Microwave‐Assisted, Asymmetric Synthesis of 3‐Amino‐2,3‐Dihydrobenzofuran Flavonoid Derivatives from Chalcones

Abstract

A route to access 3-amino-2,3-dihydrobenzofurans that utilizes microwave-assisted organic synthesis to rapidly generate analogues has been developed. The route begins with an acid-catalyzed, microwave-assisted aldol condensation to generate chalcone intermediates, followed by a Corey-Bakshi-Shibata reduction and subsequent Sharpless asymmetric epoxidation to access stereoisomeric epoxyalcohols. The final step is a one-pot, microwave-assisted, regioselective, acid-catalyzed epoxide opening with various amines followed by an intramolecular nucleophilic aromatic substitution reaction to generate the 3-amino-2,3-dihydrobenzofurans. This route provides ready access to stereochemically and structurally diverse analogues of these flavonoid scaffolds. Additionally, a pilot library was synthesized, and the biological activity diversity of the chalcones and dihydrobenzofurans was explored in human carcinoma cell lines.

Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product‐Inspired Library

“…In the synthesis of the benzofuran derivatives, a one-pot, two-step reaction was implemented. [40] Eu(OTf) 3 catalyzed the epoxide opening with various amines followed by nucleophilic aromatic substitution using Cs 2 CO 3 to generate the benzofurans S3-S6 in acceptable yields (25-70 %). Suzuki-Miyaura couplings using diverse boronic acids provided the desired final products 1 a-n and 2 a-n (15-86 %).…”

“…Suzuki-Miyaura couplings using diverse boronic acids provided the desired final products 1 a-n and 2 a-n (15-86 %). [40] In the synthesis of the benzopyran derivatives, the protection of the epoxyalcohol as a TBS ether generated silyl ethers S7-S8 in excellent yields (96-100 %). In order to override the selectivity for benzofuran formation, the alcohol resulting from the epoxide opening was protected as a benzyl ether with good yields (40-85 % over 2 steps).…”

“…We have previously described a route to selectively access epoxyalcohols from chalcones by a microwave-assisted aldol reaction followed by a Corey-Bakshi-Shibata (CBS) reduction and Sharpless asymmetric epoxidation. [40] From the common epoxyalcohol intermediates, a divergence in the synthesis occurs. Benzofurans are accessed through our optimized protocol for microwave-assisted, acid-catalyzed epoxide open-ing and nucleophilic aromatic substitution (S N Ar).…”

“…Benzofurans are accessed through our optimized protocol for microwave-assisted, acid-catalyzed epoxide open-ing and nucleophilic aromatic substitution (S N Ar). [40] To access the benzopyran scaffold, the free alcohol was first protected before subsequent epoxide opening, followed by benzyl protection of the resulting free alcohol and S N Ar cyclization. [41] Our synthetic strategy allowed us to systematically generate a library that was diverse in scaffold, appendage, and stereochemistry.…”

Enantioselective Synthesis of 4-Amino-3-hydroxybenzopyran Flavanol Derivatives from Chalcones

“…We have recently described a microwave-assisted method to selectively access 3-amino-2,3-dihydrobenzofurans. 13 However, this route did not en- We have previously shown that a one-pot, microwaveassisted, acid-catalyzed epoxide opening and subsequent intramolecular nucleophilic aromatic substitution reaction could be used to access benzofuran scaffolds. 13 Conveniently, both of these reactions can also be carried out separately to give a readily isolable diol as an intermediate.…”