Angelw: collective total synthesis of natural product xanthanolide

Xanthanolide is a group of sesquiterpene lactones isolated from Xanthium in Compositae So far, there are hundreds of xandhanolide confirmed, most of which have 5 / 7 double ring skeleton According to the stereochemistry of C-8 site, xanthanolide can be further divided into two categories: 5 / 7 trans structure and 5 / 7 CIS structure, which are xanthatin (1) and 8-epi-xanthatin (2) shown in Fig 1, respectively 1 and 2 are the two most important substances in the xanthanolide family, because they can be derived into other more complex and novel structures For example, after a series of double bond isomerization, 6 π electron cyclization and intermolecular Da reaction, 2 can be transformed into xanthipungolide (3), which has the most complex monomer structure In addition to the monomer xantanolide, there are many dimers in nature, which are called pungiolide Most of the pungiolide can be obtained from the biosynthesis of 2 Figure 1 Xanthanolide monomer and dimer and their biosynthesis sources: angelw Chem Int ed in addition to structural diversity, xanthanolide also has a wide range of biological activities, such as anti-cancer, antiviral, antibacterial, antimalarial and anti-inflammatory, which provides valuable resources for new drug research and development There are many studies on the chemical synthesis and structure activity relationship of these compounds However, only a few bicyclic xantanolides have been fully explored Other molecules with more complex structures, such as 3 - 10, have not been fully synthesized so far Professor Yefeng Tang's research group, from the school of pharmacy, Tsinghua University, has long been committed to the full synthesis of complex natural products, including many compounds of xanthanolide family Recently, Tang Yefeng's research group published a paper online on angew Chem Int ed., reporting the synthesis of a series of xanthanolide members including 2 - 10 The author also includes Professor Lihong Hu of Nanjing University of traditional Chinese medicine and members of his research group As can be seen from Fig 1, compound 2 is a common precursor of target molecule 3 - 10, so the primary goal of research is to develop a synthesis route of 2 Although the total synthesis of 2 has been reported for a long time, its long route and low efficiency make it difficult to be used Therefore, the author tries to develop a more simple and practical synthesis method of compound 2, and the reverse synthesis analysis is shown in Figure 2 2 can be obtained by 13's cyclo and cross cyclo metathesis, 13 can be obtained by 14's functionalization, 14 can be obtained by series reaction of allyl borate 15 and allyl boronization and internal esterification of chiral β - alkynaldehyde 16 Figure 2.8-epi-xanthatin's reverse synthesis analysis source: see Figure 3 for the synthesis route of angel Chem Int ed (+) - 8-epi-xanthatin (2) Using ethyl propionate (17) as the starting material, the e-isomer 15 was obtained by alkyne addition, acetylation and boration, and the chiral aldehyde compound 16 was prepared by rhodium catalyzed asymmetric 1,4-conjugate addition After obtaining 15 and 16, the key allyl boration and internal esterification series reactions were screened (Fig 4) The results showed that the yields and enantioselectivity of the products 14 and 22 were relatively good (entry 10) under the catalysis of cat E Next, the target compound 2 was obtained by removing the protective group of tips and eliminating the oxidation of 14 So far, the author obtained (+ - 8-epi-xanthatin (2) with the longest single-line step of 7 and the total yield of 15% Fig 3 (+) - 8-epi-xanthatin's enantioselective synthesis source: angelw Chem Int ed Fig 4 Allyl boration / lactonization series reaction condition screening source: angelw Chem Int ed after successfully realizing the scalable synthesis of (+ - 8-epi-xanthatin (2), the author started to synthesize 3-10 Inspired by the previous work, the author synthesized xanthipungolide (3, figure 5) in 40% of total yield in one pot by C2 = C3 double bond isomerization, 6 π electron cyclization and singlet oxygen excited [4 + 2] cycloaddition reaction In addition, the author found that 2 reacted in ethanol at high temperature (180 ℃) for 4.5 hours to obtain a single product, pungiolide (8), while in toluene / ethanol (5:1) at 110 ℃ for 2 hours to obtain mainly prepungiolide (12) and some raw materials (Fig 6) In the process of silica gel column chromatography, differential isomerization will take place, which can be converted to 24, and then heated to 8 Figure 5 Bionic total synthesis source of xanthipungolide: angelw Chem Int ed Figure 6 Bionic total synthesis source of pungiolided: angelw Chem Int ed finally, the author obtained other pungiolide through later modification (Figure 7) 8 Under the action of Stryker reagent [(pH 3P) cuh] 6, C2 = C3 double bonds are reduced, and pungiolidem (9) is obtained; if it is replaced by oxone / NaHCO 3 oxidation, C1 = C5 double bond epoxidation occurs, and pungioliden (10) is obtained After oxidation by DABCO and O 2, and then adding me 2S, we can get pungiolide a (4) and its C-11 epimer (25), and the double bond transfer product pungiolide e (5), the yields are 18%, 36% and 26%, respectively However, the selective epoxidation of 4 and 5 can yield pungiolideb (6) and pungiolide L (7), respectively Figure 7 Source of collective total synthesis of pungiolide: angelw Chem Int ed conclusion: Tang Yefeng's team designed and synthesized a group of xanthanlide family molecules The highlights of this synthesis work are: (1) synthesis of (+ - 8-epi-xanthatin by CPA catalyzed allyl boration and internal esterification in series; (2) synthesis of xanthipungolide by a series of double bond isomerization, 6 π electron cyclization and intermolecular Da reaction biomimetic; (3) realization of the first full synthesis of pungiolide by head to tail Da reaction and later diversification Paper link: http://onlinelibrary.wiley.com/doi/10.1002/anie.201710846/abstract introduction to Professor Tang Yefeng: http://