The dried roots of Cynanchum stauntonii have been
administered in accordance with the Chinese Pharmacopoeia to relieve cough and
to promote the elimination of phlegm. The main chemical component of C. stauntonii roots that elicits the
antitussive, airway smooth muscle relaxant effects was recently identified as
an architecturally complex 13,14:14,15-disecopregnane steroidal glycoside.
Cynatratoside B (structure shown above) was shown to exhibit potent
inhibition of acetylcholine-induced tracheal contractions, which ultimately gives rise to the antitussive, expectorant and anti-inflammatory effects observed
upon oral administration of C. stauntonii
extracts. The disecosteroidal aglycone portion of cynatratoside B contains an internal
nine-membered lactone fused to a western A/B monounsaturated decalin. In
addition, the eastern cis-fused D/E
bis-furan system is densely functionalized and poses a significant synthetic
challenge. In 1983, Mitsuhashi and co-workers speculated that the biogenesis of
this unique type of carbon skeleton might involve a Grob-type fragmentation,
culminating in scission of the C13-C14 bond of a hirundigenin-type biosynthetic
precursor (as depicted above). The laboratory of Weisheng Tian at the Shanghai
Institute of Organic Chemistry was inspired by this biogenetic hypothesis to
investigate the biomimetic ferrous-mediated homolytic b-fragmentation of a related hydroperoxide species, itself
accessible through implementation of key Schenck ene reaction.
These synthetic investigations have led to the first chemical synthesis of the complex
disecopregnane steroid, glaucogenin D. An overview of their successful
synthetic campaign is provided below.
Tian’s group has pioneered the
development of a robust Baeyer-Villiger-type oxidative degradation of
plant-derived steroidal sapogenins (e.g. tigogenin) that generates the pregnane
triol 1 and related derivatives on kilogram scale. Their Baeyer-Villiger
protocol was previously applied to rockogenin acetate to produce a key western
domain intermediate in the course of Tian’s tour
de force chemical synthesis of cephalostatin 1. En route to
glaucogenin D, the pregnane derivative 1 is next advanced to the monosilylated
tetraol 2 by a seven-step sequence involving implementation of Meystre’s hypoiodite method to accomplish oxidative functionalization of the
unactivated angular methyl group at C18. Oxidative cleavage of the D14,15 olefin of 2 then induces a complex
oxidative skeletal rearrangement, resulting in formation of the polycyclic
D-seco steroid 3. It should be noted that the ozonolysis of 2 proceeds with
outstanding synthetic efficiency on 17-gram scale. Next, a variation of
Meystre’s hypoiodite-mediated intramolecular free radical C-H functionalization
reaction, using (diacetoxyiodo)benzene, is applied to intermediate 3. This synthetic
approach efficiently accomplishes chemoselective oxidation of the C20 ether of
3 to forge the highly complex cage-like product 4, containing a unique
consecutive ketal/acetal/ketal connectivity. Next, b-elimination of 4 under acidic conditions converts one of the
ketal linkages into an enol ether (5) and the acetal at C15 of 5 is then
selectively reduced by a three-step sequence, culminating in the hexacyclic hirundigenin-type derivative 6.
Cleavage of the C13-C14 bond of the
advanced intermediate 6 is now required to form the nine-membered lactone ring
of the target structure. A Schenck ene reaction/ferrous-mediated homolytic b-fragmentation strategy was projected to
achieve this synthetic goal. In the event, the Schenck ene reaction of 6 efficiently
produces the a-alkoxy hydroperoxide 7
with excellent regio- and stereoselectivity. Subsequent exposure of 7 to Fe(II)
in the presence of the stabilized radical trap reagent, TEMPO, induces a
sequence involving homolytic cleavage of the peroxide followed by alkoxy
radical b-fragmentation to produce a
tertiary carbon-centered radical which is finally trapped by TEMPO to afford
the desired lactone 8 in 70% yield. The fragmented product 8 contains a C13-TEMPO
substituent on the alpa face of the D/E bis-furan domain that is processed
through the entirety of the endgame sequence. Stereoselective
keto-hydroxylation of the olefin of 8 is achieved in two steps to secure the
oxygenated trans-decalin 9. Next, a
Grieco selenoxide syn-elimination
sequence introduces the requisite unit of unsaturation across C5-C6. The
resultant enone 11 is then dehydroxylated with samarium iodide to produce the
conjugated enol 12 and subsequent Luche reduction of 12 primarily furnishes the
C7b-allylic alcohol. Finally, thermal
elimination of the TEMPO substituent selectively generates the D/E-exocyclic
C12-C13 olefin, which is isomerized upon exposure to a ruthenium catalyst to
the requisite endocyclic bis-furan enol ether system of glaucogenin D. The
first chemical synthesis of glaucogenin D was completed in 25 steps from the
readily available plant-derived sapogenin, tigogenin. The route is highly
practical in terms of its conciseness, given the complexity involved, and
features several fascinating biomimetic oxidative rearrangements and/or fragmentations
of the steroidal carbon skeleton.
