Conspectus
Steroids continue to play a
significant role in organic chemistry,
medicinal chemistry, and drug discovery due to their important biological
activities and diverse intriguing structures. Although synthetic organic
chemists have successfully constructed and elaborated the classical
[6–6–6–5] tetracyclic steroid skeleton for nearly
a century, synthesis of the unusual rearranged steroids, particularly abeo-steroids with a medium-sized ring, remains a challenge
in the synthetic community. Furthermore, the structures of abeo-steroids are complex and diverse, containing a seven-membered
ring embedded in the fused or bridged A/B ring system and possessing
numerous stereogenic centers. Besides their structural complexity,
various abeo-steroids have shown remarkable biological
activities. However, the relative scarcity of abeo-steroids in natural sources has impeded the systematic evaluation
of their biological activities. In addition, direct strategies to
build the core structures of abeo-steroids are very
rare, partially because of the high ring-strain energies of their
rearranged A/B ring systems. Therefore, the development of direct
and efficient synthetic approaches to these complex molecules is highly
desired.
Our long-standing interest in the total synthesis of abeo-steroids and the development of new cycloaddition reactions
for
streamlining complex molecule synthesis have led us to develop a series
of unique and powerful intramolecular cycloaddition strategies to
access a diverse array of highly strained abeo-steroids.
These strategies include Ru-catalyzed [5 + 2] cycloaddition, acid-promoted
type I [5 + 2] cycloaddition, Rh-catalyzed [2 + 2 + 1] cycloaddition,
and type II [5 + 2] cycloaddition. Since 2018, we have accomplished
the first total syntheses of five synthetically challenging abeo-steroids, i.e., bufogargarizins A and B, phomarol,
bufospirostenin A, and cyclocitrinol, thus facilitating the evaluation
of their pharmacological potentials. In this Account, we summarize
our laboratory’s systematic efforts in the total synthesis
of these abeo-steroids via cycloaddition strategies.
We highlight the efficiency and versatility of each cycloaddition
strategy for constructing structurally complex abeo-steroid cores by forming the A/B ring system. The evolution of each
strategy and key lessons learned from the synthetic journey are also
discussed. We believe that our unique perspective in this field will
promote advances in the total synthesis of abeo-
and related steroids.