A 10-step synthesis of the C25 steroid natural product cyclocitrinol from inexpensive, commercially available pregnenolone is reported. This synthesis features a biomimetic cascade rearrangement to efficiently construct the challenging bicyclo[4.4.1] A/B ring system, which enabled a gram-scale synthesis of the bicyclo[4.4.1] enone intermediate 18 in only nine steps. This work also provides experimental support for the biosynthetic origin of cyclocitrinol.
Bridged
ring systems are found in a wide variety of biologically
active molecules including pharmaceuticals and natural products. However,
the development of practical methods to access such systems with precise
control of the planar chirality presents considerable challenges to
synthetic chemists. In the context of our work on the synthesis of
cyclocitrinols, a family of steroidal natural products, we herein
report the development of a point-to-planar chirality transfer strategy
for preparing bridged ring systems from readily accessible fused ring
systems. Inspired by the proposed pathway for biosynthesis of cyclocitrinols
from ergosterol, our strategy involves a bioinspired cascade rearrangement,
which enabled the gram-scale synthesis of a common intermediate in
nine steps and subsequent unified synthesis of 10 cyclocitrinols in
an additional one to three steps. Our work provides experimental support
for the proposed biosynthetic pathway and for the possible interrelationships
between members of the cyclocitrinol family. In addition to being
a convenient route to 5(10→19)abeo-steroids,
our strategy also offers a generalized approach to bridged ring systems
via point-to-planar chirality transfer. Mechanistic investigations
suggest that the key cascade rearrangement involves a regioselective
ring scission of a cyclopropylcarbinyl cation rather than a direct
Wagner–Meerwein rearrangement.
Herein we report the first total synthesis of polychlorinated steroids clionastatins A and B, which was accomplished asymmetrically by means of a convergent, radical fragment coupling approach. Key features of the synthesis include an Ireland− Claisen rearrangement to introduce the C5 stereocenter (which was ultimately transferred to the C10 quaternary stereocenter of the clionastatins via a traceless stereochemical relay), a regioselective acyl radical conjugate addition to join the two fragments, an intramolecular Heck reaction to install the C10 quaternary stereocenter, and a diastereoselective olefin dichlorination to establish the synthetically challenging pseudoequatorial dichlorides. This work also enabled us to determine that the true structures of clionastatins A and B are in fact C14 epimers of the originally proposed structures.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.