Research group of Professor Ye Tao, Shenzhen Graduate School, Peking University: Total Synthesis of polyketide natural product psymberin (irciniastin a)

The natural product of marine polyketones, psymberin, which was isolated by Yu Jie in 2005, has excellent antitumor activity Psymberin has obvious inhibitory activity on many tumor cell lines, especially for some melanoma cell lines and breast cancer cell lines, which have reached the level of nanomolar concentration (LC 50 < 2.5x10-9m), and for colon cancer cell line hcc-2998 The inhibitory activity of LC 50 was also at the micromolar level (LC 50 < 3.76x10-7m) Psymberin consists of a polysubstituted trans-2,6-tetrahydropyran ring, a psymberic acid segment and a pyran segment passing through an unstable n, At the same time, the structure of dihydroisocoumarin in the molecule is also found for the first time in the natural products of the family It is worth noting that the preliminary study shows that the structure is of great significance for the excellent anti-cancer activity of psymberin Since the separation, the research on the synthesis and activity of the star molecule has never been interrupted Up to now, seven research groups have completed the total synthesis of psymberin, and another two research groups have completed the total synthesis of the natural product form Based on the interest in the anticancer activity and structural characteristics of the compound, relying on the National Key Laboratory of cancer chemical genomics jointly established by the provincial and ministry, Professor Ye Tao's research group of Shenzhen Graduate School of Peking University has recently completed the full synthesis of the natural product with novel synthesis strategy, which is also the ninth full synthesis report of psymberin Relevant research results were published in org Lett (DOI: 10.1021/acs.orglett.9b01113) Professor Ye Tao's research group completed the construction of trans tetrahydropyran ring, which is the key part of psymberin, through a novel cross epoxy Michael addition / lactone reduction strategy Then, in the later stage of the synthesis, Diels alder reaction was used to realize the introduction of multi substituted aromatic ring, and finally completed the full synthesis of psymberin The specific inverse synthesis analysis is as follows (Fig 1): according to its structural characteristics, due to N in psymberin (1), Because of the instability of o-hemiacetamide structure, the author intends to construct this structure at last For the dihydroisocoumarin structure in the key fragment 3, its polysubstituted aryl parent nucleus can be constructed by Diels alder / aromatization reaction, in which the introduction of three consecutive chiral centers at C15 to C17 positions in compound 4 is via brown crotylation Reaction and electrophilic cyclization were realized, while trans tetrahydropyran segment 5, which is the most important natural product, could be realized by the cross ring Michael addition / lactone reduction strategy Figure 1 Reverse synthesis analysis of psymberin (source: org Lett.) on the basis of the above-mentioned reverse synthesis analysis, starting from the known aldehyde compound 8, the author obtained a pair of non corresponding isomer compounds 16 and 17 (DR 1.7:1) through the isoamylation reaction participated by zinc, in which the non target compound 16 can be obtained through Swern Two steps of oxidation and stereoselective reduction were used to transform the target isomer efficiently The end double bond of 17 was then oxidized and cut off under ozone condition, and then under the condition of still gennarimodified HWE olefinization reaction, the one pot method of cyclization of aldehydes 18 through Z-type unsaturated ester intermediate 20 and transesterification process realized the efficient preparation of unsaturated lactones 7 It is worth pointing out that, according to the synthesis idea, the author thinks that the biggest difficulty in the next cross epoxide Michael addition reaction may be the potential steric resistance of gemaldimethyl After a series of experiments, the one pot method was used to remove the protection group and the target cross epoxide Michael addition reaction at ppts / water / toluene / 100 ℃ Finally, the bridge ring intermediate 23 was successfully converted into the target polysubstituted trans tetrahydropyran ring compound 5 under the reduction condition of lithium borohydride / methanol (Fig 2) Fig 2 After the synthesis route of trans tetrahydropyran ring 5 (source: org Lett.) obtained the key trans tetrahydropyran compound 5, the author began to explore the construction method of dihydroisocoumarin structure (Fig 3) Compound 26 was obtained by the following reactions: the first-order hydroxyl group protected by TES, the first-order hydroxyl group protected by selective oxidation of TEs and the subsequent brown crotylation reaction Then, by introducing carbonate group on the newly formed second-order hydroxyl group of compound 26 in advance, compound 27 was obtained by electrophilic cyclization and hydrolysis reaction under the condition of iodine bromide, and the enantioselectivity was 5:1 The introduction of C17 chiral hydroxyl group was successfully completed Furthermore, Diels alder / aromatization precursor compound 29 can be obtained by introducing alkyne group and protecting hydroxyl group Figure 3 Construction method of amphiphilic 29 (source: org Lett.) by Professor danishefsky (J am Chem SOC 2003, 125, 9602; J am Chem SOC 2004, 126, 7881; J am Chem SOC 2006, 128, 14185), through a series of conditions and substrate screening, alkynyl ester compound 29 as a amphiphilic and cyclodiene 30 successfully completed the introduction of polysubstituted aromatic ring parent nucleus through intermolecular Diels alder reaction Then, the further functional group modification of the target aryl structure was completed through the protection of phenolic hydroxyl, selective Bromination and lithium halide exchange alkylation At the same time, the structure of dihydroisocoumarin was constructed by lactonization, and then the other two naked hydroxyls were protected by tes to obtain compound 37 (Fig 4) Figure 4 Synthesis route of dihydroisocoumarin 37 (source: org Lett.) after obtaining key compound 37, the author started to complete the total synthesis of psymberin (Figure 5) Firstly, a series of functionalization of the primary hydroxyl group protected by PMB was carried out to obtain the primary amide compound 39 Then, the key intermediate compound 3 can be obtained by removing the protection of mom and TEs and replacing it with acetyl protection Finally, the author uses Professor de branbender in the total synthesis of psymberin (j.am.chem.soc 2005, 127, 11254; j.am.chem.soc 2012, 134, 17083) the one pot strategy of imidate construction acylation reduction reaction was developed The coupling of key segment 3 and psymberic acid segment 2 was realized, and the synthesis of the target natural product psymberin was finally completed Figure 5 Completion of total synthesis (source: org Lett.) conclusion: Professor Ye Tao's research team completed the total synthesis of psymberin through a flexible synthesis route The synthesis route includes the following highlights: (1) the key trans-2,6-tetrahydropyran ring structure has been synthesized efficiently and stereoselectively by the Michael addition / lactone reduction strategy The novel strategy has important guiding significance for the synthesis of trans-2,6-tetrahydropyran ring structure with similar substitution characteristics; (2) the cyclization reaction mediated by IBR has been realized (3) the synthesis of key dihydroisocoumarins was facilitated by the strategy of intermolecular Diels alder cycloaddition / aromatization The completion of the synthesis also laid a solid foundation for the subsequent structural transformation and the study of structure-activity relationship This achievement was recently published in org Lett (DOI: 10.1021 / ACS Orglett 9b01113) The corresponding authors are Dr Guo Yi'an and Professor Ye Tao The experimental part of this study was completed by Yu Jie and Yang Mingze of Professor Ye Tao's research group The research work was supported by nnsf21772009 and Shenzhen peacock plan (kqtd2015071714043444).