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

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journal contribution
posted on 12.07.2018, 00:00 by Srinivasarao Tenneti, Souvagya Biswas, Glen Adam Cox, Daniel J. Mans, Hwan Jung Lim, T. V. RajanBabu
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.