Thomas A. Bryson

Synthesis of α-Methylene-γ-Butyrolactones

Abstract The development of natural product synthesis is synonomous with the chemistry of unsaturated carbonyl compounds. Central to numerous steroid, terpene and alkaloid syntheses has been the construction of carbocyclic systems using the conjugated enone functional group (e.g. Robinson annelations, Michael additions and similar reactions).1 In addition the unsaturated carbonyl group, which is often used for reductive alkylations, extended enolate alkylations and many other important synthetic operations,2 has been found to be an integral part of the structure of many naturally occurring compounds. The long standing importance of conjugated olefinic carbonyl compounds has resulted in numerous synthetic studies related to the preparation or incorporation of this functional group into natural products. An interesting new phase of these studies has been generated from the recent isolation of naturally occurring sequiterpenoid α-methylene-γ-butyrolactones many of which possess cytotoxic activity.3 Many rese...

Hydroperoxoferric heme intermediate as a second electrophilic oxidant in cytochrome P450-catalyzed reactions

Experimental evidence supporting the catalytic activity of the peroxoferric and hydroperoxoferric cytochrome P450 intermediates as alternative oxidants to the compound I (ferryl) state in the oxygenation of organic substrates is reviewed. The peroxoferric P450 state is proposed to function as a nucleophile in the lyase step of the P450-aromatase reaction. Several systems are reviewed in which the hydroperoxoferric P450 intermediate likely functions as a second electrophilic oxidant, the “two-oxidants” model. These include alkene epoxidation, sulfoxidation, and hydroxylation of methyl groups on cyclopropane rings. The key use of the P450 mutants from different sources in which the conserved threonine in the distal substrate binding pocket is replaced with alanine, in order to minimize the formation of the compound I intermediate and unmask the reactivity of the hydroperoxoferric state, is emphasized. These data are discussed in the context of the “two-states” model, which proposes that the compound I P450 intermediate has both high- and low-spin states with different reactivities. A complicated reaction profile emerges for the wide range of P450 reactions involving up to three reactive intermediates, of which the most reactive, the compound I P450 state, has two spin states with different reactivities.

A green and selective reduction of aldehydes

Abstract Aldehydes are reduced to alcohols with sodium formate in subcritical water at temperatures and pressures below those required to reduce cyclic ketones. Acyclic ketones afford only minor amounts of alcohol with sodium formate even under more forcing conditions.

A 1,5-Diene synthesis via titanium and aluminum mediated reactions

Abstract (1) 1,5-Dienes are readily prepared by titanium mediated methylenation of allyl esters, Claisen rearragement followed by a second methylene transfer reaction. (2) The same 1,5-diene may be approached in “one pot” combining an allyl acetate and 3 equivalents biscyclopentadienyl-titanium-μ-methylidene-bismethyl aluminum.

Boron annulation: total synthesis of (±)-estrone methyl ether

Abstract The stereoselective hydroboration and carbonylation of highly functionalized 1,4-dienes affords trans -hydrindanones in good yield. These trans -hydrindanones are synthons for norpregnenolone, estrone and related estradiol derivatives.

Green heterocycle synthesis, isochromenones and artemidin

Organic transformations in near critical water, generated in heated stainless steel pressure reactors or microwave irradiated Teflon or glass pressure reactors, yield a green synthesis of isochromen-1-ones or isocourmarins. A synthesis of the isochromen-1-one artemidin using a combination of synthetic microwave and commercial microwave equipment is presented.

Cyclopropane chemistry related to the alkaloid CC-1065

Abstract Aspects of cylcopropane chemistry relative to the subunits of CC-1065 are discussed.

Synthesis of quinolines, pyridine ligands and biological probes in green media

Nitrogen heterocycles are prepared using hot pressurized water under microwave and thermal conditions. Selective reduction, cyclodehydrations (Friedlander and Pfitzinger syntheses), Suzuki coupling, and ligand exchange have been effected in water or water–protic solvent media.

Nuclear magnetic resonance studies on pyridine dinucleotides: The pH dependence of the carbon-13 nuclear magnetic resonance of NAD+ analogs☆

Abstract The pH dependence of the 13 C chemical shifts for nicotinamide adenine dinucleotide (NAD + ), thionicotinamide adenine dinucleotide (TNAD + ), pyridine adenine dinucleotide (PyrAD + ), N -methyl-nicotinamide adenine dinucleotide (N-Me-NAD + ), acetylpyridine adenine dinucleotide (AcPyAD + ), nicotinamide hypoxanthine dinucleotide (NHD + ), and nicotinamide adenine dinucleotide phosphate (NADP + ) are reported. In these analogs the 13 C chemical shifts of the pyridinium moiety reflect the p K a of the opposing purine base, while the 13 C chemical shift dependence on pD for the pyridinium carbons of nicotinamide mononucleotide (NMN + ) and adenosine monophosphate (AMP), 1,4-dihydronicotinamide adenine dinucleotide (NADH), 1,4-dihydronicotinamide adenine dinucleotide phosphate (NADPH), and nicotinic acid adenine dinucleotide (N(a)AD + ) are not influenced by the adenine ring in the pD range tested. Through the use of 13 C-labeled NAD + , the source of the pH dependence of the 13 C chemical shifts was shown to be intramolecular in origin. However, serious doubt is cast on the utility of employing the pD dependence of chemical shift data to determine the nature of solution conformers or their relative populations.

The syntheses of 1R- and 1S-5-methylenylcamphor and their epoxidation by cytochrome P-450-CAM

Abstract The syntheses of 1R- and 1S-5-methylenylcamphor, camphor analogues in which the two methylene hydrogens at C-5 have been replaced with an exocyclic methylene group, are described. The stereospecific epoxidations of both olefins by Pseudomonas putida cytochrome P450-CAM to give the exo -epoxides are reported. The turnover rates for the epoxidation of the 1R and 1S olefins are ten- and three-fold slower, respectively, than the rates of hydroxylation of 1R- and 1S-camphor.