Computational investigation of the competition between the concerted Diels-Alder reaction and formation of diradicals in reactions of acrylonitrile with nonpolar dienes.

The energetics of the Diels-Alder cycloaddition reactions of several 1,3-dienes with acrylonitrile, and the energetics of formation of diradicals, were investigated with density functional theory (B3LYP and M06-2X) and compared to experimental data (Hall et al., J. Org. Chem.1993, 58, 7049-7058). For the reaction of 2,3-dimethyl-1,3-butadiene with acrylonitrile, the concerted reaction is favored over the diradical pathway by 2.5 kcal/mol using B3LYP/6-31G(d); experimentally, this reaction gives both cycloadduct and copolymer. The concerted cycloaddition of cyclopentadiene with acrylonitrile is preferred computationally over the stepwise pathway by 5.9 kcal/mol; experimentally, only the Diels-Alder adduct is formed. For the reactions of (E)-1,3-pentadiene and acrylonitrile, both cycloaddition and copolymerization were observed experimentally; these trends were mimicked by the computational results, which showed only a 1.2 kcal/mol preference for the concerted pathway. For the reactions of (Z)-1,3-pentadiene and acrylonitrile, the stepwise pathway is preferred by 3.9 kcal/mol, in agreement with previous experimental findings that only polymerization occurs. M06-2X is known to give more accurate activation and reaction energetics (Pieniazek, et al., Angew. Chem. Int.2008, 47, 7746-7749), but the energies of diradicals are too high.

Quantum mechanical investigation of the effect of catalyst fluorination in the intermolecular asymmetric Stetter reaction.

The asymmetric intermolecular Stetter reaction was investigated using the B3LYP and M06-2X functionals. Fluorination of a triazolium bicyclic catalyst had been found to significantly influence reaction yields and enantiomeric ratios. Computations indicate that the improved reactivity of the fluorinated catalyst is due to better electrostatic interactions between the nitroalkene and catalyst. Computational investigations of preferred conformations of the ground state catalyst and acyl anion equivalent, and the transition structures leading to both enantiomers of the products, are reported.

Oxyallyl exposed: an open-shell singlet with picosecond lifetimes in solution but persistent in crystals of a cyclobutanedione precursor.

Photoinduced decarbonylation of 2,4-bis(spirocyclohexyl)-1,3-cyclobutanedione 1 in the crystalline solid state resulted in formation of a deep blue transient with λ(max) = 550 nm and a half-life of 42 min at 298 K, identified as kinetically stabilized oxyallyl. Support for an open-shell singlet species was obtained by spectroscopic analysis and (4/4) CASSCF calculations with the 6-31+G(d) basis set and multireference MP2 corrections. The electronic spectrum of the singlet biradical, confirmed by femtosecond pump-probe studies in solution, was matched by coupled cluster calculations with single and double corrections.

Nature of intermediates in organo-SOMO catalysis of alpha-arylation of aldehydes.

The intramolecular alpha-arylation of aldehydes via organo-SOMO catalysis was investigated using density functional theory (B3LYP and M06-2X functionals). The geometries, spin densities, Mulliken charges, and molecular orbitals of the reacting enamine radical cations were analyzed, and the nature of the resulting cyclized radical cation intermediates was characterized. In agreement with experimental observations, the calculated 1,3-disubstituted aromatic system shows ortho selectivity, while the 1,3,4-trisubstituted systems show para, meta (instead of ortho, meta) selectivity. The selectivity change for the trisubstituted rings is attributed to a distortion of the ortho substituents in the ortho, meta cyclization transition structures that causes a destabilization of these isomers and therefore results in selectivity for the para, meta product.

Transition states and origins of 1,4-asymmetric induction in alkylations of 2,2,6-trialkylpiperidine enamines.

The asymmetric C-alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6-trialkylpiperidides has previously been shown to provide alpha-alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6-31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C-6 alkyl substituent in an axial position due to A(1, 3) strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C-6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.

Computational investigations of the stereoselectivities of proline-related catalysts for aldol reactions.

Computational investigation of the aldol reaction of benzaldehyde with acetone catalyzed by various proline derivatives and 2-azetidine carboxylic acid reveal the origins of stereoselectivities of these reactions. Structural differences between catalysts and transition states were analyzed with density functional theory geometries in order to establish the key factors that will help in the design of new catalysts.

Thermodynamic control of the electrocyclic ring opening of cyclobutenes: C=X substituents at C-3 mask the kinetic torquoselectivity.

The thermal ring-opening reactions of 4-phenyl-1,3,3-triethoxycarbonylcyclobutene and 4-methyl-1,3,3-triethoxycarbonylcyclobutene yield dienes that result from an unexpected selectivity for "inward" rotation of the phenyl and methyl groups. With 1-ethoxycarbonyl-4-phenylcyclobutene, "outward" rotation of the phenyl group occurs exclusively. Density functional theory was used to investigate the role of the 3,3-geminal diester groups and the origin of torquoselectivity in these electrocyclic reactions. The rules of torquoselectivity still hold, with a calculated 6-8 kcal/mol preference for outward rotation of the methyl and phenyl substituents. However, cyclization of the "out" dienes to pyran intermediates allows for isomerization and thermodynamic control of stereoselectivity.

Synthesis and C-alkylation of hindered aldehyde enamines.

A new reactivity mode of hindered lithium amides with terminal epoxides is described whereby aldehyde enamines are produced via a previously unrecognized reaction pathway. Some of these aldehyde enamines display unprecedented C-alkylation reactivity toward unactivated primary and secondary alkyl halides. For comparison, the reactivity of aldehyde enamines synthesized via a traditional condensation method was examined. C- rather than N-alkylation was the dominant reaction pathway found with a range of electrophiles, making this route to alpha-alkylated aldehydes more synthetically useful than previously reported.

Origin of stereoselectivity in the reduction of a planar oxacarbenium.

The Kishi reduction of a planar oxacarbenium was investigated theoretically. The high diastereoselectivity for hydride transfer to the oxacarbenium intermediate is attributed to the conformation of the transition state that places the allyl side chain in an equatorial position in the major transition state and axial position in the minor. The minor transition state is destabilized by a 1,3-diaxial strain between the attacking hydride and the syn allyl side chain.

Origins of stereoselectivity in the oxido-alkylidenation of alkynes.

A mild, convenient oxido-alkylidenation of alkynes is described. The three-step sequence involves the 1,3-dipolar cycloaddition of a nitrone and an alkynoate, oxidation of the resulting isoxazoline, and stereoselective extrusion of nitrosomethane. Quantum mechanical calculations identified the interactions of R3 with the oxidant and the preferred conformation of a diradical intermediate as major factors controlling the stereoselectivity of the oxidation and torquoselectivity of the extrusion.

Stereoselective synthesis of an anti-HIV drug candidate.

The asymmetric synthesis of a Merck anti-HIV drug candidate is described. The target molecule contains four stereogenic centers, three of which are located in a highly functionalized cyclopentane unit. The convergent synthesis involves the preparation of two key advanced intermediates: the cyclopentane unit and a substituted pyrazole unit. The cyclopentane unit was prepared via two different procedures; a highly diastereoselective Diels-Alder reaction with a chiral oxazolidinone auxiliary and a sequence that incorporated a molybdenum-catalyzed asymmetric allylic alkylation reaction to set the stereocenters. The other key step was a highly diastereoselective hydroxyl-directed reductive amination. The overall yield for the 16-step synthesis was 10%.

Development of a new and practical route to chiral 3,4-disubstituted cyclopentanones: asymmetric alkylation and intramolecular cyclopropanation as key C-C bond-forming steps.

An efficient and practical asymmetric synthesis of (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone (1) is described. An asymmetric Mo-catalyzed alkylation reaction was used to establish the first stereocenter and a Cu-catalyzed intramolecular diastereoselective cyclopropanation reaction was used to set the second stereocenter. The last step involved a one-pot ring-opening/deprotection/hydrolysis/decarboxylation sequence that furnished the desired product in good yield.