Friday, September 13, 2013

Functionalization of Unactivated Angular Methyl Substituents on the Steroidal Molecular Framework: Yoshii’s Classic Semisynthesis of Strophanthidin

            The Baran Laboratory’s partial synthesis of the cardiotonic steroid ouabagenin starting from adrenosterone was recently highlighted here. It is intriguing to note that a related synthetic campaign was conducted no less than 35 years ago in Japan by Eiichi Yoshi’s research group. Yoshii’s team successfully synthesized strophanthidin from the readily available tetracyclic precursor pregnenolone acetate. The cardiotonic steroid strophanthidin is structurally analogous to the renowned mammalian endogenous hormone ouabagenin by virtue of its characteristic C17 butenolide system, ring junction stereochemistry and, perhaps most importantly, oxidized angular C19 methyl substituent. The installation of oxygenated functionality at ‘unactivated’ angular groups on the steroidal nucleus has been a longstanding synthetic challenge of great medicinal relevance, dating back to the manufacture of synthetic progestogens, components of the first oral contraceptive pills for women. Yoshii’s partial synthesis of strophanthidin relied on a redox relay strategy in which the oxidation state of the steroidal C6 position in the D5-steroid pregnenolone acetate (1) was systematically transferred to the angular C19 position. The butenolide moiety was then introduced and elaborated in a somewhat linear fashion followed by additional stereocontrolled oxidative modification of the steroidal framework to complete the synthesis. It should be noted that, in the absence of contemporary (convergent) C-C bond forming processes such as the Stille coupling, Yoshii’s butenolide construction was highly inventive for its time. Ultimately, as a result of this pioneering synthetic study, 13 mg of strophanthidin was produced and fascinating reactivity patterns associated with cardiotonic steroids were uncovered.
            Elegant technologies for the regioselective oxidative functionalization of the angular steroidal C19 position had been previously developed by chemists at Syntex Research Laboratories and by D. H. R. Barton in the early 1960s (see below). Yoshii’s group exploited those methods to gain rapid access to the pentacyclic intermediate 2, which was then advanced to the D14-butenolide derivative 3 by an 11-step synthetic sequence.
            The synthesis of oxidatively modified steroidal congeners related to 2, bearing heteroatom functionality at the C19 methyl group, facilitated the commercialization of various synthetic 19-norsteroids that were constituents of the first combined orally active hormonal contraceptives. The combination birth control pill usually contains a synthetic estrogen and progestogen (progestin) component. These hormones induce a physiological state resembling pregnancy wherein no additional ova can mature in the ovary for eventual fertilization. Most of the commercial estrogenic and progestogenic active pharmaceutical ingredients (APIs) belong to the 19-norsteroid series in which the unactivated angular 19-methyl group is eliminated. We will briefly examine a few classical examples of C-H functionalization of the steroidal C19 methyl group before returning to an overview of Yoshii’s partial synthesis of strophanthidin.
            The 1962 Syntex route to 19-norprogesterone (8) is shown in the scheme below. The addition of hypobromous acid to the D5-steroid pregnenolone acetate (1) generates a 6b-hydroxy bromohydrin intermediate which, on exposure to lead tetraacetate, undergoes intramolecular functionalization of the axial 19-methyl group to afford the 6b,19-oxido-steroid (2) in high yield (Intermediate 2 is also used in Yoshii’s synthesis of strophanthidin). Subsequent zinc reduction of the bromoketone 5 then yields a 19-hydroxy enone (6) that can be readily oxidized and decarboxylated to furnish 19-norprogesterone. In this groundbreaking work, the intramolecular functionalization of the 19-methyl group is the enabling technology that provides access to a molecular species (7) from which C19 can be eliminated under mild conditions.
            In the early 1960s, D. H. R. Barton showcased his nitrite photolysis methodology in an expedient partial synthesis of 19-noraldosterone acetate, a highly active mineralocorticoid salt-retaining hormone of the adrenal cortex. In brief, photolysis of the nitrite ester 10 results in formation of a carbon-centered C19 radical and nitric oxide (see Int-II), which then recombine to give an oxime (11) upon rearrangement of Int-III. The oxime 11 is then hydrolyzed and reduced to 19-hydroxycorticosterone (13) via the intermediacy of the lactol 12. Treatment of 13 with methoxide under thermodynamic conditions effectively excises the C19 substituent by means of a retro-vinylogous aldol process in which the intermediate enolate is protonated exclusively on the b-face. A second redox relay from C11 to the angular C18 methyl group then fashions the requisite lactol and completes the semisynthesis of 19-noraldosterone acetate (15). The nitrite photolysis methodology described herein was also famously executed by Barton in his classic synthesis of b-amyrin as well as by Corey in the first total synthesis of the limonoid natural product azadiradione. Analogous oxidative remote functionalization of angular methyl groups on the steroidal skeletal framework has been accomplished by implementation of Meystre’s photochemical hypoiodite method developed at Ciba Pharmaceuticals (discussed here and here).
            Thus, synthetic access to the 6b,19-oxido-steroid 2 by utilization of the C-H functionalization technologies summarized above not only facilitated the commercial development of the first oral contraceptives for women, but also enabled pioneering synthetic work on complex cardiotonic steroids such as strophanthidin. As depicted in the scheme below, the D14-butenolide derivative 3 (obtained from 2) was successfully converted into strophanthidin by a 10-step sequence (key transformations highlighted in red). This late-stage portion of Yoshii’s route entailed installation of the 14b-hydroxy group via the intermediacy of the bromohydrin derivative 17. Subsequent nucleophilic epoxidation directed by the 19b-hydroxy functionality then led to the advanced intermediate 19, which underwent reductive oxirane cleavage upon exposure to chromous acetate. Stereoselective reduction of the C3 ketone resident in 20 was promoted by treatment with Urushibara nickel, a nonpyrophoric version of Raney nickel that is known for catalysis of highly regio- and stereoselective carbonyl reductions. Finally, exposure of the polyol 21 to chromic trioxide in hexamethylphosphoric triamide (HMPA) induced selective oxidation of the 19-hydroxy group to the requisite angular formyl moiety found in strophanthidin. The magnitude of the impact of Yoshii’s 1978 synthesis of a highly complex cardiotonic steroid cannot be overstated. Indeed, the development and optimization of semisynthetic methods analogous to the conversion of 1 into strophanthidin are currently underway more than 35 years after the disclosure of Yoshii’s JOC manuscript.