Exploring an expedient IMDA reaction approach to construct the guanacastepene core

Article abstract of DOI:10.1021/ol051312f

(Chemical Equation Presented) Construction of the [5-7-6] tricyclic core of guanacastepenes was attempted by using the intramolecular Diels-Alder (IMDA) reaction and Me₃Al-mediated ring opening of the oxabridge as key synthetic steps. The illustrated chemistry demonstrated a synthetic feasibility to build up the framework of guanacastepenes by the IMDA reaction.

Full text of DOI:10.1021/ol051312f

ORGANIC
LETTERS
2
005
Vol. 7, No. 17
709-3712
Exploring an Expedient IMDA Reaction
Approach to Construct the
Guanacastepene Core
3
†
†
‡
†
Chuang-Chuang Li, Shuang Liang, Xin-Hao Zhang, Zhi-Xiang Xie,
Jia-Hua Chen,*, Yun-Dong Wu,*
†
,†,‡
and Zhen Yang*
,†,§
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, State Key Laboratory of Natural and Biomimetic
Drugs, School of Pharmaceutical Science, and Laboratory of Chemical Genomics,
Shenzhen Graduate School, Peking UniVersity, Beijing, 100871, Department of
Chemistry, The Hong Kong UniVersity of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong, China, and ViVoQuest, Inc., 711 ExecutiVe BouleVard,
Valley Cottage, New York 10989
zyang@pku.edu.cn
Received June 5, 2005
ABSTRACT
Construction of the [5-7-6] tricyclic core of guanacastepenes was attempted by using the intramolecular Diels
−Alder (IMDA) reaction and
3
Me Al-mediated ring opening of the oxabridge as key synthetic steps. The illustrated chemistry demonstrated a synthetic feasibility to build
up the framework of guanacastepenes by the IMDA reaction.
4
b
Guanacastepenes are a novel class of richly functionalized
diterpenoids isolated by Clardy and co-workers in 2000 (see
selected examples 1-6 in Figure 1). Some of the family
and two formal total syntheses by the laboratories of Snider
4
c
in 2003 and Hanna in 2004.
1
5
Drug resistance of bacteria poses a serious public
health threat and demands effective countermeasures. Given
6
members (such as guanacastepene A) are known to be active
against methicillin-resistant strains of Staphylococcus aureus
the potential of guanacastepenes as leads to find new
(
MRSA) and vancomycin-resistant Enterococcus faecalis
2
(3) (a) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569-572. (b)
Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V. Tetrahedron Lett. 2001,
(VREF). However, their hemolytic activity against human
red blood cells prevents them from being directly used as
therapeutic agents.
Because of their novel structural features and important
biological activities, guanacastepenes have attracted the
interest of synthetic laboratories around the world since they
42, 4947-4950. (c) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3,
2399-2402. (d) Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J. M.;
Danishefsky, S. J. Tetrahedron Lett. 2001, 42, 6789-6791. (e) Snider, B.
B.; Shi, B. Tetrahedron Lett. 2001, 42, 9123-9126. (f) Dudley, G. B.;
Danishefsky, S. J. Tetrahedron Lett. 2002, 43, 5605. (g) Mehta, G.; Umarye,
J. D. Org. Lett. 2002, 4, 1063-1066. (h) Gradl, S. N.; Kennedy-Smith, J.
J.; Kim, J.; Trauner, D. Synlett 2002, 3, 411-414. (i) Shipe, W. D.;
Sorensen, E. J. Org. Lett. 2002, 4, 2063. (j) Nguyen, T. M.; Seifert, R. J.;
Mowrey, D. R.; Lee, D. Org. Lett. 2002, 4, 3959. (k) Nakazaki, A.; Sharma,
U.; Tius, M. A. Org. Lett. 2002, 4, 3363. (l) Boyer, F.-D.; Hanna, I.
Tetrahedron Lett. 2002, 43, 7469. (m) Du, X.-H.; Chu, H. V.; Kwon, O.
Org. Lett. 2003, 5, 1923. (n) Brummond, K. M.; Gao, D. Org. Lett. 2003,
5, 3491. (o) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett.
2003, 5, 4113. (p) Srikrishna, A.; Dethe, D. H. Org. Lett. 2004, 6, 165. (q)
Mandal, M.; Danishefsky, S. J. Tetrahedron Lett. 2004, 45, 3831.
(4) (a) Lin, S.; Dudley, G. B.; Tan, D. S.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2002, 41, 2188. (b) Shi, B.; Hawryluk, N. A. Snider, B. B.
J. Org. Chem. 2003, 68, 1030. (c) Boyer, F.-D.; Hanna, I.; Richard, L.
Org. Lett. 2004, 6, 1817.
3
were initially isolated, culminating in the total syntheses of
guanacastepene A by the laboratory of Danishefsky in 2002
4a
†
‡
§
Peking University.
The Hong Kong University of Science and Technology.
VivoQuest, Inc.
(1) (a) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am. Chem.
Soc. 2000, 122, 2116. (b) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am.
Chem. Soc. 2001, 123, 9900.
(2) Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.;
Greenstein, M.; Maiese, W. M. J. Antibiot. 2000, 53, 256.
1
0.1021/ol051312f CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/29/2005

antibacterial agents, development of efficient approaches
to rapidly access a variety of functionalized guanacas-
tepene derivatives is imperative.
Scheme 1. Construction of [5-7-6] Tricyclic Core by IMDA
at C8, ideally in a stereoselective manner. A search of the
primary literature yielded no relevant study in this aspect,
1
1
which encouraged us to initiate our program.
To put the proposed synthetic transformation into practice,
8
, 11, 12, and 13 (Scheme 2) were selected as substrates to
test the cyclization tendency of their IMDA reactions.
Scheme 2. Designed Precursors for IMDA Reaction
Figure 1. Naturally occurring guanacastepenes.
Inspired by the increasing number of seven-membered-
ring-containing natural products being identified and their
7
interest to the academic and pharmaceutical communities,
we started our synthetic study of guanacastepenes in early
2001. We expected that our developed synthetic approach
would be efficient in synthesizing the [5-7-6] tricyclic core
of guanacastepenes, as well as other [n-7-6] tricyclic ring
systems. We report herein our study on the development of
an IMDA reaction approach to construct the guanacastepenes
framework, which allows us to effectively and conveniently
construct structurally diverse compounds having the [5-7-6]
tricyclic framework similar to the guanacastepenes.
Structurally, guanacastepenes share a common [5-7-6]
tricyclic core decorated with a variety of functional groups.
This feature inspired us to stereoselectively construct the
Scheme 3 illustrates the synthesis of 8 and 11 and their
IMDA reactions to form the tricyclic products 20 and 21.
The synthesis started with furan-2-aldehyde 14, which was
first converted to cis-vinyl bromide 15 in 92% yield first by
8
tricyclic core B from the furan-tethered dieneophile A
9
through the IMDA reaction by taking advantage of the
conformationally preorganized feature of substrate A (see
1
0
Scheme 1). We also expected that the Lewis acid-assisted
1
2
Corey-Fuchs reaction in 90% yield, followed by debro-
methylation of B could provide C with a quaternary carbon
1
3
mination with Pd(PPh
3 4 3
) /Bu SnH. Compound 15 was then
utilized to synthesize 18 by a modification of Noyori’s
(
5) Neu, H. C. Science 1992, 257, 1064.
14
(6) (a) Nicolaou, K. C.; Hughes, R.; Cho, S. Y.; Wingssinger, N.;
tandem reaction procedure. In the event, compound 15 was
first treated with t-BuLi in Et O at -94 °C to form the
vinyllithium and then treated with CuI and Bu P; the resultant
cuprate reagent was then coupled with 3-methyl cyclopen-
tenone 16 in the presence of BF ‚Et O at -78 °C for 1 h,
Smethurst, C.; Labischinski, H.; Endermann, R. Angew. Chem., Int. Ed.
000, 39, 3823. (b) Chiosis, G.; Boneca, I. G. Science 2001, 293, 1484. (c)
Liu, H. T.; Sadamoto, R.; Sears, P. S.; Wong, C. H. J. Am. Chem. Soc.
001, 123, 9916. (d) Kohli, R. M.; Walsh, C. T.; Burkart, M. D. Nature
002, 418, 658.
2
2
3
2
2
3
2
(7) (a) Fraga, B. M. Nat. Prod. Rep. 1996, 13, 307. (b) Wender, P. A.;
1
5
Love, J. A. In AdVances in Cycloaddition; Harmata, M., Ed.; JAI Press:
Greenwich, CT, 1999; Vol. 5, pp 1-45. (c) Lautens, M.; Klute, W.; Tam,
W. Chem. ReV. 1996, 96, 49.
followed by reaction with aldehyde 17 to give the desired
product 18 in 67% overall yield.
(8) (a) For a recent review on Furan Diels-Alder chemistry, see: Kappe,
C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179. (b) For
application of intramolecular Diels-Alder reaction of furans to construct
the 5,7,6-tricyclic ring system of phorbols, see: Brickwood, A. C.; Drew,
M. G. B.; Harwood, L. M.; Ishikawa, T.; Marais, P.; Morisson, V. J. Chem.
Soc., Perkin Trans. 1 1999, 913.
(11) It is of note that the groups of Kwon and MacMillan recently
revealed their attempts to generate the [5-7-6] core by an IMDA reac-
tion (see refs 3m and http://etd.caltech.edu/etd/available/etd-10282003-
135857/).
(12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(13) (a) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji, J.
Tetrahedron Lett. 1996, 37, 6759. (b) Uenishi, J.; Kawahama, R.; Shiga,
Y.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996, 61, 5716.
(14) (a) Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988,
110, 4718. (b) Suzuki, M.; Yanagishi, T.; Suziki, T. Noyori, R. Tetrahedron
Lett. 1982, 23, 4057. (c) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; John Wiley & Sons: New York, 1994.
(
9) (a) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp 513-
50. (b) Brieger, G.; Bennet, J. N. Chem. ReV. 1980, 80, 63. (c) Winkler,
J. D. Chem. ReV. 1996, 96, 167.
10) (a) Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16. (b) Diedrich, M.
5
(
K.; Klarner, F.-G.; Beno, B. R.; Houk, K. N.; Senderowitz, H.; Still, W. C.
J. Am. Chem. Soc. 1997, 119, 10255.
3710
Org. Lett., Vol. 7, No. 17, 2005

be made from 18 by selective hydrogenation to remove the
double bond between C9 and C10, the synthetic transforma-
tion encountered a difficulty due to the presence of the triple
bond. Thus, an alternative approach was employed to make
Scheme 3. Synthesis of Compounds 8 and 11
1
2 and 13 as detailed in Scheme 4.
Scheme 4. Synthesis of Compounds 12 and 13
With 18 in hand, we first tested its synthetic feasibility
for constructing the [5-7-6] tricyclic core of guanacastepenes
by IMDA reaction, but no desired cyclization products were
obtained under a variety of reaction conditions. Thus, we
were led to explore the substrates with electron-deficient
dieneophiles such as enyne 11 and envisioned that the
cyclization would happen more readily. To this end, com-
pound 18 was first converted to its mesylate, followed by
elimination to give enyne 11 in 85% yield. The stereochem-
istry of the double bond in compound 11 was established
by the NMR analysis developed by Johnson.16
Interestingly, when 11 was heated in refluxing THF or
benzene, the expected IMDA reaction did not occur. How-
ever, under more forcing conditions (refluxing in toluene),
phenol 20 was obtained in 85% yield, presumably through
intermediate 19.
We next turned our attention to synthesizing the even more
active substrate 8, which has a ketone and an aldehyde as
double activating groups. Thus, following desilylation of
compound 11, the newly derived alcohol was then oxidized
to aldehyde 8 with Dess-Martin periodinane (DMP). To our
delight, the IMDA reaction of 8 could occur at 25 °C, and
the cyclized product 21 was obtained in 80% yield in two
steps.
Accordingly, aldehyde 22 was subjected to sequential
hydrogenation and oxidation, followed by Corey-Fuchs
reaction, to give bromide 23 in 76% overall yield. Subsequent
treatment with n-BuLi at -78 °C, followed by reaction with
ClCOOEt, generated 24 in 85% yield, which was then reacted
Encouraged by these results, we then started to synthesize
compounds 12 and 13. Although 12 and 13 could potentially
(
15) Journet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D. Tetrahedron
Lett. 1998, 39, 6427.
16) Johnson, C. R.; Chen, Y.-F. J. Org. Chem. 1991, 56, 3344.
(
2 2 2 2
with (EtOOCCH CH ) Zn in the presence of CuBr, Me S,
Org. Lett., Vol. 7, No. 17, 2005
3711

and HMPA to produce cyclopentenone 25 in 56% yield by
Crimmins’ procedure.17
As shown in Scheme 4, when compound 25 was treated
N
acid-assisted S 2 reaction to generate the desired regio- and
stereochemistry. It should be noted that our effort to
methylate 21 failed, presumably due to the presence of the
double bond in the seven-membered ring; thus, the cleavage
of the C8-O bond by a Lewis acid leads to aromatization.
At this stage, one of the remaining issues is how to
establish the stereochemistry of 32 and 33. At the beginning,
we attempted to use crystallography to determine their
relative stereochemistry, but we failed to get good quality
crystals for X-ray study. We then decided to use two-
dimensional NMR for the structure determination. To this
end, we eventually identified the benzyl ester 34 as the
sample for two-dimensional NMR study (see Supporting
Information for detail).
with MeCu in the presence of Bu
ketoester 26 was generated as a mixture of diastereoisomers
in 90% yield. NaBH reduction of the mixture 26 produced
3
P and BF
3
‚Et
2
O, the
4
a secondary alcohol, which was subsequently protected as
its TMS ether 27 in 79% yield for the two steps. Further
reduction of the ester 27 with DIBAL-H gave a primary
alcohol, which upon oxidation by DMP yielded 28 in 65%
overall yield. Thus, aldehyde 28 was easily converted to
alcohol 29 via lithium acetylide A in 92% yield.
To make 12, 29 was first reacted with acetic anhydride in
the presence of pyridine to convert its secondary alcohol into
the acetate. Subsequent desilylation with HF-Py afforded
another secondary alcohol, which was then subjected to
oxidation with DMP and elimination with DBU to give 12
in 32% overall yield. As a result, the expected product 30
was formed in 80% yield when compound 12 was refluxed
in toluene for 2 h.
Unfortunately, the relative stereochemistry at C5 and C8
in 34 was the opposite of the stereochemistry of desired
compound 35 (Figure 2). We therefore decided to conduct a
To get substrate 13, 29 (a mixture of diastereoisomers)
was oxidized to the corresponding ketones by DMP. Fortu-
nately, one of the diastereoisomers 13 was directly cyclized
to 31 in 30% yield at room temperature.
To complete the proposed synthetic transformation listed
in Scheme 1, we carried out the methylation of 30 and 31 to
install the quaternary methyl group at C8 by AlMe
3
-mediated
ring opening of the oxabridge.18 To do so, 30 and 31 were
Figure 2. Two-dimensional NMR study results for compound 34.
separately treated with AlMe (2.2 equiv) in CH Cl ; as
3
2
2
expected, 32 and 33 were obtained stereoselectively in 62
and 61% yields, respectively (Scheme 5).
computational study and analyze the key factors that
potentially influence the cyclization tendency. A detailed
discussion regarding this aspect of the study will be reported
in due course.
In summary, we have systematically evaluated the furan-
based IMDA reaction to construct the framework of guana-
castepenes, and their stereochemistry was determined by two-
dimensional NMR. Although the furan-based IMDA reaction
approach gave the undesired stereochemistry of the cyclized
products, the generated information eventually led us to work
out a new IMDA reaction approach to build up the
framework of guanacastepenes, and the total synthesis of the
guanacastepenes is currently underway in our laboratory.
3
Scheme 5. Me Al-Mediated Stereoselective Methylation
Acknowledgment. We gratefully acknowledge Professors
Changwen Jin and Yuxin Cui for their support with the NMR
studies. Financial support from the National Science Founda-
tion of China (Grants 20272003, 20325208), Ministry of
Education of China (985 program, and Grant 20010001027),
and VivoQuest, Inc., through a sponsored research program
is gratefully acknowledged.
We reasoned that the complex formation between AlMe
and substrates 30 or 31 is critical for this stereoselective
3
19
Supporting Information Available: Experimental pro-
outcome. Theoretical calculations indicated that when one
molecule of AlMe coordinates with the bridging oxygen,
1
13
cedure and H NMR and C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
3
the C8-O bond becomes over 0.01 Å longer than the C5-O
bond, and the former is considerably better activated.
Therefore, the methylation reaction is expected to be a Lewis
OL051312F
(19) All quantum mechanics calculations were performed using the
Gaussian 98 program. Geometries were fully optimized with the density
functional method of B3LYP using the 6-31G* basis set, which has been
shown to be reliable for the study of Diels-Alder reactions. Vibration
frequency was determined for each structure to confirm the structure to be
a local minimum or transition state and to derive thermodynamic properties.
(
17) Crimmins, M. T.; Nantermet, P. G. J. Org. Chem. 1990, 55, 4235.
(18) For information regarding the metal-catalyzed ring opening of
oxabridge, see: Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003,
6, 48.
3
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Org. Lett., Vol. 7, No. 17, 2005