Very Important Paper
Total Synthesis of Astellatol
,Shengling Xie,Hao Yan, PanRen, Gui Chen, Fang Chen, and
Abstract: Anearly-30-year-old unanswered synthetic puzzle,
astellatol, has been solved in an enantiospecific manner.The
highly congested pentacyclic skeleton of this rare sesterterpe-
noid, whichpossesses aunique bicyclo[4.1.1]octane motif,ten
stereocenters,acyclobutane that contains two quaternary
centers,anexo-methylene group,and asterically encumbered
isopropyl trans-hydrindane motif,makes astellatol arguably
one of the most challenging targets for sesterterpenoid syn-
thesis.Anintramolecular Pauson–Khand reaction was
exploited to construct the right-hand side scaffold of this
sesterterpenoid. An unprecedented reductive radical 1,6-addi-
tion, mediated by SmI
,forged the cyclobutane motif.Last,
astrategic oxidation/reduction step provided not only the
decisive solution for the remarkably challenging late-stage
transformations,but also ahighly valuable unravelling of the
notorious issue of trans-hydrindane synthesis.Importantly,the
synthesis of astellatol showcases arapid, scalable strategy to
Terpenes are alarge group of natural small molecules that
have long provided humans with numerous medicines and
drug leads,such as artemisinin and paclitaxel.
these fascinating molecules,sesterterpenoids probably form
the smallest family,constituting less than athousand mem-
bers,yet have complicated architectures combined with
diverse biological properties such as anti-inflammatory,anti-
carcinogenic,antimicrobial, and cytotoxic activities.
major type of sesterterpenoid, called isopropyl trans-hydrin-
contains common features:atrans-
hydrindane motif with an isopropyl or isopropenyl group.
Representatives of these sesterterpenoids include astellatol
(Figure 1). The
left part of these molecules varies but often possesses
acongested ring system with many stereocenters,including
quaternary centers,which creates amajor challenge for their
synthesis.Furthermore,another significant synthetic chal-
lenge results from the highly substituted, notorious trans-
hydrindane motif on the right side.
After the pioneering
synthesis of retigeranic acid Abythe group of Corey in
the groups of Paquette,
also reported their impressive syntheses of retigeranic acid. In
2014, the group of Trauner accomplished aremarkable syn-
thesis of nitidasin in an asymmetric manner.
the syntheses of the other isopropyl trans-hydrindane sester-
terpenoids have not been reported.
Astellatol was isolated from Aspergillus stellatus (syn. A.
variecolor)and structurally determined in 1989.
congested and unusual pentacyclic skeleton of this rare
sesterterpenoid, which contains aunique bicyclo[4.1.1]octane,
ten stereocenters,acyclobutane containing two quaternary
centers and an exo-methylene group,makes astellatol argu-
ably one of the most challenging targets for sesterterpenoid
synthesis.For almost three decades,only very limited
synthetic studies toward 1 have been reported.
nated by its amazing chemical architecture and unrevealed
biological properties,wereport aconcise and enantiospecific
solution for this nearly-30-year-old unanswered synthetic
Our retrosynthetic analysis was inspired by two important
studies (Scheme 1). In 2015, Yang et al. reported ahighly
Figure 1. Astellatol (1)and other structurally related isopropyl trans-
S. Xie, Dr.H.Yan, P. Ren, G. Chen, F. Chen,
Department of Chemistry,Southern University of Science and
Technology,and Shenzhen Grubbs Institute
Shenzhen, Guangdong (China)
]These authors contributed equally to this work.
Supportinginformation and the ORCID identification number(s) for
the author(s) of this article can be found under:
3386 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Angew.Chem.Int. Ed. 2018, 57,3386 –3390