Synthetic Studies toward the Guanacastepenes

Article abstract of DOI:10.1021/ol035559t

(Equation presented) An asymmetric approach toward the [6-7] ring system of the guanacastepenes is described.

Full text of DOI:10.1021/ol035559t

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4113-4115
Synthetic Studies toward the
Guanacastepenes
Chambers C. Hughes, Joshua J. Kennedy-Smith, and Dirk Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California-Berkeley, Berkeley, California 94720
trauner@cchem.berkeley.edu
Received August 19, 2003
ABSTRACT
An asymmetric approach toward the [6−7] ring system of the guanacastepenes is described.
The guanacastepenes are a family of structurally diverse
diterpenes isolated from an unidentified endophytic fungus
found in the Guanacaste Conservation Area of Costa Rica
(Figure 1).1 Some members, such as guanacastepene A,
display potent antibiotic activity against drug-resistant strains
of Staphylococcus aureus and Enterococcus faecalis. In light
of their reported hemolytic activity, however, the potential
of the guanacastepenes as lead compounds for drug develop-
ment remains to be seen.
Our synthetic strategy calls for the combination of two
enantiomerically pure building blocks, 1 and 2, representing
the six- and five-membered rings of the guanacastepenes.
Subsequently, the central seven-membered ring would be
closed along the bond indicated in Scheme 1. Cyclopenten-
one 2 has been previously obtained in racemic form through
ring-closing metathesis.2m,3 We now report the asymmetric
synthesis of furanocyclohexanol 1 and describe our first
forays into the formation of the seven-membered ring.
The synthesis starts with known 2,3-diiodofuran (3,
Scheme 2).4 Monolithiation of this compound at low tem-
perature5 followed by addition of the organolithium species
Architecturally, the natural products are marked by a
highly unsaturated and oxygenated lower rim and a nonpolar
upper half. Their common carbocyclic [6-7-5] core con-
tains two quaternary stereocenters in a 1,4-relationship and
is often fused to additional heterocycles.
Since the disclosure of their structures by Clardy et al.,
numerous synthetic approaches to the guanacastepenes have
surfaced in the literature.2 In 2002, Danishefsky reported
the total synthesis of racemic guanacastepene A2h,i using
a synthetic route that was subsequently intercepted at a
late stage by Snider.2c Alternative approaches have been
reported by the groups of Magnus,2d,e Mehta,2j-l Sorensen,2n
Lee,2o,p Tius,2q Hanna,2r and Kwon.2s The asymmetric total
synthesis of a guanacastepene, however, has not yet been
disclosed.
(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. (c) Singh, M. P.; Janso, J. E.; Luckman, S.
W.; Brady, S. F.; Clardy, J.; Greenstein, M.; Maiese, W. M. J. Antiobiot.
2000, 53, 256.
Figure 1. Selected guanacastepenes.
10.1021/ol035559t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/08/2003

Scheme 1. Retrosynthetic Analysis of Guanacastepene A
Scheme 2 a
to (E)-4-methylhex-4-enal6 and oxidation furnished furyl
ketone 4.2m Enantioselective reduction of this material was
achieved by using (-)-B-chlorodiisopino-campheylborane
(DIP-Cl) in 94% ee. The absolute configuration was assigned
by analogy with literature precedence.7
The six-membered ring was formed via intramolecular
Heck reaction,8 using the method described by Jeffery.9
Under optimized conditions, alcohol 5 cyclized to give an
inseparable 5.1:1 mixture of 1 and its diastereomer 6 in good
yield. Protection of the secondary alcohol followed by
hydroboration/oxidation gave a mixture of diastereomeric
primary alcohols from which the major isomer 8 could be
separated by column chromatography.10
The relative configuration of alcohol 7 was elucidated via
extensive NMR studies as well as an X-ray structure of diol
8 (Figure 2), formed by desilylation of 7.
The favorable diastereoselectivity of the intramolecular
Heck reaction was found to be dependent on the presence
a Reagents and conditions: (a) n-BuLi, Et2O, -78 °C, then (E)-
4-methylhex-4-enal, 62%; (b) DMP, CH2Cl2, rt, 88%; (c) (-)-DIP-
Cl, THF, -20 °C, 75%; (d) Pd(OAc)2, Et3N, (n-Bu)4NBr, MeCN,
H2O, 75 °C, 83%; (e) TBDPSCl, imid., DMAP, CH2Cl2, 0 °C, 98%;
(f) (1) 9-BBN, THF, reflx., (2) EtOH, NaOH, H2O2, rt, 81%; (g)
HF‚pyr., pyr., THF, rt, 54%.
of the free secondary hydroxy group in 5. Protected versions
of 5 cyclized with decreased or inverted selectivity (Scheme
3). Similar observations concerning the directing effect of a
nearby functional group have been made by Overman in the
context of a total synthesis of gelsemine.11
Several methods can be envisaged to unravel the furan
and form the central seven-membered ring. A particularly
attractive one involving the rhodium-catalyzed decomposition
of a furyl diazo ester is shown in Scheme 4.
The reaction between carbenoids derived from diazocar-
bonyl compounds and furans provides rapid entry into 2,4-
diene-1,6-dicarbonyl systems. Intramolecular versions have
been described by Wenkert, Padwa, and Davies.12 To the
best of our knowledge, applications of this chemistry in the
synthesis of complex natural products have not yet been
described.
(2) (a) Snider, B. B.; Shi, B. Tetrahedron Lett. 2001, 42, 9123. (b) Snider,
B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569. (c) Shi, B.; Hawryluk, N.
A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030. (d) Magnus, P.; Waring,
M. J.; Ollivier, C.; Lynch, V. Tetrahedron Lett. 2001, 42, 4947. (e) Magnus,
P.; Ollivier, C. Tetrahedron Lett. 2002, 43, 9605. (f) Dudley, G. B.;
Danishefsky, S. J. Org. Lett. 2001, 3, 2399. (g) Dudley, G. B.; Tan, D. S.;
Kim, G.; Tanski, J. M.; Danishefsky, S. J. Tetrahedron Lett. 2001, 42, 6789.
(h) Tan, D. S.; Dudley, G. B.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2002, 41, 2185. (i) Lin, S.; Dudley, G. B.; Tan, D. S.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2002, 41, 2188. (j) Mehta, G.; Umarye, J. D. Org.
Lett. 2002, 4, 1063. (k) Mehta, G.; Umarye, J. D.; Gagliardini, V.
Tetrahedron Lett. 2002, 43, 6975. (l) Mehta, G.; Umarye, J. D.; Srinivas,
K. Tetrahedron Lett. 2003, 44, 4233. (m) Gradl, S. N.; Kennedy-Smith, J.
J.; Kim, J.; Trauner, D. Synlett 2002, 411. (n) Shipe, W. D.; Sorensen, E.
J. Org. Lett. 2002, 4, 2063. (o) Nguyen, T. M.; Lee, D. Tetrahedron Lett.
2002, 43, 4033. (p) Nguyen, T. M.; Seifert, R. J.; Mowrey, D. R.; Lee, D.
Org. Lett. 2002, 4, 3959. (q) Nakazaki, A.; Sharma, U.; Tius, M. A. Org.
Lett. 2002, 4, 3363. (r) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43,
7469. (s) Du, X.; Chu, H. V.; Kwon, O. Org. Lett. 2003, 5, 1923.
(3) Efforts to render the RCM enantiotopos-selective have thus far met
with limited success.
(4) Kraus, G. A.; Wang, X. Synth. Commun. 1998, 28, 1093.
(5) Gorzynski, M.; Rewicki, D. Liebigs Ann. Chem. 1986, 625.
(6) Ho, N.; le Noble, W. J. J. Org. Chem. 1989, 54, 2018.
(7) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539.
(8) (a) Kwon, O.; Su, D.-S.; Meng, D.; Deng, W.; D’Amico, D. C.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1880. For reviews,
see: (b) Link, J. T.; Overman, L. E. In Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: Weinheim, Germany,
1998; Chapter 6, pp 231-269. (c) Dounay, A. B.; Overman, L. E. Chem.
ReV. 2003, 103, 2945.
(9) Jeffery, T. Tetrahedron 1996, 52, 10113.
(10) The 9-BBN adduct was also found to readily engage in Suzuki
couplings.
Figure 2. X-ray structure of compound 8.
Org. Lett., Vol. 5, No. 22, 2003
4114

Scheme 3 a
Scheme 4a
a Reagents and conditions: (a) TBSCl, imid., DMAP, CH2Cl2,
rt, 98%; (b) (1) NaH, THF, 0 °C, (2) MeI, 72%; (c) Pd(OAc)2,
Et3N, (n-Bu)4NBr, MeCN, H2O, 75 °C.
In our model study for a synthesis of guanacastepene A,
alcohol 713 was converted into homologated aldehyde 11 with
use of a standard sequence of steps. The DBU-catalyzed
addition of ethyl diazoacetate to this aldehyde then afforded
12.14 Since direct oxidation of 12 to diazoester 13 was met
with difficulties, the compound was first treated with rhodium
acetate to give the corresponding â-ketoester. Diazo transfer
with p-acetamidobenzenesulfonyl azide (p-ABSA) then
furnished 13. Finally, exposure of 13 to rhodium acetate led
to formation of aldehyde 15 in 50% unoptimized yield. This
reaction presumably proceeds through intermediate 14, which
could exist as a cyclopropane derivative or as a zwitterionic
structure.12g Note that the product 15 includes the entire
unsaturated lower half of the guanacastepenes and the fully
substituted cyclohexene ring.
a Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 °C, 91%; (b) MePPh3Br, n-BuLi, THF, 0 °C, 95%; (c) (1)
9-BBN, THF, rt, (2) EtOH, NaOH, H2O2, rt, 92%; (d) (COCl)2,
DMSO, Et3N, CH2Cl2, -78 °C; (e) ethyl diazoacetate, DBU (cat.),
MeCN, rt, 76% (two steps); (f) Rh2(OAc)4, CH2Cl2, rt, 95%; (g)
p-ABSA, Et3N, MeCN, rt, 92%; (h) Rh2(OAc)4, CH2Cl2 (0.002 M),
rt, 50%.
efficient linkage of the two segments. Total syntheses of
enantiomerically pure guanacastepenes are well underway
in our laboratories and will be reported in due course.
In summary, we have demonstrated that the central seven-
membered ring of the guanacastepenes can be established
through intramolecular reaction between a carbenoid and a
furan. Though the synthesis of diazoester 13 could certainly
be streamlined, the focus of future investigations will lie in
the procurement of enantiomerically pure enone 2 and the
Acknowledgment. We thank Dr. Frederick J. Hollander
and Dr. Allen G. Oliver for the crystal structure determination
of compound 8. This work was supported by the ACS
Petroleum Research Fund (PRF No. 37520-AC1). Financial
support by Merck & Co. is also gratefully acknowledged.
(11) Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33, 4859.
(12) (a) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1986,
51, 5036. (b) Wenkert, E.; Guo, M.; Pizzo, F.; Ramachandran, K. HelV.
Chim. Acta 1987, 70, 1429. (c) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J.
Org. Chem. 1989, 54, 299. (d) Wenkert, E.; Decorzant, R.; Na¨f, F. HelV.
Chim. Acta 1989, 72, 756. (e) Wenkert, E.; Guo, M.; Lavilla, R.; Porter,
B.; Ramachandran, K.; Sheu, J.-H. J. Org. Chem. 1990, 55, 6203. (f) Davies,
H. M. L.; McAfee, M. J.; Oldenburg, C. E. M. J. Org. Chem. 1989, 54,
930. (g) Davies, H. M. L.; Calvo, R. L. Tetrahedron Lett. 1997, 38, 5623.
(13) For the sake of convenience and cost, racemic material was
elaborated in the subsequent steps.
Supporting Information Available: Spectroscopic and
analytical data for compounds 1, 3-7, 11-13, and 15, as
well as X-ray structural data of compound 8 (CCDC-
219930). This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285.
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