Regioselective synthesis of the tricyclic core of lateriflorone

Article abstract of DOI:10.1021/ol034276y

(Matrix presented) An efficient synthetic approach to the tricyclic core 8 of lateriflorone is described. Essential to the synthesis was the implementation of a biomimetic tandem Claisen/Diels-Alder reaction that produced the desired tricyclic scaffold as a single isomer. A rationalization of the excellent regio and stereoselectivity of this transformation is also proposed.

Full text of DOI:10.1021/ol034276y

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1491-1494
Regioselective Synthesis of the Tricyclic
Core of Lateriflorone
Eric J. Tisdale, Hongmei Li, Binh G. Vong, Sun Hee Kim, and
Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@chem.ucsd.edu
Received February 17, 2003
ABSTRACT
An efficient synthetic approach to the tricyclic core 8 of lateriflorone is described. Essential to the synthesis was the implementation of a
biomimetic tandem Claisen/Diels−Alder reaction that produced the desired tricyclic scaffold as a single isomer. A rationalization of the excellent
regio and stereoselectivity of this transformation is also proposed.
Plants of the genus Garcinia (Guttiferae) are encountered
largely in the tropical rainforests of Indo China, Malaysia,
and Borneo and have been used in traditional medicine for
their wound healing, antibacterial, and cytotoxic activities.1
Efforts to isolate and structurally identify the bioactive
components of these plants have led to a new family of caged
xanthonoids that include morellin (1),2 morellic acid (2),3
scortechinones A and B (3, 4),4 1-O-methylneobractatin (5),5
and lateriflorone (6)6 (Figure 1). The chemical structure of
these natural products is distinguished by the presence of a
remarkable 4-oxa-tricyclo[4.3.1.03,7]decan-2-one scaffold, in
which a highly substituted tetrahydrofuran core with three
quaternary carbon centers is featured. This uncommon caged
structure constitutes an intriguing synthetic target and may
account for the reported biological activities.7 An additional
level of architectural complexity is found in the structure of
lateriflorone (6), in which the tricyclic motif is attached to
an unprecedented spiroxalactone core.
From a biosynthetic point of view,8 the caged scaffold of
these natural products is presumed to derive from a tandem
Claisen/Diels-Alder rearrangement,9,10 implying polypre-
nylated aromatic rings as plausible biosynthetic precursors.
Moreover, two related biosynthetic scenarios were proposed
for the unique spiroxalactone core of lateriflorone (6). The
first is based on an oxidative rearrangement of a xanthone
precursor, while the second rests upon condensation of two
(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.
(7) 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.
(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.
(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.
(8) Bennett, G. J.; Lee, H.-H. J. Chem. Soc., Chem. Commun. 1988, 619-
620. Roberts, J. C. Chem. ReV. 1961, 61, 591-605.
(5) Thoison, O.; Fahy, J.; Dumontet, V.; Chiaroni, A.; Riche, C.; Tri,
M. V.; Se´venet, T. J. Nat. Prod. 2000, 63, 441-446.
(9) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Chem. Commun. 1971,
966-967.
(6) 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) For a recent demonstration of this tandem rearrangement, see:
Nicolaou, K. C.; Li, J.; Angew. Chem., Int. Ed. 2001, 40, 4264-4268.
10.1021/ol034276y CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/01/2003

tonization, to produce 6. The tricyclic motif of 8 was
projected to be formed via Diels-Alder cycloaddition of
intermediate 9, which in turn could arise from aryl ether 10
by a Claisen rearrangement.11 Further disconnection of
benzodioxanone 10 reveals benzopyran 11 as a synthetic
precursor, the aromatic ring of which, can be traced back to
commercially available 4-hydroxysalicylic acid (12). Herein,
we disclose the results of our studies based on these
retrosynthetic considerations.
Our studies commenced with 4-hydroxysalicylic acid (12)
that, upon regioselective bromination, afforded 5-bromo-4-
hydroxysalicylic acid (13) in 75% yield (Scheme 1).12 This
compound was selectively protected in the presence of
acetone and TFAA/TFA to furnish dioxanone 14 in 61%
yield.13 Alkylation of 14 with 3-chloro-3-methyl-butyne (15)
in the presence of K2CO3, KI, and catalytic CuI in refluxing
acetone gave rise to alkyne 16,14 which upon heating at 140
°C overnight produced benzopyran 17 in 90% combined
yield. Conversion of 17 to phenol 18 was accomplished in
36% yield via treatment with t-Buli, quenching of the
resulting anion with trimethyl borate, and one-pot oxidation
with H2O2.15 The resulting phenol 18 was subsequently
protected with SEMCl and DIPEA to afford SEM ether 11
in 77% yield.16
Figure 1. Selected natural products from Garcinia plants.
Dihydroxylation of chromene 11 in the presence of
catalytic amounts of OsO4 and NMO,17 followed by oxidative
cleavage with LTA,18 gave dialdehyde 19 in 86% combined
yield. Formation of lactol 20 from 19 through Baeyer-
Villiger oxidation19 and subsequent saponification proved to
be more problematic than expected, presumably due to the
steric encumbrance imposed by the acetonide group on the
adjacent aldehyde. After several attemps, it was found that
treatment of a dilute solution of 19 at 0 °C with 0.5 equiv
of mCPBA in CH2Cl2 every 0.5 h was the key to success.
Careful saponification of the resulting formate ester with 1
N NaOH in MeOH gave lactol 20, albeit in only 25% yield.
This compound was subjected to a Wittig olefination
reaction20 to form phenol 21 in 43% yield. Treatment of the
fully functionalized fragments such as 7 and 8 (Figure 2).
In the synthetic direction, these two fragments are envisioned
to combine at the C3′ center of 7 (lateriflorone numbering)
through a biomimetic type of condensation, i.e., spirolac-
(11) 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. Rhoads, S. J.; Raulins, N. R. In Organic
Reactions; Dauben, W. G., Ed.; John Wiley & Sons: New York, 1975;
Vol. 22, Chapter 1, pp 1-252. Wipf, P. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; 1991; Vol. 5, p 827.
(12) Under these conditions, a minor byproduct identified as 3,5-
dibromohydroxysalicylic acid was formed and was easily separated from
the monobrominated adduct by column chromatography.
(13) Rheinheimer, J.; Vogelbacher, U. J.; Bauman, E.; Ko¨nig, H.; Gerber,
M.; Westphalen, K.-O.; Walter, H. U.S. Patent 5,569,640, Oct. 29, 1996.
(14) Pernin, R.; Muyard, F.; Be´valot, F.; Tillequin, F.; Vaquette, J. J.
Nat. Prod. 2000, 63, 245-247. Pettus, T. R.; Hoarau, C. Synlett. 2003,
127-137.
(15) Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1 1989, 2463-
2471.
(16) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
(17) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
23, 1973-1976. Trost, B. M.; Crawley, M. L.; Lee, C. B. J. Am. Chem.
Soc. 2000, 122, 6120-6121.
(18) Chauret, D. C.; Chong, J. M.; Ye, Q. Tetrahedron: Asymmetry 1999,
10, 3601-3614.
(19) For a review of the Baeyer-Villiger reaction, see: Krow, G. R.
Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New York,
1993; Vol. 43, Chapter 3, pp 251-798.
Figure 2. Retrosynthetic analysis of lateriflorone (6).
1492
Org. Lett., Vol. 5, No. 9, 2003

With alkene 10 in hand, the stage was set for the
implementation of a tandem Claisen/Diels-Alder reaction.
Along these lines, heating of bis-(R,R-dimethylallyl) aryl
ether 10 in toluene at 110 °C gave rise to a single product,
23, in 85% yield (Scheme 2). The structure and composition
Scheme 1. Synthesis of Fragment 10a
Scheme 2. Synthesis of Tricyclic Fragment 8a
a Reagents and conditions: (a) PhCH3, 1 h, 110 °C, 85%; (b)
excess 2 N HCl (aq), MeOH, 0.5 h, 25 °C, 95%; (c) 5.0 equiv of
pyridine, 4.0 equiv of CH3COCl, 0.2 equiv of DMAP, CHCl3, 80
°C (sealed tube), 10 h, 92%; (d) excess 5% NMe4OH (aq), MeOH,
2.5 h, 25 °C, 56%; (e) excess 2 N HCl (aq), MeOH, 0.5 h, 25 °C,
95%.
a Reagents and conditions: (a) 1.1 equiv of Br2, HOAc, 5 h, 25
°C, 75%; (b) 3.0 equiv of (CH3)2CO, 3.0 equiv of TFAA, TFA, 10
h, 0 to 25 °C, 61%; (c) 2.0 equiv of 3-chloro-3-methyl-1-butyne
(15), 1.1 equiv of K2CO3, 1.1 equiv of KI, 0.1 mol % CuI,
(CH3)2CO, 0.5 h, reflux, then DMF, 10 h, 140 °C, 90%; (d) 2.2
equiv of t-BuLi, 3.0 equiv of B(OMe)3, THF, 0.5 h, -78 to -30
°C, then excess 30% H2O2 (aq), 1 N NaOH (aq), 10 h, -30 to 25
°C, 36%; (e) 3.0 equiv of SEMCl, 4.0 equiv of DIPEA, 10 h, 0 to
25 °C, 77%; (f) 1.6 equiv of NMO, 0.3 mol % OsO4, H2O/THF/
t-BuOH, 12 h, 25 °C; (g) 1.2 equiv of Pb(OAc)4, CH2Cl2, 0.3 h,
25 °C, 86% (over two steps); (h) 0.5 equiv of mCPBA per 0.5 h,
CH2Cl2, 6 h, 0 °C, then 0.3 equiv of 1 N NaOH (aq) per 0.2 h,
MeOH, 1 h, 25 °C, 25%; (i) 3.0 equiv of methyltriphenylphospho-
nium bromide, 2.5 equiv of NaHMDS, THF, 1 h, 0 to 25 °C, 43%;
(j) 1.0 equiv of t-BuOK, THF, 0.5 h, 0 to 25 °C, then 1.5 equiv of
R-bromoisobutyraldehyde (22), 1.0 equiv of 18-C-6, CH3CN, 1.0
h, 0 to 60 °C; (k) 2.0 equiv of methyltriphenylphosphonium
bromide, 1.5 equiv of NaHMDS, THF, 1 h, 0 to 25 °C, 54% (over
two steps).
of 23 were ultimately confirmed by crystallographic analysis
of derivative 25, which divulged that the tandem rearrange-
ment produced exclusively the desired tricyclic scaffold.
Subsequent studies also showed that compound 10 can be
converted to 23 simply upon sitting at room temperature for
a number of days. Such facile rearrangement could be
attributed to a cumulative electron-donating effect of the four
oxygens attached to the aromatic ring of 10, prompting its
dearomatization through a tandem Claisen/Diels-Alder
reaction cascade.
Having confirmed the structure of 23, we turned our
attention to deprotection of both the silyl ether and the
acetonide units. To this end, exposure of 23 to 5% NMe4-
OH (aq) in MeOH was found to provide the optimum
saponification conditions and produced the desired â-hydroxy
carboxylic acid in 56% yield.21 Finally, desilylation of the
O1-silyl ether was best accomplished in the presence of 2 N
potassium salt of 21 with R-bromoisobutyraldehyde (22) in
the presence of 18-C-6 produced the corresponding R-phen-
oxycarboxaldehyde that was subsequently converted to
alkene 10 using Wittig olefination (54% combined yield).10
Org. Lett., Vol. 5, No. 9, 2003
1493

HCl in MeOH22 and gave rise to desired compound 8 in 94%
yield.
mind, it appears that having preinstalled all functionalities
at the correct oxidation state in compound 10 triggers the
desired rearrangement, producing tricycle 23 exclusively.
Such regiochemical preference during this tandem rearrange-
ment is also manifested in the vast majority of the Garcinia
natural products, the structure of which is highlighted by
the same homochiral scaffold (Figure 1). The sole exception
to this trend is found in the structure of O-methylneobractatin
(5), which as one would expect has been isolated only as a
minor product.
The excellent regioselectivity observed during the tandem
Claisen/Diels-Alder reaction deserves some additional com-
ments. In principle, compound 10 can undergo two different
ortho-Claisen rearrangements giving rise to structures 9 and
26, which after the sequential Diels-Alder reaction can
produce adducts 23 and 27, respectively (Figure 3).23 The
In conclusion, we present herein an efficient synthetic
strategy for the synthesis of tricyclic fragment 8 of lateri-
florone (6). Essential to our strategy is the implementation
of a biomimetic and completely regioselective Claisen/
Diels-Alder cascade reaction. Application of this process
to a biomimetic synthesis of lateriflorone and related natural
products is currently in progress in our laboratories.
Acknowledgment. Financial support from the NIH
(CA086079) is gratefully acknowledged. We thank Dr. P.
Gantzel (UCSD, X-ray Facility) for the reported crystal-
lographic structure and the San Diego Chapter of the ARCS
Foundation and the Department of Education for their support
through graduate student fellowships to E.J.T. and B.G.V.,
respectively.
Supporting Information Available: Spectroscopic and
analytical data available for compounds 10, 11, 17, 18, 20,
23, and 25 and X-ray data for compound 25. This material
is available free of charge via the Internet at http://pubs.acs.org.
Figure 3. Possible isomers anticipated from the tandem Claisen/
Diels-Alder reaction of compound 10.
OL034276Y
(22) Reported fluoride-based deprotection methods for SEM ethers were
completely ineffective. For selected references on this protecting group,
see: Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343-
3346. Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. Tetrahedron
Lett. 1988, 29, 5417-5418.
absence of 27 and complete conversion of compound 10 to
desired regioisomer 23 could be due to an intrinsic preference
of 10 to form Claisen adduct 9. This preference may be
attributed to the substitution pattern and the electronic effects
of the substituents on the aromatic ring.11,24,25 With this in
(23) Tricyclic alkene cannot participate as a dienophile during the Diels-
Alder reaction due to its decreased reactivity.
(24) There exists support for a dipolar transition state in the Claisen
rearrangement. For selected references on this issue, see: Coates, R. M.;
Rogers, B. D.; Hobbs, S. J.; Peck, D. R.; Curran, D. P. J. Am. Chem. Soc.
1987, 109, 1160-1170. Wilcox, C. S.; Babston, R. E. J. Am. Chem. Soc.
1986, 108, 6636-6642. Gajewski, J. J.; Jurayi, J.; Kimbrough, D. R.; Gande,
M. E.; Ganem, B.; Carpenter, B. K. J. Am. Chem. Soc. 1987, 109, 1170-
1186. Wipf, P.; Rodriguez, S. AdV. Synth. Catal. 2002, 344, 434-440.
(25) For a recent application of the aromatic Claisen rearrangement in
natural products synthesis, see: Pettus, T. R.; Inoue, M.; Chen, X.-T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160-6168. Pettus, T.
R.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 12684-
12685.
(20) Tisdale, E. J.; Chowdhury, C.; Vong, B. G.; Li, H.; Theodorakis,
E. A. Org. Lett. 2002, 4, 909-912. McClure, K. F.; Danishefsky, S. J.;
Schulte, G. K. J. Org. Chem. 1994, 59, 355-360.
(21) Although both acidic and basic conditions are known to open
dioxanones, only basic hydrolysis was found to bring about the desired
change in 23. For related references, see: Harada, T.; Yoshida, T.;
Kagamihara, Y.; Oku, A.; J. Chem. Soc., Chem. Commun. 1993, 1367-
1370. Marriot, J. H.; Barber, A. M. M.; Hardcastle, I. R.; Rowlands, M.
G.; Grimshaw, R. M.; Neidle, S.; Jarman, M. J. Chem. Soc., Perkin Trans.
1 2000, 4265-4278.
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Org. Lett., Vol. 5, No. 9, 2003