Selective Activation/Coupling of Polyhalogenated Nucleophiles in Ni/Cr-Mediated Reactions: Synthesis of C1–C19 Building Block of Halichondrin Bs

• Published in: Journal of the American Chemical Society Vol. 137; no. 19; pp. 6219 - 6225
• Main Authors: Yan, Wuming, Li, Zhanjie, Kishi, Yoshito
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.05.2015; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; NI(II)/CR(II)-MEDIATED COUPLING REACTION; NORHALICHONDRIN-B; CHROMIUM(II) CHLORIDE; SPONGE LISSODENDORYX SP; RING-SYSTEM; ANTITUMOR POLYETHER MACROLIDES; ANION EQUIVALENTS; MARINE SPONGE; ORGANOCHROMIUM REAGENTS; D-GLUCOSE
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.5b03498

The C1–C19 building block 46 of halichondrin Bs was synthesized via a selective activation/coupling of β-bromoenone 34 with aldehyde 35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a “naked” vinylogous anion with an aldehyde. The study with the coupling of 9 + 10 → 11 revealed: (1) β-bromoenone 9b is a better nucleophile than the corresponding β-iodo- and β-chloroenones 9a,c; (2) (Me)2Phen­(OMe)2·NiCl2 13b is a better Ni-catalyst than (Me)2Phen­(H)2·NiCl2 13a; and (3) a low Ni-catalyst loading, for example, 0.05–0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of polyhalogenated nucleophiles such as 34. The competition experiment of 10 + 9b over 10 + 31a–c revealed: (1) (Me)2Phen­(OMe)2·NiCl2 13b is more effective than (Me)2Phen­(H)2·NiCl2 13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example, 0.05–0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for discriminating β-bromoenone 9b from the three types of vinyl iodides 31a–c. The third phase of study was an application of the developed method to execute the proposed coupling of 34 + 35 → 36. For this application, a polyether-type Ni-catalyst 37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange resin-based device, the coupling product 36 was transformed to the C1–C19 building block 46 of halichondrin Bs without purification/separation of the intermediates.