Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control

A stereogenic center,
placed at an exocyclic location next to a
chiral carbon in a ring to which it is attached, is a ubiquitous structural
motif seen in many bioactive natural products, including di- and triterpenes
and steroids. Installation of these centers has been a long-standing
problem in organic chemistry. Few classes of compounds illustrate
this problem better than serrulatanes and amphi­lectanes, which
carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed
asymmetric hydro­vinylation (AHV) of vinyl­arenes and 1,3-dienes
such as 1-vinyl­cycloalkenes provides an exceptionally facile
way of introducing these chiral centers. This Article documents our
efforts to demonstrate the generality of AHV to access not only the
natural products but also their various diastereo­isomeric derivatives.
Key to success here is the availability of highly tunable phosphor­amidite
Ni­(II) complexes useful for overcoming the inherent selectivity of
the chiral intermediates. The yields for hydro­vinylation (HV)
reactions are excellent, and selectivities are in the range of 92–99%
for the desired isomers. Discovery of novel, configurationally fluxional,
yet sterically less demanding 2,2′-biphenol-derived phosphor­amidite
Ni complexes (fully characterized by X-ray) turned out to be critical
for success in several HV reactions. We also report a less spectacular
yet equally important role of solvents in a metal–ammonia reduction
for the installation of a key benzylic chiral center. Starting with
simple oxygenated styrene derivatives, we iteratively install the
various exocyclic chiral centers present in typical serrulatane [e.g.,
a (+)-p-benzo­quinone natural product, elisabetha­dione, nor-elisabetha­dione, helioporin D, a known advanced
intermediate for the synthesis of colombiasin and elisa­pterosin]
and amphi­lectane [e.g., A–F, G–J, and K,L pseudo­pterosins]
derivatives. A concise table showing various synthetic approaches
to these molecules is included in the Supporting Information. Our
attempts to synthesize a hitherto elusive target, elisabethin A, led
to a stereo­selective, biomimetic route to pseudo­pterosin
A–F aglycones.