Enantiopure simple analogues of annonaceous acetogenins with remarkable selective cytotoxicity towards tumor cell lines

Article abstract of DOI:10.1002/1521-3773(20000602)39:11<1934::AID-ANIE1934>3.0.CO;2-W

Structure simplification with conservation of the essential functionalities for biological activity has been achieved with the design and synthesis of four analogues of annonaceous acetogenins. The compounds ((15 R/S, 24 R/S)-1) are easily synthesized wit

Full text of DOI:10.1002/1521-3773(20000602)39:11<1934::AID-ANIE1934>3.0.CO;2-W

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scopy. A Physicochemical View, Longman Scientific & Technical,
Harlow, 1983, p. 194.
[6] The isotope effects on 59Co were measured in the temperature range
from 273 to 313 K, where the signals are narrow enough (linewidths at
half height of about 2000 ± 3500 Hz). The linewidth increases with
decreasing temperature.
proton (d(H)[RCo(Hdmg)(Ddmg)L] À d(H)[RCo(Hdmg) L]), as well as that
2
for the deuteron (d(D)[RCo(Ddmg) L] À d(D)[RCo(Hdmg)(Ddmg)L]) is
2
about À70 ppb. The two hydrogen bonds are coupled[16] in a
cooperative way: not only the hydrogen bond where deutera-
tion occurs is weakened, but also the other. The deuteration of
either one or two hydrogen bonds results in further long-range
[7] N. Godbout, E. Oldfield, J. Am. Chem. Soc. 1997, 119, 8065 ± 8069.
[8] L. J. Altman, D. Laungani, G. Gunnarsson, H. Wennerström, S.
n
secondary isotope shifts D (n is the number of intervening
Â
Forsen, J. Am. Chem. Soc. 1978, 100, 8264 ± 8266.
ˆ
bonds). The equatorial C N carbon atoms of 1 are 64 ppb less
[9] G. A. Kumar, M. A. McAllister, J. Org. Chem. 1998, 63, 6968± 6972.
[10] S. Mazzini, L. Merlini, R. Mondelli, G. Nasini, E. Ragg, L. Scaglioni, J.
Chem. Soc. Perkin Trans. 2 1997, 2013 ± 2021.
shielded for [MeCo(Ddmg)2py] than for the undeuterated
complex. The same 3D value is observed on the side of the D
bridge for [MeCo(Hdmg)(Ddmg)py], where the inequiva-
[11] The isotope effects on the shifts of 1H, 2H, and 13C were determined at
low temperature, where the peaks are narrower because the effects of
scalar coupling to cobalt are averaged out by the faster cobalt
relaxation and because the H/D exchange is slower.
[12] L. Randaccio, S. Geremia, R. Dreos-Garlatti, G. Tauzher, F. Asaro, G.
Pellizer, Inorg. Chim. Acta 1992, 194, 1 ± 8 .
ˆ
lence of the C N carbon atoms clearly evidences the
symmetry decrease caused by deuteration of one bridge. A
long-range effect with opposite sign (5D ˆ À4 ppb) was
observed for the equatorial methyl protons in 2. The axial
methyl protons show a 5D of about ‡14 ppb for each
deuteration step in both 1 and 2.
[13] R. Blinc, D. Hadzi, J. Chem. Soc. 1958, 4536 ± 4540.
[14] C. Engdahl, A. Gogoll, U. Edlund, Magn. Reson. Chem. 1991, 29, 54 ±
62.
[15] P. W. R. Bessonette, M. A. White, J. Chem. Phys. 1999, 110, 3919 ±
3925.
[16] S. S. Smirnov, N. S. Golubev, G. S. Denisov, H. Benedict, P. Schah-
Mohammedi, H.-H. Limbach, J. Am. Chem. Soc. 1996, 118, 4094 ±
4101.
[17] M. J. T. Robinson, K. M. Rosen, J. D. B. Workman, Tetrahedron 1977,
33, 1655 ± 1661.
1
2
The dependence of the H and H chemical shift of the
hydrogen bond on temperature is linear with a negative slope
(À0.004 ppmKÀ1 for 1 (Figure 2) and 2), as was already found
for enolates,[17] which have the same kind of potential shape. It
is noteworthy that such a negative dependence is also shared
with the important class of hydrogen bonds whose lowest
vibrational energy is higher than the potential barrier and
Â
[18] M. Garcia-Viloca, R. Gelabert, A. Gonzalez-Lafont, M. Moreno, J. M.
Lluch, J. Am. Chem. Soc. 1998, 120, 10203 ± 10209.
[19] H. A. O. Hill, K. G. Morallee, J. Chem. Soc. A 1969, 554 ± 559.
p
which are characterized by negative D and negative secon-
dary geometric effects.[18]
From the above results, it can be concluded that the
hydrogen bonds of cobaloximes have double-well potentials
with a low central barrier and high anharmonicity and are
subject to a positive secondary geometric effect upon
deuteration. The latter is accompanied by a lengthening and
À
weakening of the Co N bonds that is large enough to
Enantiopure Simple Analogues of
Annonaceous Acetogenins with
Remarkable Selective Cytotoxicity towards
Tumor Cell Lines**
drastically increase the 59Co chemical shift.
Experimental Section
All the compounds were prepared according to literature procedures.[19]
NMR spectra were recorded on a 400 MHz JEOL EX-400 spectrometer on
[D6]acetone solutions. For 59Co spectra, a pulse width of 458, a relaxation
delay of 0.1 s, a sweep width of 60240 Hz, 8192 points, 10000 scans, and a
broadening factor of 30 were used, and the data were zero-filled once
before Fourier transformation. The solvent signal was used as internal
standard at d ˆ 2.00 for 1H and 2H, and at d ˆ 30.30 for 13C. The 59Co
chemical shift data were referred to [K3Co(CN)6] at 300 K. The isotopic
substitution was accomplished by adding a few microliters of D2O to the
2 Â 10À2 m solutions of the cobaloximes in [D6]acetone.
Bu-Bing Zeng, Yikang Wu, Qian Yu, Yu-Lin Wu,*
Yan Li, and Xiao-Guang Chen
Annonaceous acetogenins, a relatively new class of natural
products so far only found in Annonaceae, have been
attracting worldwide attention in recent years because of
their potent biological activities, especially as growth inhib-
[*] Prof. Yu.-L. Wu, B.-B. Zeng, Prof. Dr. Y. Wu, Dr. Q. Yu
State Key Laboratory of Bioorganic & Natural Products Chemistry
and
Received: December 1, 1999
Revised: February 7, 2000 [Z14340]
Shanghai ± Hong Kong Joint Laboratory in Chemical Synthesis
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
[1] W. von Philipsborn, Chem. Soc. Rev. 1999, 28, 95 ± 105.
[2] a) C. Tavagnacco, G. Balducci, G. Costa, K. Täschler, W. von Philips-
born, Helv. Chim. Acta 1990, 73, 1469 ± 1479; b) F. Asaro, R. Gobetto,
L. Liguori, G. Pellizer, Chem. Phys. Lett. 1999, 300, 414 ± 420; c) A.
Medek, V. Frydman, L. Frydman, Proc. Natl. Acad. Sci. USA 1997, 94,
14237 ± 14242.
354 Fenglin Road, Shanghai 200032 (China)
Fax : (‡86)21-6416-6128
E-mail: ylwu@pub.sioc.ac.cn
Y. Li, Prof. X.-G. Chen
Institute of Materia Medica
Chinese Academy of Medical Sciences
1 Xiannongtan Street, Beijing 100050 (China)
[3] C. J. Jameson, D. Rehder, M. Hoch, J. Am. Chem. Soc. 1987, 109,
2589 ± 2594.
[4] G. B. Benedek, R. Englman, J. A. Armstrong, J. Chem. Phys. 1963, 39,
3349 ± 3363.
[5] a) J. G. Russell, R. G. Bryant, M. M. Kreevoy, Inorg. Chem. 1984, 23,
4565 ± 4567; b) R. K. Harris, Nuclear Magnetic Resonance Spectro-
[**] This work was supported by the Chinese Academy of Sciences (nos.
KJ951-A1-504-04, and KJ952-S1-503), the National Natural Science
Foundation of China (nos. 29472070, 29790126, and 29832020), and the
Ministry of Science and Technology of China (no. 970211006-6).
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Angew. Chem. Int. Ed. 2000, 39, No. 11

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itors of certain tumor cells.[1] They have been shown to
function by blocking complex I in mitochondria[2] as well as
ubiquinone-linked NADH oxidase in the cells of specific
tumor cell lines, including some multidrug-resistant[3] ones.
These features make the acetogenins excellent leads for new
antitumor agents. However, due to the scant natural resour-
ces, the substantial amounts of enantiomerically pure samples
required for further biological and clinical studies appear to
be attainable only by means of chemical synthesis. Unfortu-
nately, all the total syntheses of annonaceous acetogenins
which have so far appeared in the literature[4] still require
more than 10 reaction steps, which makes the scale-up very
difficult. Herein we wish to report a potential solution to the
problem, which relies on structure simplification while main-
taining all essential functionalities of the acetogenins.
2a (15R,24R) 2b (15S,24R)
2c (15S,24S) 2d (15R,24S)
(R)
(S)
I
I
O
O
7
7
OMOM 3a
3b
OMOM
OH
OH
HO
4b
HO
4a
12 CO2Me
CO2Me
(S)
(R)
12
5b
O
O
5a
and/or
O
O
CHO
CHO
Figure 2. The chiral centers adjacent to the ethereal links in the targets can
be attained from proper combination of 3a, 3b, 4a, and 4b, which are
derived from 5a and/or 5b or from l-lactate.
It has been postulated that the antitumor activities of the
acetogenins are associated with their ionophoric ability.[5]
Therefore, the hydroxy and ethereal oxygen atoms in the
acetogenins appear to be essential for the biological activities.
The THF rings, however, do not seem to be essential. A
straightforward means of structural simplification is hence to
remove the ethylene bridge in the THF rings,[6] which
eliminates two chiral centers and greatly simplifies the
synthesis. Thus, the bis-THF annonaceous acetogenin isode-
sacetyluvaricin 1 and its isomers may be reduced to the
linear[7] mimics 2 (Figure 1). In the latter case, four chiral
screening, using different combinations four components 3a,
3b, 4a, and 4b, which were in turn derived from one of the
protected glyceraldehydes 5a or 5b.
The synthesis is exemplified with preparation of 2a, which
starts with 5a derived from l-ascorbic acid following a
literature procedure.[7] After chain extension[8] at the carbonyl
end by Wittig reaction and hydrogenation, the acetonide 7a
was converted into diol 8a and combined with 2-benzyloxy-
ethyl iodide through a cyclic stannate (Scheme 1).[9] The
O
a
O
b
O
O
O
1 O
6
CHO
5a
15
HO
6a
3
O
16
OH
O
c
O
d
HO
19
C10H21
C10H21
20
6
7a
8a
O
C
10H21
23
f
e
O
O
OBn
OBn
I
9a
OH
OMOM
10a
HO 24
33
1a (15R,16R,19R,20R,23R,24R),
isodesacetyluvaricin
C10H21
C
10H21
g
O
O
1b (15S,24R)
OH
OMOM
11a
3a OMOM
1c (15S,24S)
1d (15R,16R,19R,20R,23R,24S),
desacetyluvaricin
ˆ
Scheme 1. a) C8H17CH PPh3, 90%; b) H2, EtOH, Pd-C, 95%; c) HCl,
MeOH; d) 1) Bu2SnO, CHCl3:MeOH (10:1), reflux, 2) CsF, ICH2CH2OBn,
DMF, 80% over 2 steps; e) MOMCl, iPr2NH, CH2Cl2, 96%; f) H2, EtOH,
Pd-C, 90%; g) I2, imidazole, PPh3, 8 2%. Bnˆ benzyl, MOM ˆ methoxy-
methyl.
O
OH
20
33
23
3
24
O
1
O
O
15
19
16
11
7
OH
hydroxy group was masked as a MOM ether and the terminal
benzyl protective group was removed by hydrogenation. The
newly released primary hydroxyl functionality was then
transformed into the desired iodide 3a.
2a (15R,24R) 2b (15S,24R)
2c (15S,24S) 2d (15R,24S)
Figure 1. Representation of the general idea of simplifying bis-THF
natural annonaceous acetogenins into linear analogues.
The other fragment required for the construction of target
molecule 2a, is the diol 4a, which was prepared from cis-eruic
À
centers are removed from the molecule. This greatly reduces
the difficulty encountered in the synthetic endeavors and thus
promises easier scale-up in the future.
In order to explore the potential influence of the config-
uration of the hydroxy groups on the biological activities, we
planned from the beginning to synthesize all four possible
isomers of the simplified analogues (Figure 2) for biological
acid 12 as shown in Scheme 2. The C C double bond was first
cleaved with ozone following a literature procedure[10] to give
the hydroxy acid 13, which was transformed to corresponding
methyl ester in methanol in the presence of SOCl2. Smooth
bromination with CBr4 in the presence of PPh3 provided the
bromo ester 14 as an immediate precursor to the correspond-
ing phosphonium salt. In preparative runs, formation of 14
Angew. Chem. Int. Ed. 2000, 39, No. 11
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Table 1. The preliminary results of in vitro tests (using the MTT method)
against KB, A2780, HCT-8, and HT-29 human solid tumor cell lines.
CO2H
11
a
HO
CO2H
10
6
13
12
Compound
EC50 [mgmLÀ1
]
KB
A2780
HCT-8
HT-29
0.272
1.12
0.11
7.83
c
b
Br
CO2Me
10
2a
2b
2c
2d
19
> 1
> 1
> 1
> 1
> 1
> 1
> 1
> 1
> 1
> 1
0.066
0.097
0.032
0.065
> 1
14
(R)
d
O
11 CO2Me
15a
> 1
4a
O
Scheme 2. a) 1) O3, 0 ± 58C, EtOH:cyclohexane (1:5), 2) KBH4; b) 1) Me-
OH, SOCl2, 87% from 12, 2) CBr4, PPh3, C6H6, 87%; c) 1) PPh3, 2) tBu-
OK, then 5a, 3) H2, EtOH, Pd-C, 67% over 3 steps; d) H , MeOH, 91%.
analogues against KB and A2780 cell lines. However,
impressive EC50 values were observed with HCT-8, which all
are on the nm order. Other interesting results are obtained
with HT-29 cell line, different com-
‡
could be combined with the following treatment with PPh3
without separation, to give the desired phosphonium salt at
elevated temperature in a one-pot manner. The subsequent
binations of the chiral moieties show
remarkable difference in the activity.
Corresponding EC50 values for 19
HO
O
HO
À
Wittig reaction with 3a, after hydrogenation of the C C
10
are also listed in Table 1 for compar-
O
double bond and removal of the acetonide protective group,
led to 4a.
ison.
19
In conclusion, we have developed
The coupling of 3a and 4a (Scheme 3) was achieved using a
protocol similar to the one employed in the chain extension of
8a above. The newly formed hydroxyl group was protected as
a class of structurally simplified ana-
logues of natural annonaceous acetogenins. The synthetic
routes are significantly shortened. The remaining stereogenic
centers are derived from the easily accessible chiral building
blocks 5a and/or 5b or from l-lactate. All four analogues
show remarkable activity against the HCT-8cell line, while
better differentiation between the four analogues is found
with HT-29 cell line. Further work along this line is currently
in progress in our laboratory.
HO
a
O
+
3a
4a
O
CO2Me
12
8
OMOM
16a
MOMO
O
b
c
O
CO2Me
12
8
Received: January 4, 2000 [Z14505]
OMOM
17a
MOMO
d
2a
(R)
O
O
(15R,24R)
O
(R)
[1] Reviews: a) J. K. Rupprecht, Y. H. Hui, J. L. McLaughlin, J. Nat.
Prod. 1990, 53, 237; b) X. P. Fang, M. J. Rieser, Z. M. Gu, J. L.
McLaughlin, Phytochem. Anal. 1993, 4, 27; c) L. Zeng, Q. Ye, N. H.
Oberlies, G. E. Shi, Z. M. Gu, K. He, J. L. McLaughlin, Nat. Prod.
8
12
O
OMOM
18a
Scheme 3. a) 1) Bu2SnO, CHCl3:MeOH (10:1), reflux, 2) CsF, DMF, 75%
over steps; b) MOMCl, iPr2NH, CH2Cl2, 100%; c) 1) LDA, (S)-
2
Á
Rep. 1996, 275; d) A. Cave, B. Figadere, A. Laurens, D. Cortes, Prog.
Me(OTHP)CHCHO, 2) 9% H2SO4, THF, 3) (F3CCO)2O, NEt3, CH2Cl2;
Chem. Org. C 1997, 70, 8 1.
d) HCl, MeOH, 45 ± 52% from 17a. LDA ˆ lithium diisopropylamide.
[2] M. C. Gonzalez, J. R. Tormo, A. Bermejo, M. C. Zafra-polo, E.
Estornell, D. Cortes, Bioorg. Med. Chem. Lett. 1997, 7, 1113, and
references therein.
[3] N. H. Oberlies, V. L. Croy, M. L. Harrison, J. L. McLaughlin, Cancer
Lett. 1997, 115, 73.
a MOM ether before the chiral center in the butenolide was
introduced by an aldol condensation. After removal of the
THP protective group with concurrent lactone ring closure,
the hydroxyl was converted into trifluoroacetate and elimi-
[4] For recent reviews, see: a) G. Cassiraghi, F. Zanardi, L. Battistini, G.
Rassu, G. Aappendino, Chemtracts: Org. Chem. 1998, 11, 803; b) A.
Tanaka, T. Oritani, J. Org. Synth. Chem. Soc. Jpn. 1997, 55, 877.
[5] a) S. Sasaki, K. Muruta, H. Naito, H. Sugihara, K. Hiratani, M. Maeda,
Tetrahedron Lett. 1995, 36, 5571; b) S. Sasaki, K. Muruta, H. Naito, R.
Maemura, E. Kawahara, M. Maeda, Tetrahedron 1998, 54, 2401.
[6] Our efforts along this line started in the early 90ꢁs Y.-L. Wu, Z.-J. Yao
and Q. Yu, 1997, CN-A 97 1 06368.0).
À
nated to give the C C double bond. Finally, the MOM
protective group was hydrolyzed using HCl in MeOH to
afford the target molecule 2a. It should be noted that in the
present context, this strategy for construction of the lactone
moiety after completion of the chain extension[11] gave much
better yields than the previously adopted one, where the
lactone was formed at early stages of the synthesis.[12]
Â
[7] During the preparation of this manuscript, Gree et al. published a
Â
synthetic endeavor aimed at similar target molecules: Y. L. Huerou, J.
Â
Doyon, R. L. Gree, J. Org. Chem. 1999, 64, 6782. However, they have
currently only finished construction of the two chiral centers adjacent
to the ethereal links, without introduction of the butenolide moiety.
[8] Y.-F. Wang, Y.-L. Wu, Hecheng Huaxue 1993, 1, 215 (Chem. Abstr.
1994, 121, 133755p).
[9] a) N. Nagashima, M. Ohno, Chem. Lett. 1987, 141; b) H.-S. Byun, E. R.
Kumar, R. Bittman, J. Org. Chem. 1994, 59, 2630; c) R. Martínez-
Other target molecules[13] were synthesized in a similar
manner by choosing proper forms of precursors 3 and 4. Thus,
coupling of 3a and 4b led to 2b, while reaction of 3b with 4a,
and 3b with 4b, yielded 2c and 2d, respectively.
The preliminary results (Table 1) of the in vitro tests against
several human solid tumor cell lines show interesting cell line
selectivity. Practically no activity was found with all the four
Â
Bernhardt, P. P. Castro, G. Godjoian, C. G. Gutierrez, Tetrahedron
1998, 54, 8919.
[10] Y.-C. Wang, F.-C. Liu, Synth. Commun. 1994, 24, 1265.
1936
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Angew. Chem. Int. Ed. 2000, 39, No. 11

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[11] Similar strategies have been employed in the total synthesis of natural
acetogenins. For example, see: a) J. Marshall, H.-J. Jiang, J. Org.
Chem. 1998, 63, 7066; b) S. Hanessian, T. A. Grillo, J. Org. Chem.
1998, 63, 1049.
[12] For example, see: Q. Yu, Y.-K. Wu, Y.-L. Wu, J. Chem. Soc. Perkin
Trans. 1 1999, 1183, and references therein.
reorganization to produce o-quinone dimethides (5,6-dime-
thylenecyclohexa-1,3-diene derivatives, such as 2), which
function as dienes in DA reactions to produce products of
type 3 (Scheme 1).
[13] 1H NMR data (CDCl3, 600 MHz) and optical rotations for 2a ± d.
Compound 2a: d ˆ 6.98(d, J ˆ 1.2 Hz, 1H), 4.99 (dq, J ˆ 7.2, 1.2 Hz,
1H), 3.83 ± 3.74 (m, 2H), 3.72 ± 3.60 (m, 4H), 3.53 (dd, J ˆ 9.6, 10.2 Hz,
2H), 3.32 (dd, J ˆ 9.6, 8.4 Hz, 2H), 2.26 (br.t, J ˆ 7.8Hz, 2H), 1.55
(quint, J ˆ 6.6 Hz, 2H), 1.40 (d, J ˆ 7.2 Hz, 3H), 1.50 ± 1.20 (m, 40H),
0.88 (t, J ˆ 6.9 Hz, 3H); [a]D ˆ ‡3.4 (c ˆ 2.31 in CHCl3). Compound
2b: d ˆ 6.98(br.s, 1H), 4.99 (br.q, J ˆ 6.6 Hz, 1H), 3.82 ± 3.74 (br.m,
2H), 3.72 ± 3.60 (br.m, 4H), 3.54 (br.d, J ˆ 9.6 Hz, 2H), 3.32 (br.t, J ˆ
9.0 Hz, 2H), 2.26 (br.t, J ˆ 7.5 Hz, 2H), 1.54 (quint, J ˆ 7.2 Hz, 2H),
1.40 (d, J ˆ 6.6 Hz, 3H), 1.48± 1.16 (br.m, 40H), 0.88 (t, J ˆ 7.2 Hz,
3H); [a]D ˆ À6.9 (c ˆ 0.4 in CHCl3). Compound 2c: d ˆ 6.97 (d, J ˆ
1.2 Hz, 1H), 4.98(dq, J ˆ 7.2, 1.2 Hz, 1H), 3.81 ± 3.75 (m, 2H), 3.71 ±
3.61 (m, 4H), 3.52 (dd, J ˆ 9.6, 10.2 Hz, 2H), 3.31 (dd, J ˆ 9.6, 8.4 Hz,
2H), 2.50 (br.s, 2H, OH), 2.26 (t, J ˆ 7.8Hz, 2H), 1.53 (quint, J ˆ
7.8Hz, 2H), 1.40 (d, J ˆ 6.6 Hz, 3H), 1.48± 1.20 (m, 40H), 0.87 (t, J ˆ
7.2 Hz, 3H); [a]D ˆ 16.3 (c ˆ 2.17 in CHCl3). Compound 2d: d ˆ 6.98
(d, J ˆ 1.2 Hz, 1H), 4.99 (dq, J ˆ 1.2, 6.6 Hz, 1H), 3.78(m, 2H), 3.72 ±
3.62 (m, 4H), 3.53 (dd, J ˆ 2.4, 9.6 Hz, 2H), 3.32 (dd, J ˆ 9.6, 8.4 Hz,
2H), 2.26 (br.t, J ˆ 7.8Hz, 2H), 2.15 (br.s, 2H, OH), 1.55 (quint, J ˆ
7.2 Hz, 2H), 1.40 (d, J ˆ 6.6 Hz, 3H), 1.48± 1.20 (m, 40H), 0.88(t, J ˆ
6.9 Hz, 3H); [a]D ˆ À87.4 ( c ˆ 0.35 in CHCl3).
A
OR
OSiR3
OSiR3
OSiR3
OSiR3
A
H
R = SiR3
1
2
OR
3
Scheme 1. A ˆ activator.
While this kind of cycloaddition is well known, its primary
applications have been at the intramolecular level. Thus,
many of the elegant sequences that have traditionally been
used to generate o-quinone dimethides as a prelude to
cycloaddition work well only when the putative dienophile
is tethered to the diene.[4] A particularly impressive illustra-
tion of our recently discovered ªtrans-1,2-bissiloxy effectº was
seen in the uncatalyzed, near-quantitative formation of 6 from
the cycloaddition of 4 with 2-cyclohexen-1-one (a notoriously
sluggish dienophile) at 408C! (Scheme 2).[5] It was subse-
quently discovered that 4 will also effect cycloaddition with
2-cyclohexen-1-one even at ambient temperatures, presum-
ably via 5.
OR
H
Thermal Intermolecular Hetero Diels ± Alder
Cycloadditions of Aldehydes and Imines via
o-Quinone Dimethides**
OTBS
O
OTBS
OTBS
DA
+
H
OR
4
5
O
OTBS
Martin F. Hentemann, John G. Allen, and
Samuel J. Danishefsky*
6
R = TBS
96 %
In memoryof Wolfgang Oppolzer
Scheme 2. TBS ˆ tert-butyldimethylsilyl.
The value of the Diels ± Alder (DA) reaction in chemical
synthesis can scarcely be overstated.[1] Our research group has
been continuing to pursue its long-term interest in such
cycloadditions, especially using suitable benzocyclobutenes.[2]
In particular, we have focused on 1,2-trans-disubstituted
disilyloxy compounds of the type 1 and have found that such
systems partake in intermolecular DA cycloadditions with
suitable dienophiles under remarkably mild conditions.[3]
These results strongly suggest that 1 undergoes facile bond
We subsequently noted that benzocyclobutene 4 exhibits
thermochromic behavior, a characteristic that simplifies the
monitoring of these types of reactions. Compound 4 exists as a
colorless oil, either neat, or in benzene solution at temper-
atures below 08C. However, it becomes yellow upon being
warmed to room temperature. This color is discharged upon
recooling. The color also disappears following exposure to a
dienophile. Accordingly, it seems reasonable[6] to interpret
our findings in terms of a low equilibrium concentration of 5,
although in insufficient amount for detection by NMR
analyses.
The initial successes with carbon dienophiles prompted us
to expand the scope of our inquiry by focusing on hetero-
dienophiles. In an extensive series of investigations in the
1980s our research group discovered and developed the first
examples of diene ± aldehyde and diene ± imine condensations
in cases where the formal heterodienophile was not especially
activated.[7] However, in those studies it was necessary to take
recourse to Lewis acid catalysis to accomplish such reactions
with general, as opposed to specially activated, heterodieno-
[*] Prof. S. J. Danishefsky,[‡] Dr. M. F. Hentemann, Dr. J. G. Allen
Laboratory for Bioorganic Chemistry
Sloan-Kettering Institute for Cancer Research
1275 York Avenue, Box 106, New York, NY 10021 (USA)
Fax : (‡1)212-772-8691
E-mail: s-danishefsky@ski.mskcc.org
‡
[ ] Department of Chemistry
Columbia University
New York, NY 10027 (USA)
[**] This work was supported by the National Institutes of Health
(AI 16943/CA 28824). Postdoctoral Fellowship support is gratefully
acknowledged by M.F.H. (5T32 CA62948-05) and J.G.A (NIH, CA-
80356). We are grateful to Dr. George Sukenick (NMR Core Facility,
Sloan-Kettering Institute) for NMR and mass spectral analyses.
Angew. Chem. Int. Ed. 2000, 39, No. 11
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