Theoretical Study Halogenated Lactone Reaction Catalyzed Asymmetric Small Organic Molecules

Lactones are the fundamental units of many natural products and exhibit a varietyof biological activities and have very high medical value. Halolactonization is a veryimportant method to synthesis lactones while metal, metal complex andorganocatalyst are often utilized as the catalyst. Halolactonization catalyzed byorganocatalyst has high yield, high enantioselectivity, low toxicity and low pollution.It is often regarded as "green chemistry". Our work is focused on thehalolactonization which is catalyzed by organocatalyst including the investigation inmechanism, the confirmation of the catalytic center and the survey of reaction processdriven force, etc. It plays important roles in improving the experimental condition,and synthesizing new catalysts.Our specific research and conclusions are as follows:1. A detailed mechanism for the non-catalyzed and bromolactonization catalyzedby sulfur-based catalyst has been systematically investigated by performing DFTcalculations. The results suggest that the non-catalyzed reaction proceeds in threemajor steps involving electrophilic addition, ring-closure and H transference, whilethe catalyzed process involves Cat-NBS interaction, H transference, and ring-closurewith the regeneration of the catalyst.Electrophilic addition is the rate-determining step in non-catalyzed process, whileCat-NBS interaction is that of catalyzed one. Path4with the lowest energy barrier isthe preferred pathway leading to exo-five-lactone3. In addition,3with4.48kcal/mollower energy is more stable than4. In this way,3is the major product not onlykinetically but also thermodynamically. According to our calculation, S-pxmakesmuch contribution to the formation of HOMO-LUMO of the four TSs, and it isexpected that S promotes the electrophilic addition ability of Br with charge changes(-0.118â†'-0.104,-0.050,-0.054,-0.068). It reduces the electrophilic addition energybarrier from65.26kcal/mol to2.12kcal/mol. Thus, S is the catalytic center.2. DFT calculation is preformed to investigate the detailed mechanism foruncatalyzed and bromolactonization catalyzed by selenium-based catalystsystematically. The results reveal that the uncatalyzed process proceeds in three majorsteps involving electrophilic addition, ring-closure and H transference, while thecatalyzed process involves Cat-NBS interaction, H transference, and ring-closurewith the regeneration of the catalyst. From the energetic analysis, it can be concluded that the electrophilic addition isthe rate-determining step in the uncatalyzed process while Cat-NBS interaction isthat of catalyzed one. The intramolecular cyclization is the regioselectivy-determiningstep. Path4is the preferred pathway leading to the major product exo-five-lactone3.Besides, exo-five-lactone3with4.4kcal/mol lower energy is more stable thanendo-six-lactone4. In this way,3is the major product not only kinetically but alsothermodynamically.Se is supposed to be the catalytic center. Se-pzand Se-pxorbitals make muchcontributon to LUMO and HOMO of the four TSs: TSâ…¢-1, TS â…¢ ’-2, TSâ…¢ ’-3andTSâ…¢-4. It is expected that Se promotes the electrophilic addition ability of Br withcharge changes (-0.118â†'-0.173,-0.143,-0.106,-0.094). It reduces the electrophilicaddition energy barrier from64.49kcal/mol to18.89kcal/mol.This conclusion is in agreement with the experiment result, and it is similar withthe sulfur-based catalyzed bromolactonization. In this way, it is expected that theprocess including NBS as the halogen donor and unsaturated carboxylic acid as thereactant contains three steps: Initially, the catalyst reacts with NBS to form a complexto improve the electrophilic addition ability. Then the hydrogen transference happens.Finally, it is the ring-closure process with the regeneration of the catalyst.