Total synthesis of (±)-jiadifenin, a non-peptidyl neurotrophic modulator

Article abstract of DOI:10.1021/ja045939p

We report the first total synthesis of jiadifenin (1), the establishment of a modality for its biological evaluation, and the discovery of apparently more potent neurotrophic activity in fully synthetic compound 17, an intermediate en route to 1. Copyright

Full text of DOI:10.1021/ja045939p

Published on Web 10/16/2004
Total Synthesis of (()-Jiadifenin, a Non-peptidyl Neurotrophic Modulator
†
†
§
§
,†,‡
Young Shin Cho, David A. Carcache, Yuan Tian, Yue-Ming Li, and Samuel J. Danishefsky*
Laboratory for Bioorganic Chemistry and Laboratory of Biochemistry and Pharmacology, Sloan-Kettering
Institute for Cancer Research, 1275 York AVenue, New York, New York 10021, and Department of Chemistry,
Columbia UniVersity, HaVemayer Hall, 3000 Broadway, New York, New York 10027
Received July 7, 2004; E-mail: s-danishefsky@ski.mskcc.org
Fukuyama and colleagues recently reported the isolation of the
majucin cage-like sesquiterpene jiadifenin (1) as an inseparable
anomeric mixture in 0.001% yield from the methanol extract of
Scheme 1
1
the pericarps of Illicium jiadifengpi. (2S)-Hydroxy-3,4-dehydro-
neomanjucin (2), also obtained from I. jiadifengpi, is a potential
biosynthetic precursor of 1. Indeed, Fukuyama and co-workers
demonstrated that 2 could be converted by chemical means to
jiadifenin (1) through the intermediacy of ketones 3 and 4,
2
themselves isolated from Illicium majus (Scheme 1).
From a purely chemical perspective, the densely oxygenated and
highly compact structure of jiadifenin (1) poses significant issues
that invite propositions directed to its synthesis. Moreover, Fuku-
yama has shown that compound 1 promotes neurite outgrowth in
the primary cultures of rat cortical neurons in concentrations as
Scheme 2
1
low as 0.1 µM. Thus, the jiadifenins are appropriately classi-
3
fied as non-peptidyl neurotrophic factors. Conceivably, the im-
proved bioavailablity prospects of such compact non-peptidyl
structures could be of value in the treatment of various neurode-
generative diseases.3b Recently, our laboratory has begun investigat-
ing this general field, starting with total syntheses as points of
4
departure for broader explorations. Herein, we report the first total
synthesis of racemic jiadifenin (1), the establishment of a modality
for its biological evaluation, and the discovery of somewhat more
potent neurotrophic activity in fully synthetic compound 17 (vide
infra).
Given the reported convertibility of 4 to 1, we envisioned a
related oxidative ring contraction of a C(10) hydroxylated variant
of 5 as the final stage of the synthesis of jiadifenin (Scheme 1).
Preparation of 5 itself was to be accomplished through ring-closing
operations of an R,R′-tetrasubstituted cyclohexanone, obtained from
the commercially available 1,4-cyclohexanedione monoethylene
ketal (6, Scheme 2).
with 7. Sequential C(9) allylation and C(9) carboethoxymethylation
afforded 8 and 9 in the yields and ratios shown.
Conversion of the ester moiety in 8 to a â-ketophosphonate,
Methylation of ketone 6, followed by hydroxymethylation (under
7
followed by intramolecular Horner-Wadsworth-Emmons reaction
5
the thermodynamic conditions) and protection of the resulting
and global deprotection, as shown, led to cyclopentenone 12 in
primary alcohol, produced 7 (Scheme 2). Anticipating difficulties
in achieving full stereochemical control in the correlation of
quaternary carbons 5 and 9, we explored desymmetrization of R,R′-
diallycyclohexanone 10. The hope was to distinguish the diaste-
reotopically related allylic functions on the basis of their stereo
relationships to the resident hydroxymethyl group at C(5). In the
event, treatment of 10 as shown provided 11 in 66% yield and a
7
0% yield for three steps (Scheme 3). The use of a carbonate (see
intermediate 12a) as a one-carbon interpolation moiety served us
well in obtaining diketolactone 13. Oxidation of the latter with
mCPBA furnished the desired R-hydroxy product 13a in 90% yield
as a single isomer. Following stereoselective reduction, trans-diol
1
generated stereocenters were verified by single-crystal X-ray
analysis of 14.
Methylation of 14 via trianion formation, followed by a two-
step oxidative cyclization, generated lactone 15 (Scheme 4).
Stereoselective reduction of 15 under Luche conditions and C(10)
8
4 was in hand. The assigned relative configurations of the newly
6
mixture of other diastereomers in 24% yield. Thus this formation
of two tetrahydrofurans, via intervention of the formal “ketone
hydrate”, superseded participation of the primary alcohol at C(14)
in the bromination event. While the exploitation of various internal
structural implements in this series remains our long-term goal for
stereocontrol, in the interim we turned to a program which starts
9
hydroxyl incorporation via Davis’s oxaziridine afforded the
R-hydroxy lactone 16.10 We hoped to accomplish simultaneous
oxidation of the C(2) and C(10) hydroxyl groups, thereby prompting
rearrangement of the R-ketolactone into the hydroxytetrahydro-
furancarboxylate acetal moiety of jiadifenin (1). In practice, this
†
Laboratory for Bioorganic Chemistry.
§
Laboratory of Biochemistry and Pharmacology.
‡
Columbia University.
14358
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J. AM. CHEM. SOC. 2004, 126, 14358-14359
10.1021/ja045939p CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Figure 1. Images of neurons after treatment with (A) DMSO + NGF, (B)
compound 17 in DMSO (0.3 µM) + NGF, and (C) compound 1 in DMSO
(0.3 µM) + NGF.
17 and 1 were 184% (P < 0.01) and 162% (P < 0.05), respectively,
relative to the DMSO-NGF control.
Given the encouraging results described above, research into this
field continues in earnest in our laboratory at the level of chemical
synthesis as well as biological follow-up.
Scheme 4
Acknowledgment. Support for this research was provided
by the National Institutes of Health (AI-16943-25 and CA
103823-25). D.A.C. gratefully acknowledges the Novartis Founda-
tion and Roche Research Foundation for a postdoctoral fellowship.
We thank Dr. William F. Berkowitz for helpful discussions, Dr.
Louis Todaro (Hunter College New York) for X-ray structure
analyses, and Dr. George Sukenick, Ms. Sylvi Rusli, and Ms. Anna
Dudkina (NMR Core Facility, Sloan-Kettering Institute, CA-02848)
for mass spectral analyses.
Supporting Information Available: Spectroscopic and analytical
data for all intermediates, experimental procedures, and assay proto-
cols. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(
(
(
(
1) Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. J. Nat. Prod.
2002, 65, 527.
2) Kouno, I.; Baba, N.; Hashimoto, M.; Kawano, N.; Takahashi, M.; Kaneto,
H.; Yang, C.-S. Chem. Pharm. Bull. 1990, 38, 422.
3) (a) Hefti, F. Annu. ReV. Pharmacol. Toxicol. 1997, 37, 239. (b) Luu, B.;
de Aguilar, J.-L. G.; Girlanda-Junges, C. Molecules 2000, 5, 1439.
4) (a) Pettus, T. R. R.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc.
1998, 120, 12684. (b) Pettus, T. R. R.; Inoue, M.; Chen, X.-T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160. (c) Birman, V. B.;
Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080.
protocol led to isolation of a mixture of (1R*,10S*)-2-oxo-3,4-
dehydroneomajucin (17) and jiadifenin (1). Following separation,
17 was further submitted to oxidative ring contraction to yield 1 in
46% yield after a prolonged reaction time. The overall consolidated
(5) Brieskorn, C. H.; Schwack, W. Chem. Ber. 1981, 114, 1993.
(
6) Literature precedents of such a reaction: (a) Heusler, K.; Ueberwasser,
H.; Wieland, P.; Wettstein, A. HelV. Chim. Acta 1957, 40, 787. (b) Ernst,
L.; Gorlitzer, K.; Boventer, K. Arch. Pharm. 1990, 323, 361.
yield for the conversion of 16 to jiadifenin was 53%. The
spectroscopic data measured from fully synthetic 17 are in full
accord with the published data of the compound, in tabular form.2
(7) Halterman, R. L.; Vollhardt, K. P. C. Organometallics 1988, 7, 883.
(
8) Cf. Goldsmith, D. J.; John, T. K.; Van Middlesworth, F. Synth. Commun.
1980, 10, 551.
9) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919.
Further confirmation came from the identity of the NMR spectra
(
of synthetic jiadifenin (()-1 with spectra of natural jiadifenin, kindly
(
10) (a) Incorporation of the C(10) hydroxyl group was hampered by
decomposition of both starting compound and product under the reaction
conditions. Accordingly, it was necessary to cease the reaction well before
the conclusion. We isolated the desired product 16 and the starting material
in 26% and 73% yield, respectively. The recovered starting material was
resubmitted to the reaction conditions to give 16 in 42% combined yield
after one recycle. (b) A mixture of diastereomers was observed at C(10)
of 16 (6:1 ratio, a major diastereomer as shown in 16).
1
provided by professor Fukuyama. Thus, as a consequence of this
interim, nonoptimized total synthesis (18 steps, current isolated yield
1.9%), jiadifenin, hitherto obtainable with only the greatest of
difficulty, is now eminently available for biological investigation.
It was important to validate the claimed neurotrophic activity of
fully synthetic 1. This was accomplished by measuring the ability
of 1 to stimulate NGF-mediated neurite outgrowth under the
protocols provided below.11 Thus, in our assay it is particularly
clear that the effect of jiadifenin is that of upregulating the action
of the NGF rather than functioning independently.12 Remarkably,
fully synthetic 17, an intermediate en route to 1, displays even
stronger activity in this assay. Thus, neurite lengths enhanced by
(11) Rat pheochromocytoma cells (PC12) were cultured in a 96-well collagen-
coated plate in F-12K medium supplemented with 0.5% fetal calf serum
and 50 ng/mL of NGF (2.5 S) with or without each compound at 0.3 µM
in DMSO solution for 48 h. Fresh medium with the same supplements
was placed on the cell for an additional 48 h. The cells were then fixed
and examined by microscopy. From our PC-12 assay, the neurite outgrowth
associated with neuronal differentiation was determined.
(
12) In the absence of NGF, no neurite outgrowth was observed.
JA045939P
J. AM. CHEM. SOC.
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VOL. 126, NO. 44, 2004 14359