Theoretical Study On Rhodium And Silver Catalyzed Cyclization Reaction For Building The Frameworks Of Natural Products

Since transition metals have underfilled d orbitals,based on the eighteen-electron rule,their properties should be significantly different from other elements.Due to the existence of empty d orbitals,transition metals can easily form complexes with a variety of organic compounds,and thus can be used as catalysts for the synthesis of heterocyclic molecules with diverse structures.Due to its concision,high efficiency and excellent selectivity,transition metal catalysis has been widely used in cycloaddition reaction,for construction of natural products possessing structural diversity,biological activity and antibacterial activity.The role of transition metal catalysis in the construction of complex polycyclic natural products has become increasingly widespread recently.In-depth discussion on the application of transition metal-catalyzed cycloaddition reactions in constructing complex natural product frameworks can help to shed a light on the sustainable utilization of natural medicinal resources,as well as on the development of chemical total synthesis of bioactive natural products.In this thesis,density functional theory（DFT）was used to carry out theoretical research on rhodium and silver-catalyzed cycloaddition reactions.At the computational level of IDSCRF-B3LYP/GEN and IDSCRF-M06-2X/DGDZVP in solution,all possible reactants,products,intermediates and transition states involved in the reaction were optimized,with frequency calculations performed accordingly.All energies reported here were corrected Gibbs free energies in solution at experimental temperature.In theoretical study about the rhodium-catalyzed[2+2+2]cycloaddition reaction of enyne and terminal phenylacetylene derivatives,two possible reaction mechanisms were explored:（1）Rh（cod）₂BF₄ first removes（cod）₂BF₄^-and reacts with ligand L to generate a catalyst,which catalyzes the asymmetric intramolecular oxidative cyclization of alkenynes to generate a chiral rhodium-containing cyclopentene intermediate.Followed that,the phenylacetylene derivative enters and rhodium atom of the intermediate coordinates with the alkynyl group in phenylacetylene,leading to the formation of a rhodium-containing seven-membered ring intermediate through insertion of alkynyl into the metal-carbon（M-C）bond.Finally,reduction elimination happens,with the catalyst removed while generating a fused tricyclic hydronaphthofuran derivative.（2）The rhodium atom coordinates with the alkynyl group of the enyne and phenylacetylene derivatives to form a stable complex,leading to the formation of a rhodium-containing cyclopentene intermediate through insertion of alkynyl into the metal-carbon（M-C）bond.Then,the intermediate is transformed into a rhodium-containing seven-membered ring intermediate through the intramolecular asymmetric oxidative cyclization reaction.Finally,reduction elimination happens,with the catalyst removed while generating the fused tricyclic hydronaphthofuran derivative.Among these two possible reaction mechanisms mentioned above,four possible reaction paths,Path I-IV,were located due to the regioselective insertion of asymmetric terminal alkynes.Based on present computatinal results obtained,the following conclusions can be drawn:when the p-substituent on the phenylacetylene benzene ring in substrates is electron-donating group-OMe,PathⅣis the dominant path.In Path IV,R2a reacts with intermediate COM1 to form complex COM2a-IV,the insertion of metal-carbon（M-C）bond through transition state TS1a-IV needs to overcome a free energy barrier of 27.8 kcal·mol^-1 at the IDSCRF-B3LYP/GEN computaional level,which acts as the rate-determining step of the whole reaction and leads to the major product Pa-Ⅰ.when the p-substituent on the phenylacetylene benzene ring in substrates is electron-withdrawing group-CF₃,PathⅢis the dominant path.In PathⅢ,R2b reacts with intermediate COM1 to form complex COM2b-Ⅲ,the insertion of metal-carbon（M-C）bond through transition state TS1b-Ⅲneeds to overcome a free energy barrier of 23.0 kcal·mol^-1 at the IDSCRF-B3LYP/GEN computaional level,which acts as the rate-determining step of the whole reaction and leads to the dorminant product Pb-Ⅱ.Our computaitonally predicted major products are consistent with Teng’s experimental results.Finally,comparion of computational results derived from IDSCRF-B3LYP/GEN,IDSCRF-B3LYP-D3/GEN and IDSCRF-M06-2X/GEN computaional levels in solution show that the results obtained at the IDSCRF-B3LYP-D3/GEN level are the best ones when comparing with corresponding experimental data.In theoretical study about the silver-catalyzed formation of（±）-nor-berkelic acid methyl ester,the whole reaction process can be divided into three stages,（1）cyclization of acetylenic alcohol to form enol ether,（2）Deethanolization of diphenol compounds to form o-Quinone methides and（3）enol ether and o-Quinone methides react through[4+2]cycloaddition and convert to（±）-nor-berkelic acid methyl ester in the end.Based on optimization of geometric configurations of each stationary point on the reaction path and analysis of aforementioned computaitoanl results,the reaction mechanism of each stage was located.The preferred path to form enol ether R3 is Path a1.In Path a1,the catalyst first coordinates with the alkynyl group in the alkynyl alcohol R1 to form complex COM1.Then,under the help of catalyst,O（1）-C（5）bond forms through transition state TS1 and COM1 is transferred into intermediate INT1.1,3-Hydrogen migration in intermediate INT1 ccurs subsequently,with the hydrogen atom Ha transferred from O（1）to the olefin carbon atom C（6）to form intermediate INT2 via transition state TS2.This process is the rate-determining step of the reaction and needs to overcome a free energy barrier of 37.8 kcal·mol^-1 at the IDSCRF-M06-2X/DGDZVP computational level in solution.In the process of diphenol R2 convered o-Quinone methides compounds R4,Ag Sb F₆ coordinates with both oxygen atoms in ester group of R2 and the o-hydroxyl group to form complex COMa.Then,the C（1）-O（2）and H（3）-O（4）bonds break,and O（2）-H（3）forms simultaneously through transition state TS,with the new complex COMb formed.Finally,COMb transfers to R4 by removing ethanol and catalyst,this process needs to overcome a free energy barrier of 25.2 kcal·mol^-1 at the IDSCRF-M06-2X/DGDZVP computational level in solution,indicates a relatively easy transformation at an experimental temperature of 25℃.The regioselectivity generates during the conversion of enol ether and o-Quinone methides into（±）-nor-berkelic acid methyl ester through[4+2]cycloaddition reaction.Due to different coordination modes of catalyst and the two reactants,the difference in steric hindrance of catalyst,as well as the possibility of stepwise and synchronous[4+2]cycloaddition,there are three possible reaction paths（Path I-III）.Path III,which corresponds to the synchronous[4+2]cycloaddition,is proved to be the dominant path,while PathⅠandⅡneeds to get over a rate-determining free energy barrier of 32.3 and35.0 kcal·mol^-1（TS3-Ⅰ,TS3-Ⅱ）respectively about 11.9 and 14.6·kcal·mol^-1 higher than that of PathⅢ（TS3-Ⅲ）.So,when taking energy barrier into consideration,the reaction is more likely to proceed via PathⅢ.In order to understand the influence of different computational methods on the results,we employed B3LYP,ωB97XD and B3LYP-D3 density functional methods to study the system further.Considering both the formation of enol ether R3 and the formation of（±）-nor-berkelic acid methyl ester,computaitonal results obtained by using B3LYP-D3 method is most reasonable.The rate-determining step of the whole reaction is corresponding to the formation of enol ether R3.On the dominant Path a1,it needs to overcome a free energy barrier of 37.8 kcal·mol^-1to form enol ether R3 at IDSCRF-M06-2X/DGDZVP computaitonal level（TS2）.When employing B3LYP,ωB97XD and B3LYP-D3 methods,the free energy barriers of TS2 are 35.0,40.9 and30.3 kcal·mol^-1,respectively.The computaitonal results obtained by using B3LYP-D3method is most reasonable.Howerver,a free energy barrier as high as 30.3 kcal·mol^-1indicates the reaction is still difficult to achieve under room temperature,which means the B3LYP-D3 method also overestimates the energy barrier of TS2.We guess a higher free energy barrier of TS2 is caused by the ring tension in the process of 1,3-H migration.On the optimal PathⅢ,Enol ether R3 and o-Quinone methides R4 are converted into（±）-nor-berkelic acid methyl ester synchronously through[4+2]cycloaddition,and it needs to overcome a free energy barrier of 22.7 kcal·mol^-1at the IDSCRF-B3LYP-D3/DGDZVP computaitonal level（TS3-Ⅲ）.A free energy barrier of22.7 kcal·mol^-1 indicates the reaction can be achieved easily at room temperature.The free energy barriers of TS3-Ⅲare 36.8,23.5 and 20.4 kcal·mol^-1 respectively when using B3LYP,ωB97XD and M06-2X methods.It’s obvious the free energy barriers obtained by employing M06-2X,ωB97XD and B3LYP-D3 methods are significantly lower than the B3LYP one,and are in better fit with corresponding experimental conditions.All of this indicates it is necessary to consider weak interactions in the calculation of this kind and similar reactions.