Design and synthesis of bisenediyne bissulfones and their reactivity under basic condition

Article abstract of DOI:10.1016/j.bmcl.2009.03.094

A new class of bisenediyne bis sulfones has been synthesized. These molecules underwent cycloaromatization under basic conditions via isomerization to allene and were able to cleave ds-stranded plasmid DNA.

Full text of DOI:10.1016/j.bmcl.2009.03.094

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2815–2818
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of bisenediyne bissulfones and their reactivity under
basic condition
*
Sanket Das, Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of bisenediyne bis sulfones has been synthesized. These molecules underwent cycloaroma-
Received 9 January 2009
Revised 3 March 2009
Accepted 23 March 2009
Available online 26 March 2009
tization under basic conditions via isomerization to allene and were able to cleave ds-stranded plasmid
DNA.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Bisenediyne bissulphone
Allene
Cycloaromatization
DNA cleavage
Bergman cyclization
Myers–Saito cyclization
Apart from Myers–Saito cyclization1, (Z)-allene-ene-yne sys-
tems can undergo Schmittel cyclization2 (as shown in Scheme 1)
under certain structural perturbations, especially when the hydro-
gen at the alkyne termini is replaced by an aryl group or by a bulky
substituent. Recently, enediyne sulfones have also emerged as a
new class of DNA-cleaving agents.3 Under alkaline conditions,
these can be isomerized to eneyne–allene–sulfone, which sponta-
neously cyclized to form biradical intermediates following the
MSC pathway. Recently, Wu and Lin have exploited the double
cycloaromatization of the (Z,Z)-11-sulfonylundecan-3,7-diene-
1,5,9-triyne system through an eneyne–allene–sulfone forming
the enediyne 4 in 85% yield. After removal of silyl group, com-
pound 5 was further coupled with iodo alkyne 3 under Sonogashira
conditions to provide the bis THP ether in 55% yield. Treatment of 6
with catalytic amount of PPTS in EtOH produced the bisalcohol 7
which was then converted to the bis sulfide 9 following a reported
procedure.9 Finally, m-CPBA oxidation of 9 provided the bis sulfone
1 in 75% yield (Scheme 3).
The synthesis of compound 2 was similar to what was followed
for compound 1. Only difference was a Glaser type of coupling10
which was performed instead of 3rd Sonogashira coupling. For
that, the enediyne
5 was treated with CuI (5 mol %) and
an
a
,6-didehydro-
a
-methylnaphthalene.4
N,N,N0,N0-tetramethyl ethylenediamine (5 mol %) in acetone under
oxygen atmosphere to afford compound 10 in 77% yield. The syn-
thetic scheme for compound 2 is presented below (Scheme 4). All
the compounds were characterized by NMR and mass spectro-
scopic data. In addition, the structure of compound 1 was further
confirmed by single crystal X-ray analysis11 (Fig. 1).
Much of the current research has paid attention to the design,
synthesis and reactivity of molecules that generate new types of
dehydroaromatic biradical intermediates at different locations of
the molecule.5 Several workers have reported cyclization behav-
iour of bis-aryl-triynes and related systems.6 Based on the pioneer-
ing work of Wang7 on cascade Schmittel cyclization, we have
designed and subsequently synthesized novel bis enediyne bis
sulfones 1 and 2 (Scheme 2). Their chemical and biological reactiv-
ity under basic conditions are also studied.
The synthesis of the representative compound 1 is outlined in
Scheme 3. Palladium catalyzed coupling of 1,2-diiodobenzene with
protected propargyl alcohol afforded 3 in 70% yield. Another round
of Sonogashira coupling8 of eneyne 3 with TMS–acetylene afforded
The chemical reactivity of the sulfones 1 and 2 were then eval-
uated. Under neutral conditions, the compounds are stable with no
isomerization occurring. However, treatment of 1 with triethyl-
amine (2 equiv) in diluted degassed benzene solution containing
1,4-cyclohexadiene (20 equiv) at room temperature resulted in
slow disappearance of 1 with conmittant production of a mixture
of unidentified products after 24 h at room temperature. However,
by carefully controlling the reaction for over 4 h at 15 °C, we were
able to isolate the monoallene bissulfone 14 (Scheme 5).
The isolation of monoallene 14 strongly suggested that the
isomerization to the bisallene is either very slow or may not be
* Corresponding author. Tel.: +91 3222283300; fax: +91 3222282252.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
0960-894X/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.03.094

2816
S. Das, A. Basak / Bioorg. Med. Chem. Lett. 19 (2009) 2815–2818
C
H
H
C2-C6
Schmittel
cyclization
Myers-Saito
cyclization
R
R
R
R
R= Ar
R
R= H
Scheme 1. Cyclization mode of eneyne allene.
occurring. If the stirring at 15 °C was continued for 36 h, the mono-
allene also disappeared and a mixture of two inseparable products
was isolated (combined yield ꢀ33%, ratio 2:1). These could not be
separated even by HPLC. However, considering all the spectro-
scopic data, like appearance of four acetylenic carbon signals, four
2H singlets (for both the isomers) and the tendency of 7-phenyl
substituted eneyne allenes to undergo Schmittel type cyclization,
isomeric structures 17 and 18 were assigned for the two products
(Scheme 6). The benzylidine hydrogens in the two isomers ap-
peared as broad singlets at d 6.59 and 7.17, similar to what has
been reported by Wu et al.5c in benzfulvene systems. Moreover,
the 1H-COSY spectrum also showed the connectivity (allylic cou-
pling) between the benzylidine hydrogen and the methylene
hydrogens attached to the sulfonyl moiety. Mass spectrum showed
SO2Ar
SO2Ar
SO2Ar
SO2Ar
1
2
Scheme 2. The target bispropargyl bissulfones.
OTHP
OTHP
a
OTHP
OTHP
c
b
I
5
3
4
TMS
OH
6
OTHP
OMs
SPh
e
d
g
f
1
7
OH
8
9
OMs
SPh
Scheme 3. Synthesis of sulfone 1. Reagents and conditions: (a) TMS–acetylene, CuI, Pd(PPh3)4, Et3N, 85%; (b) KF/MeOH, 88%; (c) 3, Pd(PPh3)4, CuI, Et3N, 55%; (d) PPTS/EtOH,
75%; (e) MsCl/Et3N, DCM, 0 °C, 90%; (f) PhSH/Et3N/DCM, 78%; (g) m-CPBA/DCM, rt, 75%.
OTHP
OH
c
b
d
a
5
10
OMs
OTHP
OH
SPh
11
e
2
13
SPh
OMs
12
Scheme 4. Synthesis of sulfone 2. Reagents and conditions: (a) CuI/O2, TMED, acetone, 77%; (b) PPTS, EtOH, 70%; (c) MsCl, Et3N, DCM, 0 °C, 88%; (d) PhSH/ET3N, DCM, 82%; (e)
m-CPBA, DCM, rt, 77%.

S. Das, A. Basak / Bioorg. Med. Chem. Lett. 19 (2009) 2815–2818
2817
ical to undergo 5-endo-dig cyclization12 might be due to its rapid
quenching of the radical or perhaps due to geometric constrains.13
The other sulfone 2, upon treatment with triethylamine
(2 equiv) in presence of 1,4-cyclohexadiene (20 equiv) in benzene
at 15 °C temperature for 4 h yielded only a distinct product identi-
fied as the monoallene 19. Thus like the previous one, here also we
isolated the monoallene 19 under controlled reaction condition.
This monoallene was found to be more reactive than the previous
one 14. Spectral characterization for this mono allene was done in
similar fashion as that for 1. Again, if the stirring was continued for
24 h at 15 °C in CHCl3, a mixture of two inseparable compounds
were isolated. One of the structures was identified as a bisnaphthyl
derivative 22 produced by double Myers–Saito cyclization of the
bisallene 21. The structure was mainly based on the absence of
any vinyl hydrogen in the 1H NMR, absence of any acetylenic car-
bon in the 13C NMR and appearance of peak at m/z 563.2 from mass
spectral data.
Figure 1. X-ray structure of sulfone 1.
Since both the sulfones 1 and 2 can isomerize initially to mono-
allenes in presence of base, it is expected to show DNA cleavage
activity via both alkylation as well as oxidative diradical pathway.
Based on this, the cleavage experiments were carried out with both
the molecular ion peak at m/z 537 commensurate with the molec-
ular formula (MH+). Both the products were produced by Schmittel
cyclization of the monoallene. The failure of the intermediate rad-
SO2Ph
SO2Ph
.
H
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
15
17
C
SO2Ph
H
.
SO2Ph
1
14
SO2Ph
SO2Ph
18
16
Scheme 5. Reactivity of sulfone 1 in Et3N.
SO2Ph
SO2Ph
C
SO2Ph
H
Et3N / CHCl3
15 0C, 4h
Et3N / CHCl3
15 0C, 24h
H
H
C
SO2Ph
C
SO2Ph
H
SO2Ph
2
H
20
19
SO2Ph
SO2Ph
SO2Ph
SO2Ph
22
21
Scheme 6. Reactivity of sulfone 2 in Et3N.

2818
S. Das, A. Basak / Bioorg. Med. Chem. Lett. 19 (2009) 2815–2818
Engl. 1996, 35, 1843; (f) Schmittel, M.; Keller, M.; Kiau, S.; Strittmatter, M.
Chem. Eur. J. 1997, 3, 807.
3
2
1
Form II (nicked form)
3. (a) Nicolaou, K. C.; Skokotas, G.; Fuyura, S.; Suemune, H.; Nicolaou, D. C. Angew.
Chem., Int. Ed. Engl. 1990, 29, 1064; (b) Nicolaou, K. C.; Wendeborn, S.; Maligres,
P.; Isshiki, K.; Zein, N.; Ellestad, G. Angew. Chem., Int. Ed. Engl. 1991, 30, 418; (c)
Haruna, K.-i.; Tanabe, K.; Ishii, A.; Dai, W.-M.; Min-Dai, W.; Hatta, H.;
Nishimoto, S.-i. Bioorg. Med. Chem. 2003, 11, 5311.
Form I (supercoiled form)
5
4
1
4. Wu, M. J.; Lin, C. F. J. Org. Chem. 1997, 62, 4546.
Form II (nicked form)
5. (a) Bharucha, K. N.; Marsh, R. M.; Minto, R. E.; Bergman, R. G. J. Am. Chem. Soc.
1992, 114, 3120; (b) Miyawaki, K.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1998,
39, 6923; (c) Wu, H. H.; Lin, C. F.; Lee, J. L.; Lu, W. D.; Lee, C. Y.; Chen, C. C.; Wu,
M. J. Tetrahedron 2004, 60, 3927.
6. (a) Bharucha, K.; Marsh, R.; Minto, R.; Bergman, R. J. Am. Chem. Soc. 1992, 114,
3120; (b) Matzger, A.; Vollhardt, P. Chem. Commun. 1997, 1415; (c) Lewis, K. D.;
Rowe, M. P.; Matzger, A. J. Tetrahedron 2004, 60, 7191; (d) Alabugin, I. V.;
Gilmore, K.; Patil, S.; Manoharan, M.; Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J.
Am. Chem. Soc. 2008, 130, 11535.
Form I (supercoiled form)
Figure 2. DNA cleavage experiment of compound 1 and 2 after 8 h and 16 h
incubation at 37 °C.
1
2
3
4
5
7. (a) Han, X.; Zhang, Y.; Wang, K. K. J. Org. Chem. 2005, 70, 2406; (b) Wang, K. K.
Chem. Rev. 1996, 96, 207.
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.
Form II (nicked form)
Form I (supercoiled form)
9. (a) Mitra, D.; Kar, M.; Pal, R.; Basak, A. Bioorg. Med. Chem. Lett. 2007, 17, 4514;
(b) Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861.
10. Okamoto, T.; Kudoh, K.; Wakamiya, A.; Yamaguchi, S. Org. Lett. 2005, 7, 5301.
11. The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC 721862.
12. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
Figure 3. DNA cleavage experiment of compound 14 and 19 after 8 h and 16 h in
incubation at 37 °C.
13. It may be mentioned here that Alabugin et al. have shown that 6-endo-dig
processes involving vinyl radicals in conjugated systems are
thermodynamically more favourable as compared to the corresponding 5-
exo processes; Alabugin, I. V.; Manoharan, M. J. Am. Chem. Soc. 2005, 127,
12583. In our case, such substantial aromatic stabilization is lacking (fulvene
from 5-endo vs benzene from 6-endo). Wu et al.5c have also reported the
failure of an aryl radical to undergo 6-endo-dig cyclization involving a cyanide
functionality as the dig component.
the sulfones at 37 °C using pBR 322 supercoiled plasmid DNA at pH
7.2 in presence of Et3N (Figs. 2 and 3). The results showed higher
cleavage efficiency for sulfone 2 as compared to the other. For
the sulfone 2, the percent cleavage efficiency increased with grad-
ual increase in time of incubation (62% at 16 h and 47% at 8 h). This
is because of the increase of concentration of monoallene or dirad-
ical intermediates with time. For the sulfone 1, the efficiency was
45% at 8 h which remained same after 16 h of incubation. Same re-
sults were also observed when the monoallene 14 and 19 were
incubated with double stranded plasmid DNA (pBR 322) at 37 °C
at pH 7.2 without using any base.
Selected spectral data: All the 1H and 13C NMR spectra were recorded at
400 MHz and 100 MHz respectively in CDCl3.For 1 dH 4.27 (4H, s), 7.26–7.37
(6H, m), 7.43–7.55 (8H, m), 8.02 (4H, d, J = 7.6 Hz); dC: 49.5, 80.6, 86.1, 91.6,
123.9, 125.7, 128.2, 128.8, 128.9, 128.9, 128.9, 132.3, 132.5, 134.1, 137.6; Mass
(ESI): m/z 535 (MH+).
For 2 dH: 4.29 (4H, s), 7.30–7.38 (6H, m), 7.50–7.65 (8H, m), 8.06 (4H, d,
J = 7.2 Hz); dC: 49.6, 77.7, 81.0, 81.4, 85.6, 124.3, 125.1, 128.8, 128.9, 129.0,
129.2, 129.4, 129.4, 132.7, 133.3, 134.3, 137.7, Mass (ESI): m/z 559.4 (MH+).
For 14: dH: 4.22 (2H, s), 6.68 (1H, d, J = 6.4 Hz), 7.27–7.36 (3H, m), 7.39–7.57
(10H, m), 7.61–7.63 (1H, d, J = 7.6 Hz) 7.96–7.99 (5H, m); dC: 49.4, 81.1, 86.3,
90.6, 93.2, 101.4, 104.9, 122.1, 124.0, 125.4, 127.3, 127.6, 128.4, 128.8, 128.8,
128.8, 128.9, 129.0, 129.3, 131.5, 131.9, 132.3, 132.6, 132.7, 133.7, 134.0, 137.6,
208.4; Mass (ESI): m/z 535 (MH+).For 19: dH: 4.22 (2H, s), 6.68 (1H, d,
J = 6.4 Hz), 7.27–7.65 (14H, m), 7.96–7.99 (5H, m); Mass (ESI): m/z 559 (MH+).
Mixture of compound 17 and 18 dH: 3.25 (2H, s, major), 3.29 (2H, s, minor), 3.74
(2H, s, major), 3.82 (2H, s, minor), 6.59 (1H, s, minor), 7.17 (1H, s, major), 7.19–
7.39 (26H, m, major + minor), 7.57 (2H, m, minor), 7.84 (2H, d, J = 8.2 Hz,
major), 8.04 (2H, dd, J = 8.8, 2.0 Hz, minor), 8.11 (2H, dd, J = 8.8, 2.0 Hz, major),
8.25 (2H, d, J = 4.8 Hz, minor), 8.27 (2H, d, J = 4.8 Hz, major); dC: 49.3, 49.5, 54.2,
54.3, 81.8, 81.9, 85.3, 85.7, 127.6, 127.7, 128.2,, 128.2, 128.5, 128.6, 128.7,
128.8, 128.9, 128.9, 129.0, 129.1, 129.2, 129.3, 129.6, 129.8, 129.9, 132.4, 132.7,
132.7, 132.9, 133.0, 133.4, 133.5, 133.7, 133.9, 134.0, 134.1, 134.3, 145.6,
146.4; Mass (ESI): m/z 537 (MH+); HRMS: calcd for C32H24O4S2 + H+ 537.1194
found 537.1197.
Acknowledgments
The author S.D. is grateful to CSIR, Government of India for a fel-
lowship. DST is thanked for providing funds for 400 MHz NMR
facility under the IRPHA programme.
References and notes
1. (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111, 8057; (b)
Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc. 1989, 111, 9130; (c) Nagata, R.;
Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron Lett. 1989, 30, 4995; (d) Nagata,
R.; Yamanaka, H.; Murahashi, E.; Saito, I. Tetrahedron Lett. 1990, 31, 2907.
2. (a) Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975; (b)
Gillmann, T.; Hulsen, T.; Massa, W.; Wocadlo, S. Synlett 1995, 1257; (c) Garcia, J.
G.; Ramos, B.; Pratt, L. M.; Rodriguez, A. Tetrahedron Lett. 1995, 36, 7391; (d)
Schmittel, M.; Kiau, S.; Siebert, T.; Strittmatter, M. Tetrahedron Lett. 1996, 37,
999, 7691; (e) Schmittel, M.; Strittmatter, M.; Kiau, S. Angew. Chem., Int. Ed.
For 22 dH: 4.66 (4H, br s), 7.39–7.47 (6H, m), 7.53–7.60 (8H, m), 7.67–7.72 (4H,
m), 8.09 (4H, d, J = 8.0 Hz); Mass (ESI): m/z 563.2 (MH+); HRMS: calcd for
C34H26O4S2 + H+ 563.1350 found 563.1354.