Total Synthesis Of Cyclodepsipetides Janadolide And Alotamide A

Recently,various cyclodepsipeptides from marine microbes have drawn considerable attention because of their unique structures and biological activities in anti-cancer,anti-infective,and neuroactive fields.Due to the extremely limited amount of these active metabolites in natural source,the efficient synthesis should be developed for further research.In addition,modifications on these bioactive compounds would lead to the potential candidates in drug discovery.In this thesis,the total synthesis of marine cyclodepsipeptides janadolide and alotamide A were achieved,and some of their diastereomers were developed as well.1.Total synthesis of janadolide and its 7-epi analogueJanadolide is a cyclodepsipeptide isolated from marine cyanobacterium Okeania sp.,and is more effective than the clinical antitrypanosomal drug Suramin in vitro.In this study a concise synthesis of janadolide was achieved,and the total yield was 7.6%.The application of the selected cross metathesis strategy in construction of the key polyketide fragment resulted in good yield and E/Z selectivity.Evans protocol and CBS reduction established C2 and C7 stereocenters respectively,and completed the asymmetric synthesis of polyketide fragment.The improved macrocyclization at the less steric site between Gly and L-N-Me-Ala gave janadolide in 75%yield without dimer or polymer product.Given that C7 position might be involved in the active region,its 7R-diastereomers was also completed and available for further SAR study.2.Total synthesis of alotamide AAlotamide A is a cyclodepsipeptide isolated from marine cyanobacterium Lyngby sp.and possesses a unique activation of calcium influx in murine cerebrocortical neurons(EC₅₀ 4.18?M).Due to its limited source,three stereocenters?C19,C28,and C30?in its polyketide fragment remain undetermined.In this study,the first asymmetric synthetic route of alotamide A was achieved,and four diastereomers?19S,28R,30S?-1-117e,?19S,28R,30R?-1-117f,?19S,28S,30R?-1-117g and?19S,28S,30S?-1-117h were generated.The utilization of Julia-Kocienski olefination constructed the E-diene fraction with good yield and E/Z selectivity.Boron-mediated asymmetric aldol reaction and CBS reduction were applied in the following asymmetric synthesis of 1,3-diols fraction,and eight polyketide isomers 3-1a to 3-1h were obtained respectively.The final macrocyclization between L-N-Me-Val and C7 position established the ring skeleton and generated four diastereomers 1-117e,1-117f,1-117g and 1-117h for the first time.Briefly,the asymmetric synthesis of two cyclodepsipeptides,along with their diastereomers were achieved,and available for further SAR study.Moreover,the synthetic strategy could be used by other depsipeptides in their constructions and modifications.