Illicium sesquiterpenes: Divergent synthetic strategy and neurotrophic activity studies

Article abstract of DOI:10.1002/chem.201300198

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 architecture and remarkable neurotrophic activities. As such, they represent attractive 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 synthesis of 7 is highlighted by the use of an enantioselective Robinson annulation reaction (construction of the AB rings), a Pd-mediated carbomethoxylation 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 identification of several highly potent small molecules that significantly enhanced the activity of nerve growth factor (NGF) in PC-12 cells. Moreover, efforts to define the common pharmacophoric 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 might not be critical to the neurotrophic activity. Copyright

Full text of DOI:10.1002/chem.201300198

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
E-mail: jix001@ucsd.edu
etheodor@ucsd.edu
[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
under http://dx.doi.org/10.1002/chem.201300198.
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that led to the first enantioselective synthesis[22] of 2, 3, and
4 and related analogues. Biological evaluation of these com-
pounds led to the identification of more potent neurotrophic
agents and allowed us to propose a critical pharmacophoric
motif.
Results and Discussion
Divergent retrosynthetic analysis: The key strategic bond
disconnections toward a divergent synthesis of 2–4 and relat-
ed analogues are shown in Scheme 1. We envisioned that
these natural products could derive from “core” structure 7
by following late-stage modifications. Key to the conversion
of 7 to (ꢀ)-jiadifenolide would be an oxidative translactoni-
zation reaction cascade that formed the E ring of 6 leading,
after C-10 oxidation and hemiketalization, to 2. On the
other hand, hydroxylation at C-10 of 7 followed by further
A-ring functionalization would produce ODNM (4). An oxi-
dation and hemiketalization reaction would then form jiadi-
fenin (3) from 4. Furthermore, the divergent functionaliza-
tion of 7 would produce a set of designed analogues.
We theorized that the tetracyclic motif of 7 could be
formed from compound 8 through a sequence of reactions
among which the key step is a one-pot oxidation/“6-exo-tet”
epoxide-opening cascade. In turn, the C ring lactone of 8
could arise from a Pd-catalyzed carbomethoxylation. This
disconnection opens the possibility to construct compound 8
from a Hajos–Parrish-type enone 9. Importantly, this com-
pound could be produced from 1,3-cyclopentadione (10) by
C-9 alkylation followed by an enantioselective Robinson an-
nulation.
Figure 1. Structures of selected neurotrophic majucin-subtype Illicium
sesquiterpenes and their common scaffold.
PC-12 cells at concentrations between 10 to 100 nm. This is
particularly interesting since it suggests that these com-
pounds rather than acting independently of NGF, enhance
its activity. Among them, jiadifenolide is reportedly the
most active compound inducing neurite outgrowth at
10 nm.[13]
Due to the combination of a complex ring motif and sig-
nificant therapeutic potential, these compounds represent
attractive targets for synthetic and biological studies.[16] De-
spite various successful syntheses of similar sesquiterpenes,
such as anisatin[17] and merrilactone,[18] synthetic efforts to-
wards the majucin-subtype seco-prezizaane-type sesquiter-
penes are rather limited.[19] To date, two impressive synthe-
ses of jiadifenin (3) have been reported by the Danishef-
sky[20] and Zhai groups.[21] Intrigued by the synthetic chal-
lenge and medicinal potential of these compounds, we
sought to develop a unified synthetic strategy. We hypothe-
sized that such a divergent strategy would provide access to
a library of related molecules for subsequent structure–ac-
tivity relationship studies. Herein, we describe the strategy
Scalable synthesis of core intermediate 7: Our synthesis of 7
commenced from commercially available dione 10, which
was readily converted to 11 in two steps and 63% combined
yield.[23] Robinson annulation of 11 to 9 was accomplished
by optimizing the Tu/Zhang conditions.[23c] At the onset of
Scheme 1. Unified retrosynthetic strategy for jiadifenolide, jiadifenin, and ODNM. TBS=tert-butyldimethylsilyl?.
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the study, we found that treatment of 11 with 30% d-pro-
“pre-activated” C-5 center of 14 by using TBAF/MeI condi-
A
tions, thereby producing compound 15 as a single dia
ACHTUNGTRENNUNGstereo-
and 70% ee. On the other hand, at room temperature this
reaction needed up to 60 days to completely consume the
starting material, thus yielding enantiomerically pure (ꢀ)-9
(> 99% ee). To balance reaction efficiency with acceptable
enantioselectivity we choose to perform this annulation at
408C over 14 days producing 9 in 70% yield and 90% ee
(50-gram scale). Chemoselective hydride reduction of the
C-1 ketone followed by TBS protection[24] yielded enone 12
ACHTUNGTRENNUNG
ring would require incorporation of a carboxyl group at C-6
and lactonization with the pendant C-14 hydroxyl group.
With this in mind, 15 was converted to the silyl-ether 16
through a sequence of three steps that included: 1) global
reduction with LiAlH4, 2) selective TBS-protection of the
primary C-14 hydroxyl group, and 3) IBX oxidation of the
secondary C-6 hydroxyl group (85% over 3 steps). Treat-
ment of 16 with McMurry reagent (PhNTf2)[29] yielded enol
(92%
combined
yield).
Stilesꢁ
reagent
(MMC,
MeO2CMgOMe)[25] selectively introduced a sensitive car-
boxylic acid group at C-5, which was subsequently esterified
triflate 17, which underwent a Pd0-mediated carbo
oxyla
tion[30] under a carbon monoxide atmosphere (1 bar) to
ACHTUNGTRENNUNGmeth-
G
ACHTUNGTRENNUNG
ꢀ
by using Meerweinꢁs salt (Et3O+BF4 ) to form b-keto ester
produce uncyclized compound 19 (60%) together with a
small amount of lactone 8 (23%). Without purification, this
mixture was treated with TFA to cleanly produce the de-
sired lactone 8 (69% overall yield from 16). Similarly, com-
pound 8 can be made from vinyl iodide 18, albeit in a slight-
ly lowered overall yield (60% from 16; Scheme 2).
13.[26] This procedure provides a safer alternative to the
commonly used diazomethane-based esterification of
a
“Hajos-Parrish-type” b-keto acid.[27] Construction of the C-5
quaternary center was accomplished by forming the extend-
ed enolate 14 (TMSOTf/lutidine)[28] and methylating the
Scheme 2. Scalable synthesis of tetracyclic scaffold 7: a) N,O-bis(trimethylsilyl)acetamide (1.0 equiv), allyl acetate (1.0 equiv), [PdCl2ACTHNUTRGNEUNG(allyl)] (0.01 equiv),
DPPE (0.05 equiv), NaOAc (0.03 equiv), 708C, 40 h; b) methyl vinyl ketone (2.0 equiv), H2O/AcOH (67:1), 1008C, 4 h, 63% from 10; c) d-prolinamide
(0.3 equiv), PPTS (0.3 equiv), MeCN (808C, 12 h: 75%, 70% ee; 408C, 14 d: 74%, >90% ee; RT, 60 d, 70%, >99% ee); d) NaBH4 (0.25 equiv), EtOH,
08C, 1 h; e) TBSCl (2.0 equiv), NH4NO3 (3.0 equiv), DMF, RT, 12 h, 92% from 9; f) Stilesꢁ reagent (methyl methoxymagnesium carbonate, 4.0 equiv),
ꢀ
DMF, 1308C, 3 h, then Et3O+BF4 (1.0 equiv), iPr2NEt (1.5 equiv), CH2Cl2, 08C, 5 min; g) TMSOTf (1.3 equiv), 2,6-lutidine (2.0 equiv), CH2Cl2, 08C to
RT, 1 h; h) TBAF (1.0 equiv), MeI (10 equiv), THF, ꢀ788C to RT, 3 h, 43% from 12; i) LiAlH4 (7.5 equiv), THF, 08C to RT, 1 h; j) TBSCl (1.1 equiv),
imidazole (2.0 equiv), CH2Cl2, 08C, 30 min; k) IBX (3.0 equiv), DMSO, 808C, 1 h, 85% from 15; l) KHMDS (5.0 equiv), PhNTf2 (3.0 equiv), THF,
ꢀ788C, 1 h, 95% (17); m) NH2NH2 (3.0 equiv), Et3N (4.0 equiv), EtOH, 508C, 5 h, then I2 (10 equiv), DBU (6.0 equiv), Et2O, 0 8C, 80 % (18); n) CO
(1 atm.), [PdACHTUNGTRENNUNG(PPh3)4] (0.01 equiv), MeOH/DMF (1:3), Et3N (3.0 equiv), 508C, 2 h; from 17: 60% (19) and 22% (8); from 18: 61% (19) and 23% (8);
o) TFA (3.0 equiv), CH2Cl2, RT, 5 h, 85%; p) H2O2 (10 equiv), 3m NaOH, THF, 08C to RT, 5 h, 99%; q) OsO4 (0.01 equiv), NaIO4 (4.0 equiv), 2,6-luti-
dine (2.0 equiv), 1,4-dioxane/H2O (3:1), RT, 12 h, 99%; r) Jones reagent (6.0 equiv), acetone, 08C, 30 min, 70% of 22 and 20% of 23; s) TBAF
(2.0 equiv), THF, RT, 30 min, 95% (22), 20% (23). The TBS group of 22 and some hydrogen atoms in the X-ray structure were omitted for clarity.
DBU=1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene, DPPE=1,2-bis(diphenylphosphino)propane, IBX=2-iodoxybenzoic acid, PPTS=pyridinium p-toluenesulfo-
nate.
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Possessing a readily functionalizable ABC ring system
with two quaternary centers, lactone 8 provided a solid scaf-
fold for further chemical modifications (Scheme 2). The
next task was the installation of the C-6–C-7 trans-diol
moiety and the construction of the D-ring lactone. To this
end, the electronically deficient C-6=C-7 double bond was
stereoselectively epoxidized under alkaline hydrogen perox-
ide conditions to generate epoxide 20 in 99% yield. This ep-
oxidation proceeded selectively from the a-face in a sub-
strate-controlled manner. Oxidative cleavage of the terminal
double bond of 20 proceeded best by an osmium-catalyzed
dihydroxylation and in situ cleavage of the resulting diol
with NaIO4. The corresponding aldehyde 21 was treated
under Jones conditions to form the corresponding carboxylic
acid. Concomitant activation of the neighboring epoxide
led, in a one-pot reaction cascade, to lactone 22 (70%
yield). The absolute stereochemistry of 22 was unambigu-
ously confirmed by single-crystal X-ray analysis.[31] In addi-
tion to 22 we also isolated a small amount (20%) of a desi-
lylated compound, as suggested by 1H NMR spectroscopic
analysis. This byproduct was shown to be lactone 23, the
structure of which was confirmed by X-ray analysis.[31] This
compound might arise from concomitant cleavage of the
C-1 silyl ether under acidic Jones conditions and lactoniza-
tion of the resulting hydroxyl group with the C-11 carboxylic
acid. Another possibility is the rapid desilylation of the C-1
hydroxy moiety resulting in the attack on the C-11 formyl
group to form the corresponding lactol followed by oxida-
tion to give this side product. Attempts to convert 23 to 22
were unsuccessful. Deprotection of the TBS group of 22 by
using TBAF then afforded the crucial di-lactone 7, the “core
intermediate” for the divergent synthesis. Notably, only one
column purification was needed for the conversion of triflate
17 to 7 (6 steps). More importantly, the synthesis of 7 from
commercially available 1,3-cyclopentadione was readily re-
producible and scalable (>5 g prepared), thus providing a
robust platform for further investigations.
Total synthesis of (ꢀ)-jiadifenolide (2): With sufficient
amounts of 7 in hand, we sought to establish a strategy for
the oxygenation at C-4. At the onset of these studies, we
treated 22 with catalytic OsO4 but could not detect any di-
hydroxylation product (Scheme 3), presumably due to the
steric hindrance of the trisubstituted double bond. Interest-
ingly, treatment of 22 with stoichiometric amounts of OsO4
in the presence of pyridine produced a moderately stable
osmium–pyridine complex 24[32] that upon treatment under
reductive conditions (sodium thiosulfate) yielded a C-3–C-4
cis-diol. To our surprise, we observed a rapid and irreversi-
ble translactonization between the C-4 and C-11 functionali-
Scheme 3. Total synthesis of (ꢀ)-jiadifenolide (2) from core intermediate 7: a) OsO4 (1.0 equiv), THF/pyridine (2:1), RT, 30 min, 90%; b) Na2S2O3
(10 equiv), MeOH/H2O (3:1), 608C, 1 h, 87 %; c) mCPBA (4.0 equiv), THF, 508C, 3 h, 80%; d) Dess–Martin periodinane (2.0 equiv), acetone, RT, 2 h,
38% from 7; e) H2 (6 atm.), 10% Pd/C (0.05 equiv), MeOH, RT, 24 h; f) TESOTf (2.0 equiv), 2,6-lutidine (4.0 equiv), THF, 08C to RT, 30 min, 90% for
2 steps; g) KHMDS (1.5 equiv), Comins reagent (N-(5-chloro-2-pyridyl)triflimide, 1.1 equiv), THF, ꢀ788C to RT, 1.5 h; h) AlMe3 (20 equiv), [Pd
ACHTUNGTRENNUNG(PPh3)4]
(0.5 equiv), THF, RT, 2 h, 57% from 30; i) H2 (90 atm.), PtO2 (0.2 equiv), MeOH, RT, 24 h; j) NaHMDS (4.0 equiv), (ꢁ)-trans-2-(phenylsulfonyl)-3-phe-
nyloxaziridine (Davis oxaziridine, 5.0 equiv), THF, ꢀ788C to RT, 1.5 h; k) Jones reagent (5.0 equiv), acetone, 08C, 15 min, 33% for 3 steps. Some hydro-
gen atoms were omitted for X-ray structure clarity. mCPBA=meta-chloroperoxybenzoic acid, KHMDS=potassium hexamethyl disilazide, TESOTf=
triethylsilyl trifluoromethanesulfonate.
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ties that formed 25 containing the E-ring structure of the
target molecule (78% from 22). The resulting C-3 and C-7
secondary hydroxyl groups of 25 were found to be difficult
to differentiate. Nonetheless, the tendency of the C-4 hy-
droxyl group to translactonize suggested a suitable way to
construct the E ring of jiadifenolide. With this in mind, com-
pound 7 was treated with mCPBA to produce epoxide 26 as
a single diastereomer in 80% yield.[31] We postulated that
the selectivity arises from a combination of steric hindrance
of the C-5 methyl group and the directing effect of the C-1
hydroxyl group.[33] Treatment of 7 with Dess—Martin peri-
odinane initiated the desired oxidative translactonization
cascade converting epoxide 26 to lactone 6 in 48% yield.
The moderate yield of this reaction might be due to the
poor solubility of 26. Although none of the cascade inter-
mediates could be isolated, a mechanistic rationale for this
critical transformation could involve: 1) oxidation of the C-1
hydroxyl group to form ketone 27, 2) opening of the pend-
ant epoxide under acidic conditions to form 29, and 3) irre-
versible translactonization of the C-4 hydroxyl group of 29
to produce 6. X-ray analysis of 6 proved unambiguously that
the desired E ring of jiadifenolide has been formed.[31]
to this challenge. Thus, chemoselective triflation of the C-1
ketone of 30 by using Comins reagent [N-(5-chloro-2-pyri-
dyl)triflimide][38] followed by treatment with trimethylalumi-
num/[PdACHTUNGTRNEUNG
(PPh3)4][39] cleanly yielded compound 31 (57% over
two steps). In turn, the C-1=C-2 double bond of 31 was se-
lectively hydrogenated from the h-face (PtO2, H2, 90 bar,
24 h) to produce the desired C-1 methylated compound 32.
It should be noted that under a higher pressure of H2
(>110 bar) the hydrogenation was mildly accelerated but
we observed concomitant desilylation of the C-7 triethylsilyl
ether.[40] The last functionalization at the C-10 center was in-
spired by Danishefskyꢁs synthesis of jiadifenin.[20] h-Hydroxy-
lation with the Davis oxaziridine[41] produced h-hydroxy lac-
tone 33 (stereochemistry not assigned). Ultimately, the h-hy-
droxyl group of 33 was oxidized under Jones conditions to
produce, after concurrent desilylation of the C-7 silyl ether,
(ꢀ)-jiadifenolide (2) in one-pot (33% yield over 3 steps).
The isolated sample of synthetic 2 was found to be identical
in all aspects with naturally occurring jiadifenolide.[13] The
absolute stereochemistry of 2 was also confirmed by X-ray
analysis.[31]
The last task toward 2 would be the installation of the C-1
methyl group and the formation of the d-ring hemiketal. To
this end, enone 6 was converted to ketone 30 by hydrogena-
tion under Pd/C conditions and subsequent silylation of the
C-7 hydroxyl group (90% over 2 steps). The requirement of
up to 6 bars pressure of H2 to saturate the C-2=C-3 double
bond of 6 indicated a significant steric hindrance of the A
ring. Therefore, not surprisingly, direct methylenation at-
tempts to install the C-15 carbon atom at the C-1 center
(Wittig reaction, Peterson reaction,[34] titanium-[35] or zinc-
based[36] reagents) proved to be ineffective. Gratifyingly, a
Pd0-catalyzed cross-coupling reaction[37] provided a solution
Total synthesis of (ꢀ)-jiadifenin (3) and (ꢀ)-ODNM (4): In-
itial attempts to perform a C-1 radical deoxygenation of 7[42]
en route to the synthesis of 3 were unsuccessful (Scheme 4).
However, treatment of 7 with Martin sulfurane[43] under de-
hydrating conditions led to diene 34, which was directly and
selectively reduced under Pd/C-catalyzed hydrogenation to
give compound 35 in 72% combined yield. Various reagents
and methods, involving selenium-, chromium-, palladium-,
and rhodium-based oxidants, were tested to oxidize the C-2
allylic center, but proved to be insufficient.[44] Eventually,
we were able to isolate small amounts of enone 36 (~10%)
by using Mn3OACTHNUTRGNEUNG
(OAc3)9/tert-butylhydroperoxide (TBHP)[45]
Scheme 4. Total synthesis of (ꢀ)-jiadifenin (3) and (ꢀ)-ODNM (4) from core intermediate 7: a) Martin sulfurane (6.0 equiv), THF, RT, 2 h; b) H2
(1.1 atm.), 10% Pd/C (0.3 equiv), MeOH, 30 min, 72% from 8; c) tBuOOH (10 equiv), Mn3O(OAc)9 (0.2 equiv), EtOAc, 3 ꢂ MS, 408C, 16 h, 65%;
AHCTUNGTRENNUNG
d) LDA (5.0 equiv), MeI (3.0 equiv), THF, ꢀ78 to ꢀ108C, 1.5 h, 50% of 39 and 25% of 40; e) NaHMDS (3.0 equiv), (ꢁ)-trans-2-(phenylsulfonyl)-3-phe-
nyloxaziridine (1.0 equiv), THF, ꢀ788C, 30 min, 61% of 41 and 19% of 42; f) LDA (5.0 equiv), MeI (1.2 equiv), HMPA (1.2 equiv), THF, ꢀ78 to ꢀ108C,
5 h, 38% (60% brsm); g) Jones reagent (15 equiv), acetone, RT, 20 min, then MeOH, 15 min, 45%. Some hydrogen atoms were omitted for X-ray struc-
ture clarity. HMPA=hexamethylphosphoramide, LDA=lithium diisopropylamide.
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J. Xu, E. A. Theodorakis et al.
under the reported conditions (72 h, RT). Gratifyingly, this
oxidation occurred much faster by raising the reaction tem-
perature (24 h, 408C) increasing significantly the yield of 36
to 65%. Next in line was projected to be a chemoselective
C-1 methylation of 36 followed by a-hydroxylation at the
C-10 position. However, all methylation attempts suggested
that the C-10 position is more reactive, leading exclusively
to monomethylated product 37. When excess base and
methyl source (such as LDA and MeI) were applied, the
C-10 and C-1 dimethylated product 38 was isolated, which
suggested that the significantly less hindered C-10 carbon
atom was competing for the methylation.[31] Based on these
findings, we decided to invert the functionalization se-
quence. Enone 36 was initially a-hydroxylated with the
Davis oxaziridine to afford the hydroxy lactone 39 (61%
yield) together with dihydroxylated product 40 (19% yield).
Subsequently, the C-1 methylation was performed by sub-
jecting 39 to the LDA/MeI/HMPA conditions to produce
(ꢀ)-ODNM (4) in 38% yield (60% brsm, based on recov-
ered starting material). The following transformation pro-
ceeded under Jones conditions with methanolic workup
leading to the isolation of jiadifenin (3) in 45% yield. Both
synthetic 4 and 3 were found to have identical spectroscopic
and analytical properties with those of the natural prod-
ucts.[14,20,21]
methyl moiety. After several unsuccessful attempts (DBU,
LDA, or tBuOK) to invert the C-1 stereochemistry of
ODNM, we were prompted to develop an alternative route
that could install the C-1 methyl moiety before constructing
the C-2 enone motif. To this end, the C-1 hydroxyl group of
7 was oxidized under PCC conditions (0.5 h, RT) to afford
ketone 41 in 65% yield (Scheme 5). It should be noted that
the Swern oxidation was ineffective while Dess–Martin-peri-
odinane or IBX oxidations led to complete migration of the
C-3=C-4 double bond to give the corresponding enone.
Treatment of 41 under 2,6-bis(tert-butyl)-4-methylpyridine/
Tf2O conditions selectively formed the corresponding C-1
triflate that was subsequently subjected to AlMe3/[Pd-
A
ACHTUNGTRENNUNGdroACHTUNGTRENNUNGgen-
ACTHUNGTRENNUGaAHCTUNGTRENNNUG
C-1 methyl moiety, albeit with moderate yield (23% over
3 steps). Allylic oxidation by using the manganese-based
conditions (Mn3OACTHNUTRGNEUNG
(OAc)9/TBHP)[45] was able to effectively
deliver enone 45 without any C-1 epimerization (60%
yield). We then attempted a Davis-based a-hydroxylation at
the C-10 center of 45. To our surprise, we isolated (ꢀ)-
ODNM (4) as the only product in 59% yield. The formation
of 4 under these conditions can be explained by considering
that the C-1 methyl group of 45 undergoes a rapid ep
ACHTUNGTRENNUNGiACHTUNGTRENNUNGmerACHTUNGTRENNUNGi-
ACHTUNGTERNzNUNG aHCATUNGTRENNtUNG ion during the C-10 hydroxylation. To overcome this
issue, we first reduced the C-2 carbonyl group under Luche
conditions. Interestingly, this reduction was selectively ac-
complished from the top face of the enone motif, presuma-
bly due to the steric hindrance of the adjacent C-5 stereo-
center. The resulting allylic alcohol was then converted to
46 upon treatment with NaHMDS and the Davis oxaziridine
(40% combined yield). The C-10 stereochemistry could be
further modified by a two-step sequence with a Dess–
Martin periodinane-based global oxidation followed by ste-
Synthesis of designed analogues: Examination of the chemi-
cal structures of the Illicium natural products indicates that
subtle variations at carbon atoms C-1, C-2, and C-10 play a
significant role in the neurotrophic activities of these com-
pounds. For instance, ODNM was found to be one of the
most potent neurotrophic natural products (as low as
100 nm), whereas the 10-epi-ODNM and the 1,10-diepi-
ODNM were devoid of any activity.[14] Synthetically, the first
challenge proved to be the creation of the b-substituted C-1
ACHUTNRGENNUrG eoCAHTUNGTERNNsUGN elective reduction with NaBH4 to produce 47 (40%
Scheme 5. Synthesis of designed analogues from core intermediate 7: a) PCC (2.0 equiv), Celite, CH2Cl2, RT, 30 min, 65%; b) Tf2O (2.0 equiv), DTBMP
(3.0 equiv), THF, 08C to RT, 12 h; c) AlMe3 (10 equiv), [Pd(PPh3)4] (0.3 equiv), THF, RT, 1 h; d) H2 (3 atm.), Pd/C (10% w/w), MeOH, 3 h, 23% from
43; e) NaHMDS (2.5 equiv), (ꢁ)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine (1.1 equiv), THF, ꢀ788C, 30 min, 57%; f) tBuOOH (10 equiv), Mn3O-
AHCTUNGTRENNUNG
(OAc)9 (0.2 equiv), EtOAc, 3 ꢂ MS, 408C, 16 h, 60%; g) NaHMDS (3.0 equiv), (ꢁ)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine (1.0 equiv), THF,
ꢀ788C, 30 min, 59%; h) NaBH4 (3.0 equiv), CeCl3·7H2O (3.0 equiv), THF/MeOH (3:1), ꢀ78 to ꢀ508C, 30 min; i) NaHMDS (2.5 equiv), (ꢁ)-trans-2-
(phenylsulfonyl)-3-phenyloxaziridine (1.1 equiv), THF, ꢀ788C, 10 min, 40% for 2 steps; j) Dess–Martin periodinane (2.0 equiv), THF, RT, 2 h; k) NaBH4
(3.0 equiv), MeOH, ꢀ208C, 1 h, 40% for 2 steps. DTBMP=2,6-di-tert-butyl-4-methylpyridine, PCC= pyridinium chlorochromate.
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combined yield). In a similar fashion, analogue 44 was pre-
pared from lactone 43 by using the Davis oxaziridine (57%
yield). The stereochemistries of new compounds 44, 46, and
47 have been assigned based on 2D NOESY analyses.
We then evaluated the in vitro neurotrophic activity of
the synthetic analogues in PC-12 cells. The results related to
neurite outgrowth and the percentage of cells with neurites
are summarized in Figures 3 and 4. The most active ana-
Evaluation of neurotrophic activity and pharmacophore
mapping: Earlier studies by the Danishefsky group[20] estab-
lished that certain synthetic analogues have activities com-
parable to jiadifenin, further justifying the studies toward
the identification of a common pharmacophoric motif. Our
synthetic approach gave access to several highly active natu-
ral products and a library of designed analogues that can be
used to map the unexplored neurotrophic pharmacophore.
Our first task was to validate the biological profile of syn-
thetic jiadifenolide (2), jiadifenin (3), and ODNM (4) with
regard to NGF-mediated neurite outgrowth in PC-12 cells.
This cell line undergoes neuronal differentiation into
neuron-like cells with elongated neurite outgrowth in re-
sponse to NGF. As such, it has been broadly applied to
study NGF activity.[20,46] The ability of synthetic natural
products 2–4 to promote neurite outgrowth was measured
both in the presence and absence of NGF. In the presence
of NGF (50 ngmLꢀ1), a significant increase of neuronal dif-
ferentiation could be observed upon 72 h of incubation
Figure 3. Length of neurite outgrowth. All compounds were dissolved in
1% DMSO (v/v) and tested at concentration of 0.3 mm in the presence of
50 ngmLꢀ1 of NGF. C*=control: 50 ngmLꢀ1 of NGF and 1% DMSO
(v/v).
Figure 4. Percentage of cells with neurites. All compounds were dissolved
in 1% DMSO (v/v) and tested at a concentration of 0.3 mm in the pres-
ence of 50 ngmLꢀ1 of NGF. C*=control: 50 ngmLꢀ1 of NGF and 1%
DMSO (v/v).
logue was found to be enone 37, which enhanced neurite
outgrowth by more than 180%. Notably, 37 contains a
methyl group at C-10 and a carbonyl group at C-2 and
shows superior activity in comparison to the natural prod-
ucts. This suggests that the hemiketal functionality of 2 and
3 might be not essential to the neurotrophic activity. The
C-1 methylated analogue 38 also exhibits excellent activity,
promoting neurite outgrowth by 162%. Interestingly, com-
pounds lacking a C-10 substituent, such as 43 and 45, have
dramatically reduced neurotrophic activity. The C-1 and
C-10 bis(hydroxylated) analogue 40 was found to be active
(138%), although less active than the bis(methylated) com-
pound 38 (162%). A comprehensive summary of these re-
sults is shown in Tables 1 and 2. The pharmacophore map-
ping (Table 2) suggests that all the C-10 b-substituted com-
pounds are inactive (Table 2, row 2), while all compounds
that possess a C-10 a-substituted moiety have shown moder-
ate to excellent neurotrophic activities (Table 2, rows 3 and
4). Interestingly, a-methyl substitution at C-10 increases the
activity (compounds 37 and 38) relative to the related a-hy-
Figure 2. Neurite outgrowth studies with selected synthetic compounds in
PC-12 cells. All compounds were dissolved in 1% DMSO (v/v) and
tested at a concentration of 0.3 mm in the presence of 50 ngmLꢀ1 of NGF;
1% DMSO (v/v) in the presence of 50 ngmLꢀ1 of NGF was used as a
control.
(Figure 2). Specifically, the neurite length outgrowth in-
duced by 2, 3, and 4 (at 0.3 mm) was 166, 148, and 145%, re-
spectively, (relative to DMSO+NGF control). No out-
growth was observed in the absence of NGF, in agreement
with previous findings.[20] This supports the notion that these
compounds operate by enhancing the action of NGF rather
than functioning independently.[20] Interestingly, our synthet-
ic (ꢀ)-jiadifenin displayed similar activity with the one pre-
viously reported for racemic jiadifenin.[20] Similar observa-
tions have been reported in merrilactone A studies.[18k]
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J. Xu, E. A. Theodorakis et al.
Table 1. Neurite outgrowth studies of illicium natural products and analogues.[a]
2 (166%)
23 (104%)
43 (94%)
3 (148%)
26 (106%)
44 (110%)
4 (145%)
37 (183%)
45 (96%)
6 (109%)
7 (104%)
8a[b] (103%)
40 (138%)
47 (103%)
38 (162%)
39 (121%)[20]
45a (104%)
46 (147%)
[a] All compounds were dissolved in 1% DMSO (v/v) and tested at a concentration of 0.3 mm in the presence of 50 ngmLꢀ1 of NGF; 1% DMSO (v/v) in
the presence of 50 ngmLꢀ1 of NGF as the control. [b] Prepared from 8 upon treatment with TBAF in THF at RT for 1 h.
Table 2. Pharmacophore mapping.[a]
36, inactive[b][20]
–
48, inactive[20]
50, inactive[14]
4, active
–
45, inactive
7, inactive
45a, inactive
47, inactive
46, active
–
–
49, inactive[14]
–
40, active
–
–
44, active
–
–
–
–
39, active[b]
37, active
–
–
38, active
[a] Due to the highly substrate-controlled diastereoselectivity profile, some compounds are only available with certain stereochemistry on the C-10 and
C-1 positions. [b] “Inactive” indicates less than 110% of neurite outgrowth, as compared to control; “active” indicates equal to or greater than 110% of
neurite outgrowth, as compared to control.
droxylated compounds (39 and 40). Moreover, C-10 nonsub-
stituted compounds were found to all be inactive (Table 2,
row 1). The pharmacophore mapping efforts thus suggest
that an a-substituent at C-10 is essential to the neurotrophic
activity of this family. Two pairs of compounds support this
conclusion: the C-10 a-substituted compounds 4 and 46 ex-
hibit good to excellent activities while their C-10 b-substitut-
ed diastereomers 50[14,15] and 47 are essentially inactive. This
conclusion may also explain why many Illicium natural
product family members possess highly similar structures
with ODNM (4) but are devoid of neurotrophic activities.
We also assume that the potent activity of jiadifenolide (1)
and jiadifenin (2) might have benefited from their suitable
oriented C-10 hemiketalic hydroxyl group.
Conclusion
Jiadifenolide (2), jiadifenin (3), and (1R,10S)-2-oxo-3,4-de-
hydroxyneomajucin (4, ODNM), three highly neurotrophic
Illicium natural products, have been synthesized in a diver-
gent manner. Key to the synthesis is an enantioselective
Robinson annulation reaction[47] that produces the AB ring
system 9. Functionalization at the periphery of the B ring
produces the C-ring lactone, while a one-pot oxidation and
epoxide-opening reaction cascade form tetracyclic motif 7.
Compound 7 represents the branching point for the synthe-
sis of the natural-product targets and designed analogues.
Evaluation of the neurotrophic activities of these com-
pounds in PC-12 cells leads to identification of simplified
analogues 37 and 38 that induce more than 160% neurite
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outgrowth at 0.3 mm by enhancing the activity of NGF. In
addition, pharmacophore mapping studies suggest that the
substituent at the C-10 center plays a critical role in the neu-
rotrophic activity. On the other hand, the hemiketal moiety
of 2 and 3, and the substitution at C-1 might not be impor-
tant to the bioactivity. The designed strategy along with the
pharmacophore mapping studies may pave the way for the
rational design of potent agents against neurodegenerative
diseases.
Acknowledgements
We gratefully acknowledge the National Institutes of Health (NIH) for
financial support of this work through Grant Number CA 133002. We
thank the National Science Foundation for instrumentation grants
CHE97091837 and CHE0741968. We also thank Dr. A. Mrse (UCSD
NMR Facility), Dr. Y. Su (UCSD MS Facility), and Drs. A.L. Rheingold
and C.E. Moore (UCSD X-Ray Facility). We appreciate the technical
support from Ms. K.N. Wright (Dept. of Neurosciences, UCSD). We also
thank W.K. Chang for synthesizing early-stage material.
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Illicium Sesquiterpenes
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Received: January 19, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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J. Xu, E. A. Theodorakis et al.
Natural Products
L. Trzoss, J. Xu,* M. H. Lacoske,
W. C. Mobley,
E. A. Theodorakis* .......... &&&& — &&&&
Illicium Sesquiterpenes: Divergent
Synthetic Strategy and Neurotrophic
Activity Studies
Enantioselective synthesis: A unified
strategy toward the synthesis of several
illicium natural products is reported
(see scheme). Key steps include an
enantioselective Robinson annulation
reaction and a one-pot oxidative lacto-
nization cascade. The synthetic strat-
egy allows access to various potent
analogues. Structure–activity studies
revealed that the C-10 stereocenter
significantly affected the neurotrophic
activity.
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These are not the final page numbers!