David M. Barnes

Cationic bis(oxazoline)Cu(II) Lewis acid catalysts. Enantioselective furan Diels-Alder reaction in the synthesis of ent-shikimic acid

Abstract The highly enantioselective Diels-Alder reaction between acryloyl oxazolidinone and furan, catalyzed by cationic bis(4- tert -butyloxazoline)Cu(II) complex 1 , is presented. Though the reaction equilibrates rapidly at −20 °C, reaction at −78 °C permits isolation of the kinetic product mixture. The synthetic utility of the reaction is demonstrated by the conversion of the cycloadduct to ent -shikimic acid.

Cationic bis(oxazoline)Cu(II) lewis acid catalysts. Application to the asymmetric synthesis of ent-Δ1-tetrahydrocannabinol

Abstract The Diels-Alder reaction of acryloyl oxazolidinone and 1-acetoxy-3-methylbutadiene is catalyzed by the cationic bis(oxazoline)Cu(II) complex 4 in high enantioselectivity. The cycloadduct is converted to ent - Δ 1 -tetrahydrocannabinol (THC) in four steps.

Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

This laboratory and others have shown that agents that inhibit the in vitro catalytic activity of methionine aminopeptidase-2 (MetAP2) are effective in blocking angiogenesis and tumor growth in preclinical models. However, these prototype MetAP2 inhibitors are clearly not optimized for therapeutic use in the clinic. We have discovered an orally active class of MetAP2 inhibitors, the anthranilic acid sulfonamides exemplified by A-800141, which is highly specific for MetAP2. This orally bioavailable inhibitor exhibits an antiangiogenesis effect and a broad anticancer activity in a variety of tumor xenografts including B cell lymphoma, neuroblastoma, and prostate and colon carcinomas, either as a single agent or in combination with cytotoxic agents. We also have developed a biomarker assay to evaluate in vivo MetAP2 inhibition in circulating mononuclear cells and in tumors. This biomarker assay is based on the N-terminal methionine status of the MetAP2-specific substrate GAPDH in these cells. In cell cultures in vitro, the sulfonamide MetAP2 inhibitor A-800141 caused the formation of GAPDH variants with an unprocessed N-terminal methionine. A-800141 blocked tumor growth and MetAP2 activity in a similar dose–response in mouse models, demonstrating the antitumor effects seen for A-800141 are causally connected to MetAP2 inhibition in vivo. The sulfonamide MetAP2 inhibitor and GAPDH biomarker in circulating leukocytes may be used for the development of a cancer treatment.

A highly diastereoselective vinylogous Mannich condensation and 1,4-conjugate addition of (Z)-propenyl cuprate in the synthesis of an influenza neuraminidase inhibitor

A practical synthesis of neuraminidase influenza inhibitor, A-322278, has been developed. Asymmetry is introduced into the synthesis by an enzyme mediated ester hydrolysis. A highly diastereoselective vinylogous Mannich condensation reaction of N-Boc-2-tert-butyldimethylsilyloxypyrrole (TBSOP) and an N-(triphenylmethylsulfenyl)imine proceeds under thermodynamic control to assemble the framework. A significant temperature dependent rate difference for the transfer of (Z)- and (E)-propenyl moieties from a cuprate reagent during a 1,4-conjugate addition was observed. A very selective addition of cyanide to an N-acyliminium intermediate was employed to control the final stereocenter.

A facile method for the preparation of MOM-protected carbamates.

A novel method for the preparation of MOM-protected carbamates is described that avoids the use of MOM-Cl, a regulated carcinogen. The two-step, one-pot procedure generates a reactive N-chloromethyl carbamate that is quenched with methanol to afford MOM-protected carbamates. The process is tolerant of a variety of functionalities, including Boc, sulfonamide, and acetamide protecting groups. Mild conditions for the removal of the MOM group are also described; selective deprotection of the MOM group in the presence of a Boc group has been demonstrated.