Periodic Reporting for period 1 - TETRASYN (Practical and Catalytic Stereoselective Synthesis of Versatile Tetrasubstituted Alkenes)
Periodo di rendicontazione: 2021-10-01 al 2023-09-30
Alkene-containing molecules and their derivatives play a major role in medicine, food and energy production, as well as materials research and polymer science. In most applications, particularly in medicine, alkenes are needed in isomerically pure form. Numerous methods have been developed for the synthesis of 1,2-disubstituted alkenes over the past decades. While strategies for stereoselective preparation of olefins have been the subject of substantial interest, methods relating to synthesis of tetrasubstituted alkenes are still an open challenge that could impact construction of many bioactive compounds containing such moieties, especially those that are catalytic. What is more, the small number of available protocols are often not highly selective or broadly applicable.
The goal of the proposed studies is to introduce a practical, scalable, modular and highly stereoselective synthesis of a large assortment tetrasubstituted alkenes from readily available Cu-based catalysts, nitriles, allenes, and a commercially available diboron compound. The tetrasubstituted alkene products will contain readily modifiable functional groups, such as a ketone (e.g. enantioselective reduction), and a boronate moiety (e.g. catalytic cross-coupling), thus offering direct access to a larger collection of otherwise difficult-to-prepare and much sought-after derivatives. The applicability of the approach will be highlighted by a concise and practical gram-scale stereoselective synthesis of two important bioactive compounds. The first will be neocurcumenol, a natural product with anti-inflammatory properties, and the second will be acolbifene, currently in third phase clinical trials for treatment of breast cancer. Equally important, the versatility of the catalytic strategy will allow for facile preparation of host of related analogues – entities that might display superior pharmacological properties and cannot be synthesized easily by the available methods.
The goal of the proposed studies is to introduce a practical, scalable, modular and highly stereoselective synthesis of a large assortment tetrasubstituted alkenes from readily available Cu-based catalysts, nitriles, allenes, and a commercially available diboron compound. The tetrasubstituted alkene products will contain readily modifiable functional groups, such as a ketone (e.g. enantioselective reduction), and a boronate moiety (e.g. catalytic cross-coupling), thus offering direct access to a larger collection of otherwise difficult-to-prepare and much sought-after derivatives. The applicability of the approach will be highlighted by a concise and practical gram-scale stereoselective synthesis of two important bioactive compounds. The first will be neocurcumenol, a natural product with anti-inflammatory properties, and the second will be acolbifene, currently in third phase clinical trials for treatment of breast cancer. Equally important, the versatility of the catalytic strategy will allow for facile preparation of host of related analogues – entities that might display superior pharmacological properties and cannot be synthesized easily by the available methods.
At beginning, we developed the copper-catalyzed practical and broadly applicable multicomponent reactions. After identifying the optimal reaction conditions for the key step. We carried out an efficient 7-step synthesis of racemic acolbifene, The racemic acolbifene can be obtained in 7 steps with 42% overall yield in our chemistry. It is worth to note that previous work on the synthesis of acolbifene need 7 steps with some limitations, such as no catalytic protocol, long reaction time, low conversion, and need chiral HPLC separation or chiral resolution method to obtain the final target. And interestingly, we also got two indene analogues, which can be found in many drug molecules and natural products. What's more, the use of diastereoselectivity and different time to control of alkene isomerization strategy, the enantioenriched acolbifene could be generated in 35% overall yield and with 93:7 e.r. in 8-step. Meanwhile, For the total synthesis of neocurcumenol natural product, we developed an copper-catalyzed intramolecular regio- and stereoselective synthesis of cyclic tetrasubstituted borylenones reactions, which can be used as a key step for the total synthesis of neocurcumenaol natural product. So far, we have solved the most difficult problem, and continue to finish the total synthesis.
The studies will introduce the first set of catalytic strategies that may be used for efficient and highly stereoselective synthesis of a large assortment of linear and exocyclic tetrasubstituted alkenyl boronates, which can be easily converted to an even broader range of highly desirable and otherwise difficult-to-access tetrasubstituted olefins. The considerable utility of the advance will be highlighted by two concise and easily modifiable total synthesis routes for preparation of bioactive complex molecules. The project is expected to have the significant potential for commercialization, and has great potential for application in biological and pharmaceutical chemistry.