Expedient construction of the vibsanin E core without the use of protecting groups

Article abstract of DOI:10.1021/ol0501222

(Chemical Equation Presented) The tricyclic core of vibsanin E was constructed without the use of a protecting group in six steps. The El Gaied Baylis-Hillman variant was key to allowing the Bronsted acid induced tandem cyclization forming rings B and C i

Full text of DOI:10.1021/ol0501222

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1327-1329
Expedient Construction of the
Vibsanin E Core without the Use of
Protecting Groups
Ralf Heim, Stefan Wiedemann, Craig M. Williams,* and Paul V. Bernhardt
School of Molecular and Microbial Sciences, UniVersity of Queensland,
St. Lucia, 4072 Queensland, Australia
c.williams3@uq.edu.au
Received January 19, 2005
ABSTRACT
The tricyclic core of vibsanin E was constructed without the use of a protecting group in six steps. The El Ga1ıed Baylis−Hillman variant was
key to allowing the Brønsted acid induced tandem cyclization forming rings B and C in one operation.
Vibsanine E (1) (Figure 1), later truncated to vibsanin E,
was first isolated from Viburnum awabuki by Kawazu1 in
lesser extent Shen4 and Duh,5 have studied the Viburnum
species elucidating an entire vibsane family [e.g., vibsanin
C (2) and vibsanin B (3)] (Figure 1). In addition, Fukuyama4
has synthesized 6-epi-vibsanin F (4) proving the absolute
configuration of vibsanin F (Figure 1).
Vibsanin E (1), however, has a slightly more complex and
unique tricyclic structure than the other family members,
which attracted the interest of our group. Considering no
synthetic endeavors to this system have been reported,6 we
undertook a brief investigation into the construction of the
central core, details of which are disclosed herein.
In the process of elucidating vibsane biochemical path-
ways, Fukuyama investigated the conversion of vibsanin C
(2) to vibsanin E (1)7 and found that conversion proceeded
(3) Fukuyama, Y.; Kubo, M.; Minami, H.; Yuasa, H.; Matsuo, A.; Fujii,
T.; Morisaki, M.; Harada, K. Chem. Pharm. Bull. 2005, 53, 72-80 and
references therein.
(4) (a) Shen, Y.-C.; Prakash, C. V. S.; Wang, L.-T.; Chien, C. Y.; Hung,
M.-C. J. Nat. Prod. 2002, 65, 1052-1055. (b) Shen, Y.-C.; Lin, C.-L.;
Chien, S.-C.; Khalil, A. T.; Ko, C.-L.; Wang, C.-H. J. Nat. Prod. 2004, 67,
74-77.
Figure 1. Strutures of vibsanin B, C, E, and F.
(5) (a) Duh, C.-Y.; El-Gamal, A. A. H.; Wang, S.-K. Tetrahedron Lett.
2003, 44, 9321-9322. (b) El-Gamal, A. A. H.; Wang, S. K.; Duh, C.-Y. J.
Nat. Prod. 2004, 67, 333-336.
1978, and the absolute stereochemistry was determined in
1980 by K. Y. Fukuyama.2 Since then, Fukuyama,3 and to a
(6) Studies toward the total synthesis of vibsanin E were recently
presented: Davies, H. M. L.; Loe, Ø. Abstract of Papers. 228th ACS
Meeting, Aug 22-27, Philadelphia, PA; American Chemical Society:
Washington, DC, 2004; Abstract No. 563.
(7) Fukuyama, Y.; Minami, H.; Kagawa, M.; Kodama, M.; Kawazu, K.
J. Nat. Prod. 1999, 62, 337-339.
(1) Kawazu, K. IUPAC Int. Symp. Chem. Nat. Prod. (11th) 1978, 2, 101-
103. Full paper: Kawazu, K. Agric. Biol. Chem. 1980, 44, 1367-1372.
(2) Fukuyama, K.; Katsube, Y.; Kawazu, K. J. Chem. Soc., Perkin Trans.
2 1980, 1701-1703.
10.1021/ol0501222 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/11/2005

smoothly, albeit in moderate yield (50%), using boron
trifluoride etherate (BF3‚Et2O). This precedent formed the
basis of our retrosynthetic frame (Scheme 1) and is in effect
the key step for the formation of rings B and C.
recovered starting material (27%)] after 10 h at 50 °C
(Scheme 2). More recently reported procedures either failed
Scheme 2
Scheme 1
to react14 or gave a lower yield16,17 of product in our hands.
Utilizing the cyclization procedure reported by Fukuyama7
[38.4 mM (CH2Cl2), BF3‚Et2O (10 equiv), -78 °C, 20 min]
and variations thereof afforded only trace amounts of the
desired cyclization product 11 (Scheme 3). It was soon
It was envisaged that 3-methylcyclohex-2-enone 7 could
be converted to a cyclohexenone of type 6 which would set
the stage for boron trifluoride etherate mediated ring forma-
tion (i.e., 11).
In the event that this failed, “fall back” measures, such as
Danishefsky’s reductive cyclization of mercurial enones,8
Semmelhack’s tandem oxy-palladation vinylation,9 and Bart-
lett’s thallium(III)-induced tetrahydropyran synthesis,10 were
expected to suffice. Following tandem cyclization, regiose-
lective 6- to 7-membered ring expansion (e.g., 5) would be
induced with stablized carbenes.11
Scheme 3
Cyclohexenone 7 was reacted with the homoprenylcuprate
giving the 1,4-addition product 8 in 85% yield. Dehydro-
genation with IBX‚NMO, as reported by Nicolaou,12 pro-
ceeded smoothly, affording the R,â-unsaturated ketone 9
(64%). At this point we utilized the increasingly important
work of El Ga¨ıed13,14 who reported modified Baylis-
Hillman15 conditions suitable for cyclic enones. Of the two
procedures available, that is, using N,N-(dimethylamino)-
pyridine [DMAP/60 °C/5 days]13 or imidazole [imid/rt/17
days]14 as the catalyst, the lower yielding DMAP procedure
was chosen based on time conservation. In our case,
considerable optimization and modification was required.
However, it wasfound that reaction of 9 using DMAP
afforded the allylic alcohol 10 in 32% yield [43% based on
realized that BF3‚Et2O was most likely not the active agent,
but rather hydrofluoric acid. Treating 10 with anhydrous
ethereal hydrochloric acid conversely gave cyclized product
11 in 58% yield with no accompanying diastereoisomers
(e.g., 12) (Scheme 3).
Conformational analysis of the stereochemical models (i.e.,
13 and 14) suggests 14 is significantly more strained than
13; however, these two compounds are epimeric alpha to a
carbonyl. Therefore, irrespective of the kinetic ratio of 11
and 12, the reaction should be under thermodynamic control
because 11 and 12 would easily equilibrate under the reaction
conditions (Figure 2).
(8) Danishefsky, S.; Chackalamannil, S.; Uang, B.-J. J. Org. Chem. 1982,
47, 2231-2232.
(9) Semmelhack, M. F.; Epa, W. R. Tetrahedron Lett. 1993, 34, 7205-
7208.
(10) Michael, J. P.; Ting, P. C.; Bartlett, P. A. J. Org. Chem. 1985, 50,
2416-2423.
(11) Liu, H.-J.; Yeh, W.-L.; Browne, E. N. C. Can. J. Chem. 1995, 73,
1135-1147.
(12) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem. Int.
Ed. 2002, 41, 993-996. (b) Nicolaou, K. C.; Gray, D. L. F.; Montagnon,
T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.
(13) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965-
5966.
(14) Gatri, R.; El Ga¨ıed, M. M. Tetrahedron Lett. 2002, 43, 7835-7836.
(15) Baylis, A. B.; Hillman, M. E. D. German Patent 2,155,113, 1972;
Chem. Abstr. 1972, 77, 341174q. (b) Basavaiah, D.; Rao, A. J.; Satya-
narayana, T. Chem. ReV. 2003, 103, 811-891.
Ring expansion of the cyclohexanone moiety of 11 to the
vibsanin E core with stabilized carbenoids (e.g., EtO2-
CCHN2), known to insert regioselectively at the least
subsituted carbon alpha to ketones, using BF3‚Et2O11 or
Meerwein’s salt18 failed.
(16) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org.
Chem. 2002, 67, 510-514
(17) Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555-
558.
(18) Ahmad, Z.; Goswami, P.; Venkateswaran, R. V. Tetrahedron 1989,
45, 6833-6840.
1328
Org. Lett., Vol. 7, No. 7, 2005

Scheme 4
Figure 2. Stereochemical models 13 and 14,
In addition, failed attempts at ring expansion were also
experienced with nonstabilized carbenoids,19 ethyl diazo-
lithioacetate,20 and silyloxycyclopropane homologation.21
Considering ring expansion of 1,3-dicarbonyl functions are
prevalent, for example, Beckwith-Dowd22 and variant23
protocols, 11 was converted to 15 in 81% overall yield, via
Mander’s reagent24 and subsequent treatment with ethoxide
(retro Claisen/Claisen reaction). A requirement of the Beck-
with-Dowd protocol is the installation of a methylene halide
function, however, all attempts to convert 15 to the methylene
iodide 17 or bromide 18 failed when 15 was reacted directly
with diiodo- or dibromomethane. Reaction of 15 with
formalin25 gave the methylene hydroxy derivative 19 in 84%
yield, which underwent smooth conversion to the methylene
iodide 17 in 75% yield, using triphenylphosphine, iodine and
imidazole. Unfortunately, treating iodide 17 with samarium
diiodide26 afforded separable mixtures of cyclopropanol 16
(72%) and unidentified products, whereas recent develop-
ments with zinc metal27 promoted ring expansion returned
only starting material (Scheme 4). Surprisingly, brief attempts
(e.g., DBU, NaOEt) to ring open 16 have been disappointing.
Thanks to the ingenious Zercher reaction,28 however,
treating 15 with diethyl zinc and diiodomethane gave in one
step the vibsanin E core 2029 in 50% yield (dr >95:5)
(Scheme 5).
Scheme 5
In conclusion, we have demonstrated that the core of
vibsanin E (1) can be constructed expediently and astonish-
ingly without the use of a single protecting group. We believe
that new developments in asymmetric 1,4-additions to
cyclohexenones30 in conjunction with the El Ga¨ıed Baylis-
Hillman variant and the remarkable Zercher reaction will
pave the way for a successful total synthesis and structural
confirmation of vibsanin E (1).
(19) Maruoka, K.; Concepcion, A. B.; Yamamoto, H. Synthesis 1994,
1283-1290.
(20) Nagao, K.; Chiba, M.; Kim, S.-W. Synthesis 1983, 197-199.
(21) (a) Yoshihiko, I.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41,
2073-2074. (b) Patel, H. A.; Stothers, J. B.; Thomas, S. E. Can. J. Chem.
1994, 72, 56-68.
(22) (a) Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W.
J. Chem. Soc., Chem. Commun. 1987, 666-667. (b) Beckwith, A. L. J.;
O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565-
2575. (c) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93, 2091-2115.
(23) Sugi, M.; Sakuma, D.; Togo, H. J. Org. Chem. 2003, 68, 7629-
7633 and references therein.
(24) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-5428.
(25) (a) Tsuda, Y.; Ishiura, A.; Takamura, S.; Hosoi, S.; Isobe, K.; Mohri,
K. Chem. Pharm. Bull. 1991, 39, 2797-2802. (b) Tsuji, J.; Nisar, M.;
Shimizu, I. J. Org. Chem. 1985, 50, 3416-3417.
(26) (a) Takano, M.; Umino, A.; Hakada, M. Org. Lett. 2004, 6, 4897-
4900. (b) Chung, S. H.; Cho, M. S.; Choi, J. Y.; Kwon, D. W.; Kim, Y. H.
Synlett 2001, 1266-1268. (c) Hasegawa, E.; Kitazume, T.; Suzuki, K.;
Tosaka, E. Tetrahedron Lett. 1998, 39, 4059-4062.
(27) Sugi, M.; Sakuma, D.; Togo, H. J. Org. Chem. 2003, 68, 7629-
7633.
Acknowledgment. We thank The University of Queens-
land for financial support and Dr. D. J. Brecknell for
molecular mechanics calculations.
Supporting Information Available: Characterization
data of compounds 8-11, 15, and 20, X-ray crystal structure
analysis data of 11, and copies of 1H and 13C NMR sprectra
of compound 20. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0501222
(29) The stereochemistry at C2 has not been assigned, but molecular
mechanics calculations suggest the lowest energy arrangement is where C2
has the ester function â.
(30) Feringa, B. L.; Badorrey, R.; Pe´na, D.; Harutyunyan, S. R.;
Minnaard, A. J. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5834-5838.
(28) Brogan, J. B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444-6446.
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