Angelw: asymmetric synthesis of chiral 2-aryl-2,3-dihydrobenzofuran derivatives

Chiral 2-aryl-2,3-dihydrobenzofuran derivatives widely exist in natural products and bioactive compounds (Figure 1) Therefore, the development of new methods for the synthesis of functional 2-aryl-2,3-dihydrobenzofuran derivatives has become the focus of chemists The synthesis methods of these compounds mainly include asymmetric hydrogenation, C-H insertion reaction and [3 + 2] cycloaddition reaction Among them, the transition metal catalyzed asymmetric intramolecular C-H insertion reaction of diazides has developed rapidly, but there are few reports about the intramolecular C-H insertion reaction of polysubstituted aryl diazides (image source: angelw Chem Int ed.) recently, the do Hyun Ryu team at chengjunguan University in South Korea developed a new strategy to synthesize asymmetric cyclopropane through the closed-loop reaction initiated by Michael In addition, the asymmetric rearrangement of cyclopropane in situ catalyzed by chiral oxazoliborane ions has been successfully developed Therefore, it is assumed that the o-quinone formed in situ by O-hydroxybenzyl alcohol 1 can react with diazo ester to form chiral donor acceptor cyclopropane 2, and then 2 undergoes intramolecular rearrangement reaction to form chiral 2-aryl-2,3-dihydrobenzofuran 3 and 4 (scheme 1) So far, only one case of asymmetric cyclopropane / intramolecular rearrangement of o-quinone and α - diazone catalyzed by chiral phosphoric acid has been reported, but only when the electron substituted o-quinone is used as the substrate, the reaction can yield 2,3-dihydrobenzofuran in high yield, so the substrate range of the reaction is relatively limited, and the enantioselectivity of the reaction is not high Therefore, a new Lewis acid catalyzed asymmetric cyclopropane / intramolecular rearrangement of O-hydroxybenzyl alcohol 1 and α - diazo ester was developed by the do Hyun Ryu team of chengjunguan University in South Korea to synthesize 2-aryl-2,3-dihydrobenzofuran compounds with two adjacent chiral centers Relevant research results were published in angew.chem Int ed (DOI: 10.1002 / anie 201906954) (picture source: angelw Chem Int ed.) the author used O-hydroxybenzyl alcohol 1a and ethyl diazoacetate as template substrates, through the screening of substrates, catalysts and solvents and other conditions, determined that the optimal conditions were (Table 1): O-hydroxybenzyl alcohol 1a and tert butyl diazoacetate in 20 mol% chiral oxazoliborane ion 5b as catalyst, DCM as solvent, 3 Å The corresponding products can be obtained with 87% yield, 99% enantioselectivity and > 20:1 non enantioselectivity when the molecular sieve is used as additive and reacted at - 40 ℃ for 2 hours (picture source: angelw Chem Int ed.) under the optimal reaction conditions, the author investigated the substrate range (scheme 2) of O-hydroxybenzyl alcohol The benzyl alcohols with R 3 as various 4-and 3-me substitutions and R 4 substitutions can adapt to the reaction conditions well, and the corresponding products can be obtained with good to excellent yield and excellent stereoselectivity Among them, benzyl alcohol substituted by electron donor R4 and 4-methoxyphenyl can obtain trans products with medium to excellent yield and excellent stereoselectivity Moreover, methyl diazoacetate can also obtain corresponding products with excellent yield and stereoselectivity (image source: angelw Chem Int ed.) next, the author investigated the range of substrates for the synthesis of 2-aryl-2,3-dihydrobenzofuran derivatives containing two consecutive chiral centers and quaternary carbon centers (scheme 3) All kinds of ester substituted α - benzyldiazo esters can obtain the corresponding products with high yield and stereoselectivity Among them, the larger the steric hindrance of the ester alkyl part of α - benzyldiazo ester is, the higher the yield and stereoselectivity of the product are Therefore, the range of the substrate of O-hydroxybenzyl alcohol was investigated with α - benzyl tert butyl diazo ester as the template substrate All kinds of R 3 and R 4 substituted O-hydroxybenzyl alcohol can adapt to the reaction conditions well, and the corresponding products can be obtained with good to excellent yield and stereoselectivity Moreover, 4-halogens, 3-or 4-cf 3 and 2-naphthyl substituted O-hydroxybenzyl alcohol with R4 have good tolerance, and can obtain corresponding products with good yield and excellent stereoselectivity The absolute configuration of 4a is determined by single crystal, and the absolute configuration of other products is consistent with that of 4A (Figure 2) (picture source: angelw Chem Int ed.) (picture source: angelw Chem Int ed.) then, the author investigated the substrate range of various α - alkyl diazonides (scheme 4) All kinds of electrophilic and electric absorption substituted benzyl diazo esters, alkyl, allyl or propargylic diazo esters have good tolerance, and can obtain corresponding products with good to excellent yield and excellent stereoselectivity In addition, diazo ester with larger substituent steric hindrance can also react with O-hydroxybenzyl alcohol well, and the corresponding products can be obtained with medium to good yield and excellent stereoselectivity (picture source: Angew Chem Int Ed.) according to the experimental results, the author speculated the possible reaction mechanism (Figure 3): the reaction mode of O -QM and 5b was the same as that of the asymmetric carbon insertion reaction of α - benzyldiazepine and cyclohexene ketone previously reported As shown in the intermediate transition state 6 in Figure 3, o-qms is located above the m-xylene group, and there is a dipole dipole interaction between the carbonyls Therefore, α - diazo ester will attack o-qms from the re plane, and nucleophilic addition reaction will take place to generate intermediate 7 7 The cyclization reaction takes place to produce donor acceptor cyclopropane 2 2 can induce the C-C 1 bond adjacent to the electron donor group (AR 1) to polarize and form the zwitterion intermediate 2 ' Finally, alkoxy group attacks carbon positive ion C 1 to form 2-aryl-2,3-dihydrobenzofuran 3 and 4 (photo source: angelw Chem Int ed.) Summary: the do Hyun Ryu team of chengjunguan University in South Korea has developed a new Lewis acid catalyzed asymmetric cyclopropane / intramolecular rearrangement of O-hydroxybenzyl alcohol 1 and α - diazo ester to synthesize 2-aryl-2,3-dihydrobenzofuran compounds with two adjacent chiral centers.