Highly Efficient Asymmetric Synthesis Of Eight-membered Lactam-containing Alkaloid Balasubremide Among Clausena Indica(Datz). Oliv And Its Derivatives

Natural products are important leading compounds for discovery of new drugs.They provide a template for the design of drug and even directly are applied toclinical practice. However, limited resources of natural product, especially thecomplex extraction technology, impact further research of their application value.Therefore, studies on the total synthesis of natural products can provide thepharmacological experiment samples for natural products with low content in plants.This is an important way to explore in depth the biological activity of the templatemolecules. Furthermore, based on the reactivity of the template molecules, tosynthesize natural product analogues with structure diversity to develop new activemolecule, is an important exploring field for the natural product research.(+)-Balasubramide, an eight-membered lactam-containing alkaloid, was isolatedby Hofer and co-workers from Clausena indica which grows in the central montanerainforests in Sri Lankan. According to modern pharmacology, the lactam-containingalkaloids from the genus Clausena have been associated with important biologicalactivities. However, due to the complex structure of eight-membered lactam ring anda plurality of chiral site, the synthesis of balasubramide was only reported by threeliteratures. This dissertation aims at the studies toward the total synthesis of natural product (+)-balasubramide and its derivatives. We designed an asymmetric synthesisroute toword the total synthesis (+)-balasubramide and its derivatives and affordhighly enantioselective target compounds successfully.The dissertation mainly focuses on the following3aspects:1. The isolation of natural balasubramide, potential research value, the researchprogress of total synthesis of balasubramide and other studies on synthesis of keyintermediate α, β-epoxy esters are summarized.2. The evaluating of synthesis method for the key intermediate α,β-epoxy esters.According to the reported method in the literature, we optimized the reactionconditions. First, epoxidation of trans cinnamaldehydes have been catalyzed byS-2-[diphenyl[(triethylsilyl)oxy]Methyl]-Pyrrolidine with40%hydrogen peroxideaqueous under the condition of the ice bath. Subsequently, the mixture was dilutedwith methanol and1.3equiv. of N-bromosuccinimide (NBS) was added. As a result, avariety of α, β-epoxy esters were synthesized and excellent enantioselectivities (up to99%ee) and good yields were obtained for a variety of α,β-epoxy esters. The resultsshow that one-pot organocatalytic epoxidation and consequent oxidative esterificationafford a convenient and efficient method for the asymmetric synthesis of α,β-epoxyesters.3. Synthesis of the target compounds. Through one-pot organocatalyticepoxidation and consequent oxidative esterification, chiral α,β-epoxy esters wereobtained. Subsequently, α,β-epoxy esters react with tryptamine and its analogues toafford prebalasumide and its derivatives. Then prebalasumide and its derivativesundergo intra-molecular cyclization in the presence of Yb(CF3SO3)3. As a result,natural (+)-balasubramide and a series of its derivatives were obtained. The overallyield and ee value of the synthetic natural (+)-balasubramide is45%and97%.