Total Synthesis And Research Of Natural Products With Chiral 1,3-Dimethyl Fragments

Natural products with chiral 1,3-dimethyl fragments are ubiquitous in nature,and their structure determines the diversity of their biological activities.Such natural products have been widely used in the field of medicine.In this paper,two diastereomers of natural product p-Aminoacetophenonic Acid(p-APA)and four diastereomers of Santinol D with chiral 1,3-dimethyl fragment were synthesized for the first time.At the same time,the synthesis and racemic kinetics of model molecules ?-methyl-?-ketones were studied.Sixty-two new compounds were synthesized and their structures were characterized by nuclear magnetic resonance,optical rotation,infrared and mass spectrometry.Total synthesis of natural product p-APA(2-1)studies.2-1 is a natural product similar to amino acid structure.This kind of natural product has high medicinal value in the treatment of various cancers.Therefore,the total synthesis of natural products 2-1 was studied.The natural product 2-1 contains two chiral centers,namely chiral C-2 and chiral C-4.The C-4 chiral center was established by Evans Aldol reaction,and the C-2 chiral center was obtained from commercially purchased(S)-(+)-3-hydroxyisobutyrate methyl ester.In this paper,a method was found to effectively inhibit the Michael addition of terminal hydroxyl groups and enones to form cyclic ethers.Two diastereoisomers of 2-1 namely(2R,4R)-2-1 and(2R,4S)-2-1 were finally obtained.By comparing with natural product's 1H NMR,13C NMR and OR,it was finally determined that(2R,4R)-2-1 was the absolute configuration of natural products.During the preparation of(2R,4R)-2-1 and(2R,4S)-2-1,it was found that the 1H NMR,13C NMR,IR and OR of the same compound changed after normal phase column chromatography and reversed phase column chromatography.By analysing the NMR and IR spectra,it is found that this phenomenon was caused by the different hydrogen bond structures formed by the ketone carbonyl group when using different chromatographic solvents.The natural product Santinol D(4-1)is a kind of ?-methyl-?-keto ester compound,which is easy to enolize and racemize.Therefore,before the synthesis of natural product 4-1,this paper completed the synthesis of the model molecule?-methyl-?-keto ester 3-13,which had the same 1,3-dimethyl fragment with 4-1.Compound 3-13 contains two chiral carbons C-4 and C-2.In this paper,two chiral centers at C-4 and C-2 were successfully established by Evans alkylation and Aldol reaction.Finally,3-13 was obtained by mild Dess-Martine oxidation and conditional column chromatography at 15?.Simultaneously,the racemization kinetics of 3-13 was studied,it was found that compound 3-13 was stable in both protic and aprotic solvents,and basically stable in neutral and acidic conditions.Compound 3-13 would racemize rapidly only in alkaline conditions.Under the same concentration of alkaline conditions,the racemization rate of 3-13 with 1,3-dimethyl fragment was slower than that of ?-keto ester with only one chiral.Total synthesis of natural product Santinol D(4-1).4-1 is a kind of triglyceride,which provides energy for various tissues of human body.Therefore,it is of great significance to study the total synthesis of this kind of natural product.4-1 contains two chiral carbons,C-4"' and C-2"'.In this paper,two chiral centers at C-4"' and C-2"'were established by Evans alkylation and Aldol reaction,then three acyl fragments in natural products were constructed by three esterification reactions.Finally,four diastereoisomers of natural product 4-1 and compounds(2"'S&R,4"'R)-4-1 and(2"'S&R,4"'S)-4-1 were obtained by using the same reaction conditions and separation methods as those in the process of synthesizing model molecule 3-13.Finally,the absolute configuration of natural product was determined to be(2"'R,4"'S)-4-1,and it was verified by experiments that the hydrogen spectrum data given in the separation literature was racemic at C-2"'.However,the racemized product at C-2"',(2"'S&R,4"'S)-4-1 had a large difference in optical rotation with the natural product.This may be due to the fact that the optical rotation of the natural product was measured first in the literature,and racemization did not occur at that time,and then racemization occurred when the hydrogen spectrum was measured.