Abstract
Polyketide oligomers containing the structure of tetracyclic isochroman comprise a large class of natural products with diverse activity. However, a general and stereoselective method towards the rapid construction of this structure remains challenging due to the inherent instability and complex stereochemistry of polyketide. By mimicking the biosynthetic pathway of this structurally diverse set of natural products, we herein develop an asymmetric hetero-Diels–Alder reaction of in-situ generated isochromene and ortho-quinonemethide. A broad range of tetracyclic isochroman frameworks are prepared in good yields and excellent stereoinduction (up to 95% ee) from readily available α-propargyl benzyl alcohols and 2-(hydroxylmethyl) phenols under mild conditions. This direct enantioselective cascade reaction is achieved by a Au(I)/chiral Sc(III) bimetallic catalytic system. Experimental studies indicate that the key hetero-Diels-Alder reaction involves a stepwise pathway, and the steric hindrance between in-situ generated isochromene and t-Bu group of Sc(III)/N,N’-dioxide complex is responsible for the enantioselectivity in the hetero-Diels–Alder reaction step.
Highlights
Polyketide oligomers containing the structure of tetracyclic isochroman comprise a large class of natural products with diverse activity
It is known that Au(I) complexes have been used in the cascade reactions[35,36,37,38,39] and could promote the intramolecular cyclization of benzyl alcohol-functionalized alkynes to isochromene intermediate[40,41], and the ortho-quinone methide (o-QM) intermidiate could be generated from the proper precursor in the presence of either acid or base
Kang and coworkers realized the same reaction by employing a Au(I)/chiral Rh(III) catalytic system two years later[51]. Inspired by these elegant works, we envisioned that a combination of a Au(I) catalyst and a chiral lewis acid catalyst might enable the HDA reaction of in-situ generated isochromene and o-QM to deliver the optically active tetracyclic isochromans, despite of that the acceptors of reported asymmetric Au/Lewis acid bimetallic catalysis were limited to α, β-unsaturated γ-keto esters, and the most of known asymmetric cascade reactions of alkynyl alcohols delivered spiro products rather than fused products[50,52,53,54,55,56,57,58,59,60,61]
Summary
Studies commenced by screening effective precursors of o-QMs and the corresponding catalysts. Either electrondonating or electron-withdrawing substituents at the para- or meta-position of the benzene ring (2a-g) were well tolerated, affording the corresponding poliketide oligomers in moderate yields and with good to excellent diastereoselectivities and enantioselectivities. A wide range of α-propynyl benzyl alcohols 3b-i bearing different substituted aryl groups reacted with 2 h quite well to form the corresponding poliketide. 2-(Propynyl)phenol 3m was tolerated as well under the standard reaction condition and gave the corresponding chiral spiro product 5d in 31% yield with 37% ee. The corresponding product, tetracyclic isochroman poliketide oligomer 4h, could be obtained with 52% yield, 9:1 d.r. and 90% ee (Fig. 5a). TMS substituted ortho-hydroxybenzyl alcohol 8s gave the product 9a with the skeleton of natural product directly under standard conditions in 90% ee albeit with somewhat eroded yield (Fig. 5c). O 7 73 %, 63:37 d.r. major: 87% ee
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