Total synthesis of tovophyllin B

Article abstract of DOI:10.1016/j.tetlet.2008.12.096

The first total synthesis of tovophyllin B (2), an antimicrobial xanthone derived from mangosteen, has been accomplished through a convergent strategy from building blocks 6 and 7 involving lithium-mediated coupling, dehydrative cyclization, and 6π electr

Full text of DOI:10.1016/j.tetlet.2008.12.096

Tetrahedron Letters 50 (2009) 1161–1163
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Total synthesis of tovophyllin B
*
Valer Jeso, K. C. Nicolaou
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of tovophyllin B (2), an antimicrobial xanthone derived from mangosteen, has
been accomplished through a convergent strategy from building blocks 6 and 7 involving lithium-med-
Received 9 December 2008
Accepted 14 December 2008
Available online 25 December 2008
iated coupling, dehydrative cyclization, and 6
p
electrocyclization as key steps.
Ó 2008 Elsevier Ltd. All rights reserved.
Tovophyllin B, a prenylated pentacyclic xanthone, was first iso-
lated in 1972 from the wood of Tovomita macrophylla by de Oliveira
et al.1 The originally proposed structure (1; Fig. 1) was corrected in
1975 on the basis of chemical and spectroscopic data to the cur-
rently accepted structure (2, Fig. 1) in which one of the phenolic
groups is H-bonded to the carbonyl moiety of the molecule.2 Re-
cent investigations of the antituberculosis potential of the fruit
hulls of mangosteen (Garcinia mangostana), traditionally used in
Thai folk medicine for alleviation of a number of maladies, led to
re-isolation of this natural product, and revealed that tovophyllin
B (2) possesses a significant inhibitory activity against Mycobacte-
xanthone 4 through a retro dehydrative cyclization leads to bisaryl
ketone 5, whose disassembly through a retro lithium-mediated
coupling as shown reveals benzaldehyde 6 and benzopyran deriv-
ative 7 as the required building blocks for the projected synthesis.
Scheme 2 summarizes the synthesis of advanced intermediate
bisaryl ketone 5. Thus, O-propargylation4 of the readily available
phenol 8 (prepared from 2,4-dihydroxybenzaldehyde in three
steps)5 with methyl 2-methyl-3-yn-2-yl carbonate (9) in the
rium tuberculosis (MIC = 25 l
g/mL).3 Therefore, as a lead compound
OH
O
O
OH
O
O
3
O
O
a)
for drug discovery, the total synthesis of tovophyllin B and its ana-
logs is deemed important. In this Letter, we report a short and effi-
cient total synthesis of this molecule that may also serve to prepare
designed analogs.
Scheme 1 shows the retrosynthetic analysis of the molecule of
tovophyllin B (2) in which a 6p electrocyclization (a) plays the role
O
OH
O
OH
2: tovophyllin B
of casting the final heterocyclic ring in the synthetic direction
(3?2). An aldol/dehydration sequence (b) then traces 3, expected
to be a transient intermediate, back to xanthone 4 and prenal
(40). Disconnection of the indicated carbon–oxygen bond within
CHO
OH
b)
aldehyde-lithium species
coupling/oxidation
4'
OH
O
O
O
O
HO
OH
HO
O
OH
H
OH OH
O
O
O
O
O
O
dehydrative
cyclization
5
4
O
O
O
OH
HO
OH
O
OMOM
CHO
+
1: tovophyllin B
[original structure]
2: tovophyllin B
[revised structure]
MOMO
OMOM
BnO
OBn
Figure 1. Originally proposed (1) and revised (2) structures of tovophyllin B.
6
7
* Corresponding author. Tel.: +1 858 784 2400; fax: +1 858 784 2469.
E-mail address: kcn@scripps.edu (K.C. Nicolaou).
Scheme 1. Retrosynthetic analysis of tovophyllin B (2): (a) 6
(b) aldol/dehydration.
p
electrocyclization;
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.096

1162
V. Jeso, K. C. Nicolaou / Tetrahedron Letters 50 (2009) 1161–1163
OH
O
OH
O
O
O
O
O
OH
a) SiO2
a) DBU, CuCl2
+
− [H2O]
OCO2Me
HO
OH
HO
OH
MOMO
OMOM
MOMO
OMOM
OH OH
10
8
9
5
4
b) toluene,
Δ
b) CaO,
CHO
4'
O
O
c) nBuLi;
OH
O
O
OH OH O
MOMO
OMOM
MOMO
OMOM
O
O
Br
11
− [H2O]
O
OH
HO
O
OH
7
16
3
d) nBuLi
OMOM
CHO
MOMO
OBn
e)
6π electro-
cyclization
OH
Li
MOMO
O
O
BnO
OH
O
O
6
O
OMOM
BnO
OMOM
OBn O
MOM
13
O
OH
12
2: tovophyllin B
f) DMP
Scheme 3. Completion of the total synthesis of tovophyllin B (2). Reagents and
conditions: (a) impregnation on a silica gel plate (1.5 h); then elution with EtOAc,
65% (for two steps), (b) CaO (7.5 equiv), prenal (40) (15 equiv), MeOH, 25 °C, 16 h,
55%.
MOMO
O
OR
O
g) Pd/C, Et3N,
HCO2H
O
O
BnO
OMOM
HO
OR
OBn O
MOM
14
OH OR
yield), from which the MOM groups were removed by exposure
to CSA in MeOH at ambient temperature, leading to the desired tri-
cyclic precursor 5.
15: R=MOM
5 : R=H
h) CSA
The final steps of the synthesis of tovophyllin B (2) are shown in
Scheme 3. Thus, cycloetherification of 5 under the influence of sil-
ica gel (impregnation of the substrate on a silica gel plate, followed
by elution with EtOAc)11 furnished, through dehydration, xanthone
49 in 65% yield (for two steps). The missing 2,2-dimethylchromene
ring of the growing molecule was finally forged through a cascade
sequence involving CaO-induced aldol-type reaction12 of xanthone
4 with prenal (40) that proceeded via intermediates 16 and 3 to af-
ford the target molecule (2) in 55% overall yield as shown in
Scheme 3. Synthetic tovophyllin B (2) exhibited identical physical
properties to those reported for the naturally derived material.1,2
The described chemistry demonstrates the power of cascade
reactions in total synthesis,13 and provides a practical route to
tovophyllin B (2) and related compounds, including designed ana-
logs for biological investigations.
Scheme 2. Synthesis of bisaryl ketone 5. Reagents and conditions: (a) 9 (3.0 equiv),
DBU (3.0 equiv), CuCl2 (0.01 equiv), MeCN, 0 °C, 12 h; (b) toluene, 140 °C, 48 h, 74%
(over two steps); (c) nBuLi (1.3 equiv), THF, 25 °C, 15 min; then prenyl bromide
(1.5 equiv), THF, 25 °C, 2 h, 86%; (d) nBuLi (1.5 equiv), THF, 25 °C, 15 min; (e) 6
(1.5 equiv), THF, ꢀ78 °C, 15 h, 58%; (f) DMP (1.4 equiv), NaHCO3 (5.0 equiv), CH2Cl2,
25 °C, 2 h, 80%; (g) 10% Pd/C (0.34 equiv), Et3 N (1.0 equiv), HCO2H (32 equiv),
acetone, 25 °C, 1.5 h, 89%; (h) CSA (5.0 equiv), MeOH, 25 °C, 8 h.
presence of DBU and catalytic amounts of CuCl2 proceeded
smoothly to afford 1,1-dimethylpropargyl ether 10, which, upon
heating in toluene at 140 °C, underwent Claisen rearrangement,
leading to 2,2-dimethylchromene 11, in 74% overall yield for the
two steps.6
Regioselective lithiation of 11 facilitated by the two OMOM
groups (nBuLi, THF, 25 °C), followed by quenching of the resulting
lithiated species with prenyl bromide furnished prenylated chro-
mene 7 in 86% yield. Pleasantly, the generation of the lithiated spe-
cies 12 from 7 proceeded smoothly on exposure of the latter to
nBuLi in THF at 25 °C and was essentially complete within
15 min (ca. 95% deuterium incorporation upon quenching with
D2O). Addition of bis-benzyl-MOM-protected benzaldehyde deriv-
ative 6 (prepared from phloroglucinol carboxaldehyde in two
steps)7 to lithiated species 12 at ꢀ78 °C furnished coupling product
13 (58% yield),8 whose hydroxy group was oxidized with Dess–
Martin periodinane to afford ketone 14,9 in 80% yield. Initial at-
tempts to selectively remove the benzyl groups from the latter
compound with hydrogen and a variety of catalysts failed primar-
ily due to the interference of the olefinic bonds residing within the
molecule. This problem was, however, solved through the employ-
ment of a palladium-catalyzed transfer hydrogenation protocol
utilizing a triethylammonium formate/formic acid buffer system.10
Under these conditions, the two benzyl groups were cleanly
cleaved from 14 to form the corresponding diphenol (15, 89%
Acknowledgments
We thank Drs. Dee H. Huang and Gary Siuzdak for NMR spectro-
scopic and mass spectrometric assistance, respectively. Financial
support for this work was provided by the National Institutes of
Health (USA) (AI 055475-08), the National Science Foundation
(CHE-0603217), and the Skaggs Institute for Chemical Biology.
References and notes
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725.3320. Compound 4: IR (film): mmax 3356, 2973, 2925, 2876, 1650, 1612,
1570, 1431, 1321, 1293, 1253, 1167, 1138, 1084, 1031, 966, 893, 830, 813,
768 cmꢀ1 1H NMR (400 MHz, MeOH-d4) d 7.92 (d, J = 10 Hz, 6.22 (s, 1H), 6.09
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(s, 1H), 5.76 (d, J = 10 Hz, 1H), 5.23 (t, J = 7.6 Hz, 1H), 3.51 (d, J = 7.2 Hz, 2H),
1.87 (s, 3H), 1.67 (s, 3H), 1.45 (s, 6H); 13C NMR (100 MHz, MeOH-d4) d 182.54,
164.73, 163.37, 163.36, 157.33, 151.05, 150.22, 137.61, 131.59, 131.40, 131.38,
121.53, 120.84, 117.50, 177.49, 115.60, 107.35, 102.77, 97.49, 92.82, 75.75,
26.05, 24.74, 22.21, 16.96; HRMS (ESI-TOF) m/z calcd for C23H23O6 (M+H+)
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2928, 1650, 1600, 1582, 1430, 1322, 1206, 1152, 1112, 1067, 926, 843, 731,
696 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.40–7.18 (m, 10H), 6.43 (d, J = 9.9 Hz,
1H), 6.42 (s, 1H), 6.28 (d, J = 1.8 Hz, 1H), 5.53 (d, J = 9.9 Hz, 1H), 5.18 (t,
J = 6.6 Hz, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 4.96 (s, 2H), 4.94 (s, 2H), 4.69 (s, 2H),
3.56 (s, 3H), 3.41 (d, J = 6.3 Hz, 2H), 3.31 (s, 3H), 3.29 (s, 3H), 1.71 (s, 3H), 1.63
(s, 3H), 1.41 (s, 6H); 13C NMR (100 MHz, CDCl3) d 192.99, 162.03, 159.07,
158.08, 146.98, 144.88, 141.80, 136.12, 136.09, 131.03, 130.36, 129.98, 129.45,
128.54, 128.34, 128.14, 127.61, 127.58, 126.84, 120.30, 119.09, 115.39, 101.27,
98.59, 94.72, 94.63, 94.28, 75.41, 70.39, 70.06, 57.37, 57.23, 55.99, 27.50, 25.58,
24.01, 17.89; HRMS(ESI-TOF) m/z calcd for C43H49O10 (M+H+) 725.3320, found