Ni/Antphos-catalyzed Asymmetric Reductive Cyclization To Chroman With High Enantioselectivity

Chromodihydropyran structural units with chiral tertiary alcohols are widely present in natural products and drug molecules,and have important biological activities such as anticancer,antibacterial,and hypoglycemic.Only a few reports have used transition metals such as palladium,gold,and rhodium as catalytic metals to synthesize racemic chroman alcohols,while nickel-catalyzed asymmetric synthesis of benzodiols with an allyl alcohol structure is more challenging.The method of hydropyranol has not yet been reported.In this work,a nickel-catalyzed intramolecular reductive cyclization of alkynones is reported for the first time to synthesize chiral chroman molecules with an allyl alcohol（silyl ether）structure with high enantioselectivity.It mainly includes the following two parts.The first part of this work reported the Ni/AntPhos-catalyzed asymmetric synthesis of a series of multifunctional functionalized 4-hydroxychroman structures.The reaction exhibited excellent enantioselectivity（98:2 er）,excellent yield（99%）,and good substrate universality.In the reaction,it was found that the chiral alcohol product can be directly obtained by using boronate/methanol as a reducing agent.At the same time,different boronate esters have a great influence on the enantioselectivity.At present,the ideal enantioselectivity has not been achieved,and the work is in the process of further development.The second part of this work reported the Ni/AntPhos-catalyzed intramolecular reductive cyclization of alkynones to construct a series of chiral 3-silyl ether chroman derivatives with excellent enantioselectivity and yield（up to 96:4 er,98 % yield）.The reaction is well tolerated for different electrical properties,different sites,different steric hindrance,polysubstituted aromatic,heterocyclic and aliphatic substrates.The absolute configuration of the product was determined to be（R）by single crystal.Desilylation to obtain 3-hydroxychroman with chiral tertiary alcohols.The anticancer activity tests on four types of cancer cells showed that most of the 21 samples tested had good anticancer activities,and different structures were also found.Types of molecules have a greater impact on anticancer activity,some molecules show specificity to certain cancer cells,and normal cells are not toxic.In general,3-hydroxychroman derivatives are a class of anticancer lead compounds with important research significance.Next,we will further study their biological activities.In general,we have developed a Ni/AntPhos-catalyzed efficient and high enantioselective synthesis of a series of functionalized 4-hydroxychromans and3-silyl ether benzos from cheap and readily available raw materials.Dihydropyran.The anticancer activity test of 3-silyl ether chroman desilylation product shows that this kind of compound has good anticancer activity,and it is a kind of anticancer leading compound with important research significance in the field of biomedicine.