Studies Toward The Total Synthesis Of Natural Product Scabrosin Esters And Malacidins

Bioactive natural compounds have always attracted the attention of organic synthetic chemists.This thesis focuses on the studies toward the total synthesis of natural product scabrosin esters and malacidins（1）Studies towards the asymmetric total synthesis of natural products scabrosin esters.Scabrosin esters belong to dithiodiketopiperazines.Isolated from the lichens Xanthopannelia scabrosa in 1978,the family consists of five members with different ester chain lengths.Scabrosin esters are the sole subgroup of dithiodiketopiperazine compounds currently found to contain epoxy parts consisting of 3-6-5-6-5-6-3 structure.These compounds showed patient anticancer activities(murine leukemia P388:IC₅₀=16 nM;human breast MCF7:IC₅₀=1 nM)and have generated considerable interest in the research community.Their unique chemical structure and excellent biological activities attracted us to conduct the total synthesis studies.We designed two strategies toward the total synthesis of scabrosins in this thesis.In the first strategy,we exploited the reductive amination method to construct the C9-N chemical bond and completed the synthesis of the pyrrole ring,but the chiral centre at the C9 position was incorrect.We tried to adjust the configuration of C9 chiral center by using steric hindrance and changing the way of the 5-member ring closing,again neither of them succeeded.Later,we first guaranteed the correct configuration at the C9 position by Mitsunobu reaction and then constructed the C3-C4 chemical bond.We attempted the Heck reaction,free radical reaction,Michael addition reaction,etc.,but failed to complete the synthesis of the pyrrole ring.In the second strategy we changed the ring-closing position,first using the Mitsunobu reaction to ensure the correct hydrogen configuration at the C9 position and then using the intramolecular nucleophilic substitution reaction under the strong base to complete the C2-C3 chemical bond construction,and successfully completed the synthesis of monomeric compounds.With the monomer in hand,the synthesis of the scabrosins skeleton and its diastereomers were successfully completed by deprotection,condensation reaction,etc.Next,we dedicated a lot of efforts to the disulfide bond construction,including 1)direct sulfurization under basic conditions;2)oxidized to hydroxyl group followed by a Lewis acid-catalyzed sulfurization reaction;3)sulfurization after the epoxy-opening;However,all these efforts failed to install the disulfide bridge.We synthesized a number of dimeric analogs containing different side chains and chiral centers and then tested their bioactivities.We are the first to complete the synthesis of the scabrosins skeleton containing all functional groups.（2）Total synthesis studies of natural malacidins.Malacidins are lipopeptide calcium-dependent antibiotics obtained from soil bacteria using gene extraction and heterologous expression methods.The compounds consist of nine amino acids in the macrocyclic structure and are linked by an unsaturated fatty acid chain,of which six fragments are derived from unnatural amino acids.The compounds have good inhibitory activity against a variety of Gram-positive bacteria and vancomycin-resistant Staphylococcus aureus,and no obvious toxicity to mammals.Due to the increasing resistance of bacteria and the increasing risk of drug-resistant infections,the demand for new antibiotics is ever growing.Malacidins are a class of compounds with high bacteriostatic activity and low toxicity,and attract us to conduct their total synthesis.We utilized the solid phase synthesis strategy for the total synthesis of malacidins.We designed two synthetic routes.In Route 1,we link the side chain carboxyl group of aspartic acid to the resin,and use the amino group of glycine and the carboxyl group of aspartic acid as the site for the ring-closing reaction.We connected the amino acids in sequence,and successfully prepared precursor compounds 3-76 and 3-85.We tried different condensation conditions,but the synthesis of the macrocycle was not successful.We thus initiated the second synthetic route.The glycine was introduced to the main chain in advance and the amino group of methyl aspartic acid and the carboxyl group of glycine were used as the site of the ring closure,We first prepared compound 3-91 and then compound 3-105 after sequential condensation of the amino acids.Next,we plan to complete the synthesis of malacidins on this basis,and determine the absolute configuration of its multiple chiral centers to fully establish the structure of the natural products.