Deepa Janardanan

Does the TauD Enzyme Always Hydroxylate Alkanes, While an Analogous Synthetic Non-Heme Reagent Always Desaturates Them?

This theoretical work addresses the mechanistic switch between hydroxylase (alcohol formation) and desaturase (olefin formation) activities during alkane oxidation by two non-heme high-valent oxoiron reagents, the enzyme taurine:α-ketoglutarase dioxygenase (TauD) and the synthetic shape-selective catalyst (TpOBzFe), toward cyclohexadiene, cyclohexane, cyclopentane, and ethane. As we show, the desaturase/hydroxylase steps obey unique orbital selection rules, and the mechanistic switch is determined by intrinsic reactivity factors that depend on the ligand-sphere flexibility of the oxoiron species, the substrate, and the spin states of the reaction pathways. Testable predictions are outlined.

Enantio-and Diastereoselectivities in Chiral Sulfur Ylide Promoted Asymmetric Aziridination Reactions

Density functional theory investigation on the factors controlling enantio- and diastereoselection in asymmetric aziridination reaction by the addition of chiral bicyclic sulfur ylides to substituted aldimines is presented. High levels of enantioselection are predicted toward the formation of (2S,3S)-cis and (2R,3S)-trans aziridines by the addition of stabilized ylide (R = COMe) respectively to SO2Me and CO2Me protected aldimines. Similarly, high %ee is predicted for the formation of (2S,3R)-cis aziridines from semistabilized (R = Ph) ylide. Moderate to high levels of diastereoselectivity is noticed as well. The present study highlights that a correct prediction on extent of enantioselection requires the knowledge of the activation barriers for elementary steps beyond the initial addition step. In the case of stabilized ylides the ring-closure (or elimination of sulfur compound) is found to be crucial in controlling enantio- and diastereoselection. A cumulative effect of electronic as well as other weak interactions is identified as factors contributing to the relative energies of transition states leading to enantio- and diastereomeric products for the stabilized ylide addition to aldimines. On the contrary, steric control appears quite dominant with semistabilized ylide addition. With the smallest substituent on ylide (R = Me), high enantioselectivity is predicted for the formation of (2R,3R)-trans aziridines although the %de in this case is found to be very low.

Chemo-, regio-, and diastereoselectivity preferences in the reaction of a sulfur ylide with a dienal and an enone

Mechanistic insights into an interesting class of reaction between sulfur ylides with (i) a dienal, and (ii) an enone, obtained by using density functional theory, is reported. The kinetic and thermodynamic factors responsible for chemo-, regio-, and diastereoselectivities are established by identifying all key transition states and intermediates along the reaction pathway for 1,2-, 1,4-, and 1,6- modes of attack of dimethylsulfonium benzylide to 5-phenylpenta-2,4-dienal. The reaction profiles for 1,2- and 1,4- modes of addition are also evaluated for the reaction between dimethylsulfonium benzylide and pent-3-en-2-one. Our results show that the final outcome of the reaction with both these substrates would be decided by the interplay between kinetic and thermodynamic factors. It is found that the addition of a semi-stabilized ylide to conjugated carbonyl compounds prefers to proceed through a 1,4- (conjugate) pathway under thermodynamic conditions, which is in accordance with the available experimental reports. However, the formation of epoxides via a 1,2- (direct) addition pathway is computed to be equally competitive, which could be the favored pathway under kinetic conditions. Even though the lower barrier for the initial addition step is kinetically advantageous for the direct (or 1,2-) addition pathway, the higher energy of the betaine intermediates--as well as the reversibility of the accompanying elementary step--may disfavor product formation in this route. Thus, high diastereoselectivity in favor of 2,3-trans cyclopropanecarbaldehyde is predicted in the case of the dienal, using the most favored conjugate addition (1,4-addition) pathway. Along similar lines, ylide addition to the enone is identified to exhibit a preference toward conjugate addition over direct (1,2-) addition. The importance of transition state analysis in delineating the controlling factors towards product distribution and diastereoselectivity is established.

Design of Catalysts for Asymmetric Organic Reactions Through Density Functional Calculations

The current decade being a golden era in the history of organocatalysis, designing new organocatalysts for synthetically valuable reactions is of high importance. A fine blend of theoretical techniques and knowledge gathered from the experimental observations can help one design highly selective organocatalysts. The present chapter summarizes our efforts in designing organocatalysts for two synthetically important reactions; namely, the aldol reaction and sulfur ylide mediated ring formation reactions. In order to identify the crucial elements that affect the stereoselection process, detailed mechanistic studies are performed initially. Thus, factors controlling the vital energy differences between the diastereomeric transition states are identified and rationalized. Later on, insights from these model studies are utilized toward designing the new catalyst framework. In the last stage, the catalytic efficiency with the designed catalysts is evaluated for selected reactions. Conformationally constrained catalysts designed in this manner are predicted to be more effective with improved selectivities in comparison to the experimentally employed analogues.