Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines
Yukihiro Fukata1, Koichi Yao1, Ryota Miyaji1
1Department of Material Chemistry, Graduate School of Engineering, Kyoto University , Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan.
The Journal of Organic Chemistry
|November 4, 2017
Summary
A novel isothiourea-catalyzed cycloaddition reaction efficiently synthesizes optically active 1,5-benzothiazepines. This method provides a versatile route to chiral pharmaceutical candidates with high selectivity.
Area of Science:
- Organic Chemistry
- Asymmetric Catalysis
- Medicinal Chemistry
Background:
- 1,5-Benzothiazepines are important heterocyclic scaffolds in medicinal chemistry.
- Developing efficient and enantioselective synthetic methods for these compounds is crucial.
Purpose of the Study:
- To develop an isothiourea-catalyzed enantioselective formal [4+3] cycloaddition reaction.
- To synthesize optically active 2- and 3-substituted 1,5-benzothiazepines.
- To explore the synthesis of chiral 2,3-disubstituted 1,5-benzothiazepines.
Main Methods:
- Isothiourea-catalyzed enantioselective formal [4+3] cycloaddition.
- Reaction of α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols.
- Mechanistic studies involving sulfa-Michael addition and seven-membered ring formation.
Main Results:
- Successful development of the cycloaddition reaction.
- Facile and divergent synthesis of optically active 1,5-benzothiazepines.
- Excellent regioselectivities and high enantioselectivities achieved for 2- and 3-substituted products.
- High regio-, enantio-, and diastereoselectivities for chiral 2,3-disubstituted 1,5-benzothiazepines.
Conclusions:
- The developed protocol offers a versatile and efficient method for synthesizing diverse chiral 1,5-benzothiazepines.
- The protocol is suitable for constructing libraries of potential pharmaceutical candidates.
- The reaction proceeds via a reversible sulfa-Michael addition followed by enantioselective cyclization.
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