In this report we highlight the significant potential of ethylene as a reagent for the introduction of a vinyl group with excellent stereoselectivity at three different stages in the synthesis of a broad class of natural products, best exemplified by syntheses of pseudopterosins. The late-stage applications of the asymmetric hydrovinylation reaction further illustrate the compatibility of the catalyst with complex functional groups. We also show that depending on the choice of the catalyst, it is possible to either enhance or even completely reverse the inherent diastereoselectivity in the reactions of advanced chiral intermediates. This should enable the synthesis of diastereomeric analogs of several classes of medicinally relevant compounds that are not readily accessible by the existing methods, which depend on ‘substrate-control’ for the installation of many of the chiral centers, especially in molecules of this class.

The production of polyisobutylene with Lewis acid catalysts has been in widespread use for over 60 years, but no validated molecular-level understanding of the reaction mechanism exists. We have computed initiation and propagation reaction pathways for isobutylene polymerization under industrially relevant conditions with an AlCl3/H2O initiator from density functional theory calculations. The initiator/catalyst complex we identified is fundamentally different from the putative complex identified in the literature, which typically assumes that the AlCl3OH2 complex is the active catalyst. We found that the reaction pathway with the AlCl3OH2 complex is infeasible due to unreasonably high energy barriers. Our calculations indicate that a minimum of two AlCl3 groups and one H2O molecule is required to initiate the reaction and that the complex must produce a highly acidic proton. It is the extreme acidity of the complex that is crucial for successful initiation of the reaction. The active catalyst moiety we identified produces low-energy-barrier pathways for both initiation and propagation steps. This complex was identified using the growing-string method to identify possible reaction pathways with various AlCl3/H2O complexes. The initiation reaction with our proposed complex was observed to occur naturally in an ab initio molecular dynamics simulation under typical operating conditions, confirming the activity of the complex.

No abstract

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 (+)-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. Our attempts to synthesize a hither-to elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A–F aglycone.