A convergent synthesis of the tricyclic architecture of the guanacastepenes featuring a selective ring fragmentation.

Article abstract of DOI:10.1021/ol0259342

[reaction: see text] This Letter describes a concise, diastereoselective synthesis of the tricyclic carbon framework of the guanacastepene family of natural products. An intermolecular Diels-Alder reaction established a remote stereochemical relationship

Full text of DOI:10.1021/ol0259342

ORGANIC
LETTERS
2002
Vol. 4, No. 12
2063-2066
A Convergent Synthesis of the Tricyclic
Architecture of the Guanacastepenes
Featuring a Selective Ring
Fragmentation
William D. Shipe and Erik J. Sorensen*
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
sorensen@scripps.edu
Received March 26, 2002
ABSTRACT
This Letter describes a concise, diastereoselective synthesis of the tricyclic carbon framework of the guanacastepene family of natural products.
An intermolecular Diels−Alder reaction established a remote stereochemical relationship and facilitated a synthesis of allylic acetate 3, which
was subsequently joined with vinylstananne 9 via a Stille coupling. An intramolecular [2 + 2] photocycloaddition then afforded complex
cyclobutyl ketone 19, which underwent a stereoelectronically controlled fragmentation to the guanacastepene architecture on treatment with
samarium diiodide.
Clardy and co-workers recently discovered the structurally
diverse guanacastepene family of secondary metabolites
during an investigation of the endophytic fungus CR115
found in the Guanacaste Conservation Area in Costa Rica.1,2
These diterpenes possess novel carbon skeletons, and several
members have shown promising antibiotic activity against
drug-resistant strains of Staphylococcus aureus and Entero-
coccus faecalis.2,3 As a result, there has been great interest
in the chemical problems posed by the guanacastepenes, and
approaches toward the synthesis of guanacastepene A (1a)
have already been described by the groups of Snider,
Magnus, Danishefsky, Mehta, and Trauner.4
In this Letter, we describe a convergent synthesis of the
[5-7-6] tricyclic ring system of the guanacastepenes based
on the design shown in Scheme 1. We envisioned that a
union of appropriately functionalized five- and six-membered
rings, such as 2 and 3 (P, P′ ) unspecified protecting groups),
could furnish enone 4 and set the stage for an intramolecular
[2 + 2] photocycloaddition.5 If successful, the latter process
would afford a complex tetracyclo[7.5.0.0.1,1103,8]tetradecane
(1) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am. Chem. Soc.
2000, 122, 2116-2117.
(2) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am. Chem. Soc. 2001, 123,
9900-9901.
(3) Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.;
Greenstein, M.; Maiese, W. M. J. Antibiot. 2000, 53, 256-261.
(4) (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,
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) Mehta, G.; Umarye,
J. D. Org. Lett. 2002, 4, 1063-1066. (g) Gradl, S. N.; Kennedy-Smith, J.
J.; Kim, J.; Trauner, D. Synlett 2002, 3, 411-414.
10.1021/ol0259342 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/16/2002

in the one-electron reduction step, the convergent synthetic
design permits easy omission of an R-oxy substituent.
A five-membered ring lacking the isopropyl group and
R-oxygenation found in guanacastepene A (1a) was chosen
to serve as a readily accessible setting in which to test the
proposed photocycloaddition/fragmentation chemistry (Scheme
2). Cyclopentenone 7 was converted to R-iodoenone 8
Scheme 1
Scheme 2a
ring system 5 wherein one of the bonds of the cyclobutane
ring is more conjugated with the ketone carbonyl than the
other. On this basis, we hoped that a transient cyclobutyl-
carbinyl radical produced by a one-electron reduction of the
keto group of 5 would undergo a selective, stereoelec-
tronically favored ring fragmentation to the guanacastepene
[5-7-6] ring framework.6 Rearrangements of cyclobutyl-
carbinyl radicals were described in some of the earliest
reports of radical fragmentations7 and have a broad utility
in synthesis.8 An analysis of molecular models of 5 suggested
that the cyclobutane bond that is exocyclic to the five-
membered ring should be predisposed to fragment owing to
its nearly parallel relationship to the p-orbital of the putative
ketyl radical anion. This expectation is substantiated by
several literature reports.9,10 A noteworthy feature of this type
of ring fragmentation is that it would leave in its wake a
regiodefined enolate ion that could conceivably permit the
controlled introduction of an alkene into the central seven-
membered ring. Should R-deoxygenation prove troublesome
a Reagents: (a) I2, pyridine, CH2Cl2, 0 °C f rt, 18 h, 77%. (b)
Me3SnSnMe3, Pd(PPh3)4 (0.05 equiv), PhH, 80 °C, 3 d, 90%. (c)
H2NOMe‚HCl, pyridine, MeOH, rt, 12 h, 83%.
following the procedure of Johnson.11 A palladium-catalyzed
reaction of 8 with hexamethylditin under the conditions
shown then furnished 9 in good yield.12
Construction of the six-membered ring of the guanacas-
tepenes began from commercially available cyclohexenone
10 (Scheme 3). Formation of the kinetic enolate of 10,
followed by enolate trapping with TMSCl, gave diene 11.13
Diels-Alder reaction of 11 with dimethylacetylenedi-
carboxylate cleanly gave the bridged bicyclic ketone 12 after
acidic hydrolysis of the silyl enol ether. Subsequent Baeyer-
Villiger oxidation was regiospecific and provided lactone 13
as a white solid. This three-step sequence afforded large
quantities of a substance having the appropriate stereochem-
ical relationship and useful functionality for a synthesis of
key intermediate 3.
Acid-catalyzed methanolysis of the bridged lactone was
achieved in quantitative yield, and the resulting hydroxytri-
ester was protected in the form of PMB ether 14. A complete
reduction of the three methyl ester groups with lithium
aluminum hydride produced a triol that was selectively
converted to a mixture of diastereomeric benzylidene acetals
shown as 15. The alkene side chain of 16 was installed by
reaction of the o-nitrophenylselenide derived from alcohol
15 with hydrogen peroxide.14 The diol produced by acid-
catalyzed methanolysis of the benzylidene acetal in 16 was
(5) For a comprehensive review of enone olefin [2 + 2] photochemical
cycloadditions, see: Crimmins, M. T.; Reinhold, T. L. Org. React. 1993,
44, 297-588.
(6) For pioneering studies of reductive ring openings of conjugated
cyclopropyl ketones, see: (a) Norin, T. Acta Chem. Scand. 1965, 19, 1289-
1292. (b) Dauben, W. G.; Deviny, E. J. J. Org. Chem. 1966, 31, 3794-
3798. (c) Dauben, W. G.; Schutte, L.; Wolf, R. E.; Deviny, E. J. J. Org.
Chem. 1969, 34, 2512-2517.
(7) (a) Oldroyd, D. M.; Fisher, G. S.; Goldblatt, L. A. J. Am. Chem.
Soc. 1950, 72, 2407-2410. (b) Dupont, G.; Dulou, R.; Cle´ment, G. Bull.
Soc. Chim. Fr. 1950, 1056-1057. (c) Dupont, G.; Dulou, R.; Cle´ment, G.
Bull. Soc. Chim. Fr. 1950, 1115-1120.
(8) (a) Beckwith, A. L. J. Spec. Publ. Chem. Soc. 1970, 24, 239-269.
(b) Yet, L. Tetrahedron 1999, 55, 9349-9403.
(9) For examples of selective cyclobutyl bond cleavages, see: (a)
Crimmins, M. T.; Mascarella, S. W. Tetrahedron Lett. 1987, 28, 5063-
5066. (b) Ziegler, F. E.; Zheng, Z. J. Org. Chem. 1990, 55, 1416-1418.
(c) Cossy, J.; Aclinou, P.; Bellosta, V.; Furet, N.; Baranne-Lafont, J.; Sparfel,
D.; Souchaud, C. Tetrahedron Lett. 1991, 32, 1315-1316. (d) Crimmins,
M. T.; Dudek, C. M.; Cheung, A. W.-H. Tetrahedron Lett. 1992, 33, 181-
184. (e) Crimmins, M. T.; Wang, Z.; McKerlie, L. A. Tetrahedron Lett.
1996, 37, 8703-8706. (f) Ziegler, F. E.; Kover, R. X.; Yee, N. N. K.
Tetrahedron Lett. 2000, 41, 5155-5159.
(10) For examples of selective cyclopropyl bond cleavages, see: (a)
Stork, G.; Uyeo, S.; Wakamatsu, T.; Grieco, P.; Labovitz, J. J. Am. Chem.
Soc. 1971, 93, 4945-4947. (b) Corey, E. J.; Virgil, S. C. J. Am. Chem.
Soc. 1990, 112, 6429-6431. (c) Batey, R. A.; Motherwell, W. B.
Tetrahedron Lett. 1991, 32, 6649-6652. (d) Kirschberg, T.; Mattay, J.
Tetrahedron Lett. 1994, 35, 7217-7220. (e) Ziegler, F. E.; Zheng, Z. J.
Org. Chem. 1990, 55, 1416-1418.
(11) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917-
918.
(12) (a) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277-279. (b) Scott, W. J.; Stille, J. K. J. Am. Chem.
Soc. 1986, 108, 3033-3040.
(13) Rubottom, G. M.; Gruber, J. M.; Juve, H. D., Jr.; Charleson, D. A.
Org. Synth. 1986, 64, 118-126.
2064
Org. Lett., Vol. 4, No. 12, 2002

Scheme 3a
Scheme 4a
a Reagents: (a) 9, LiCl, Pd2dba3 (0.2 equiv), NMP, 50 °C, 16 h,
87%. (b) hν, diisopropylethylamine (0.25 equiv), Et2O, 3 h, 76%.
(c) SmI2 (2.1 equiv), HMPA, THF, rt, 5 min; then PhSeBr, rt, 5
min, 44%. (d) mCPBA, CH2Cl2, -78 °C, 5 min, 84%. (e) PPTS
(0.25 equiv), CH3CN, H2O, rt, 7 h, 49% of 23 and 45% of 24.
PMP ) p-MeOC6H4.
a Reagents: (a) LDA, TMSCl, THF, -15 °C f rt, 12 h, 98%.
(b) Dimethylacetylenedicarboxylate, THF, 0 °C f rt; then 1 N aq
HCl, 0 °C f rt, 12 h, 99%. (c) mCPBA, NaHCO3, CH2Cl2, rt, 16
h, 96%. (d) CSA (0.07 equiv), MeOH, reflux, 12 h, 100%. (e)
p-Methoxybenzyl trichloroacetimidate, CSA (0.1 equiv), CH2Cl2,
rt, 15 h. (f) LiAlH4, Et2O, 0 °C f rt, 1 h, 87% (over 2 steps). (g)
Anisaldehyde dimethyl acetal, PPTS (0.1 equiv), CH2Cl2, rt, 90
min, 80%. (h) o-Nitrophenylselenocyanate, n-Bu3P, THF, 30 min,
0 °C f rt; then 30% aq H2O2, i-Pr2EtN, 0 f 45 °C, 3 h, 71%. (i)
PPTS (0.25 equiv), MeOH, rt, 3 h, 85%. (j) DDQ, CH2Cl2, rt, 30
min, 69% and 9% starting material. (k) Ac2O, DMAP, pyridine, rt,
10 min, 100%. TMS ) SiMe3; PMP ) p-MeOC6H4; PMB )
CH2C6H4-pOMe.
Having accomplished the desired photocycloaddition, we
were in a position to address the crucial cyclobutane
18
fragmentation. The reduction of ketone 19 with SmI2 in
THF containing HMPA as a cosolvent was attended by the
desired cyclobutane fragmentation and resulted in the forma-
tion of 20 in 72% yield after an aqueous quench. This
favorable outcome invited the possibility of trapping the
putative, regiodefined samarium(III) enolate with a suitable
electrophile10a,c that could facilitate the goal of introducing
a needed alkene into the seven-membered ring. When the
reaction mixture for the samarium-mediated reduction of 19
was treated with phenylselenenyl bromide at room temper-
ature, compound 21 was obtained in 44% yield. Exposure
of 21 to mCPBA smoothly afforded 22, a substance embody-
ing the tricyclic dienone system of the guanacastepenes. To
our knowledge, this is the first reported example of the use
of this type of fragmentation to create the hydroazulene
substructure.19 Acidic hydrolysis of the benzylidene acetal
produced diol 23, which bears much structural similarity to
guanacastepene C (1c). Compound 23 slowly isomerizes to
differentiated in the course of an oxidation with DDQ.15
Finally, allylic acetate 3 was obtained in quantitative yield
by treatment of alcohol 17 with acetic anhydride and a
catalytic amount of DMAP in pyridine.
Palladium-catalyzed π-allyl Stille coupling16 of stannane
9 and allylic acetate 3 proceeded efficiently, furnishing
cycloaddition substrate 18 in 87% yield (Scheme 4). Irradia-
tion of 18 with a 450-W Hanovia medium-pressure mercury
vapor lamp effected the desired intramolecular enone-olefin
[2 + 2] cycloaddition and provided cyclobutyl ketone 19 in
76% yield.17
(14) (a) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976,
41, 1485-1486. (b) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975,
40, 947-949.
(15) Oikawa, Y.; Yoshioka, T.; Yonemitsu, U. Tetrahedron Lett. 1982,
23, 889-892.
(18) For an excellent review, see: Molander, G. A. Org. React. 1994,
46, 211-367.
(19) For application of the intramolecular de Mayo reaction to the
synthesis of the hydroazulene skeleton, see: (a) Begley, M. J.; Mellor, M.
J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1983, 1905-1912. (b)
Seto, H.; Sakaguchi, M.; Fujimoto, Y.; Tatsuno, T.; Yoshioka, H. Chem.
Pharm. Bull. 1985, 33, 412-415.
(16) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(17) The benzylidene acetal of 18 was found to be rather labile to the
photochemical conditions, but this problem was overcome by the addition
of 0.25 equiv of diisopropylethylamine to the reaction mixture prior to
irradiation. Compound 19 was the only diastereomer observed.
Org. Lett., Vol. 4, No. 12, 2002
2065

dihydrofuran 24, a close relative of guanacastepene E (1e),
and this process is accelerated by silica gel.20
In an effort to form the hydroazulenone substructure of
the guanacastepenes directly in the course of the reductive
fragmentation, we performed the chemistry shown in Scheme
5. Oxidation of alcohol 17 with Dess-Martin periodinane
resistant to cleavage but could be hydrolyzed with 1 N HCl.
Interestingly, these conditions gave not the expected epimeric
triols resulting from benzylidene acetal cleavage but rather
dihydrofurans 28. When this mixture was irradiated, one of
the dihydrofuran epimers underwent [2 + 2] cycloaddition
to pentacycle 30 in 25% yield; the other dihydrofuran
diastereomer was recovered unchanged in 48% yield.22 This
product distribution reflects the ratio of stereoisomers formed
in the carbonyl addition step. The constitution and relative
stereochemistry of 30 was confirmed by an X-ray crystal-
lographic analysis of the crystalline derivative methoxime
31.
Scheme 5a
Reasoning that compound 30, a cyclobutyl ketone with a
heteroatom in the â-position, could conceivably undergo a
tandem ring fragmentation/â-elimination sequence in the
presence of reducing metals, we treated it with samarium
diiodide. This reaction, which afforded the interesting
tetracycle 32 as the only isolable product, caused three
changes: a selective, reductive fragmentation of the strained
ring, the desired â-elimination, and a transannular conjugate
addition. This outcome suggests that the desired enone
system exists only transiently in this process.
In this Letter, we described a convergent approach to the
tricyclic architecture of the guanacastepenes featuring an
efficient Stille cross-coupling, a diastereoselective [2 + 2]
photocycloaddition, and a selective fragmentation of a
putative cyclobutylcarbinyl radical. From two five- and six-
membered ring building blocks, this approach can furnish
guanacastepene systems in four steps. Efforts are currently
underway to employ fully functionalized cyclopentenone
derivatives in this chemistry and to accomplish enantio-
selective syntheses of these intriguing, biologically active
diterpenes.
Acknowledgment. We thank Dr. R. Chadha for the X-ray
crystallographic analysis of 31 and Drs. D.-H. Huang and
L. B. Pasternack for NMR spectroscopic assistance. Our
work was supported by The Skaggs Institute for Chem-
ical Biology at TSRI, Merck Research Laboratories, an Eli
Lilly Award, a Beckman Young Investigator Award, an
AstraZeneca Excellence in Chemistry Award, a Camille-
Dreyfus Teacher-Scholar Award, and a predoctoral fellow-
ship from the Skaggs Institute (W.D.S.).
a Reagents: (a) Dess-Martin periodinane, CH2Cl2, 0 °C f rt,
20 min, 100%. (b) 25, t-BuLi, Et2O, -70 °C, 30 min, 78%. (c) 1
N aq HCl, CH3CN, 30 min, 84%. (d) hν, acetone, 2 h, 48% of 29,
25% of 30. (e) SmI2 (3.0 equiv), THF, rt, 20 min, ∼25%. PMP )
p-MeOC6H4.
Supporting Information Available: Characterization
data and experimental procedures for 3, 9, 13, 17-24, 26,
and 32; ORTEP drawing of X-ray structure of 31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
afforded aldehyde 26, which was to serve the role of electro-
phile in a carbonyl addition reaction with the organolithium
reagent derived from iodomethoxime 25 (Scheme 2). In the
event, sequential addition of tert-butyllithium and aldehyde
26 to a solution of 25 in ether at -70 °C resulted in the
formation of a ca. 2:1 mixture of diastereoisomeric alcohols
shown as 27 in 78% yield.21 The methoxime function was
OL0259342
(21) Attempts to add the dioxolane-protected cyclopentenyllithium to 26
using various protocols were unsuccessful.
(20) Thus, flash chromatographic purification of the hydrolysis reaction
yielded both products 23 and 24. Stirring a solution of 23 in Et2O with
silica gel results in the formation of 24. The structure of 24 is supported by
gHMBC, gHSQC, gdqCOSY, and ROESY experiments.
(22) Examination of molecular models indicates that 29 is not confor-
mationally inclined to undergo [2 + 2] photocycloaddition. However, the
epimer giving rise to 30 can easily access the necessary alignment for
cycloaddition.
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Org. Lett., Vol. 4, No. 12, 2002