Regioselective synthesis of the bridged tricyclic core of Garcinia natural products via intramolecular aryl acrylate cycloadditions

Article abstract of DOI:10.1021/ol017278w

(equation presented) Two different routes to the tricyclic core of Garcinia-derived natural products are described. The first approach is based on a tandem Claisen/ Diels-Alder rearrangement and delivers the desired lactone 14. The second approach, employ

Full text of DOI:10.1021/ol017278w

ORGANIC
LETTERS
2002
Vol. 4, No. 6
909-912
Regioselective Synthesis of the Bridged
Tricyclic Core of Garcinia Natural
Products via Intramolecular Aryl
Acrylate Cycloadditions
Eric J. Tisdale, Chinmay Chowdhury, Binh G. Vong, Hongmei Li, and
Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@ucsd.edu
Received December 20, 2001
ABSTRACT
Two different routes to the tricyclic core of Garcinia-derived natural products are described. The first approach is based on a tandem Claisen/
Diels−Alder rearrangement and delivers the desired lactone 14. The second approach, employing a Wessely oxidation/Diels−Alder protocol,
leads to the same caged heterocycle, albeit with modified constitution.
The Guttiferae family of tropical plants, specifically those
of the genus Garcinia, has yielded an abundance of biologi-
cally active and structurally intriguing natural products.1
Among them, morellin (1)2 (Figure 1), produced by Garcinia
morella, is the first known example of a xanthonoid natural
product containing the 4-oxatricyclo[4.3.1.03,7]decan-2-one
scaffold. Since the initial disclosure of morellin’s intriguing
structure, many other natural products sharing the same caged
skeleton have been reported, including morellic acid (2),3
scortechiones A and B4 (3, 4), forbesione5 (5), and gaudi-
chaudione H6 (6) (Figure 1). In addition to their striking
chemical architecture, most of these compounds exhibit
interesting antibacterial activity and cytotoxicity. It has been
postulated that such bioactivity results from the 4-oxatricyclo-
[4.3.1.03,7]decan-2-one moiety as planar xanthones alone do
not show a marked biological profile.6 Undoubtedly, the most
exceptional example of structure and bioactivity in a Garcinia
natural product is that of lateriflorone (7)7 in which the
familiar tricyclic scaffold is attached to an unprecedented
spiroxalactone core.
(1) For selected general references on this topic, see: Ollis, W. D.;
Redman, B. T.; Sutherland, I. O.; Jewers, K. J. Chem. Soc., Chem. Commun.
1969, 879-880. Kumar, P.; Baslas, R. K. Herba Hungarica 1980, 19, 81-
91. Thoison, O.; Fahy, J.; Dumontet, V.; Chiaroni, A.; Riche, C.; Tri, M.
V.; Sevenet, T. J. Nat. Prod. 2000, 63, 441-446.
From the biosynthetic standpoint, these natural products
are presumed to derive from a common benzophenone
intermediate of a mixed shikimate-acetate pathway that has
(2) Rao, B. S. J. Chem. Soc. C 1937, 853-857. Kartha, G.; Ramachan-
dran, G. N.; Bhat, H. B.; Nair, P. M.; Raghavan, V. K. V.; Venkataraman,
K. Tetrahedron Lett. 1963, 4, 459-472.
(6) Cao, S.-G.; Sng, V. H. L.; Wu, X.-H.; Sim, K.-Y.; Tan, B. H. K.;
Pereira, J. T.; Goh, S. H. Tetrahedron 1998, 54, 10915-10924. For related
gaudichaudiones, see: Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K. H.;
Pereira, J. T.; Wong, W. H.; Hew, N. F.; Goh, S. H. Tetrahedron Lett.
1998, 39, 3353-3356. Wu, X.-H.; Tan, B. K. H.; Cao, S.-G.; Sim, K.-Y.;
Goh, S. H. Nat. Prod. Lett. 2000, 14, 453-458.
(3) Karanjgaongar, C. G.; Nair, P. M.; Venkataraman, K. Tetrahedron
Lett. 1966, 7, 687-691.
(4) Rukachaisirikul, V.; Kaewnok, W.; Koysomboon, S.; Phongpaichit,
S.; Taylor, W. C. Tetrahedron 2000, 56, 8539-8543.
(5) Leong, Y.-W.; Harrison, L. J.; Bennett, G. J.; Tan, H. T.-W.; J. Chem.
Res., Synop. 1996, 392-393.
(7) Kosela, S.; Cao, S.-G.; Wu, X.-H.; Vittal, J. J.; Sukri, T.; Masdianto;
Goh, S.-H.; Sim, K.-Y. Tetrahedron Lett. 1999, 40, 157-160.
10.1021/ol017278w CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/16/2002

Li during their pursuit of the total synthesis of forbesione
(5).10
Inspired by the unusual tricyclo[4.3.1.03,7]decan-2-one
scaffold and the biosynthetic issues mentioned above, we
sought to design a general approach to these caged natural
products (Figure 3). The strategy was envisioned to lead
Figure 1. Selected natural products from Garcinia plants.
undergone plant-specific prenylations, rearrangements, and/
or oxidation reactions.8 In 1971, Quillinan and Scheinmann
suggested that the caged scaffold of these molecules arises
in Nature from a tandem Claisen/Diels-Alder rearrangement
(Figure 2).9 Setting out to prove the feasibility of such a
Figure 3. Retrosynthetic analysis of tricyclic fragment 14.
exclusively to the desired structure while allowing the
flexibility to create analogues of the biologically active
portion of the Garcinia-derived caged xanthonoids. With the
C1-oxygenated Garcinia natural products in mind (lateri-
florone numbering), we selected compound 14 because it
mapped onto the variable retrosynthetic target 13 in a
desirable manner. From a retrosynthetic standpoint, the gem-
dimethyl group at the C5 carbon center of 13 was pictured
to arise from an organometallic addition to lactone 14
followed by cyclodehydration.11 The tricyclic structure of
14 could be formed via a Diels-Alder cycloaddition of
intermediate 15, which in turn could arise from either 16 or
17 after a Wessely oxidation12 or a Claisen rearrangement,13
respectively. Both 16 and 17 could be produced from readily
available 2,5-dimethoxybenzaldehyde (18), thereby increas-
Figure 2. Proposed biosynthesis of the caged structures 10 and
12 starting from precursor 8 (see ref 9).
postulate, they heated compound 8 and obtained an isomeric
mixture of Claisen/Diels-Alder adducts 10 and 12. An initial
nonregioselective Claisen rearrangement leads to the forma-
tion of intermediates 9 and 11 and, thus, the mixture of 10
and 12. A similar mixture of isomers, produced via a Claisen/
Diels-Alder reaction, was also reported by Nicolaou and
(8) Bennett, G. J.; Lee, H.-H. J. Chem. Soc., Chem. Commun.1988, 619-
620.
(9) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Chem. Commun. 1971,
966-967.
(10) Nicolaou, K. C.; Li, J.; Angew. Chem., Int. Ed. 2001, 40, 4264-
4268.
(11) Raghavan, S.; Rao, G. S. R. S. Tetrahedron 1994, 50, 2599-2616.
910
Org. Lett., Vol. 4, No. 6, 2002

ing the convergency of both strategies. Herein, we disclose
the results of our studies based on these retrosynthetic
considerations.
The synthesis of the Wessely oxidation/Diels-Alder
precursor 16 is shown in Scheme 1. Commercially available
conjunction with DBU and catalytic copper(II) chloride.15
Under these conditions, ether 21 was produced in consistent
yields of 84%. Lindlar-catalyzed partial hydrogenation16 of
alkyne 21 gave rise to alkene 22, which upon heating at 140
°C produced Claisen adduct 1617 (71% combined yield),
thereby setting the stage for a tandem Wessely oxidation/
Diels-Alder reaction.18 To this end, compound 16 was
treated with Pb(OAc)4 in acrylic acid/dichloromethane and
the resulting intermediate heated in refluxing benzene to
produce tricyclic lactone 24 in 82% combined yield. Crystal-
lographic studies established that 24 was a constitutional
isomer of desired structure 14. The connectivity of compound
24 suggested that during the Wessely oxidation the acrylate
unit was attached exclusively at the C1 center of 16, instead
of the anticipated C3 carbon. This produced diene 23, which
subsequently underwent Diels-Alder cycloaddition with the
pendant dienophile. The outcome of the Wessely oxidation
can be rationalized if we consider that addition at the C1
center is preferred due to the electron-donating effect of the
attached methoxy group. Despite the discrepancy in con-
nectivity, lactone 24 assured us an entry point to the tricyclo-
[4.3.1. 03,7]decan-2-one caged system and suggests that the
outcome of the reaction can be altered by decreasing the
electron-donating effect of the substituent at the C1 carbon
center.
Scheme 1. Synthesis of Lactone 24a
Concurrent with the above studies, we examined the
feasibility of the tandem Claisen/Diels-Alder rearrangement
as an entry point to the 4-oxatricyclo[4.3.1.03,7]decan-2-one
scaffold (Scheme 2). To this end, 2,5-dimethoxybenzalde-
hyde (18) was transformed to alkyne 21, which after a
subsequent Claisen rearrangement in refluxing m-xylene,
produced benzopyran 25 (61% combined yield). Lactol 26
was acquired from pyran 25 in 22% yield by a fairly
consistent three-step protocol involving ozonolysis, a chemo-
selective Baeyer-Villiger oxidation, and basic hydrolysis.
Each step in this string of reactions was carried out on crude
material as purification of the intermediates proved to be
difficult.19 After purification, compound 26 was subjected
to a Wittig olefination protocol to afford phenolic ether 27,20
which upon a straightforward acryloylation produced the
Claisen/Diels-Alder precursor 17 in 93% yield. Heating of
a Reagents and conditions: (a) 1.3 equiv of mCPBA, CH2Cl2, 4
h, 25 °C; (b) 10% NaOH (aq)/MeOH (1:1), 25 °C, 30 min, 97%;
(c) 1.2 equiv of 20, 1.3 equiv of DBU, 0.3 mol % of CuCl2, CH3CN,
0 °C, 24 h, 84%; (d) 10% Pd/BaSO4 (3.2%/weight), quinoline
(3.2%/weight), H2, EtOH, 0.5 h, 89%; (e) m-xylene, 140 °C; 2 h,
80%; (f) 1.2 equiv of Pb(OAc)4, acrylic acid (excess), CH2Cl2, 25
°C, 10 min; (g) PhH, 80 °C, 2 h, 82% (over two steps).
(15) Godfrey, J. D., Jr.; Mueller, R. H.; Sedergran, T. C.; Soundararajan,
N.; Colandrea, V. J. Tetrahedron Lett. 1994, 35, 6405-6408.
(16) Hlubucek, J.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1971, 24,
2355-2363.
2,5-dimethoxybenzaldehyde (18) was subjected to Baeyer-
Villiger oxidation, and the resulting formate ester was
hydrolyzed under basic conditions to produce phenol 19 in
97% yield.14 Various propargylating reagents and conditions
were used to alkylate alcohol 19, among which carbonate
20 was found to give optimum results when used in
(17) Rhoads, S. J.; Raulins, N. R. Organic Reactions; Dauben, W. G.,
Ed.; John Wiley & Sons: New York, 1975; Vol. 22, Chapter 1, pp 1-252.
(18) The tandem Wessely oxidation/Diels-Alder reaction has been
utilized extensively by Yates and co-workers. For selected examples on
this work, see: Bhamare, N. K.; Granger, T.; John, C. R.; Yates, P.
Tetrahedron Lett. 1991, 32, 4439-4442. Bhamare, N. K.; Granger, T.;
Macas, T. S. Yates, P. J. Chem. Soc., Chem. Commun. 1990, 739-740.
Bichan, D. J.; Yates, P. J. Am. Chem. Soc. 1972, 94, 4773-4774. Yates,
P.; Kaldas, M. Can J. Chem. 1992, 70, 2491-2501. Yates, P.; Langford,
G. E. Can J. Chem. 1981, 59, 344-355. Yates, P.; Auksi, H. J. Chem.
Soc., Chem. Commun 1976, 1016-1017. Yates, P.; Auksi, H. Can. J. Chem.
1979, 57, 2853-2863.
(12) Wessely, F.; Sinwell, F. Monatsch. Chem. 1950, 81, 1055. Wessely,
F.; Swoboda, J.; Guth, V. Monatsch. Chem. 1964, 95, 649. Bubb, W. A.;
Sternhell, S. Tetrahedron Lett. 1970, 11, 4499-4502. For recent synthetic
applications of the Wessely oxidation, see: Cox, C.; Danishefsky, S. J.
Org. Lett. 2000, 2, 3493-3496. Feldman, K. S.; Lawlor, M. D. J. Am.
Chem. Soc. 2000, 122, 7396-7397.
(13) Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157. For recent and
selected reviews on Claisen rearrangement, see: Nowicki, J. Molecules 2000,
5, 1033-1050. Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28, 43-50.
Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219-225. Ziegler, F. E. Chem.
ReV. 1988, 88, 1423-1452. Wipf, P. In ComprehensiVe Organic Syntheses;
Trost, B. M., Fleming, I., Eds.; 1991; Vol. 5, p 827.
(19) Both the ozonolysis and the Baeyer-Villiger oxidation reactions
tended to be clean. This led to the conclusion that hydrolysis of the
intermediate formate ester to lactol 26 was the bottleneck of this protocol.
Attempts were made to optimize the reaction sequence, particularly the
hydrolysis, but little ground could be gained.
(20) Wittig olefination of the pendant aldehyde was also attempted prior
to hydrolysis of the formate ester. This change in reaction sequence,
however, did not change overall product yields.
(14) Wriede, U.; Fernandez, M.; West, K. F.; Harcourt, D.; Moore, H.
W. J. Org. Chem. 1987, 52, 4485-4489.
Org. Lett., Vol. 4, No. 6, 2002
911

Compound 14 was crystalline, and X-ray diffraction
studies revealed that it possessed the desired connectivity
across the central tetrahydrofuran core. The remarkably
efficient and regioselective Claisen/Diels-Alder process
owes much of its success to the reversibility of the Claisen
rearrangement. While the R,R-dimethylallyl substituent of
17 can migrate and, thus, prenylate either of two adjacent
positions, only the desired isomeric intermediate 15 (see
Figure 3) adopts a geometry that allows it to be trapped as
the Diels-Alder adduct. Consequently, all the available
starting material eventually funnels through the desired
mechanistic pathway to generate the preferred adduct 14.
Scheme 2. Synthesis of Tricyclic Lactone 14a
In conclusion, we have demonstrated, using two different
methods, the ability to access the 4-oxatricyclo[4.3.1.03,7]-
decan-2-one scaffold encountered in many of the Garcinia-
derived natural products. Both strategies are very efficient
and afford the tricyclic structures with excellent regiocontrol.
The tandem Claisen/Diels-Alder strategy proceeds in 10
steps (from aldehyde 18) and produces the desired tricyclic
scaffold 14. The efficiency of the Claisen/Diels-Alder
rearrangement presented here allows access to the desired
natural product scaffold in a high-yielding and predictable
process. In contrast, the alternative sequence of Wessely
oxidation/Diels-Alder reaction gives rise to isomeric struc-
ture 24, whose application to the synthesis of the above
natural products should await some fine-tuning, especially
as related to the electronic effects of the substituents of the
aromatic ring. Nonetheless, adduct 24 may be useful for the
preparation and biological investigation of nonnatural ana-
logues of the above natural products.
a Reagents and conditions: (a) 1.3 equiv of mCPBA, CH2Cl2, 4
h, 25 °C; (b) 10% NaOH (aq)/MeOH (1:1), 25 °C, 30 min, 97%;
(c) 1.2 equiv of 20, 1.3 equiv of DBU, 0.3 mol % of CuCl2, CH3CN,
0 °C, 24 h, 84%; (d) m-xylene, 140 °C, 2 h, 74%; (e) O3, CH2Cl2,
-78 °C, 30 min, then DMS, 30 min; (f) 1.3 equiv of mCPBA,
CH2Cl2, 25 °C, 4 h; (g) 10% NaOH (aq)/MeOH (1:1) 30 min, 25
°C, 22% (over three steps); (h) 5.0 equiv of H3CPPh3Br, 4.6 equiv
of NaHMDS, THF (inverse addition), 25 °C, 2 h, 65%; (i) 1.1 equiv
of acryloyl chloride, 1.2 equiv of TEA, 0.1 equiv of DMAP, CH2Cl2,
0 °C, 1 h, 93%; (j) m-xylene, 140 °C, 45 min, 92%.
Acknowledgment. Financial support from the NIH
(CA086079) is gratefully acknowledged. We thank Dr. P.
Gantzel (UCSD, X-ray Facility) for the reported crystal-
lographic structures. We also thank the Department of
Education for a GAANN Fellowship to B.G.V.
Supporting Information Available: 1H and 13C NMR
spectra available for compounds 14, 16, 17, 22, 24, 26, and
27. Experimental procedures, spectroscopic, and analytical
and X-ray data for compounds 14 and 24. This material is
available free of charge via the Internet at http://pubs.acs.org.
17 in boiling m-xylene allowed the tandem Claisen/Diels-
Alder to take place, thereby producing tricyclic structure 14
in a remarkably efficient process (92% overall yield).
OL017278W
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Org. Lett., Vol. 4, No. 6, 2002