An electrochemical approach to the guanacastepenes

Article abstract of DOI:10.1021/ol047387l

(Chemical Equation Presented) An asymmetric approach toward the [6-7-5] ring system of the guanacastepenes is described.

Full text of DOI:10.1021/ol047387l

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3425-3428
An Electrochemical Approach to the
Guanacastepenes
Chambers C. Hughes, Aubry K. Miller, 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 December 20, 2004 (Revised Manuscript Received May 27, 2005)
ABSTRACT
An asymmetric approach toward the [6−7−5] ring system of the guanacastepenes is described.
The guanacastepenes are a family of diterpenes sharing a
common carbon skeleton that has been modified through
various oxidations. Their simpler members, for instance,
guanacastepene A and C, feature a tricyclic ring system with
a highly oxidized “lower” and an unfunctionalized “upper
rim” (Figure 1). Several more complex congeners, such as
guanacastepenes E, I, K, and L, have been isolated that
contain additional dihydrofuran or furanone moieties.
Guanacastepene A has received considerable attention by
the synthetic community due to its interesting antibiotic
activity and attractive molecular structure. In addition to
Danishefsky’s total synthesis, more than 10 distinct synthetic
approaches toward the molecule have been reported, includ-
ing two formal syntheses.1 However, the asymmetric total
synthesis of a guanacastepene has not yet been disclosed.
In previous communications, we have outlined a conver-
gent synthetic strategy that hinges on the closure of the
central seven-membered ring at a late stage (Scheme 1).2 It
also calls for the combination of two enantiomerically pure
(1) (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) Mandal, M.; Danishefsky, S. J.
Tetrahedron Lett. 2004, 45, 3827. (k) Mandal, M.; Danishefsky, S. J.
Tetrahedron Lett. 2004, 45, 3831. (l) Mehta, G.; Umarye, J. D. Org. Lett.
2002, 4, 1063. (m) Mehta, G.; Umarye, J. D.; Gagliardini, V. Tetrahedron
Lett. 2002, 43, 6975. (n) Mehta, G.; Umarye, J. D.; Srinivas, K. Tetrahedron
Lett. 2003, 44, 4233. (o) Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4,
2063. (p) Nguyen, T. M.; Lee, D. Tetrahedron Lett. 2002, 43, 4033. (q)
Nguyen, T. M.; Seifert, R. J.; Mowrey, D. R.; Lee, D. Org. Lett. 2002, 4,
3959. (r) Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363.
(s) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. (t) Boyer,
F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817. (u) Du, X.; Chu, H.
V.; Kwon, O. Org. Lett. 2003, 5, 1923. (v) Du, X.; Chu, H. V.; Kwon, O.
Tetrahedron Lett. 2004, 45, 8843. (w) Brummond, K. M.; Gao, D. Org.
Lett. 2003, 5, 3491. (x) Srikrishna, A.; Dethe, D. H. Org. Lett. 2004, 6,
165. (y) Chiu, P.; Li, S. Org. Lett. 2004, 6, 613.
Figure 1. Selected guanacastepenes.
10.1021/ol047387l CCC: $30.25
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bromide in the presence of catalytic amounts of copper(I)
then yielded a single diastereomer,4 which upon treatment
with acid underwent elimination to furnish compound 4 in
90% ee. Presumably, this loss in enantiomeric purity results
from the reversible acid-catalyzed isomerization of the
cyclopentenone to the achiral â,γ-unsaturated ketone.
Cyclopentenone 4 was subsequently treated with Me2CuLi
in the presence of chlorotrimethylsilane (TMSCl), and the
resulting enol ether was subjected to Saegusa oxidation to
form 5 in good overall yield.5 Reaction of the lithium enolate
with the camphor-based oxaziridine developed by Davis gave
acyloin 6.6,7 Notably, both enantiomers of the oxaziridine
produced, exclusively, the trans diastereomer, indicating that
the diastereoselectivity of the process is entirely controlled
by the substrate. Finally, protection of the secondary alcohol
furnished silyl ether 7.
Scheme 1. Retrosynthetic Analysis of ent-Guanacastepene A
building blocks, 1 and 2, representing the A and C rings of
the guanacastepenes. Following a diastereoselective conju-
gate addition of organometallic compound 1 to cyclopen-
tenone 2, the central B ring would be closed along the bond
indicated in Scheme 1. While the initially envisioned
rhodium-based ring closure has not yet transpired (see
below), the remarkable synthetic versatility of the furan
moiety allowed us to forge the guanacastepene skeleton in
another way. Concomitantly, the focus of our program has
shifted toward the more complex tetracyclic guanacastepenes,
such as guanacastepenes E and I. We now wish to report
the synthesis of an advanced precursor of these targets, which
contains the entire carbon skeleton of the guanacastepenes.
For practical reasons, this study was conducted in the
nonnatural enantiomeric series.
The trans configuration of the chiral cyclopentenone was
confirmed with an X-ray crystal structure of compound 8
(Figure 2), formed via acylation of the free alcohol with
p-nitrobenzoyl chloride.
Starting with enantiopure alcohol 3, a multigram synthesis
of a chiral cyclopentenone corresponding to 2 was developed
in our laboratories (Scheme 2). This alcohol, readily obtained
Figure 2. X-ray structure of compound 8.
Scheme 2a
A synthetic route to the “left-hand” fragment (1), which
we have described previously,2 begins with 2,3-diiodofuran
(9, Scheme 3).8 Addition of the lithiated furan to aldehyde
109 and oxidation furnished the furyl ketone. Enantioselective
reduction of this material was achieved using (+)-B-
chlorodiisopinocampheylborane (DIP-Cl) to give 11 in 94%
ee. The six-membered ring was then formed via intra-
(3) (a) Deardorff, D. R.; Myles, D. C. Organic Syntheses; Wiley &
Sons: New York, 1993; Collect. Vol. 8, p 13. (b) Deardorff, D. R.;
Windham, C. Q.; Craney, C. L. Organic Syntheses; Wiley & Sons: New
York, 1998; Collect. Vol. 9, p 487.
(4) (a) Patterson, J. W., Jr.; Fried, J. H. J. Org. Chem. 1974, 39, 2506.
(b) Suzuki, M.; Kawagishi, T.; Yanagisawa, A.; Suzuki, T.; Okamura, N.;
Noyori, R. Bull. Chem. Soc. Jpn. 1988, 61, 1299.
(5) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(6) (a) Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083. (b)
Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carrol, P. J. J. Am.
Chem. Soc. 1988, 110, 8477.
a Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 °C, 94%; (b) (1) i-PrMgBr, CuBr‚DMS, HMPA, TMSCl, THF,
-78 °C f -40 °C, (2) CSA, H2O, CH2Cl2, reflx., 63%; (c) (1)
Me2CuLi, TMSCl, Et2O, -40 °C, (2) Pd(OAc)2, MeCN, rt, 70%;
(d) LDA, THF, -78 °C, then (1R)-(-)-(10-camphorsulfonyl)-
oxaziridine, -30 °C, 85%; (e) TBSCl, imid., DMF, rt, 93%; (f)
p-NO2C6H4COCl, Et3N, DMAP, CH2Cl2, reflx., 79%.
(7) None of the desired material was obtained upon reacting the enolate
with 2-(phenylsulfonyl)-3-phenyloxaziridine, described in (a) Davis, F. A.;
Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org. Chem. 1984, 49, 3241.
A known side product of this reaction, which we observed as well, is formed
from addition of the enolate to the sulfonimine. See: (b) Davis, F. A.; Wei,
J.; Sheppard, A. C.; Guberick, S. Tetrahedron Lett. 1987, 28, 5115. (c)
Smith, A. B., III; Dorsey, B. D.; Ohba, M.; Lupo, A. T., Jr.; Malamas, M.
S. J. Org. Chem. 1988, 53, 4314.
from the achiral diacetate using an electric eel acetyl-
cholineesterase (EEAC),3 was first oxidized to the cyclo-
pentenone. Conjugate addition of isopropyl-magnesium
(2) (a) Gradl, S. N.; Kennedy-Smith, J. J.; Kim, J.; Trauner, D. Synlett
2002, 411. (b) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett.
2003, 5, 4113.
(8) Kraus, G. A.; Wang, X. Synth. Commun. 1998, 28, 1093.
(9) Ho, N.; le Noble, W. J. J. Org. Chem. 1989, 54, 2018.
3426
Org. Lett., Vol. 7, No. 16, 2005

Scheme 3a
a Reagents and conditions: (a) n-BuLi, Et2O, -78 °C, then 10, 62%; (b) Dess-Martin periodinane, CH2Cl2, rt, 88%; (c) (+)-DIP-Cl,
THF, -20 °C, 75%; (d) Pd(OAc)2, Et3N, (n-Bu)4NBr, MeCN, H2O, 75 °C, 75%; (e) TBDPSCl, imid., DMAP, CH2Cl2, 0 °C, 98%; (f) (1)
9-BBN, THF, reflx., (2) EtOH, NaOH, H2O2, rt, 81%; (g) I2, PPh3, imid., THF, 0 °C f rt, 90%; (h) t-BuLi, Et2O, -78 °C, then (2-
thienyl)Cu(CN)Li, THF, then 7, BF3‚OEt2, -40 °C, 50%.
molecular Heck reaction to yield a 5.1:1 mixture of dia-
stereomers.10 Finally, in three steps, the major diastereomer
12 was further elaborated to iodide 13.
transformation either directly16 or with several R-acylated
derivatives of 14. The reaction suffers, presumably, from the
steric congestion afforded by the adjacent quaternary carbon
center.
The two fragments were then coupled through a challeng-
ing cuprate conjugate addition (see Scheme 3).11 In this event,
lithiation of iodide 13 was followed by treatment with lithium
2-thienylcyanocuprate.12 The resulting mixed, higher-order
heterocuprate was treated with cyclopentenone 7 in the
presence of boron trifluoride diethyl etherate (BF3‚OEt2) to
furnish 14. Similar yields were achieved with the Gilman
cuprate derived from copper(I) iodide and 3,3-dimethyl-
butyne as the dummy ligand.13 Again, the use of BF3‚OEt2
was indispensable for efficient addition of this cuprate to
the hindered cyclopentenone. Unfortunately, the additive
precluded interception of the enolate as the silyl enol ether.
Encouraged by previous model studies, we next sought
to unravel the furan in 14 and form the central seven-
membered ring via a rhodium-catalyzed cyclopropanation/
rearrangement reaction.14 Our efforts toward the elaboration
of 14 to the required diazo ketone 15, however, were met
with little success.15 Using various sulfonyl azides as diazo
transfer reagents, we were unable to effect the desired
The difficulty associated with making diazo compound 15
led us to consider alternatives for forming the central seven-
membered ring. We realized that coupling of the nucleophilic
furan to the enol form of the cyclopentanone moiety would
require some form of “umpolung”, most easily achieved by
oxidation of one of these components to the corresponding
radical cation. To this end, we turned our attention toward
the electrooxidative coupling of silyl enol ethers and furans.
This methodology, developed by the groups of Moeller17a,b
and Wright,17c-e has been used in the preparation of several
annulated furans, including a key intermediate in the
synthesis of the natural product (-)-alliacol A.17b Very
recently, Wright showed that a gem-dialkyl effect is required
for the efficient formation of seven-membered rings,18
rendering our system ideal for the implementation of this
methodology.
Formation of the kinetic enolate of ketone 14 in the
presence of tert-butyldimethylsilyl triflate (TBSOTf) cleanly
gave silyl enol ether 16 (Scheme 4). This material was then
dissolved in a dichloromethane/methanol mixture and sub-
(10) (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. Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: Weinheim, Germany,
1998; Chapter 6, p 231.
(11) Ibuka, T.; Yamamoto, Y. Organocopper Reagents: A Practical
Approach; Taylor, R. J. K., Ed.; Oxford University Press: Oxford, 1994;
Chapter 7, p 143.
(15) (a) Regitz, M. Synthesis 1972, 351. (b) Regitz, M.; Maas, G. Diazo
Compounds: Properties and Synthesis; Academic Press: Orlando, FL, 1986;
Chapter 13, p 326. (c) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998; Chapter 1, p 1.
(16) For example, see: Evans, D. A.; Britton, T. C.; Ellman, J. A.;
Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011.
(12) (a) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.
1987, 28, 945. (b) Lipshutz, B. H. Synthesis 1987, 325.
(13) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210.
(14) (a) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1986,
51, 5036. (b) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1989,
54, 299. (c) Wenkert, E.; Guo, M.; Pizzo, F.; Ramachandran, K. HelV. Chim.
Acta 1987, 70, 1429. (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.
(17) (a) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2003, 125, 36.
(b) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2004, 126, 9106. (c)
Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Frey, D. A.
Org. Lett. 1999, 1, 1535. (d) Whitehead, C. R.; Sessions, E. H.; Ghiviriga,
I.; Wright, D. L. Org. Lett. 2002, 4, 3763. (e) Sperry, J. B.; Whitehead, C.
R.; Ghiviriga, I.; Walczak, R. M.; Wright, D. L. J. Org. Chem. 2004, 69,
3726. For a review of anodic electrochemistry, see: (f) Moeller, K. D.
Tetrahedron 2000, 56, 9527.
(18) Sperry, J. B.; Wright, D. L. J. Am. Chem. Soc. 2005, 127, 8034.
Org. Lett., Vol. 7, No. 16, 2005
3427

Scheme 4a
a Reagents and conditions: (a) LDA, TBSOTf, THF, HMPA -78 °C, 93%; (b) RVC anode (0.2 mA), 2,6-lutidine, 0.06 M LiClO4, 20%
MeOH in CH2Cl2, rt, 17 h, 2.44 F/mol, 70%; (c) HCl, H2O, THF, rt, 85%.
jected to anodic oxidation at constant current using a
reticulated vitreous carbon (RVC) anode and a platinum
cathode. Under these carefully optimized conditions, acetal
17 was formed in good yield and as a single diastereomer.
Note that 17, whose stereochemistry was fully assigned by
detailed nOe measurements, corresponds to guanacastepenes
E and I. Acetal 17, which was stable to silica gel chroma-
tography, could be further reacted with aqueous acid to form
the corresponding furan 18. The relative stereochemistry of
this advanced intermediate was also confirmed by 2D
NOESY experiments, as a strong correlation was observed
between the R and R′ protons of the C ring (see Scheme 4).
In summary, we have procured the tricyclic framework
found in the guanacastepene family of natural products using
an electric eel esterase-catalyzed saponification, several
conjugate additions, and an electrochemical oxidation as key
steps. Current work in our laboratories is devoted to the
elaboration of either acetal 17 or furan 18 to one of the
guanacastepenes and the development of other cyclopenten-
one building blocks corresponding to 2. Alternative methods
of installing the R-diazo group onto ketone 14, and so
accessing other members of the guanacastepene family via
rhodium-catalyzed cyclopropanation/rearrangement, are also
being explored.
Acknowledgment. We thank Prof. Kevin Moeller for his
invaluable advice and encouragement and Dr. Frederick J.
Hollander and Dr. Allen G. Oliver for the crystal structure
determination of compound 8. Special thanks to Andy Malec
(Majda group, UC Berkeley) for help with the potentiostat.
This work was supported by the ACS Petroleum Research
Fund (PRF No. 37520-AC1). A.K.M. was supported by an
NSF predoctoral fellowship. Financial support by Merck &
Co. is also gratefully acknowledged.
Supporting Information Available: Spectroscopic and
analytical data for compounds 4-7, 13, 14, 16, 17, and 18.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL047387L
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Org. Lett., Vol. 7, No. 16, 2005