Studies On The Total Synthesis Of Malyngamides

This thesis was concerned with the studies on the marine natural product with novel skeleton structure-total synthesis of malyngamides.It mainly consists of the following four parts:First,the recent progress in research of malyngamides had been reviewed. Malyngamides with novel structure,a series of marine L.majuscule,and their good biological activity is owing to their special living environment.In this part,we summarized the recent studies on the progress of malyngamides on the basis of our groups' work.In chapter 2,the stereoselective synthesis of serinol-derived malyngamides was introduced.The key steps of the synthesis of E,(7S)-7-methoxyeicos-4-enoic acid involved the catalytic asymmetric allylation of octanal and the coupling reaction of a chiral alkyne with a protected bromide in the presence of t-BuLi.Natural chiral pool D-serine was selected as starting material for the construction of the amine portion (R)-methoxyamino alcohol.The amidation reaction of the chiral unsaturatecd acid with the amine accomplished the synthesis of one target molecule.Acetylation of it finished the preparation of another target molecule.Their 1'-epi-isomers have also been synthesized with a similar strategy using L-serine as natural chiral pool.In chapter 3,the first total synthesis of malyngamide M was accomplished in nine steps in 12%yield.The key steps involved Friedel-Crafts reaction of o-cresol and the Wittig reaction for construction the skeleton of amine moiety,at the same time, using the synthesis of E,(7S)-7-methoxytetradec-4-enoic acid in chapter 2,and Johnson-Clainsen rearrangement as a key step for construction the fatty acid part,the corresponding acid was prepared in 23%and 50%overall yield,respectively.The amidation of fatty acid with amine constructed the skeleton of malyngamide M,and then transformation of Z-olefin to E-olefin completed the synthesis of target molecule. The construction of vinyl chloride functionally in highly selectivity should offer a reference value for the synthesis of other structurally related malyngamides containing vinyl chloride structure. At last,a convergent and general protocol to marine natural product,as demonstrated by the enantioselective total synthesis of malyngamides O,P,Q,R, 5"-epi-Q and 5"-epi-R bearing terminal vinylic chloride structure,was developed in detail.E,(7S)-7-methoxytetradec-4-enoic acid was prepared using the above described Johnson-Clainsen rearrangement,the terminal vinyl chloride was constructed using Wittig reaction as key step,the pyrrolidone derivative was constructed using L-serine as natural chiral pool.Starting from the synthesis of malyngamides O and P to explore the general route,an aldol reaction of methyl acetate with the vinyl chloride part in the presence of LDA gave the skeleton of amine portion,followed by amidation with the fatty acid finished the synthesis of malyngamide P.Subsequently,enol methylation of P in basic condition completed the synthesis of malyngamide O.Applied this route to the synthesis of malyngamides Q and R,the chiral unsaturated acid was connected with the vinyl chloride part by amidation,then the resulting product was converted into the corresponding aldehyde,followed by aldol condensation of the aldehyde with the chlorotitanium enolate of pyrrolidone to complete the skeleton of malyngamides Q and R,then the synthesis of them was completed via enol methylation in acid condition.The determination of absolute configurantions of C-5" as S in amine portion of Q and R were accomplished by the total synthesis of their diastereomers. The synthesis of malyngamides O,P,Q,and R were accomplished by a longest linear sequence of 12,11,13,and 14 steps in 6.5%,3.5%,2.3%and 3.7%overall yield, respectively.The seven target molecules of malyngamides and their five isomers were synthesized in this thesis which involved in the preparation of 60 new compounds. Synthesis of marine natural products solved problem about the scarcity of malyngamides in natural sources and the difficuty in enriching and extracting these materials,and provided materials for more extensive biological evaluation.The synthetic methods in the thesis should extend the preparation of other structurally related malyngamides containing the similar vinyl chloride structure and enrich the content of total synthesis of natural products and organic synthetic methodology.