A Diamino Alcohol Catalyzed Enantioselective Crossed Aldol Reaction of Acetaldehyde with Isatins – A Concise Total Synthesis of Antitumor Agents

• Published in: European journal of organic chemistry Vol. 2017; no. 26; pp. 3874 - 3885
• Main Authors: Subba Reddy, Ummareddy Venkata, Chennapuram, Madhu, Seki, Kento, Seki, Chigusa, Anusha, Bheemreddy, Kwon, Eunsang, Okuyama, Yuko, Uwai, Koji, Tokiwa, Michio, Takeshita, Mitsuhiro, Nakano, Hiroto
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 17.07.2017; Wiley Subscription Services, Inc
• Subjects: Acetaldehyde; Alcohol; Aldehydes; Aldol reactions; Alkaloids; Amino alcohols; Anticancer properties; Architecture; Catalysis; Chemical synthesis; Chemistry; Chemistry, Organic; Enantioselectivity; Organocatalysis; Physical Sciences; Science & Technology; Total synthesis; SYSTEM; Enantioselectivity; AMINO ALCOHOL; ORGANOCATALYST; ALDEHYDES; Organocatalysis; Total synthesis; STRUCTURE ELUCIDATION; 1,2-DIHYDROPYRIDINES; KETONES; Amino alcohols; Aldol reactions; DIELS-ALDER REACTION; DERIVATIVES; ALKALOIDS
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201700399

Enantioselective crossed aldol reactions of isatin derivatives and acetaldehyde have been developed with a series of simple diamino alcohol catalysts to afford 3‐substituted 3‐hydroxyindolin‐2‐ones in high chemical yields (up to 95 %) and optical purities (up to 92 % ee). The synthetic potential of the present protocol has been demonstrated by concise, enantioselective, protecting‐group‐free, and transition metal‐free total syntheses of antitumor and antiviral agents with the tryptanthrin architecture, that is, phaitanthrin B and cephalanthrin A, along with the biologically active indolidine alkaloids chimonamidine and donaxaridine as well as the formal synthesis of CPC‐1. The highly enantioselective outcome of this catalytic crossed aldol reaction was evaluated by calculating the Gibbs free energies of the possible transition states. The catalytic activities of diamino alcohols as bilateral activation catalysts for the enantioselective crossed aldol reactions of isatin derivatives with acetaldehyde are evaluated. The 3‐alkyl‐3‐hydroxyindolin‐2‐one products are used for the total synthesis of the bioactive natural products phaitanthrin B, cephalanthrin A, chimonamidine, and donaxaridine as well as the formal synthesis of CPC‐1.