Stephen P. Marsden

Synthesis of benzazoles by hydrogen-transfer catalysis.

Transition-metal-catalyzed hydrogen-transfer reactions have been used for the conversion of alcohols into benzimidazoles and aldehydes into benzoxazoles and benzothiazoles.

Iridium-catalysed amine alkylation with alcohols in water

Amines have been directly alkylated with alcohols using 1 mol% [Cp*IrI(2)](2) catalyst in water in the absence of base or other additives.

Catalytic aza-Wittig cyclizations for heteroaromatic synthesis.

The first examples of heterocycle synthesis by iminophosphorane formation/intramolecular aza-Wittig cyclizations that are catalytic in the organophosphorus component are reported. The reaction has been demonstrated in the synthesis of both azine (phenanthridine) and azole (benzoxazole) heterocycles. Catalyst loadings down to 1 mol % have been used with little or no loss in reaction efficiency. The intimate involvement of the phosphine oxide in the catalytic cycle has been verified by in situ infrared spectroscopy.

Convergent, Regiospecific Synthesis of Quinolines from o-Aminophenylboronates

A direct convergent two-component synthesis of quinolines from alpha,beta-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.

Facile and general synthesis of quaternary 3-aminooxindoles.

A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused benzodiazepines.

Rhodium(III)-Catalyzed C–H Activation/Annulation with Vinyl Esters as an Acetylene Equivalent

The behavior of electron-rich alkenes in rhodium-catalyzed C-H activation/annulation reactions is investigated. Vinyl acetate emerges as a convenient acetylene equivalent, facilitating the synthesis of sixteen 3,4-unsubstituted isoquinolones, as well as select heteroaryl-fused pyridones. The complementary regiochemical preferences of enol ethers versus enol esters/enamides is discussed.

Alkene Hydroboration: Hot Intermediates That React While They Are Cooling

Non-TST behavior has recently attracted a great deal of attention. If such behavior is general, then the standard way in which synthetic chemists rationalize and predict reactivity and selectivity would be at least partially invalid. The work in this article was inspired by recent results which highlighted a departure from the predictions of TST for rationalization of the regiochemical outcome of the hydroboration reaction mechanism, suggesting that the isomeric product ratios arise because of nonstatistical dynamical effects (J. Am. Chem. Soc. 2009, 131, 3130-3131). We suggest, based on new calculations using a weak collision RRKM-Master Equation (ME) model, an alternative interpretation of the experimental results which preserves a statistical reaction model. While it is a common assumption that all intermediates and transition states along the reaction path are in thermal equilibrium with solvent, our ME results show that hot intermediates may react while they are undergoing stepwise relaxation through weak collisions, even in solution. To our knowledge, this work represents the first application of master equation methodology to a solution phase thermal reaction in organic chemistry that cannot be otherwise explained using conventional TST. Explicit modeling of solvent and solute dynamics is often prohibitively expensive; however, the master equation offers a computationally tractable model with considerable predictive power that may be utilized to investigate whether stepwise collisional relaxation is prevalent in other polyatomic systems.

Total Synthesis of Rapamycin

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

Organic synthesis: The Wittig reaction cleans up

The formation of a phosphine oxide with its strong P=O bond is the driving force for the classical Wittig reaction, but is wasteful and can pose problems during purification. A new development allowing the use of catalytic phosphorus reagents promises to clean up olefination chemistry.

Significance of Nonstatistical Dynamics in Organic Reaction Mechanisms: Time-Dependent Stereoselectivity in Cyclopentyne−Alkene Cycloadditions

The stereochemistry of the reaction between cyclopentyne and ethene has been modeled using statistical methods, based on RRKM theory and a master equation analysis, and by molecular dynamics. We show that the stereochemical retention observed experimentally is not compatible with statistical models that invoke a diradical mechanism but that it can be rationalized through analysis of short time diradical dynamics. Within the first approximately 400 fs, reaction occurs from the initial diradical adduct to form a carbene, which may subsequently isomerize to give the final product. The carbene route has a significantly higher barrier than other channels; however, at short times the reaction energy is efficiently coupled into the reaction coordinate for carbene formation. Loss of the initial ethene stereochemistry by rotation about the former C=C bond occurs on a time scale of approximately 300 fs, so that stereochemistry is retained in the carbene on short time scales. The bond rotation required to pass directly through the low energy transition state leading from the diradical to the [2+2] cycloaddition product is slow because of the attached heavy groups, occurring on a 1-2 ps time scale. Therefore, this low energy channel only becomes active on longer time scales, when memory of the initial ethene stereochemistry has been lost. Short time retention of stereochemistry via the carbene is thus related to the time scales for randomization of both the energy and the geometry. It is argued that these effects may combine to amplify the stereochemical retention for reaction of substituted ethenes in solution.