FULL PAPER
DOI: 10.1002/chem.201300198
Illicium Sesquiterpenes: Divergent Synthetic Strategy and Neurotrophic
Activity Studies
Lynnie Trzoss,[a] Jing Xu,*[a] Michelle H. Lacoske,[a] William C. Mobley,[b] and
Emmanuel A. Theodorakis*[a]
Abstract: Majucin-type sesquiterpenes
from Illicium sp., such as jiadifenolide
(2), jiadifenin (3), and (1R,10S)-2-oxo-
3,4-dehydroxyneomajucin (4, ODNM),
possess a complex caged chemical ar-
thesis of 7 is highlighted by the use of
an enantioselective Robinson annula-
tion reaction (construction of the AB
rings), a Pd-mediated carbomethoxyla-
tion reaction (construction of the C
ring), and a one-pot oxidative reaction
cascade (construction of the D ring).
Evaluation of the neurotrophic activity
of these compounds led to the identifi-
cation of several highly potent small
molecules that significantly enhanced
the activity of nerve growth factor
(NGF) in PC-12 cells. Moreover, ef-
forts to define the common pharmaco-
phoric motif suggest that substitution
at the C-10 center significantly affects
bioactivity, while the hemiketal moiety
of 2 and 3 and the C-1 substitution
chitecture and remarkable neuro
ACHTUNGTRNEtNUNG roph-
ACHTUNGTRENNUNGic activities. As such, they represent at-
tractive small-molecule leads against
various neurodegenerative diseases. We
present an efficient, enantioselective,
and unified synthesis of 2, 3, and 4 and
designed analogues that diverge from
tetracyclic key intermediate 7. The syn-
Keywords: cascade reactions · nat-
ural products · oxidation · sesquiter-
pene · total synthesis
might not be critical to the neuro
AHCTUNGTRENNGiUN c activity.
ACHTUNGTRENNUNGtroph-
Introduction
ly degraded in the body and are inefficient in crossing the
blood–brain barrier.[6] These problems, inherent with most
protein-based therapies, have prompted the scientific com-
munity to explore nonpeptidyl small-molecule-based thera-
peutics.[7] In principle, these compounds could induce neu-
rite outgrowth by enhancing the activity or inducing the bio-
synthesis of NGF and related neurotrophic factors.
The discovery of nerve growth factor (NGF)[1] has fueled in-
tensive research in the area of neurotrophins, a family of
polypeptides that play an essential role in the development
and maintenance of neurons in both the central and periph-
eral nervous system.[2] The binding of NGF to its cell surface
receptor leads to a cascade of signaling pathways that pro-
mote axonal and dendritic branching. In turn, this activity
allows the construction of a neural network that is critical
during embryonic development and/or after neuronal injury.
Importantly, alterations in neurotrophin levels have been
implicated in various neurodegenerative[2,3] and psychiatric
disorders.[4] Moreover, preclinical studies have suggested
that administration of neurotrophins may lead to an effec-
tive treatment for various neurodegenerative disorders.[5]
However, despite such potential, clinical trials with NGF
and related polypeptides have been disappointing since
these compounds cannot be delivered orally, they are rapid-
Natural products, used in traditional medicine[8,9] or as
neutraceuticals,[10] hold significant promise as tools for bio-
logical studies and as privileged structures for the develop-
ment of new therapeutic agents against neurodegeneration.
The Illicium species of plants exemplify such a dual poten-
tial. Spreading over eastern North America, Mexico, the
West Indies, and eastern Asia, these plants are known for
their distinctive star-shaped fruits and characteristic fla-
vors.[11] Isolation of their chemical constituents has led to
the identification of three distinct families of sesquiterpenes:
the seco-prezizaanes, the anislactones, and the allo-ce-
dranes.[11] Among them, the majucin-subfamily of seco-prezi-
zaanes is particularly interesting since it contains compounds
with potent neurotrophic activities. Members of this family
include majucin (1),[12] jiadifenolide (2),[13] jiadifenin (3),[14]
[a] Dr. L. Trzoss, Dr. J. Xu, M. H. Lacoske, Prof. Dr. E. A. Theodorakis
Department of Chemistry and Biochemistry
University of California at San Diego, 9500 Gilman Drive
La Jolla, CA 92093-0358 (USA)
and
(1R,10S)-2-oxo-3,4-dehydroxyneomajucin
(4,
ODNM)[15] (Figure 1). Central to their caged architecture is
a highly substituted cyclohexane ring (B ring) that is sur-
rounded by three additional rings including a cyclopentane
(A ring) and a g-lactone (C ring). Further functionalization
at C-4 and C-10 forms a unique g-lactone ring (E ring) as in
the structure of 2.[11] Initial biological studies have shown
that compounds 2–4 significantly enhance neurite outgrowth
in primary cultured rat cortical neurons or NGF-mediated
Fax : (+1)858-822-0386
[b] Prof. Dr. W. C. Mobley
Department of Neurosciences, University of California
at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0752 (USA)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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