Enantioselective total synthesis of (-)-erinacine B

Article abstract of DOI:10.1021/ol0628816

(Chemical Equation Presented) The first enantioselective total synthesis of (-)-erinacine B has been achieved. Our approach features convergent construction of the 5-6-7 tricyclic cyathane core system via chiral building blocks prepared using asymmetric c

Full text of DOI:10.1021/ol0628816

ORGANIC
LETTERS
2007
Vol. 9, No. 2
359-362
Enantioselective Total Synthesis of
)-Erinacine B
(−
Hideaki Watanabe, Masashi Takano, Akinori Umino, Toshiya Ito,
Hiroyuki Ishikawa, and Masahisa Nakada*
Department of Chemistry, Faculty of Science and Engineering, Waseda UniVersity,
3-4-1, Ohkubo, Shinjuku, Tokyo 169-8555, Japan
mnakada@waseda.jp
Received November 28, 2006
ABSTRACT
The first enantioselective total synthesis of (−)-erinacine B has been achieved. Our approach features convergent construction of the 5-6-7
tricyclic cyathane core system via chiral building blocks prepared using asymmetric catalysis developed by us and highly stereoselective
construction of all stereogenic centers in the aglycon.
In 1994, Kawagishi et al. reported the isolation and structural
elucidation of (-)-erinacines A, B, and C.1a (-)-Erinacine
B is the first xylose-conjugated terpenoid possessing a
cyathane core, which features an unusual 5-6-7 tricyclic
carbon skeleton incorporating a trans-fused 6-7 ring system
and 1,4-anti quaternary methyl groups located at the ring
junctions. Erinacines and their congeners have been shown
to exhibit significant activity in stimulating nerve growth
factor (NGF) synthesis.1,2
have been reported; however, to our knowledge, no enan-
tioselective total synthesis of a cyathane xyloside with a
trans-fused 6-7 ring system such as erinacine has been
reported. We report herein an enantioselective total synthesis
of (-)-erinacine B in a convergent and highly stereoselective
manner via chiral building blocks prepared using asymmetric
catalysis developed by us.
Our synthetic strategy for (-)-erinacine B is based on the
retrosynthetic analysis outlined in Scheme 1. Because it was
Because of their structural complexity and significant
biological activity, much attention has been given to the
synthesis of erinacines, and several research groups have
developed different approaches to the construction of these
attractive polycyclic natural products.3,4 To date, four total
syntheses of cyathins3a-f as racemates3c-f or a product via
optical resolution3a,b and four enantioselective total syntheses4
(3) (a) Snider, B. B.; Vo, N. H.; O’Neil, S. V.; Foxman, B. M. J. Am.
Chem. Soc. 1996, 118, 7644-7645. (b) Snider, B. B.; Vo, N. H.; O’Neil,
S. V. J. Org. Chem. 1998, 63, 4732-4740. (c) Tori, M.; Toyoda, N.; Sono,
M. J. Org. Chem. 1998, 63, 306-313. (d) Piers, E.; Gilbert, M.; Cook, K.
L. Org. Lett. 2000, 2, 1407-1410. (e) Ward, D. E.; Gai, Y.; Qiao, Q. Org.
Lett. 2000, 2, 2125-2127. (f) Ward, D. E.; Gai, Y.; Qiao, Q.; Shen, J.
Can. J. Chem. 2004, 82, 254-267. For recent synthetic studies, see: (g)
Sato, A.; Masuda, T.; Arimoto, H.; Uemura, D. Org. Biomol. Chem. 2005,
3, 2231-2233. (h) Drege, E.; Morgant, G.; Desmaele, D. Tetrahedron Lett.
2005, 46, 7263-7266. For other synthetic studies, see references cited in
ref 4a.
(1) (a) Kawagishi, H.; Shimada, A.; Shirai, R.; Okamoto, K.; Ojima, F.;
Sakamoto, H.; Ishiguro, Y.; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569-
1572. For recently reported erinacines, see: (b) Kawagishi, H.; Masui, A.;
Tokuyama, S.; Nakamura, T. Tetrahedron 2006, 62, 8463-8466. For natural
products possessing a cyathane skeleton, see references cited in ref 4a.
(2) Kawagishi, H.; Furukawa, S.; Zhuang, C.; Yunoki, R. Explore 2002,
11, 46-51.
(4) (+)-Allocyathin B2: (a) Takano, M.; Umino, A.; Nakada, M. Org.
Lett. 2004, 6, 4897-4900. (b) Trost, B. M.; Dong, L.; Schroeder, G. M. J.
Am. Chem. Soc. 2005, 127, 2844-2845. (c) Trost, B. M.; Dong, L.;
Schroeder, G. M. J. Am. Chem. Soc. 2005, 127, 10259-10268. (+)-
Cyanthiwigin U: (d) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc.
2005, 127, 5334-5335. (-)-Scabronine G: (e) Waters, S. P.; Tian, Y.; Li,
Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514-13515.
10.1021/ol0628816 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/15/2006

Scheme 1
Scheme 2
mediated reduction6 and catalytic asymmetric intramolecular
cyclopropanation,7 respectively.
Consequently, the product 13 was dehydrated with thionyl
chloride and pyridine (91%) (Scheme 3), followed by double
bond isomerization using DBU (92%) and removal of MPM
ether with DDQ to produce 8 (100%).
We expected that catalytic hydrogenation of alkene 8
would proceed diastereoselectively because the â-oriented
hydroxyl group at C14 would direct the reaction; however,
hydrogenation of 8 provided no product. We also attempted
hydride reduction of 8 with various reagents, but no product
or only the corresponding allylic alcohols were obtained.
Consequently, we next examined electron-transfer reduc-
tion of this enone system and found that Birch reduction of
8 afforded a mixture of 14 and its alcohol. After several
attempts, we finally found that reduction of 8 with samarium
diiodide in the presence of HMPA afforded 14 as a single
product in 94% yield.8 It should be noted that this diaste-
reoselective reduction would arise from protonation of the
anion generated at C5 by the â-oriented hydroxyl group at
C14 because Birch reduction of the MOM ether of 8 gave
the corresponding allylic alcohol as the major product.
Reaction of 14 with isopropenyl lithium resulted in low
conversion; however, this problem was settled by use of the
isopropenyl cerium reagent (84%). The product with an
isopropenyl group was subjected to hydrogenation (95%),
followed by Dess-Martin oxidation to afford 15 (91%).
Dehydration of 15 by thionyl chloride and pyridine
proceeded cleanly (100%), and double bond isomerization
under acidic conditions generated ketone 7 with a thermo-
dynamically stable alkene (100%).
expected that (-)-erinacine B might be derived from 1 via
a consecutive intramolecular 1,4-addition and â-elimination
sequence,5 we decided to prepare 1 by a glycosylation
reaction of 2 with 3 and subsequent transformations. We
envisioned that 2 would be obtained from 4 via a base-
promoted â-elimination reaction and stereoselective reduction
of the resulting ketone. Epoxide 4 was to be produced via
stereoselective epoxidation of the homoallylic alcohol 5,
which could be prepared by stereoselective reduction of 6.
Tricyclic compound 6, possessing a cyathane core, could be
obtained from 7 by a ring-expansion reaction followed by
installation of the double bond. It was expected that the trans
C5-C6 stereochemistry in 7 could be attained by diaste-
reoselective reduction of 8 utilizing the â-oriented hydroxyl
at C14; hence, we commenced with asymmetric synthesis
of 8.
The next task was to construct the 5-6-7 cyathane core
from 7, which required a one-carbon ring-expansion reaction.
We employed Hasegawa’s method9 for this purpose because
it was successfully applied in our first enantioselective total
synthesis of (+)-allocyathin B2.4a Thus, 7 was converted to
the corresponding â-keto ester10 using Mander’s reagent
(6) (a) Iwamoto, M.; Kawada, H.; Tanaka, T.; Nakada, M. Tetrahedron
Lett. 2003, 44, 7239-7243. (b) Watanabe, H.; Iwamoto, M.; Nakada, M.
J. Org. Chem. 2005, 70, 4652-4658.
As shown in Scheme 2, we reported the preparation of
enantiopure â-hydroxy ketone 134a via a coupling reaction
of two fragments, 11 and 12. These fragments were derived
from 9 and 10 via highly enantioselective baker’s-yeast-
(7) Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.; Watanabe, H.;
Umino, A.; Matsumura, T.; Hagihara, T.; Takano, M.; Nakada, M. J. Am.
Chem. Soc. 2003, 125, 2860-2861.
(8) The structure of 14 was confirmed by the X-ray crystallographic
analysis of the corresponding 3,5-dinitrobenzoate. See Supporting Informa-
tion.
(5) Kenmoku, H.; Sassa, T.; Kato, N. Tetrahedron Lett. 2000, 41, 4389-
4393.
360
Org. Lett., Vol. 9, No. 2, 2007

Scheme 3
(79%),11 followed by iodomethylation (66%)12 and reaction
Treatment of 17 with DBU prompted a clean â-elimination
reaction to provide the γ-hydroxy-R,â-unsaturated ketone,
which was converted to benzoate 18 (78%, two steps)
because we expected that the benzoyloxy group in 18 would
be stable during the following transformations and would
be a leaving group in the final consecutive intramolecular
1,4-addition and â-elimination reaction.
Diastereoselective reduction of 18 and its derivatives was
investigated, but all reductions with readily available achiral
reagents produced an undesired isomer as a major product.
Consequently, we examined reagent-controlled stereoselec-
tive reduction and found that CBS-catalyzed reduction14 of
18 successfully generated the desired alcohol 19 as the sole
product (95%).
with samarium diiodide in the presence of HMPA. As
expected, this resulted in a ring-expansion reaction, generat-
ing the desired γ-keto ester 16 (81%, a mixture of diaster-
eomers).
Introduction of the double bond to the seven-membered
ring using the previously reported I2/LDA method4a was low
yielding, but reaction of the TMS enol ether of 16 with
PhSeCl afforded an R-phenylselenyl ketone, which was
oxidized to the corresponding selenoxide, followed by
selenoxide fragmentation (91%, two steps) to install the
double bond between the ketone and the ester in 16. This
double bond was easily isomerized by DBU to provide the
desired compound 6 (98%).
DIBAL-H reduction of 6 exclusively provided a desired
It was expected that glycosylation of 19 would be difficult
to achieve because the hydroxyl group at C14 is highly
hindered due to a quaternary carbon adjacent to C14 (Scheme
4). Most of the glycosylation reactions of 19 with several
xylose derivatives under various conditions gave no glyco-
sylated product; however, we finally found that 19 reacted
with 20 in the presence of MeOTf15 to provide the desired
product, which was exposed to HF‚Py to afford 21 as an
inseparable mixture of anomeric isomers (77%, two steps,
R/â ) 1:3.5).16
diol 5 (96%, dr ) 10:1), followed by stereoselective
13
epoxidation with TBHP/VO(acac)2 to afford the desired
epoxide as a single diastereomer. The primary alcohol of
this epoxide was converted to a TBDPS ether, and Dess-
Martin oxidation of the remaining secondary alcohol pro-
vided â,γ-epoxy ketone 17 (80%, three steps).
(9) Hasegawa, E.; Kitazume, T.; Suzuki, K.; Tosaka, E. Tetrahedron Lett.
1998, 39, 4059-4062.
(10) This â-keto ester existed exclusively in its enol form.
(11) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-5428.
(12) Clark, J. H.; Miller, J. M. J. Chem. Soc., Perkin Trans. 1 1977,
1743-1745.
(14) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553.
(13) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136-6137.
(15) Lo¨nn, H. J. Carbohydr. Chem. 1987, 6, 301-306.
1
(16) The ratio was determined by 400 MHz H NMR.
Org. Lett., Vol. 9, No. 2, 2007
361

Finally, treatment of 22 with triethylamine and LiBr in
THF, which were the conditions reported by Sassa,5 furnished
(-)-erinacine B (74%), which was successfully isolated as
a single diastereomer. Synthetic (-)-erinacine B proved to
be identical in all respects to the natural product on the
reported spectral data.1a
Scheme 4
In summary, the first enantioselective total synthesis of
(-)-erinacine B has been achieved. Our approach features
convergent construction of the 5-6-7 tricyclic cyathane core
system via chiral building blocks prepared using asymmetric
catalysis developed by us and highly stereoselective con-
struction of all stereogenic centers in the aglycon. Further
synthetic studies on other cyathanes are now in progress in
our laboratory and will be reported in due course.
Acknowledgment. This work is dedicated to Professor
K. C. Nicolaou on the occasion of his 60th birthday. We
thank Professor Yoshikazu Kawagishi (Graduate School of
Science and Technology, Shizuoka University) for kindly
1
giving us copies of H NMR and 13C NMR of erinacine B.
This work was financially supported in part by a Waseda
University Grant for Special Research Projects, a Grant-in-
Aid for Scientific Research on Priority Areas (Creation of
Biologically Functional Molecules (No. 17035082)), and a
Grant-in-Aid for Young Scientists (start-up research (No.
18850023)) from The Ministry of Education, Culture, Sports,
Science, and Technology, Japan. We are also indebted to
21COE “Practical Nanochemistry”.
Supporting Information Available: Experimental and
characterization details (PDF, CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Dess-Martin oxidation of 21 cleanly provided the cor-
responding aldehyde (96%), but subsequent removal of all
MPM groups with DDQ was troublesome and afforded a
complex mixture of products. After several attempts, we
found that exposure of the substrate to TFA17 in CH2Cl2 at
-20 °C gratifyingly provided the key intermediate 22
(100%).
OL0628816
(17) Yan, L.; Kahne, D. Synlett 1995, 523-524.
362
Org. Lett., Vol. 9, No. 2, 2007