Palladium catalyzed enantioselective synthesis and cross conversion bond rearrangement of benzofurano nine membered heterocycles

As a special class of compounds, rings of medium size, especially nine membered rings, play an important role in natural products and bioactive molecules These intermediate rings have unique conformations and often undergo unconventional stereoselective transformation The general reactions involved in this kind of molecules are rarely reported in the literature, a large part of which is due to the lack of synthesis methods There are not many catalytic synthesis methods of nine membered ring, among which the breakthrough is that [6 + 3] cycloaddition synthesis [4,1,3] double ring structure (Fig 1a, J am Chem SOC 2008, 130, 14960-14961) Recently, researchers reported an interesting method of iridium catalyzed allyl substitution and retro Mannich cascade reaction to synthesize indole-9-aza-heterocycle (Fig 1b, angelw Chem Int ed 2017, 56, 10545-10548) However, it is still necessary to develop efficient and flexible intermolecular cycloaddition methods Figure 1 Asymmetric synthesis source of nine membered ring: J am Chem SOC Recently, a team composed of Zhao Yu, associate professor of chemistry, National University of Singapore, and Lan Yu, Professor of chemistry and chemical engineering college, Chongqing University was formed in J am Chem SOC A series of benzofuran nine membered heterocycles were synthesized by palladium catalyzed enantioselective [5 + 4] cycloaddition of azadiene and vinyl carbonate (VECs) The nine membered ring products prepared by the new method can be rearranged further to form two novel kinds of polycyclic molecules with multiple chiral centers (Fig 1c) In order to develop the enantioselectivity of the reaction, a series of chiral ligands were screened with 1a and 2A as the reaction substrate and PD 2 (DBA) 3 as the catalyst (Fig 2) In our experiments, we found that some bis or mono phosphine ligands without substituents can achieve good reactivity and selectivity L6, in particular, can achieve 95% yield and 79% ee The reaction temperature decreased to 0 ℃, and the enantioselectivity increased to 88% ee Figure 2 [5 + 4] optimization source of cycloaddition conditions: J am Chem SOC With the best reaction conditions, the author expanded the reaction substrate As shown in Fig 3, VECs substrates with various benzene ring substituents, furan substituents, phenylethyl and cyclohexyl groups have good reactivity, and the yield and enantioselectivity of the product 3a-3l are considerable; azadiene substrates with different aromatic groups also have good reactivity The absolute configuration of the product 3U is given by the single crystal X-ray analysis Fig 3 [5 + 4] expanded source of cycloaddition substrate: J am Chem SOC Next, the author carried out two types of transformation for the nine membered ring products obtained from the reaction, one is epoxidation and rearrangement, the other is ring reduction and TS migration The nine membered ring contains double bond structure, which can be converted into epoxy heterocyclic compound 4 through the peripheral non enantioselective epoxidation reaction The yield and non enantioselectivity of the product are very high (Fig 4) Compound 4 can be rearranged to benzofuran hetero [6,6] polycyclic compound 5 under the action of Lewis acid BF 3, and the conversion efficiency and enantioselectivity are also very high (Fig 5) The absolute configuration of compound 5e is given by single crystal X-ray analysis Fig 4 Non enantioselective epoxidation source of nine membered ring: J am Chem SOC Fig 5 Rearrangement source of epoxy heterocyclic compound: conversion of compound 3 of J am Chem SOC Into compound 6 through ring shrinking and TS migration is the author's "unexpected delight" (Fig 6) The authors observed that after long-term storage of compound 3a, some changes would take place in NMR Therefore, the author tried to heat the toluene solution of 3a, and found exciting results: 3A was transformed into diastereomers 6a and epi-6a, and its absolute configuration can be obtained by single crystal X-ray analysis Polycyclic compound 6 has four consecutive chiral centers (including two quaternary carbon centers), three of which are formed after ring contraction and TS migration This complex transformation process proves the unique activity of intermediate heterocycles Fig 6 The sources of nine membered ring contraction and TS migration: J am Chem SOC Finally, in order to explore the mechanism of two kinds of transformation processes of nine membered ring, the author carried out corresponding DFT calculation The DFT calculation results are theoretically the special properties and reactivity of benzofuran nine membered ring Conclusion: Zhao Yu and Lan Yu team have realized the enantioselective synthesis and further transformation of benzofuran nine membered ring, and the synthesis and research of other intermediate rings are also in progress Thesis link: http://pubs.acs.org/doi/10.1021/jacs.7b09161 the Zhao research lab: http://zhaoyugroup.sg/index.html brief introduction of Professor Lan Yu: http://hgxy.cqu.edu.cn/info/1093/2463.htm Lan Yu (left) and Zhao Yu (right)