Synthesis of the ABC ring system of jiadifenin via pd-catalyzed cyclizations

Article abstract of DOI:10.1021/ol103024z

An efficient route toward the central ABC system of jiadifenin has been developed using two key Pd-catalyzed cyclizations. A protic solvent-activated Mizoroki-Heck reaction was used to construct the C₉ quaternary carbon and the A ring. A cascad

Full text of DOI:10.1021/ol103024z

ORGANIC
LETTERS
2011
Vol. 13, No. 5
988–991
Synthesis of the ABC Ring System of
Jiadifenin via Pd-Catalyzed Cyclizations
Kenichi Harada,† Akiko Imai,† Kazuharu Uto,† Rich G. Carter,§ Miwa Kubo,†
Hideaki Hioki,‡ and Yoshiyasu Fukuyama*,†
Faculty of Parmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho,
Tokushima 770-8514, Japan, Department of Chemistry, Faculty of Education,
Gunma University, Maebashi, Gunma 371-8510, Japan, and Department of Chemistry,
Oregon State University, 153, Gilbert Hall, Corrvallis, Oregon 97331, United States
fukuyama@ph.bunri-u.ac.jp
Received December 14, 2010
ABSTRACT
An efficient route toward the central ABC system of jiadifenin has been developed using two key Pd-catalyzed cyclizations. A protic solvent-
activated Mizoroki-Heck reaction was used to construct the C9 quaternary carbon and the A ring. A cascading Tsuji-Trost cyclization/
lactonization sequence was employed to establish the BC ring system and the C5,6 stereochemistry.
The genus Illicium is distinctive in producing biosynthe-
tically unique seco-prezizaane type sesquiterpenes. More
than 50 seco-prezizaane type sesquiterpenes have been iso-
lated from Illicium plants1 since their initital discovery over
50 years ago.2,3 In 2002, our laboratory reported the
isolation and structure determination of jiadifenin (1) from
the methanol extract of the pericarps of Illicium jiadifengpi
indigenous to the southern part of China.4 This seco-
prezizaane type sesquiterpene 1 consists of a highly oxygen-
ated, cage-like tetracycle involving a cyclic hemiacetal,
a γ-lactone, six stereogenic centers including two separate
all-carbon quaternary centers, and an oxo-functionalized
carbon at C10 (Figure 1). In addition to its unique struc-
ture, compound 1 was found to significantly promote
neurite outgrowth in primary cultures of fetal rat cortical
neurons at concentrations from 0.1 to 10 μM.4 This
bioactivity indicates that jiadifenin is a potential candidate
for the treatment of neurodegenerative disorders such as
Alzheimer’s disease.5 Danishefsky and co-workers have
reported the sole synthesis of (()-1 to date.6 Herein, we
report an efficient and flexible synthetic route of the ABC
tricyclic core of jiadifenin (1).
† Tokushima Bunri University.
‡ Gunma University.
§ Oregon State University.
(1) Yokoyama, R.; Huang, J.-M.; Hosoda, A.; Kino, K.; Yang, C.-
S.; Fukuyama, Y. J. Nat. Prod. 2003, 66, 799 and references cited within.
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Soc. 1952, 74, 3211.
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Backman, C.; Rose, G. M.; Hoffer, B. J.; Henry, M. A.; Bartus, R. T.;
Friden, P.; Granholm, A. C. J. Neurosci. 1996, 16, 5437.
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J. D. J. Am. Chem. Soc. 2004, 126, 14358–14359. (b) Carcache, D. A.;
Cho, Y. S.; Hua, Z.; Tian, Y.; Danishefsky, J. D. J. Am. Chem. Soc. 2006,
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r
10.1021/ol103024z
Published on Web 01/25/2011
2011 American Chemical Society

Scheme 2. Construction of A Ring
Figure 1. Structures of seco-Prezizaane-type skeleton and jiadi-
fenin (1).
Scheme 1. Retrosynthetic Analysis of Jiadifenin (1)
through a double inversion (net retention) process as
shown in intermediate 4.5d While two diastereomeric
palladium complexes 4 and 8 can result from the same
5R* carbonate 5, only Pd-complex 4 should be a mecha-
nistically viable intermediate for the formation of the de-
sired Tsuji-Trost product 3. Cyclic carbonate 5 would be
accessible from the R,β-unsaturated ester 6. Palladium-
catalyzed intramolecular Mizoroki-Heck reaction8 of
bromide 7 would establish the cyclopentene A ring.
The construction of the A ring is shown in Scheme 2.
Wittig reaction of the commercially available diethyl 4-oxo-
pimelate (9) with ethyl triphenyl phosphonium bromide
and potassium tert-butoxide provided alkene 10 in 81%
yield. Subsequent LiAlH4 reduction gave diol 11 in 81%
yield. Monoprotection using TBDPSCl and imidazole
generated the C3 alcohol 12 which was oxidized to the
aldehyde 13 under the Swern conditions. Next, Horner-
Wadsworth-Emmons olefination9 using in situ prepared
(EtO)2POCHBrCO2Et10 gave rise to R-bromo unsatu-
rated ester 7. We next explored the key Mizoroki-Heck
cyclization of bromide 7. Initially, we utilized a standard
Pd(OAc)2 (10mol %), (o-tol)3P (20mol %), Et3N (2 equiv)
system11 in a range of aprotic solvents (e.g., toluene, THF,
Our synthetic strategy focused on the construction of the
jiadifenin’s ABC ring system 3 (Scheme 1). Critical to any
synthetic approach is control of the two challenging all-
carbon quaternary centers embedded with the scaffold at
C5 and C9. Our strategy incorporates two key palladium-
catalyzed cyclizations to construct the C5 and C9 quater-
nary stereocenters as well as the ABC ring system. A Tsuji-
Trost cyclization7 of cyclic carbonate 5 followed by in situ
lactonization would generate the BC ring system 3. Con-
trol of the newly formed C5 quaternary carbon would be
derived from the 5R* stereochemistry in carbonate 5
(8) (a) Grigg, R.; Santhakumar, V.; Shidhara, V.; Thornton-Pett, M.;
Bridge, A. W. Tetrahedron 1993, 49, 5177. (b) Overman, L. E.; Ricca,
D. J.; Tran, V. D. J. Am. Chem. Soc. 1993, 115, 2042. (c) Takemoto, T.;
Sodeoka, M.; Sasaki, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115,
8477. (d) Grigg, R.; Fretwell, P.; Meerholtz, C.; Sridharan, V. Tetra-
hedron 1994, 50, 359. (e) Anacardio, R.; Arcadi, A.; D’Anniballe, G.;
Marinelli, F. Synthesis 1995, 831.
(9) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733.
(10) McKenna, C. E.; Khawli, L. A. J. Org. Chem. 1986, 51, 5467.
(11) (a) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941. (b)
Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reinsinger, C. P.;
Priermerer, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844.
(7) (a) Tsuji, J. Pure Appl. Chem. 1999, 71, 1539. (b) Tsuji, J.;
Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 4387. (c) Trost,
B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292. (d) Hayashi, T.;
Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1983, 105,
7767.
Org. Lett., Vol. 13, No. 5, 2011
989

Scheme 3. Preparation of Cyclic Carbonate
Scheme 4. Attempted Tsuji-Trost Cyclization of Carbonate
Diastereomers 5 and 20
CH3CN, DMF, and DMSO); however, these conditions
were not effective, generating low (0-39%) chemical
yields. Interestingly, the use of MeOH as solvent12 led to
a dramatic increase in the chemical yield (99%) of the
desired product 6. Other protic solvents such as EtOH and
t-BuOH were also effective, and the catalyst loading could
be reduced to 5 mol % withoutaffecting the chemical yield.
Very recently, Felpin, Sotiropoulos and co-workers re-
ported a similar effect of alcoholic solvents during an aryl-
diazonium salt Heck coupling, which they attributed to a
MeOH-stabilized oxidative addition intermediate.13
With a viable route to the cyclopentane 6, we turned our
attention to the synthesis of the Tsuji-Trost precursor 5
(Scheme 3). Hydrolysis of ethyl ester 6 with TMSOK,
followed by conversion of carboxylic acid to Weinreb
amide with EDC and DMAP, proceeded in 84% yield
over two steps. Subsequent hydroboration at C7,8 followed
by oxidative workup and silylation produced the TES
ether 15. Next, treatment of Weinreb amide 15 with
methylmagnesium bromide generated the methyl ketone
16. Rubottom oxidation14 at C14 provided the R-hydroxy
ketone 17. Introduction of the C13 methyl group was
accomplished using excess MeLi to afford a 1,2-diol as a
1:1 diastereomeric mixture at C5. Attempts to improve the
stereoselectivity of this transformation have been unsuc-
cessful todate. The diol could be readily convertedtocyclic
carbonate using CDI, Et3N, and DMAP. The C7 TES
ether was selectively removed using mildly acidic condi-
tions (AcOH-H2O, rt). Finally, Dess-Martin oxidation
at C7 followed by treatment of the resultant aldehyde 19
with ethyl diazoacetate/SnCl2 yielded β-keto ester 5/20 in
87% yield.15
We next investigated the Pd-catalyzed cyclization to
form the BC ring system using the individual dias-
tereomers16 5 and 20 separately (Scheme 4).17 Mecha-
nistically, we had expected that only diastereomer 5 would
be a viable substrate for the production of tricycle 5. As we
(15) Holmwuist, C. R.; Roskamp, E. J. J. Am. Chem. Soc. 1989, 54,
3258.
(12) Heck, R. F. Org. React. 1982, 27, 345.
(16) The identity of which diastereomer corresponds to the 5R* and
5S* stereochemistries is based on the correlation to the observed
Tsuji-Trost products.
(17) The reaction did not proceed in relatively nonpolar solvents such
as toluene and THF. Using more polar solvents such as DMF and
DMSO, preferential O-alkylation (over C-alkylation) of β-ketoester was
observed.
(13) (a) Felpin, F.-X.; Miqueu, K.; Sotiropoulos, J.-M.; Fouqet, E.;
Ibarguren, O.; Laudien, J. Chem.;Eur. J. 2010, 16, 5191. For an
alternate viewpoint, see:(b) Zhao, F.; Bhanage, B. M.; Shirai, M.; Arai,
M. J. Mol. Catal. A 1999, 142, 383.
(14) Rubottom, G. M.; Vazquez, M. A.; Pelegria, D. R. Tetrahedron
Lett. 1974, 4319.
990
Org. Lett., Vol. 13, No. 5, 2011

Table 1. Tandem Cyclization of Carbonate 5
Scheme 5. B Ring Functionalization
(entry 3). The stereochemistry of the tricycle 3 was estab-
lished via extensive 2D NMR including the key nOe data
shown in Table 1. Replacement of the reaction solvent
from EtOH to t-BuOH suppressed formation of ethyl ester
26 (entry 4). Finally, the addition of LiOAc as a base
further increased the chemical efficiency to 57% yield
(entry 5).19 The interplay between mono- and bidentate
ligands in the product distribution has yet to be clarified,
and we are actively exploring this divergent reactivity.
Exploration of functional group manipulation of the
ABC tricyclic core was also investigated (Scheme 5). Com-
pound 3 was readily functionalized by mCPBA oxidation.6
Subsequent reduction using NaBH4 gave the diol 27 in a
highly stereoselective manner. Advanced intermediate 27
contains the central ABC ring system and all the config-
urationally stable stereochemistry present in jiadifenin (1).
In conclusion, we have established an efficient route for
the ABC ring system of jiadifenin. The protic solvent-
promoted Mizoroki-Heck reaction was used to construct
the A ring moiety in high yield. A tandem Tsuji-Trost
cyclization/lactonization sequence was employed to con-
struct the BC system. Key knowledge in the relation
between carbonate stereochemistry and successful Tsuji-
Trost cyclization has been disclosed. This work should lay
a strong foundation for the total synthesis of jiadifenin,
and further synthetic studies will be reported in due course.
a Pd(PPh3)4 was used as catalyst. b 2.4 equiv were used.
had predicted, diastereomer 20 produced the undesired
ABC tricycle 2318 with incorrect stereochemistries at C5
and C6 in 66% yield. This result was in agreement with the
“double inversion” model7d for the Trost-Tsuji reaction
and demonstrated the potential of our strategy to access
the 5,6,5-tricyclic scaffold necessary for constructing jiadi-
fenin (1). Disappointingly, the alternate diastereomer 5 did
not produce the desired product 3, but instead yielded
cycloheptenone 25 in 55% yield. This compound 25 may
arise from unwanted diastereomeric π-allyl Pd complex 8,
which undergoes preferential β-hydride elimination at C14,
tautomerization, and intramolecular aldol condensation.
While neither carbonate diastereomer 5 nor 20 had
yielded the desired product, we suspected that alteration
of the catalyst might change the reaction outcome (Table 1).
Using Pd(OAc)2 as the palladium source, we first screened
a range of monodentate ligands (e.g., n-Bu3P, t-Bu3P, and
Cy3P); however, none of these conditions significantly
altered the reaction outcome. In contrast, use of bidentate
ligands such as DPPB and (R)-BINAP did produce the
desired product 3 in modest (22-27%) chemical yield
along with the uncyclized ethyl ester 26 as a byproduct
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology of
Japan (Priority Area, 19790027, 22790030). R.G.C. is a
Japan Society for the Promotion of Science Fellow (L-10568).
Ms. Yasuko Okamoto (Tokushima Bunri University) is
acknowledged for mass spectra data.
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) This structure was confirmed by X-ray crystallographic analysis.
See Supporting Information for full details.
(19) Although these conditions used (R)-BINAP, the same results
were observed using (()-BINAP.
Org. Lett., Vol. 13, No. 5, 2011
991