyrosine hydroxylation patterns. Journal of Industrial Microbiology & Biotechnology (2001) 26, 216–221.

Controlled Synthesis of 2- and 3-Substituted Benzo[b]furans

A controlled regioselective synthesis of either C-2 or C-3 substituted benzo[b]furans from readily accessible 1-(2-hydroxyphenyl)-2-chloroethanones is described. Addition of a range of Grignard reagents to the α-chloro ketones generates alkoxide intermediates, which can form either 2-substituted benzo[b]furans via a [1,2]-aryl migration or 3-substituted benzo[b]furans via a direct cyclization and dehydration sequence. A temperature-dependent [1,2]-aryl migration mechanism for the formation of 2-substituted benzo[b]furan is proposed.

An efficient and stereoselective construction of the core structure of the manzamines via an intramolecular Michael reaction

Abstract A strategically functionalized tricyclic subunit of the manzamines was efficiently synthesized with complete stereochemical control using a combination of an intramolecular Michael reaction of a pyroglutamic acid derivative and a hydrogenation.

Autooxidation of simvastatin

Abstract Autooxidation of the cholesterol-lowering agent simvastatin in ethylene dichloride solution with an azo-type free-radical initiator was investigated in kinetic studies using HPLC. The primary products were oligomers, with peroxide groups within the backbone chain, and some monomeric epoxides. These and several secondary products were isolated chromatographically and identified spectroscopically. A reaction scheme was proposed in which the oligomers arise from competitive hydrogen abstraction and addition reactions of oligomeric free radicals with simvastatin while the epoxides arise from homolytic peroxide cleavage.