| Alzheimer’s disease (AD) is one of the most critical illnesses threatening the health of elderly people and thus causes enormous cost burden on society. Alzheimer’s disease (The commonly known name "Lao Man Chi Dai Zheng" is no longer recommended to be used), is a progressive and developmental neurodegenerative disease. The disease occurs mainly in the elderly over65years, and it has long and irreversible duration. The main symptoms are listed as below:memory deterioration, learning capacity degradation, language ability loss, fluctuating emotion and so on. The patients gradually lose the body functions, and thus social or life skills, and are ultimately completely dependent on others’continous care. The pathological manifestations of Alzheimer’s disease include the loss of nerve cells in the brain and the neurotransmitter acetylcholine, specific area of the brain appearing senile plaques and neurofibrillary tangles of nerve cells and so on.The number of AD patients in China is increasing year by year, and with the average life expectancy in this country being prolonged greatly, the population aging problem is making the situation much worse. Fortunately, five drugs have been approved to treat the cognitive manifestations of AD. Among these, four are acetylcholinesterase (AchE) inhibitors. For the treatment of Alzheimer’s disease, the U.S. Food and Drug Administration have approved four acetylcholinesterase (AchE) inhibitor drugs:Tacrine, Donepezil, Galantamine, Rivastigmine. In our country, huperzine A which is isolated from herbal medicine has been approved as the second generation of acetylcholine inhibitor drug to treat Alzheimer’s disease.Huperzine A is a unique alkaloid isolated from Chinese folk herb Huperzia serrata in1986. Natural (-)-huperzine A has been found to exhibit potent, selective and reversible inhibitory activity targeting AChE, and22types of huperizine A-related pharmaceutical drugs have been approved in the treatment of AD in China. Considering the rapidly increasing demand of huperzine A and the on-edge extinction situation of the corresponding natural sources, it is of extreme urgency to develop efficient methodologies and practical asymmetric synthesis of huperzine A with scalable potential.(1) Natural (-)-huperzine A was found to exhibit much higher AchE inhibition activity by comparison with its enantiomer. Tang Xi-Can compared the acetylcholinesterase inhibitory activity of enantiomers and racemates of huperzine A. The results showed that, comparing with the naturally-derived huperzine A, the D isomer’s activity and selectivity were very poor, and its inhibition constant was too large which indicated poor combination of dextral huperzine A and acetylcholinesterase. From the crystal structure analysis of huperzine A and acetylcholinesterase, the aboved difference may be due to the failure of the formation of an effective bond between the exocyclic methyl ethylene and the amino acid His440. Therefore, in order to ensure efficient inhibitory activity and selectivity, the ideal huperzine A total synthesis’s product should be consistent with the natural configuration.Based on the first total synthesis of (±)-huperzine A by Ji’s and Kozikowski’s groups, we have successfully established a highly enantioselective organocatalytic method to construct the bicyclo[3.3.1]nona-2,6-dien-9-one core with up to95%ee in the gram-scale procedure. We designed and synthesized a series of new "Bronsted bases-Bronsted acid-Lewis base" multifunctional catalysts. Based on the new catalytic mode, we firstly achieved a highly enantioselective formal synthesis of huperzine A. Compared with the previously reported methods, we have improved the enantioselectivity of the key reaction remarkably. Futhermore, we prepared a series of chiral analogues of huperzine A, which can be used for biological activity tests. (2) Spirocycles containing nitrogen, oxygen and sulfur hetero atoms are common in natural products. Among them,1-azaspirocycles are those structures whose nitrogen atoms are shared by two rings, which can be observed in Lepadiformine, Cylindricine A, TAN1251A, FR901483and other natural alkaloids. Since the isolation and identification of these molecules, a large number of synthetic teams have explored their total synthesis methods. The key step is how to construct the asymmetric aza-spiro structure building block. We summarized the previous work and found that, without any exclusion, the reported methods were all optical substrate-controlling to achieve the asymmetric construction of the spiro center. However, we decided to develop an organocatalytic asymmetric method to establish the chiral center, with only catalytic amount of catalyst to be required. Hence, a gram-scale organocatalytic enantioselective Michael addition of a-nitrocyclohexanone to acrolein has also been developed, and it was successfully applied to a concise two-step synthesis of (15)-azaspiro[4.5]decan-6-one.(3) Among the reported synthesis procedures, the primary amine functionality of huperzine A was usually introduced by Curtius/Hofmann rearrangements, involving several steps and harsh reaction conditions.The synthetic method starting from a carboxylic ester or amide group to construct the quaternary center is quite uneconomical. The conversion process involves the introduction of the latent functional groups, the hydrolysis of ester group or a cyano group, the formation of isocyanate intermediates and the removal of protecting groups. A multi-step conversion and harsh reaction conditions are required. Recently, Lin and Sun’s group and White’s group have noticed the problem, they developed direct approaches to induce the amine group. Lin and Sun used Buchwald-Hartwig coupling to form the C-N bond and White et al induced the amino group by aza-Prins rearrangement.In this work, we have developed a simple and straightforward method to construct the nitrogen-containing quaternary carbon via oxidative dearomatization-amination. Based on the key reaction, total synthesis of huperzine A is currently ongoing in our laboratory. |
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