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.
