JACS: the Trost group of Stanford University has completed the synthesis of piericidin a, a natural product of polyene

Piericidin a (1) and B (2) are natural products isolated from Streptomyces mobaraensis and s pactam These compounds contain highly substituted pyridine segments and lipophilic side chains (scheme 1a) Its structure is similar to coenzyme Q10 (3, dotted box, scheme 1), so it has outstanding biological activity For example, piericidina is an effective inhibitor of protein I complex (nm level activity) The outstanding biological activity and interesting structural characteristics of these natural products have prompted organic synthesis chemists to study their synthesis strategies and structure-activity relationships (photo source: J am Chem SOC.) from scheme1, it can be seen that the core of the molecular structure of piericidin like natural products and other natural products and drugs is the 1,3,6-triene fragment In the past, researchers mainly used a variety of olefinization methods and cross coupling reactions to construct triene fragments Recently, Barry M Trost group of Stanford University designed an alternative synthesis strategy: they successively coupled two alkyne fragments with propylene to obtain 1,3,6-triene fragments (j.am Chem SOC., DOI: 10.1021 / JACS 8b08974); and then used it in the simple synthesis of the natural product piericidin a The C-C bond construction strategy is modularized By simply switching the coupling order of two alkenes and alkynes, we can obtain the scheme 1b with complementary substituent structure The reverse synthesis analysis of piericidin A is as follows (EQ1): piericidin a can be obtained by sequential coupling of alkyne 7 and 8 with propylene Firstly, propylene is coupled with alkyne 8, and then the product is coupled with alkyne 7 to obtain the triene fragment Alkyne 8 can be synthesized from chiral propargyl alcohol 9 by Marshall tamaru reaction Analysis of the inverse synthesis of EQ 1 piericidin a (photo source: J am Chem SOC.) the synthesis of alkyne 14 and 7, 17, 18 (scheme 2): for the synthesis of alkyne 14, the author used et 2 Zn / (R, R) - prophenol catalyst to carry out the asymmetric propynylation of acetaldehyde in THF, to obtain chiral alcohol 9 with high yield and high enantioselectivity The methanesulphonate 12 was prepared by introducing the leaving group MS on 9 and then Marshall tamaru propargylated with aldehydes 13 to obtain 14 alkynes with high yield and non enantioselectivity Then the author synthesized 7,17,18 alkynes In this paper, 2-pyridyl ketone 15 was used as raw material, and bromine atom was introduced into C6 site through free radical mediated bromination reaction to get bromopyridyl ketone 16 Under the catalysis of cuprous iodide, 16 was added with propynyl lithium to obtain alkyne 17 17 was converted to full substituted pyridine 7 by depmbmbmbylation and methylation of methyl trifluoromethylsulfonate In addition, PMB can be removed by TFA to obtain 2-pyridone 18 (photo source: J am Chem SOC.) after obtaining two alkyne fragments, the author turned his attention to the sequential alkene alkyne coupling with propylene (scheme 3), and first studied the coupling between alkyne 14 and propylene In order to improve the coupling efficiency, the author connected the propylene balloon with the reactor containing ruthenium catalyst, then added 14 acetone solution to the reaction mixture at - 78 ℃, and finally obtained 1,4-diene 20 In this method, 14 was completely consumed, and no double coupling product of propylene and bimolecular 14 was observed In addition, 14 alcohol 19, which was protected by TBS, produced 1,4-diene 21 in almost quantitative yield under the same coupling condition In order to test the feasibility of alkyne 17, 18 and 7 for the second olefin alkyne coupling, the author evaluated the reaction of them with 1-hexene (scheme 3) The results showed that 18 and 7 were uncoupled with 1-hexene, and 17 and 1-hexene obtained 22 coupling products with high yield and high selectivity The expected product 23 and the secondary branch chain coupling product 24 were obtained by coupling 17 and 21, but the PMB in 23 was not removed successfully Then, the pyridine nitrogen in 7 was protonated to prevent the catalyst from deactivation due to its coordination with pyridine After adding 2.0 equivalent camphor sulfonic acid (CSA), 7 and 1-hexene can be coupled Another strategy to reduce the coordination between pyridine and ruthenium catalyst is to introduce electron withdrawing group (scheme 4) on pyridine oh In order to reduce the electrical properties of pyridine nitrogen, the author introduced teoc protecting group into 7 to obtain 25, and then coupled with 21 to obtain a mixture of linear product 27 and branched product 26 (4:1), which are easy to separate In this reaction, the carbonate part of teoc group is very important to the coupling reaction, and the coupling product cannot be obtained after the Oh in 7 is protected by TBS Finally, piericidin a was obtained by removing the teoc and TBS protecting groups in 27 (photo source: J am Chem SOC.) after the synthesis of piericidina, the author proves the generality of the strategy (Table 1) 1,4-diene can be obtained by coupling propylene with the first alkyne (blue part), and the product can be directly coupled with the second alkyne (green part) without purification In such reactions, the ratio of branched products to linear products can be adjusted by changing reaction conditions and ruthenium complexes In addition, by changing the coupling sequence, two kinds of regional isomers can be obtained from the same starting materials The flexibility of their synthesis is of great significance in the synthesis of analogues and the establishment of compound libraries (photo source: J am Chem SOC.) conclusion: Barry M Trost's research group has completed the total synthesis of piericidina from known pyridone 15 by seven steps of the longest linear step The highlights of the synthesis are the sequence coupling of alkenes and alkynes, asymmetric propynylation of acetaldehyde, selective free radical Bromination and depmb of pyridone parent nucleus- Methylation, etc This strategy of C-C bond synthesis and the method of constructing the triphene fragment provide a model for the synthesis of other natural products of polyene.