Sunday, September 7, 2014
About eleven years ago, Crew and Clardy reported the isolation and structure elucidation of isocyclocitrinol A (shown above), a structurally unique and novel C25 steroid containing a rearranged A/B ring system (also discussed here). The natural product was isolated from a terrestrial Penicillium Citrinum and exhibited modest antibacterial activity. Within the cyclocitrinol class of rearranged steroids, the usual A/B decalin system is replaced by a relatively uncommon bicyclo[4.4.1]undecane (highlighted in blue), a carbocyclic motif that is rarely encountered in Nature. Owing to its bridgehead olefin, isocyclocitrinol A is an example of a natural product that violates Bredt’s rule.
The furanosesquiterpene spiniferin-1 is perhaps the only other example of a natural product that contains this peculiar bridged bicyclic substructure. And, as expected, synthetic methods to access a [4.4.1]-bicycle with a bridgehead double bond are lacking. No member of the cyclocitrinol family has succumbed to chemical synthesis and racemic spiniferin has only been prepared by two research groups since its isolation in 1975: 1) James Marshall in the early 1980s and 2) Weisheng Tian’s laboratory (JOC 2011). Tian’s total synthesis of spiniferin-1 (outlined below) proceeds in only eight steps with an overall efficiency of nearly 30%. The route features a rearrangement reaction initiated by polyfluoroalkanosulfonyl fluoride to contruct a strained norcaradiene-type system, which undergoes subsequent in situ 6p-electrocyclic ring-expansion to afford spiniferin-1. While elegant and expedient, this method might not be easily adapted to the preparation of more complex polycyclic molecular architectures (e.g. isocyclocitrinol A). Two approaches to the stereocontrolled chemical synthesis of highly elaborated cyclocitrinol advanced precursors have been described in the literature. The first of those is a semisynthetic strategy related to the natural product’s biosynthetic origin (see below), disclosed by the laboratory of Hans-Günther Schmalz in 2007. Schmalz’s captivating synthetic entry towards the cyclocitrinols will be the subject of this post.
It is first instructive to consider a plausible biosynthetic pathway (shown below) leading to the cyclocitrinols, advanced by Rodrigues-Filho and co-workers in 2005. The authors postulate that the angular C19 methyl group of ergosterol could undergo nucleophilic attack by the steroid A/B ring junction position C5 to produce an intermediary cyclopropane structure. Rupture of this ring system by deprotonation at C1 then generates the unique [4.4.1]-bicycle. In addition, oxidative fragmentation of the ergosterol C17 side chain with elimination of acetone also leads to the cyclocitrinols. Given this very reasonable biosynthetic hypothesis, a semisynthetic approach to the cyclocitrinols involving ring-expansion of an appropriate steroidal system containing an electronically-tuned cyclopropane, fused across the A/B junction, should constitute a viable tactic for assembly of the cyclocitrinol core. Schmalz’s group executed this chemistry by developing a samarium iodide-mediated reductive cyclopropane fragmentation reaction that was successfully applied to a highly elaborated substrate, culminating in the first stereocontrolled construction of the cyclocitrinol core structure.
In order to demonstrate the critical reductive cyclopropane cleavage step, a steroidal cyclopropyltrione intermediate was required. The synthesis of this substrate was achieved by controlled, site-selective oxidative modification of commercially available dehydroepiandrosterone. The corresponding C1-O-acetate congener was first prepared by a six-step synthetic sequence. The C19 angular methyl group is then functionalized by converting the D5,6 olefinic intermediate to its bromohydrin derivative. This provides the substrate for subsequent implementation of Meystre's hypoiodite C-H functionalization reaction (discussed here). Reduction of the resultant lactol acetate product with concomitant elimination then gave the 19-hydroxy androsterone, equipped with a pre-installed leaving group (acetate) at C1. This intermediate was converted into a cyclopropane derivative via the intermediacy of its corresponding mesylate. Finally, three additional steps involving 1) regioselective methanolysis 2) Dess-Martin oxidation and 3) elimination of the axial C1 acetoxy group secured the requisite enedione/triketone substrate for reductive cyclopropane fragmentation.
In the event, when the cyclopropyltrione substrate was added to samarium iodide in tetrahydrofuran, cyclopropane cleavage proceeded instantaneously (mechanistic pathway depicted below) to forge the bicyclo[4.4.1]undecane motif of cyclocitrinol A. The 15-step approach to the core structure proceeds in around 2% overall yield. The advanced precursor synthesized by Schmalz and co-workers may be suitable for elaboration to the cyclocitrinols provided that the reactivity of carbonyl functionality at C3 and C17 can be reasonably distinguished. Regioselective functionalization at C17 is required for side chain installation and the C3 ketone must, at some point, be reduced to a carbinol.
James Leighton’s group at Columbia University has very recently disclosed an alternate de novo synthesis of the cyclocitrinol core skeleton. The Columbia route will be examined and contrasted with the clever pioneering entry of Schmalz’s lab in a forthcoming post.