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

Abstract

<p class="first" id="P1">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 tri-terpenes 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 (HV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provide an exceptionally facile way of introducing these chiral centers. This manuscript documents our efforts to demonstrate the generality of the asymmetric HV 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 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 (+)- <i>p</i>-benzoquinone natural product, elisabethadione, <i>nor</i>-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. Our attempts to synthesize a hither-to elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A–F aglycone. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/95aae007-84ff-4a96-a6c8-0ed2bd97e27a/PubMedCentral/image/nihms981222u1.jpg"/> </div> </p>