Transition state theory fails to accurately predict the selectivity in an example where it is ubiquitously invoked, hydroboration. The hydroboration of terminal alkenes with BH 3 is moderately regioselective, affording an 88:12 -90:10 ratio of anti-Markovnikov:Markovnikov adducts. Highlevel ab initio calculations predict too large of an energy difference between anti-Markovnikov and Markovnikov transition structures to account for the observed product ratio, and the consideration of calculational error, solvent, tunneling, and entropy effects does not resolve the discrepancy. Trajectory studies, however, predict well the experimental selectivity. The decreased selectivity versus transition state theory arises from the excess energy generated as the BH 3 interacts with the alkene, and the observed selectivity is proposed to result from a combination of low selectivity in direct trajectories, moderate RRKM selectivity, and high selectivity after thermal equilibration.The hydroboration of simple alkenes with BH 3 preferentially occurs in an "antiMarkovnikov" 1 fashion. The standard explanation for this preference in the literature, 1,2 reproduced in some form in all general textbooks of organic chemistry, is that the selectivity arises from a greater stability for the anti-Markovnikov transition state over the alternative "Markovnikov" transition state. We find here that transition state theory fails to accurately account for the regioselectivity of hydroboration. Instead, a consideration of dynamic trajectories allows understanding of the selectivity.The addition of BH 3 to terminal alkenes is only moderately regioselective. With simple terminal alkenes such as 1-hexene, the ratio of primary to secondary alcohol products after hydroboration with BH 3 at 0 -25 °C followed by oxidation is approximately 94:6. 1,3 This ratio as it has been observed is a composite of the regioselectivity in three separate steps - 4 but they are more regioselective as well, so the initial reaction of BH 3 is less selective than the composite ratio. Using the observed 1-hexanol/2-hexanol ratio of 97:3 for the reaction of n-butylborane with 1-hexene 5 as a measure of the selectivity of the second and third steps of hydroboration, the regioselectivity for reaction of 1-hexene with BH 3 itself would be ≈88:12. In our hands, the hydroboration of propene-d 6 at 21 °C with 100 equiv of BH 3 •THF (to minimize the contribution of hydroboration by alkylboranes) affords a 90.0:10.0 ratio of primary and secondary alcohols (based on direct analysis of the oxidized reaction mixture by 2 H NMR). Assuming the applicability of transition state theory, the ΔΔG ‡ for the transition states leading to the two products would be 1.1 -1.3 kcal/mol.A variety of gas-phase computational approaches were explored in an attempt to predict this ΔΔG ‡ . 6 CCSD(T)/aug-cc-pvdz calculations were used to locate transition structures 1 ‡ and 2 ‡ for formation of the regioisomeric products from the precursor complex 3. The relative energetics of the anti-Markovnik...

Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a β-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the α- and β-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.

Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the alpha-side chain. Versatile strategies for modifying the delta-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.