Total Synthesis Of Hapalosin And Its Analogues: Construction Of Three Small Hapalosin C-9 Analogues Libraries And Studies On Total Synthesis Of Melleumins A And B

Cylcopeptides with complex and diversified structures are widespread in nature. Many of them exhibit various biological activities, such as, antibiotics, antitumor, antivirus, immunosuppressive effect and pesticides. As promising lead compounds in drug discovery, cylcopeptides are receiving more and more attention. And the studies on the asymmetric total synthesis of these compounds have been a new focus. In this dissertation, the application of malimides-based asymmetric synthesis methodology was expanded and the total syntheses of some cylcopeptides, which includes hapalosin, three analogues and three small libraries, as well as deoxy-analogues of melleumins A,B were achieved via these useful chiral building blocks. The main results and observations made from these studies are listed as follows:1. An improved method for the synthsis of N-methyl-malimide had been developed. By using the methylammonia hydrochloride to replace ammonia, the N-methyl malimide could be synthesized directly. The building block (R)-130 was synthesized by this method in 69% yield.2. Recent reported improved reaction condition for the Evans aldol reaction, a key step in the synthesis of fragment B of hapalosin, was used which allows replacing the organic boron reagent with titanium tetrachloride. While all the advantages of the original route were kept down, some of the shortcomings of the original method, such as using expensive organic boron reagent and troublesome work-up, have been overcome. 3. Epimerization of oxazolidine acetate was observed during the synthesis of the fragment C of hapalosin. A plausible mechanism for the epimerization is a retro-Michael addition-intramolecular Michael addition under basic conditions. The synthesis of an epimer of hapalosin (8-epi-hapalosin) was accomplished by taking advantage of this epimerization.4. An epimerization-free synthesis of theγ-amino-β-hydroxy-acid moiety of hapalosin was developed by preparing the corresponding benzyl ester of oxazolidine acetate, which can be deprotected by hydrogenolysis.5. Total synthesis of hapalosin was completed in 13 steps with an overall yield of 16.9% starting from (R)-malimide. Thus a diversity-oriented asymmetric synthesis of hapalosin was developed. 6. Diversified group was introduced to the C-5 of pyrrolidone through Grignard addition to the building block. Three hapalosin analogues modified at the C-9 (homohapalosin A, homohapalosin B and 9-i-butylhapaosin) were synthesized, based on the diversity-oriented asymmetric synthetic route.7. The reductive alkylation of malimide using a library of three membered Grignard reagents allowes to construct a three-membered library of hapalosin analogues in 13 steps. Further more, the method of liquid combinational chemistry was introduced to the Evans aldol reaction, and two hapalosin analogues libraries contained 9 members and 27 members have been constructed in 9 steps respectively. It showed high yield and homogeneous in each synthetic step. 8. The non-natural amino acid 212 was synthesized from (S)-3 in 6 steps. The asymmetric synthesis of deoxymelleumin A and deoxymelleumin B, the deoxy-analogues of the corresponding natural products melleumin A and melleumin B were achieved from 212 in 7 steps and 2 steps respectively. The accomplished work laid a basis for the total synthesis of the natural products melleumins A and B.