| Diverse synthesis of natural products is not only a powerful tool in drug discovery but also one of the most effective ways to discover new reactions, new reagents and new methods. Along with the prosperity of new drug chemical entities, new targets and proteomics, natural product chemistry should not only continue to extend the traditional research contents including structural determination, synthetic methodologies and the art of synthesis, but also spread to reveal the physiological mechanism of biological macromolecules and search for innovative drugs. Therefore, the essence of the natural product chemistry research is to construct compound libraries of natural products, sub-structural fragments and natural product mimics, aiming to discover innovative drugs or candidates for clinical research. With the gradual depletion of resources and the worsening of the environment, sustainable development and the balance of ecosystems have become a major concern of human society. Meanwhile, for the further study of interaction between natural products and biological macromolecules, it is of great significance to establish efficient methodologies for diverse natural products with interesting activities based on cheap raw materials, which could be partly achieved by diverse synthesis.In this dissertation, based on the cheap amino acids and (5)-2-methylbutan-l-ol, diverse synthesis was executed and applied in the synthesis of several structure-diversed natural products and chiral drug. The major results included:1. Starting from low-cost amino acids and followed by stereoselective reduction of α-aminoketones, a new "one pot" method for the preparation of trans-4,5-pyrrolidi.ne lactam la-g was developed via highly selective oxidation/cyclization of terminal alkene by using RuCl3·xH2O/NalO4 system.2. Based on building block la, a new synthetic route was established for preparing an optical isomer of the commercial antipsychotic Nemonapride 4. The overall yield is 27%.3. Starting from building block 1g, all the four isomers of Streptopyrrolidine 2, a marine natural product isolated recently, were synthesized, and the absolute configuration of Streptopyrrolidine was further designated to be (4S,5S) based on their spectral data including optical rotation values.4. Starting from (5)-2-methylbutan-l-ol, aldehyde 136 was obtained in 5 steps with a high stereoselectivity (dr> 99:1) with Evans asymmetric Aldol reaction as a key step. In the next addition of AllylTMS to the aldehyde 136, Me2AlCl could induce the reaction stereospecifically and gave anti alcohol 134; however, without Me2AlCl, the reaction afforded syn alcohol 179 stereoselectively (dr= 88:12); then, starting from 134, alcohol 186 was obtained efficiently by regioselective protection and stereoselective reduction.5. With tremendous efforts, usual epimerization of alanine fragment in the synthesis of many cyclopeptides could be effectively avoided. Without DMAP, the ester 170d could be produced without any epimerization (dr> 99:1) from the substituted alanine chloride and alcohol 186 in DCM under reflux condition. a. X=OH CI3C6H2COCI, TEA, DMAP 70% dr= 24:76 b. X=CI DIPEA, DCM, reflux 55% dr>99:16. Through CM reaction, the non-peptide fragments 171 of Lagunamide A 5 and its analogues were synthesized with high selectivities (trans:cis> 99:1).7. In order to determine the absolute configuration of Lagunamide A, macrolactamization at C-11-N and C-5-N was preformed and afforded 6 analogues:7, 5,5a,5b,5c,5d. By comparing with the analytic data of the isolated product, the stereochemistry of Lagunamide A 5d was confirmed to be (7S,39R)-configuration.8. We have observed that during the 1,3-migration/addition reaction between organozinc reagents and N-tert-butanesulfinamide, t-butyl group added to the imide stereospecifically, while the addition of zinc reagents to sulfoxid resuted in epimerization. Aided by quantum chemical calculation, the preliminary mechanism of this reaction was speculated to be a radical process. |
PDF Full Text Request