Sunday, September 7, 2014

Approaches to Synthesis of the Cyclocitrinols: Reductive Cyclopropane Fragmentation

            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.

Saturday, August 9, 2014

Asymmetric Synthesis of the Torgov Diene: Application to Total Synthesis of Estrone

Igor Torgov (1912 - 2007)
            Igor Vladimirovich Torgov was a Soviet chemist who served as the head of steroid chemistry at the Institute of Natural Compounds Chemistry of the Soviet Academy of Sciences (currently the Shemyakin Institute of Bioorganic Chemistry). Dr. Torgov’s famous reaction is a carbocyclization of an achiral diketone (discussed in detail below) that provided an early pathway for the total chemical synthesis of steroid hormones, and is still used for the industrial-scale production of certain steroids at the factories of Schering AG in Berlin, Germany. The product of the Torgov cyclization, the Torgov diene, is a steroidal D8,14 dienone which serves as a synthetic precursor to a range of estrol and estradiol derivatives including estrone. Torgov’s synthetic methodology provides expedient access to racemic steroids. However, since its original disclosure in 1963, the development of an enantioselective variant of the Torgov cyclization has remained elusive. Torgov and co-workers were eventually able access enantiopure steroid intermediates by resorting to an enantioselective reduction of a key intermediate, mediated by S. cerevisiae yeast culture. But the use of fermenting yeast reduction suffers from drawbacks that include large reaction volumes and difficulties encountered during extraction of water-soluble products. Additionally, in the late 1990s, workers at Schering reported studies toward the development of a catalytic asymmetric version of the Torgov cyclization, but high selectivity and turnover numbers were not achieved. Consequently, enantioselectivity in the Torgov process for steroid production has been considered a classic unsolved problem for organic chemists.
            Very recently, Benjamin List’s laboratory at the Max Planck Institute disclosed a report describing a catalytic asymmetric version of the Torgov cyclization (see above, conversion of 1 à ‘Torgov’s diene’). Mechanistically, the Torgov cyclization involves (1) isomerization of intermediate 1 to the endocyclic D8,9 isomer A (2) Prins-type cation-olefin cyclization (3) deprotonation of the ensuing carbocation to give the alcohols B and, finally, (4) isomerization and dehydration of B, which furnishes the intact Torgov diene. List and co-workers recognized that the chirogenic, stereo-determining step is likely the cyclization of intermediate A and that this transformation might be catalyzed by an enantiopure Brønsted acid. Upon screening of a range of acids, a novel chiral disulfonimide (DSI) (shown above, see box) emerged that was uniquely able to deliver the requisite diene at low temperature and with high enantioselectivity. A gram-scale Torgov cyclization of intermediate 1, catalyzed by the unique pentafluorothio- and nitro-containing DSI, proceeded in high yield to furnish Torgov’s diene with an enantiomeric ratio of 96.5:3.5. A single recrystallization provided essentially optically pure material (>99.9:0.1 e.r.). Moreover, the precious DSI could be recovered from the reaction in 88% yield. List’s group then repeated a two-step procedure that was previously developed by E. J. Corey’s laboratory to diastereoselectively reduce Torgov’s diene to estrone methyl ether (3). Methyl ether deprotection yielded fully synthetic (+)-estrone, thus completing the shortest route to the bioactive steroid reported to date.
            List’s achievement in the enantioselective chemical synthesis of estrone is rivaled in its conciseness only by the work of E. J. Corey’s group, which has previously disclosed no less than three (!!!) distinct enantioselective processes. The first, reported in 2004 (chemistry not shown), uses a catalytic enantioselective Diels-Alder reaction as the key step. The second, outlined in the scheme above, proceeds through the intermediacy of Torgov’s diene. In this work, the achiral diketone 1 is first reduced enantioselectively using oxazaborolidine catalysis in combination with the reductant catecholborane. A single recrystallization of the product from ethyl acetate-hexane affords highly enantioenriched 4 (99% ee). Torgov cyclization of mono-ketone 4 then proceeds efficiently in methanolic hydrochloric acid and the ensuing optically active dienol 5 is oxidized to Torgov’s diene by the IBX reagent. Finally, the same two-step reductive sequence from above, borrowed by List and co-workers, efficiently converts Torgov’s diene into estrone methyl ether. An alternate enantioselective total synthesis of Torgov’s diene, reported by Corey’s group in 2008, is discussed here. We should note that, these days, (+)-estrone is commercially available from Sigma-Aldrich for about $1.75/gram.