Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols via an Intramolecular Friedel–Crafts-Type 1,4-Addition: Access to Cannabidiol Analogues

TY - JOUR

T1 - Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols via an Intramolecular Friedel–Crafts-Type 1,4-Addition: Access to Cannabidiol Analogues

AU - Cobb, Andre

AU - Bryant, Laura

AU - Straker, Hannah

AU - Johnston, Callum

AU - Shankland, Kenneth

AU - Lees, Nick

N1 - Funding Information: We would like to acknowledge the support of GW Pharmaceuticals and the BBSRC for funding (to L.A.B, Grant No: BB/L015714/2) and thank the Chemical Analysis Facility (CAF) at the University of Reading for access to X‐ray diffractometers. Publisher Copyright: © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH

PY - 2021/8/13

Y1 - 2021/8/13

N2 - The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel–Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both ‘normal’ and ‘abnormal’ cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity. (Figure presented.).

AB - The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel–Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both ‘normal’ and ‘abnormal’ cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity. (Figure presented.).

KW - Synthesis

KW - Chemistry

KW - organocatalysis

KW - Cannabinoids

KW - Organic

UR - http://www.scopus.com/inward/record.url?scp=85110301751&partnerID=8YFLogxK

U2 - 10.1002/adsc.202100647

DO - 10.1002/adsc.202100647

M3 - Article

SN - 1615-4150

VL - 363

SP - 4067

EP - 4074

JO - ADVANCED SYNTHESIS AND CATALYSIS

JF - ADVANCED SYNTHESIS AND CATALYSIS

IS - 16

ER -