Copper–Hydride-Catalyzed Enantio­selective Processes with Allenyl Boronates. Mechanistic Nuances, Scope, and Utility in Target-Oriented Synthesis

Synthesis of complex
bioactive molecules is substantially facilitated
by transformations that efficiently and stereo­selectively generate
polyfunctional compounds. Designing such processes is hardly straightforward,
however, especially when the desired route runs counter to the inherently
favored reactivity profiles. Furthermore, in addition to being efficient
and stereo­selective, it is crucial that the products generated
can be easily and stereodivergently modified. Here, we introduce a
catalytic process that delivers versatile and otherwise difficult-to-access
organoboron entities by combining an allenylboronate, a hydride, and
an allylic phosphate. Two unique selectivity problems had to be solved:
avoiding rapid side reaction of a Cu–H complex with an allylic
phosphate, while promoting its addition to an allenylboronate as opposed
to the commonly utilized boron–copper exchange. The utility
of the approach is demonstrated by applications to concise preparation
of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and
enantio­selective synthesis and structure confirmation of netamine
C, a member of a family of anti-tumor and anti-malarial natural products.
Completion of the latter routes required the following noteworthy
developments: (1) a two-step all-catalytic sequence for conversion
of a terminal alkene to a monosubstituted alkyne; (2) a catalytic
SN2′- and enantio­selective allylic substitution
method involving a mild alkylzinc halide reagent; and (3) a diastereo­selective
[3+2]-cycloaddition to assemble the polycyclic structure of a guanidyl
polycyclic natural product.