First intramolecular [6+4] cycloaddition of tropone and a furan moiety: Rapid entry into a highly functionalized ingenane skeleton

Article abstract of DOI:10.1055/s-2005-872696

The expeditious construction of a highly functionalized ABC core of ingenol via an intramolecular, metal-free [6+4] cycloaddition of cycloheptatrienone and furan is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872696

LETTER
2501
First Intramolecular [6+4] Cycloaddition of Tropone and a Furan Moiety:
Rapid Entry into a Highly Functionalized Ingenane Skeleton
F
irst Intra
m
a
olecular
[
m
6+4]
C
ycloaddition
e
of Tropone
s
anda Furan
M
o
H
iety . Rigby,* Gaëlle Chouraqui
Department of Chemistry, Wayne State University, Detroit, MI 48202-3489, USA
Fax +1(313)5773585; E-mail: jhr@chem.wayne.edu
Received 21 July 2005
The key transformation in this approach to the ABC core
is the [6+4] cycloaddition depicted in Scheme 1, and the
crucial question at this point is the facility of the projected
ring formation in such an elaborate cycloaddition sub-
strate. What is noteworthy about this approach is that the
A-ring of the target natural product will emerge from the
cycloaddition fully equipped with all of the requisite func-
tionality. Furthermore, the B-ring will be formed with the
necessary oxygen substitution at C4 and C20.
Abstract: The expeditious construction of a highly functionalized
ABC core of ingenol via an intramolecular, metal-free [6+4]
cycloaddition of cycloheptatrienone and furan is reported.
Key words: ingenol, cycloaddition, bicyclic compound, hetero-
cycle, furan
Ingenol (1), a highly oxygenated diterpene, was isolated
from the genus Euphorbia as the 3-hexadecanoic acid
monoester (Figure 1).1 The structure was initially eluci-
dated by Hecker and reconfirmed by Paquette.2 This com-
pound shows variable degrees of activity, and derivatives
have displayed both tumor-promoting3 and anti-tumor4
properties. They have also been reported to inhibit HIV-1
replication5 and to stimulate the Nerve Growth Factor pro-
tein.6 Because of its potent biological activity and struc-
tural complexity this natural product has been the subject
of considerable study in recent years. To date three total
syntheses7 and one formal8 synthesis have been reported.
The foremost challenges in the synthesis of ingenol are
the construction of the unusual bicyclo[4.4.1]undecanone
unit comprising the BC-ring substructure as well as a
While tropone is known to undergo [6+4] cycloaddition
with a variety of simple diene partners,10 isobenzofuran is
the only furan derivative that has been reported to engage
this triene in this fashion.11 In previous reports, whenever
tropone was reacted with a furan moiety either no reaction
took place or it provided the alternative [4+2] cycload-
duct.12 Recently, we reported a facile entry into a simple
ingenane core structure using a Lewis acid catalyzed, in-
tramolecular [6+4] cycloaddition.13 However, all efforts
to effect cyclization between tropone and furan species
under these conditions were unsuccessful, presumably
due to the high reversibility of this diene in the [6+4]
process.
highly strained inside, outside intrabridgehead stereo- In the projected cycloaddition of 3 to give 2, it was rea-
soned that the presence of the Z-alkene in the tether should
greatly accelerate this otherwise difficult transformation.
Further support for the viability of the projected cyclo-
addition in Scheme 1 comes from the fact that the diene in
3 is more electron-rich than the dienes used in previous
approaches from our laboratory.9
chemical relationship at the BC-ring juncture.
D
C
11
O
1
8
H
A
B
3
HO
HO
O
HO
OH
O
20
1
H
O
O
R
R
Figure 1
R2O
R2O
OR1
OR1
2
3
We have previously reported that this challenging stereo-
chemical feature of ingenol can be established via a palla-
dium-mediated isomerization of an allylic epoxide
followed by a low-temperature alkoxide-accelerated 1,5-
hydrogen migration.9 Herein, we report a short and
efficient approach to a highly functionalized ingenane
species.
Scheme 1
To maximize synthetic convergency, species 3 was divid-
ed into three modules 4, 5 and 6 (Scheme 2). The synthe-
ses of compounds 414 and 515 have already been described
in the literature.
Initially, incorporation of a silyl ether at the C2 position of
the furan 6 was planned. This strategy was adopted due to
the ease in which compound 2 (R = OSiR¢3), by simple
treatment with fluoride, could lead to opening of the oxa-
bicyclic ring. Thus, providing the requisite hydroxyl
group at the AB-ring junction (C4).
SYNLETT 2005, No. 16, pp 2501–2503
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872696; Art ID: S06805ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
5

2502
J. H. Rigby, G. Chouraqui
LETTER
O
TBDPS
OTBS
I
b
a
O
TBDPS
OTBS
Cl
4
HO
6b
O
I
11
O
O
O
+
R
R
I
2
OR2
CHO
5
O
c
OR1
TBDPS
OR1
6
3
MOMO
O
O
Scheme 2
OTBS
TBDPS
12
MOMO
This plan was reduced to practice with the facile prepara-
tion of key building block 6a in six steps, according to a
reported procedure.16 When 6a was reacted with sec-BuLi
in the presence of TMEDA and quenched with 5 the
OTBS
3a
Scheme 4 Reagents and conditions: (a) i. n-BuLi, THF; ii. 5. 70%;
(b) MOMCl, DIPEA, CH2Cl2, 64%; (c) i. n-BuLi, THF; ii. 2-chloro-
somewhat labile alcohol 9 was obtained in 55% yield tropone, 68%
(Scheme 3).
cycloaddition to proceed through an exo transition
state.12,18 Thus, a highly substituted ingenane system can
be assembled in only eight steps from readily available 2-
chlorotropone and furaldehyde. The cycloaddition could
also be effected with other protecting groups with yields
ranging between 60% and 70%.
I
O
OTIPS
a
O
OTIPS
HO
MOMO
9
MOMO
6a
O
I
b
H
a
O
O
3
OTIPS
O
MOMO
O
TBDPS
OR1
TBDPS
OR1
R2O
R2O
3a–c
2a–c
MOMO
10
Scheme 5 Reagents and conditions: (a) benzene reflux, 60% (2a:
R1 = TBS, R2 = MOM); 65% (2b: R1 = MOM, R2 = Me); 70% (2c:
R1 = TBDPS, R2 = MOM)
Scheme 3 Reagents and conditions: (a) i. s-BuLi, TMEDA, THF; ii.
5, 55%; (b) MOMCl, DIPEA, CH2Cl2, 40%
In most instances, a preliminary evaluation of the product
composition could be made by examining the IR spec-
trum. Indeed, all of the previously reported [6+4] cyclo-
adducts have bridged carbonyl groups (1710–1720
cm–1)19,11,10a–c while the [4+2] species have typical enone
absorptions (1670–1690 cm–1).20 The new adducts re-
ported here (2a–c) exhibited a spectrum consistent with
the assigned structure. Furthermore, significant NOE
effects between Hb and Hc for 2a added further support
for the [6+4] cycloadduct structure (Figure 2).21
Due to the general lack of stability of this class of com-
pounds, it was then decided to explore the reactivity of a
modified furan. This material could be directly deriva-
tized at the C2 position with an appropriate silyl group as
in 6b (Scheme 4). It should be noted that the presence of
this substituent at the C7 position in tricycle 2a would al-
low for a subsequent Fleming oxidation to set the stage for
the anticipated opening of the oxabicyclic bridge, afford-
ing the required hydroxyl group at the C4 position of the
ingenol skeleton.
In this new approach to the skeleton of ingenol, we have
assembled a highly functionalized compound in only
eight steps in a sequence featuring a novel [6+4] process
in which a furan diene participated as the 4p-partner. The
resultant adduct possesses a fully formed A-ring and a B-
ring with the requisite substitution at C4 and C20.
The four-step synthesis of key building block 6b has al-
ready been reported in the literature.17 Furan 6b was then
lithiated at C5 and trapped with aldehyde 5 to provide 11
in 70% yield. After protection of the secondary alcohol in
64% yield, compound 12 successfully underwent an io-
dide–lithium exchange in the presence of n-BuLi and ad-
dition to 2-chlorotropone furnished the cycloaddition
precursor 3a in 68% yield (Scheme 4).
Hc
Hb
O
O
Ha
Ha
Ha
To our delight the [6+4] cycloaddition readily took place
in refluxing benzene to afford, in only three hours, the
cycloadduct 2a as a mixture of two inseparable dia-
stereomers at C3 in a 60:40 ratio (Scheme 5). The
assigned stereochemistry of the adduct was based on the
well-established propensity for tropone–diene [6+4]
H
TBDPS
OTBS
MOMO
Figure 2 NOE connectivity of 2a
Synlett 2005, No. 16, 2501–2503 © Thieme Stuttgart · New York

LETTER
First Intramolecular [6+4] Cycloaddition of Tropone and a Furan Moiety
2503
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Further work is underway to transform this advanced
intermediate into ingenol itself.
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Acknowledgment
We would like to thank the National Institutes of Health (grant CA-
036543) for financial support of this investigation.
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13C NMR, NOE, COSY spectroscopic analyses and the
structure was also confirmed by IR and HRMS. A solution
of 2.2 g of 3a (3.28 mmol, 1.0 equiv) in 15 mL of benzene
was refluxed during 3 h. The solution was concentrated in
vacuo. The crude oil was purified by flash chromatography
on silica gel (PE–Et2O, 97:03) and gave 2a (1.32 g, 60%) as
a red oil and as a mixture of two diastereomers (60:40). IR
(neat): 2928, 2856, 1710, 1609, 1103, 1034, 836, 700 cm–1.
1H NMR (500 MHz, CDCl3): diastereomer 1: d = 7.60–7.56
(m, 4 H, Ph), 7.40–7.31 (m, 6 H, Ph), 6.48 (s, 1 H, CH vinylic
cycle B), 5.87 (d, J = 11.5 Hz, 1 H, Hc), 5.68–5.60 (m, 2 H,
diene), 5.36–5.05 (m, 3 H, Hb, H junction cycle B and C, CH
diene), 4.74 (s, 1 H, CH–OMOM), 4.67–4.62 (m, 2 H, CH2–
OTBS), 3.82 (s, 2 H, CH2 of MOM), 3.38 (s, 3 H, Me of
MOM), 1.38 (s, 3 H, Ha), 1.12 (s, 9 H, t-Bu), 0.72 (s, 9 H,
t-Bu), –0.24 (s, 6 H, Me of TBS) ppm; diastereomer 2: d =
7.60–7.56 (m, 4 H, Ph), 7.40–7.31 (m, 6 H, Ph), 6.47 (s, 1 H,
CH vinylic cycle B), 5.81 (d, J = 12.0 Hz, 1 H, Hc), 5.68–
5.60 (m, 2 H, diene), 5.36–5.05 (m, 3 H, Hb, H junction
cycle B and C, CH diene), 4.80 (s, 1 H, CH–OMOM), 4.67–
4.62 (m, 2 H, CH2–OTBS), 3.82 (s, 2 H, CH2 of MOM), 3.12
(s, 3 H, CH3 of MOM), 1.52 (s, 3 H, Ha), 1.12 (s, 9 H, t-Bu),
0.72 (s, 9 H, t-Bu), –0.24 (s, 6 H, Me of TBS) ppm. 13C NMR
(125 MHz, CDCl3): diastereomer 1: d = 1° C: 55.8, 27.8 (3
C), 25.8 (3 C), 24.2, –5.5 (2 C); 2° C: 95.2, 57.5; 3° C: 136.1
(4 C), 131.2, 129.5 (2 C), 127.8 (4 C), 124.5, 121.0, 119.9,
110.8, 99.9, 99.3, 76.3; 4° C: 186.7, 168.9, 155.5, 149.3,
140.7, 139.7, 133.5 (2 C), 18.9, 18.2 ppm; diastereomer 2:
d = 1° C: 55.6, 27.7 (3 C), 25.8 (3 C), 22.3, –5.5 (2 C); 2° C:
94.5, 57.5; 3° C: 136.1 (4 C), 131.1, 129.5 (2 C), 127.8 (4 C),
124.3, 121.0, 119.0, 110.6, 99.9, 99.3, 76.2; 4° C: 186.7,
168.6, 155.5, 149.3, 140.5, 139.4, 133.4 (2 C), 18.9, 18.2
ppm. HRMS: m/z = 668.3350.
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Synlett 2005, No. 16, 2501–2503 © Thieme Stuttgart · New York