Activation of enediynes via intramolecular iodoetherification

Article abstract of DOI:10.1055/s-2008-1032077

Intramolecular iodoetherification can be a powerful method for activation of acyclic enediyne. However, the activation depends upon the chain length and the electronic nature of the enediyne (whether aliphatic or benzo-fused). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032077

LETTER
501
Activation of Enediynes via Intramolecular Iodoetherification
Activation of
E
a
nediynes nket Das, Amit Basak*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
E-mail: absk@chem.iitkgp.ernet.in
Received 8 August 2007
The starting precursor 1 (Figure 1) for our iodotherifica-
tion study was prepared as described in Scheme 1. It in-
volved sequential Sonogashira couplings8 followed by b-
elimination and deprotection of THP ether. The nonaro-
matic enediynes 2–4 were prepared in the same way as
compound 1 starting from cis-dichloroethylene. The iodo-
etherification was first attempted on the aryl-fused ene-
diyne 1 with both I2/MeCN and NIS/MeCN. With both
these reagents, no meaningful reaction took place; with
the latter reagent, some decomposition product could be
Abstract: Intramolecular iodoetherification can be a powerful
method for activation of acyclic enediyne. However, the activation
depends upon the chain length and the electronic nature of the ene-
diyne (whether aliphatic or benzo-fused).
Key words: enediyne, iodoetherification, Bergman cyclization
Bergman cyclization (BC)1 of enediynes converts them
into 1,4-dihydrobenzene (or p-benzene) diradicals capa-
ble of abstracting H atoms from the sugar-phosphate
backbone of the DNA ultimately leading to its cleavage.2
This ability of enediynes to inflict damage to DNA is de-
pendent upon their reactivity towards undergoing BC un-
der ambient conditions. In general, controlling of the
reactivity of enediynes can be achieved through either
strain or electronic effects.3,4 The strain factor can be in-
corporated by putting the enediyne framework in a cyclic
network of size 9 or 10 which in turn also brings the acet-
ylenic carbons (the c,d-distance5) undergoing covalent
linkage closer. Thus conversion of an acyclic endiyne into
a cyclic system of appropriate size is an attractive strategy
to activate the otherwise ambiently benign precursors. In
a recent work,6 we have shown that an intramolecular
azide–alkene cycloaddition can be employed for such pur-
pose. In this communication, we describe an intramolecu-
lar iodoetherification7 approach for the triggering of
acyclic enediynes of different chain lengths in the two
arms of the acetylenic moieties. The results are quite in-
teresting and underline the importance of electrophilic ad-
dition to a double bond in enediyne activation.
9
seen. Attempted reaction with I2/Yb(OTf)3 led to electro-
philic iodination of the aromatic ring. Realizing that the
presence of an aromatic ring is posing problem due to
electrophilic substitution, we decided to study the reactiv-
ity of the nonaromatic enediynes 2–4 (Scheme 2). Thus
the enediyne 3 was treated with I2/MeCN for three days at
room temperature. It afforded only one distinct product
characterized as the diiodobenzooxepine 5 in 18% yield.
With NIS/MeCN the reaction was better in terms of yield
(34%) and side products. The higher homologous ene-
diyne 4, however, failed to react under both the condi-
tions, thus indicating the importance of ring size to be
formed by iodoetherification. The lower homologous ene-
diyne 2 when subjected to iodoetherification conditions
(NIS/MeCN) gave one major product that could be isolat-
ed by column chromatography (hexane–EtOAc, 10:1) fol-
lowed by HPLC (ODS column, 87% MeOH and 13% H2O
at 0.6 mL/min flow rate). The compound showed pair of
doublets at d = 7.34 and 7.25 (J = 8 Hz) ppm typical of a
1,2,3,4-tetrasubstituted benzene ring. There were three
other signals at d = 5.09, 3.42, and 2.84 ppm characteristic
of an ABX system. The absence of a benzylic methylene
1
in the H NMR spectrum indicated that perhaps the ben-
zylic carbon has undergone oxidation under the reaction
conditions. The 13C NMR spectrum showed the presence
of eight carbons, which indicated loss of one carbon dur-
ing the process. Analysis of mass spectral data as well as
NMR spectral analysis showed the structure to be a ben-
zocyclobutane derivative 6. The structure was further con-
firmed by the isolation of monoacetate 6a by treatment
with acetic anhydride and pyridine.
OH
OH
1
2
OH
OH
Regarding the formation of the benzooxapene derivative
5, two mechanisms (Scheme 3) can be proposed: one in-
volving a Myers–Saito pathway10 after initial iodoetheri-
fication via an endo cyclization. The other involves
iodoetherification followed by elimination to lead to the
11-membered system, which underwent BC to give rise to
the product. Mass spectrometric study on the various frac-
tions separated by HPLC showed the presence of the com-
3
4
Figure 1
SYNLETT 2008, No. 4, pp 0501–0504
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032077; Art ID: D24507ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
08

502
S. Das, A. Basak
LETTER
OMs
OH
Br
MsCl, Et3N
CH2Cl2 (anhyd)
0 °C, 5 min
97%
Br
OTHP
OTHP
7
8
9
DBU, CH2Cl2M
3 h
90%
PPTS
EtOH (anhyd)
12 h
85%
OTHP
OH
10
1
Scheme 1 Synthesis of enediyne 1
no reaction
I2
MeCN
NIS
no reaction
MeCN
OH
I2
iodination of
benzene ring
Yb(OTf)3
MeCN
1
NIS, MeCN
no reaction
or
OH
I2, MeCN
4
I2, MeCN
I
I
3 d, r.t.
18%
O
NIS, MeCN
OH
3 d, r.t.
34%
3
5
I
I
I
OAc
OH
Ac2O
NIS, MeCN
3 d, r.t.
CH2Cl2, Et3N
95%
OH
I
2
6
6a
Scheme 2 Iodoetherification of enediynes 1–4
pound 13a in the fraction (tR = 14.8 min), which can only posed in Scheme 4. Initial oxidation to the aldehyde fol-
arise from the first mechanism. The displacement of ben- lowed by a Myers–Saito-type cyclization, as shown in
zylic iodide might have taken place during HPLC separa- Scheme 3, is a possibility. Subsequent oxidation to the
tion in which methanol was used as the mobile phase.
acid followed by a decarboxylative11 ring closure can lead
to the final product. At this point the only support that we
have is that the aldehyde 14, when subjected to the same
conditions, led to the formation of 6 as the only isolable
For the formation of the benzocyclobutane product, be-
cause of loss of a carbon, some kind of oxidative pathway
can be thought of. A possible mechanism has been pro-
Synlett 2008, No. 4, 501–504 © Thieme Stuttgart · New York

LETTER
Activation of Enediynes
503
I
H
I
C
1,3-iodine shift
iodoetherification
O
O
OH
3
11
12
– HI
Myers–Saito
cyclization
I
I
I
I
BC
O
O
O
O
13
13b
12b
12a
– HI
I
I
OMe
I
I
I
MeOH
O
O
O
H
I
5
13a
13c
Scheme 3 Probable mechanism of formation of 5
product.12,13 The displacement of the benzylic iodide
probably has taken place during work up.
OH
C
CHO
I
OI
1
14
15
I
I
I
I
I
I
H
I
H
O
H
H
I
O
O
O
I
O
I
O
16
17
18
19
I
I
I
OH
I
I
20
6
Scheme 4 Probable mechanism of formation of 6
In conclusion, we have shown that intramolecular iodo-
etherification can be a powerful method for activation of
acyclic enediyne. The importance of chain length and the
electronic nature of the enediyne, aromatic or not, is im-
portant in such an activation process.
References and Notes
(1) (a) Jones, R. P.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94,
960. (b) Bergman, R. G. Acc. Chem. Soc. 1973, 6, 25.
(c) Lockhart, T. P.; Bergman, R. G. J. Am. Chem. Soc. 1981,
103, 4082. (d) Lockhart, T. P.; Comita, P. B.; Bergman, R.
G. J. Am. Chem. Soc. 1981, 103, 4091.
Synlett 2008, No. 4, 501–504 © Thieme Stuttgart · New York

504
S. Das, A. Basak
LETTER
(2) Enediyne Antibiotics as Antitumor Agents; Border, D. B.;
Doyle, T. W., Eds.; Marcel Dekker: New York, 1995.
(3) (a) Magnus, P.; Lewis, R. T.; Huffman, J. C. J. Am. Chem.
Soc. 1988, 110, 6921. (b) Magnus, P.; Fortt, S.; Patterna, T.;
Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 4986.
(c) Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 5367.
(d) Magnus, P.; Carter, P.; Elliott, J.; Lewis, R.; Harling, J.;
Patterna, T.; Butta, W. E.; Fortt, S. J. Am. Chem. Soc. 1992,
114, 2544. (e) Magnus, P.; Fairhurst, R. A. J. Chem. Soc.,
Chem. Commun. 1994, 1541.
(4) (a) Schmittel, M.; Kiau, S. Chem. Lett. 1995, 953.
(b) Maier, M. E. Synlett 1995, 13. (c) Kim, C.; Russell, K.
C. Tetrahedron Lett. 1999, 40, 3835. (d)Basak, A.; Mandal,
S.; Bag, S. S. Chem. Rev. 2003, 103; 4077. (e) Klein, M.;
Walenzyk, T.; Koenig, B. Collect. Czech. Chem. Commun.
2004, 69, 945.
(5) (a) Nicolaou, K. C.; Zuccarello, G.; Oogawa, Y.; Schweiger,
E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 10, 4866.
(b) Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184.
(6) Basak, A.; Roy, S. K.; Das, S.; Hazra, A. B.; Ghosh, S. C.;
Jha, S. Chem. Commun. 2007, 622.
(7) (a) Bartlett, P. A.; Ting, P. C. J. Org. Chem. 1986, 51, 2230.
(b) Marai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. J.
Am. Chem. Soc. 1988, 110, 1985. (c) Freeman, F.; Robarge,
K. D. J. Org. Chem. 1989, 54, 346.
(12) To a solution of compound 3 (150 mg, 1.03 mmol) in anhyd
MeCN (10 mL), NIS (278 mg, 1.23 mmol) was added and
stirred for 3 d under inert atmosphere. The reaction mixture
was extracted with Et2O, washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude was purified
via chromatography (SiO2, hexane–EtOAc = 30:1) to yield
the desired compound 5 (34%).
Selected Spectral Data
Compound 5: 1H NMR (200 MHz, CDCl3): d = 3.35 (2 H, t,
J = 4.0 Hz, CH2CH2O), 4.26 (2 H, t, J = 4.1 Hz, CH2CH2O),
5.64 (1 H, d, J = 8.4 Hz, ArCHCHOCH2), 6.54 (1 H, d,
J = 8.4 Hz, ArCHCHOCH2), 7.28 (1 H, d, J = 8.3 Hz, ArH),
7.38 (1 H, d, J = 8.3 Hz, ArH). 13C NMR (50 MHz, CDCl3):
d = 43.02, 71.28, 100.68, 100.76, 108.71, 136.99, 138.08,
139.11, 142.38, 146.99. MS (EI): m/z = 398.87 [MH+].
Compound 6: 1H NMR (200 MHz, CDCl3): d = 2.84, 4.42 (2
H, ABX, JAX = 4.2 Hz, JBX = 0.0 Hz, JAB = 14.6 Hz,
ArCH2CHOH), 5.09 (1 H, dd, J = 1.8, 4.7 Hz,
ArCHOHCH2), 7.25 (1 H, d, J = 8.2 Hz, ArH), 7.34 (1 H, d,
J = 8.3 Hz, ArH). 13C NMR (50 MHz, CDCl3): d = 42.84,
68.66, 87.07, 89.96, 137.35, 138.69, 149.76, 153.60. MS
(EI): m/z = 395.88 [MNa+], 354.85 [M – H2O].
(13) To a solution of alcohol 6 (10 mg, 0.037 mmol) in CH2Cl2 (5
mL), Ac2O (4 mL, 0.044 mmol), Et3N (6 mL, 0.044 mmol),
and DMAP (5 mol%) were added at 0 °C. The reaction
mixture was stirred for 10 min after which it was poured into
H2O and CH2Cl2. The organic layer was washed with H2O,
dried, and then evaporated. The compound 6a was then
isolated by column chromatography (SiO2, hexane–
EtOAc = 30:1) as a white solid (98%).
(8) (a) Sonogashira, K.; Tohoda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Takahashi, S.; Kuroyama, Y.;
Sonogashira, K.; Hagihara, N. Synthesis 1980, 627.
(9) Hajra, S.; Maji, B.; Karmakar, A. Tetrahedron Lett. 2005,
46, 3073.
(10) (a) Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc. 1989,
111, 9130. (b) Nagata, R.; Yamanaka, H.; Okazaki, E.;
Saito, I. Tetrahedron Lett. 1989, 30, 4995. (c) Myers, A. G.;
Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111,
8057. (d) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am.
Chem. Soc. 1992, 114, 9369.
Selected Spectral Data
Compound 6a: 1H NMR (400 MHz, CDCl3): d = 2.14 (3 H,
s, CH3COOCH), 2.94, 3.50 (2 H, ABX, JAX = 4.4 Hz,
JBX = 0.0 Hz, JAB = 14.8 Hz, ArCH2CHOH), 5.87 (1 H, d,
J = 4.0 Hz, ArCHOHCH2), 7.28 (1 H, d, J = 8.4 Hz, ArH),
7.36 (1 H, d, J = 8.0 Hz, ArH). 13C NMR (100 MHz, CDCl3):
d = 20.87, 40.93, 69.12, 87.09, 88.71, 138.09, 139.96,
148.64, 150.16, 170.50. MS (EI): m/z = 413.35 [M+].
(11) (a) Cohen, M. J.; McNelis, E. J. Org. Chem. 1984, 49, 515.
(b) Naskar, D.; Roy, S. J. Org. Chem. 1999, 64, 6896.
Synlett 2008, No. 4, 501–504 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.