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

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.