Synthesis, double cycloaromatization, and dna-cleaving activities of (Z,Z)-11-sulfonylundeca-3,7-diene-1,5,9-triyne system

Full text of DOI:10.1021/jo970513x

4546
J . Org. Chem. 1997, 62, 4546-4548
Sch em e 1
Syn th esis, Dou ble Cycloa r om a tiza tion , a n d
DNA-Clea vin g Activities of
(Z,Z)-11-Su lfon ylu n d eca -3,7-d ien e-1,5,9-tr iyn e
System
Chi-Fong Lin and Ming-J ung Wu*
School of Chemistry, Kaohsiung Medical College,
Kaohsiung, Taiwan, Republic of China
Received March 19, 1997
(Z)-Allene-ene-yne systems have been shown to
undergo mild thermal cyclization to form the biradical
R,3-didehydrotoluene1 and also exhibit DNA-cleaving
activity.2 The barrier to cyclization of (Z)-1,2,4-hep-
tatrien-6-yne is considerably lower than that of (Z)-hex-
3-ene-1,5-diyne.1c Introduction of an alkyl substituent
at the terminus of the allenic moiety will accelerate the
reaction rate of cyclization.3 Enediyne sulfones are stable
at room temperature and are isomerized to eneyne-
allene-sulfones under alkaline conditions. These eneyne-
allene-sulfones were not isolable, spontaneously cyclized
to form biradical intermediates under mild conditions,3e,4
and exhibited good DNA-cleaving activity.5,6 In an
extension of our research in this area, we have synthe-
sized a new enediyne 1 which contains the (Z,Z)-11-
sulfonylundecan-3,7-diene-1,5,9-triyne system. The double
cycloaromatization of 1 through an eneyne-allene-
sulfone to form an R,6-didehydro-R-methylnaphthalene
and the DNA-cleaving activity of this new enediyne are
reported in this note.
Sch em e 2
The synthesis of the prototype diene-triyne 1 is
outlined in Scheme 1. Palladium-catalyzed coupling of
cis-1,2-dichloroethylene (2) with protected propargyl
alcohol 3 afforded 4 in 45% yield. Enyne 4 was subse-
quently coupled with (trimethylsilyl)acetylene using tet-
rakis(triphenylphosphine)palladium (0) as the catalyst
to give 5 in 70% yield. The silyl group of 8 was removed
with tetrabutylammonium fluoride in THF to afford 6
in 65% yield. Coupling of (Z)-vinyl chloride 71c with 6
gave 8 in 23% yield. The hydroxyl group of 8 was
converted to sulfide by the reported method4 to afford 9
in 45% yield. Finally, 9 was oxidized with mCPBA to
furnish sulfone 1 in 58% yield.
Compound 1 is a stable compound which has been
stored in the freezer for more than three months without
decomposition. Thermolysis of 1 (0.01 M, 131 °C, 12 h)
in chlorobenzene in the presence of 1,4-cyclohexadiene
resulted in the slow disappearance of 1 and gave a
mixture of unidentified products.7 However, treatment
of 1 with triethylamine (4 equiv) in diluted, degassed
benzene solution (0.01 M, 80 °C, 12 h) containing 1,4-
cyclohexadiene (1.5 M) afforded 10 in 18% yield. The
isolation of naphthalene 10 strongly suggested that the
diradical, R,6-didehydro-R-methylnaphthalene, 13, is
formed either by the concerted cyclization of allenyl
sulfone 11 or by a stepwise pathway through diradical
12. (Scheme 2).
(1) (a) Myers, A. G.; Dragovich, P. S. J . Am. Chem. Soc. 1989, 111,
9130. (b) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J . Am. Chem. Soc.
1989, 111, 8057. (c) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J . Am.
Chem. Soc. 1992, 114, 9369.
(2) (a) Toshima, K.; Kazumi, O.; Ohashi, A.; Nakamura, T.; Nakata,
M.; Tatsuta, K.; Matsumura, S. J . Am. Chem. Soc. 1995, 117, 4822.
(b) Nicolaou, K. C.; Maligres, P.; Shin, J .; de Leon, E.; Rideout, D. J .
Am. Chem. Soc. 1990, 112, 7825. (c) Saito, I.; Nagata, R.; Yamanaka,
H.; Okazaki, E. Tetrahedron Lett. 1989, 30, 4995. (d) Saito, I.; Nagata,
R.; Yamanaka, H.; Murahashi, E. Tetrahedron Lett. 1990, 31, 2907.
(e) Shibuya, M.; Sakai, Y.; Bando, Y.; Shishido, K. Tetrahedron Lett.
1992, 33, 957. (f) Morokuma, K.; Koga, N. J . Am. Chem. Soc. 1991,
113, 1907. (g) Fujiwara, K.; Sakai, H.; Hirama, M. J . Org. Chem. 1991,
56, 1688.
The DNA cleaving activity of 1 was examined by
incubation with supercoiled ΦX 174 DNA (form I) at pH
8.3 and 47 °C for 48 h. The agarose gel picture shown
in Figure 1 indicates that the proportion of single strand
cleavage product (Form II DNA) increased with increas-
(3) For recent reviews of eneyne-allene chemistry see: (a) Wang,
K. K. Chem. Rev. 1996, 96, 207. (b) Grissom, J . W.; Gunawardena, G.
U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453.
(4) Wu, M.-J .; Lin, C.-F.; Wu, J .-S.; Chen, H.-T. Tetrahedron Lett.
1994, 35, 1879.
(5) (a) Wu, M.-J .; Lin, C.-F.; Ong, C.-W. Bioorg. Med. Chem. Lett.
1996, 6, 675. (b) Wu, M.-J .; Lin, C.-F.; Chen, H.-T.; Duh, T.-H.; Wang,
S.-S.; Hsu, S.-C. Bioorg. Med. Chem. Lett. 1996, 6, 2183.
(6) Dai, W.-M.; Fong, K. C.; Danjo, H.; Nishimoto, S.-i. Angew.
Chem., Int. Ed. Engl. 1996, 35, 779.
(7) For an example of thermolysis of (Z,Z)-deca-3,7-diene-1,5,9-
triyne, see: Bharucha, K. N.; Marsh, R. M.; Minto, R. E.; Bergman, R.
G. J . Am. Chem. Soc. 1992, 114, 3120.
S0022-3263(97)00513-6 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 13, 1997 4547
EtOAc. The organic extracts were dried (MgSO4) and concen-
trated. The residue was purified by flash chromatography (silica
gel, 20% EtOAc in hexane as eluent) to give 6 (1.28 g, 65%) as
a yellow oil. 1H NMR (200 MHz, CDCl3) δ 5.95 (dt, 1 H, J )
11.9, 2.0 Hz), 5.81 (dd, 1 H, J ) 11.0, 2.4 Hz), 4.90 (t, 1 H, J )
3.5 Hz), 4.70 (d, 2 H, J ) 2.0 Hz), 3.92-3.80 (m, 1 H), 3.59-
3.49 (m, 1 H), 3.33 (d, 1 H, J ) 2.4 Hz), 1.87-1.50 (m, 6 H).
HRMS (EI) calcd for C12H14O2: 190.0994, found 190.1004.
(Z,Z)-12-[(2-Tet r a h yd r op yr a n yl)oxy]d od eca -4,8-d ien e-
2,6,10-tr iyn -1-ol (8). To a degassed suspension of 75a (0.9 g,
7.8 mmol) in dry Et2O (50 mL) containing Pd(PPh3)4 (0.7 g, 0.6
mmol) and CuI (0.5 g, 2.6 mmol) was added a solution of 6 (1.28
mL, 6.8 mmol) and nBuNH2 (1.78 mL, 18.3 mmol) in dry Et2O
(50 mL). The resulting brown suspension was stirred at 25 °C
for 6 h. The reaction mixture was poured into an aqueous
solution comprised of equal parts of saturated aqueous NH4Cl
and saturated aqueous NaHCO3. The organic phase was
separated, and the aqueous phase was extracted with EtOAc.
The combined organic layers were dried (MgSO4) and concen-
trated. The residue was purified by flash chromatography (silica
gel, 25% EtOAc in hexane as eluent) to give 8 (0.42 g, 23%) as
a brown oil. 1H NMR (200 MHz, CDCl3) δ 6.02 (d, 2 H, J ) 10.7
Hz), 5.89 (dt, 2 H, J ) 10.7, 1.9 Hz), 4.97 (t, 1 H, J ) 3.3 Hz),
4.49 (d, 2 H, J ) 1.9 Hz), 4.45 (d, 2 H, J ) 1.9 Hz), 3.91-3.79
(m, 1 H), 3.60-3.50 (m, 1 H), 2.92 (bs, 1 H), 1.89-1.51 (m, 6 H);
13C NMR (50 MHz, CDCl3) δ 119.5, 96.4, 94.0, 93.9, 93.4, 83.4,
82.4, 61.9, 54.6, 51.3, 30.0, 25.3, 18.8.
(Z,Z)-12-[(2-Tetr ah ydr opyr an yl)oxy]-1-(ph en ylth io)dode-
ca -4,8-d ien e-2,6,10-tr iyn e (9). To a stirred solution of 8 (0.42
g, 1.6 mmol) in CH2Cl2 (20 mL) was added methanesulfonyl
chloride (0.16 mL, 2 mmol), followed by Et3N (0.33 mL, 2.5
mmol). The resulting solution was stirred at 25 °C for 1 h and
quenched with 10% aqueous HCl solution and extracted with
EtOAc. The combined organic layers were dried (MgSO4) and
concentrated. The residue was dissolved in THF (5 mL) and
added into the solution of PhSH (0.41 mL, 4 mmol) in THF (16
mL) and H2O (4 mL) containing NaOH (0.1 g, 4 mmol). The
reaction mixture was stirred at 25 °C for 3 h, quenched with
10% aqueous NaOH, and extracted with EtOAc. The combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. The residue was purified by flash chromatography
(silica gel, 5% EtOAc in hexane as eluent) to give 9 (0.25 g, 45%)
as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 7.51-7.44 (m, 2
H), 7.35-7.22 (m, 3 H), 6.03-5.80 (m, 4 H), 4.88 (t, 1 H, J ) 3.4
Hz), 4.47 (d, 2 H, J ) 1.9 Hz), 3.90-3.75 (m, 3 H, including 3.85
(d, 2 H, J ) 2.2 Hz)), 3.58-3.49 (m, 1 H), 1.81-1.49 (m, 6 H);
13C NMR (100 MHz, CDCl3) δ 134.7, 130.2, 129.0, 126.8, 119.9,
119.8, 119.6, 119.4, 96.7, 94.2, 94.1, 93.9, 93.8, 83.3, 80.9, 62.0,
54.7, 30.3, 25.4, 23.9, 19.0.
(Z,Z)-12-[(2-Tetr a h yd r op yr a n yl)oxy]-1-(p h en ylsu lfon yl)-
d od eca -4,8-d ien e-2,6,10-tr iyn e (1). To a stirred solution of 9
(0.25 g, 0.7 mmol) in CH2Cl2 (10 mL) was added mCPBA (0.27
g, 1.5 mmol). The resulting solution was stirred at 25 °C for 30
min, quenched with saturated aqueous NaHCO3, and extracted
with EtOAc. The combined organic layers were dried (MgSO4)
and concentrated. The residue was purified by flash chroma-
tography (silica gel, 30% EtOAc in hexane as eluent) to give 1
(0.16 g, 58%) as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 8.03-
7.98 (m, 2 H), 7.71-7.52 (m, 3 H), 6.09-5.75 (m, 4 H), 4.87 (t, 1
H, J ) 3.5 Hz), 4.45 (d, 2 H, J ) 1.9 Hz), 4.21 (d, 2 H, J ) 2.3
Hz), 3.90-3.78 (m, 1 H), 3.58-3.50 (m, 1 H), 1.85-1.49 (m, 6
H); 13C NMR (100 MHz, CDCl3) δ 137.8, 134.1, 129.1, 128.9,
121.2, 119.9, 119.5, 118.4, 96.6, 94.7, 94.0, 93.6, 85.0, 84.8, 83.1,
62.0, 54.6, 49.6, 30.2, 25.3, 19.0.
1-[(P h en ylsu lfon yl)m et h yl]-5-[[(2-t et r a h yd r op yr a n yl)-
oxy]m eth yl]n a p h th a len e (10). The degassed solution of 1 (70
mg, 0.18 mmol) in benzene (20 mL) containing 1,4-cyclohexadi-
ene (3 mL, 31.5 mmol) and Et3N (0.1 mL, 0.76 mmol) was heated
at reflux with stirring for 12 h. After cooling to room temper-
ature, the reaction was quenched with 10% aqueous HCl and
extracted with EtOAc. The combined organic layers were dried
(MgSO4), and the solvent was evaporated. The residue was
purified by preparative TLC (silica gel, 20% EtOAc in hexane
as developing solvent system) to give 10 (13 mg, 18%) as a yellow
oil. 1H NMR (200 MHz, CDCl3) δ 7.60 (dd, 2 H, J ) 8.2, 1.2
Hz), 7.54 (t, 2 H, J ) 7.8 Hz), 7.40 (t, 2 H, J ) 7.5 Hz), 7.08 (t,
1 H, J ) 7.7 Hz), 6.89 (d, 1 H, J ) 7.7 Hz), 6.73 (d, 1 H, J ) 5.3
Hz), 6.69-6.66 (m, 2 H), 4.72-4.66 (m, 2 H), 4.51 (dd, 1 H, J )
F igu r e 1. Results of DNA cleavage by 1. ΦX 174 Form I DNA
(50 mM/bp) was incubated for 48 h at 47 °C with 1 in TBE
buffer solution (pH 8.3) containing 20% DMSO and analyzed
by electrophorisis (1% agarose gel, ethidium bromide stain).
Lane 1: DNA control without incubation. Lane 2: DNA control
with incubation. Lanes 3-6: DNA with 1, 10, 100, and 500
µM, respectively.
ing amount of 1. At a concentration of 100 µM (lane 5),
more than 90% of the form I DNA was converted into
form II DNA.
In summary, diene-triyne 1 was synthesized in eight
steps from cis-1,2-dichloroethylene. Treatment of 1 with
triethylamine in refluxing benzene in the presence of 1,4-
cyclohexadiene afforded double cycloaromatization ad-
duct 10. Compound 1 also exhibits excellent DNA-
cleaving activity. Compound 1 and its analogs may have
the potential in the development of new anticancer drugs.
Currently, biological studies on the cytotoxicity of these
molecules against human turmor cell lines are under
investigation.
Exp er im en ta l Section
(Z)-1-Ch lor o-5-[(2-t et r a h yd r op yr a n yl)oxy]-1-p en t en -3-
yn e (4). A degassed solution of 3 (3.36 mL, 24 mmol) and
nBuNH2 (3.3 g, 22 mmol) in dry Et2O (30 mL) was cannulated
into a degassed suspension of 2 (1.6 mL, 20 mmol) in dry Et2O
(40 mL) containing Pd(PPh3)2Cl2 (0.3 g, 0.8 mmol) and CuI (0.3
g, 1.55 mmol). The resulting brown suspension was stirred at
25 °C for 6 h. The reaction mixture was poured into a solution
of equal parts of saturated aqueous NH4Cl and saturated
aqueous NaHCO3. The organic phase was separated, and the
aqueous phase was extracted with EtOAc. The combined
organic layers were dried (MgSO4) and concentrated. The
residue was purified by flash chromatography (silica gel, 20%
EtOAc in hexane as eluent) to give 4 (2.4 g, 45%) as a yellow
oil. 1H NMR (200 MHz, CDCl3) δ 6.40 (d, 1 H, J ) 7.5 Hz), 5.91
(dt, 1 H, J ) 7.5, 2.0 Hz), 4.88 (t, 1 H, J ) 3.6 Hz). 4.46 (d, 2 H,
J ) 2.0 Hz), 3.92-3.81 (m, 1 H), 3.61-3.50 (m, 1 H), 1.88-1.50
(m, 6 H); 13C NMR (50 MHz, CDCl3) δ 128.7, 111.7, 96.8, 93.6,
79.7, 62.1, 54.6, 30.2, 25.4, 19.1. HRMS (EI) calcd for C10H13O2-
Cl: 200.0604, found 200.0612.
(Z)-1-(Tr im eth ylsilyl)-7-[(2-tetr a h yd r op yr a n yl)oxy]h ep t-
3-en e-1,5-d iyn e (5). To a degassed suspension of 4 (2.4 g, 12
mmol) in dry Et2O (40 mL) containing Pd(PPh3)4 (0.7 g, 0.6
mmol) and CuI (0.47 g, 2.5 mmol) was added a degassed solution
of (trimethylsilyl)acetylene (2.43 mL, 17.5 mmol) and nBuNH2
(4.8 mL, 49.5 mmol) in dry Et2O (30 mL). The resulting brown
suspension was stirred at 25 °C for 3 h. The reaction mixture
was poured into a solution of equal parts of saturated aqueous
NH4Cl and saturated aqueous NaHCO3. The organic phase was
separated, and the aqueous phase was extracted with EtOAc.
The combined organic layers were dried (MgSO4) and concen-
trated. The residue was purified by flash chromatography (silica
gel, 20% EtOAc in hexane as eluent) to give 5 (2.2 g, 70%) as a
yellow oil. 1H NMR (200 MHz, CDCl3) δ 5.85 (s, 2 H), 4.88 (t, 1
H, J ) 3.5 Hz), 4.47 (d, 2 H, J ) 2.4 Hz), 3.91-3.79 (m, 1 H),
3.60-3.52 (m, 1 H), 1.83-1.52 (m, 6 H), 0.22 (s, 9 H). HRMS
(EI) calcd for C15H22O2Si: 262.1389, found 262.1375.
(Z)-7-[(2-Tetr ah ydr opyr an yl)oxy]-h ept-3-en e-1,5-diyn e (6).
To a stirred solution of 5 (2.7 g, 10.3 mmol) in THF (100 mL)
was added a solution of TBAF (1 M in THF, 10.3 mL, 10.3 mmol)
at 0 °C. After stirring for 1 h, the reaction mixture was
quenched with saturated aqueous NaHCO3 and extracted with

4548 J . Org. Chem., Vol. 62, No. 13, 1997
Additions and Corrections
13.9, 7.1 Hz), 4.44 (s, 2 H), 3.95-3.85 (m, 1 H), 3.60-3.50 (m, 1
H), 1.85-1.42 (m, 6 H); MS(EI) m/ z 396 (M+, 1.3%), 171 (53%),
141 (62%), 128 (63%), 77 (100%), HRMS (EI) calcd for
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 1, 8, and 9 (3 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
C
23H24O4S: 396.1396, found 396.1395.
Ack n ow led gm en t. We thank the National Science
Council of Republic of China for financial support of this
work.
J O970513X
Additions and Corrections
Vol. 61, 1996
This procedure must be carried out in an efficient hood
with provisions for H2S trapping]. A three-neck flask
equipped with a fritted gas dispersion tube (initially
closed) and reflux condenser was charged with dithiooxa-
mide (3.26 g, 27.1 mmol). The N2 manifold exit line was
routed through two fritted gas washing bottles charged
with 20% aqueous NaOH to trap H2S. (An additional
trap consisting of a tube packed with acid gas absorbing
carbon granules may be used as a further precaution if
desired.) A solution of triethylenetetraamine (3.97 g, 27.1
mmol) in absolute EtOH (33 mL) was added in one
portion, the heterogeneous mixture was refluxed under
N2 for 4 h, and the reaction mixture was cooled to rt.
Residual H2S and NH3 were purged from the solution by
entrainment with N2, which was bubbled through the
reaction mixture (fritted gas dispersion tube) for 2 h.
Most EtOH was removed by simple distillation (water
aspirator) in the hood, CHCl3 (100 mL) was added, and
the solution was concentrated by rotary evaporation.
Solid residue was taken up in boiling toluene (100 mL)
and filtered through a glass wool plug (short-stemmed
funnel). Insoluble material was washed with additional
boiling toluene (75 mL), and the combined filtrates were
concentrated to afford 4.34 g (98%) of crude yellow
product (mp 144-146 °C). Sublimation (95 °C, 0.05 Torr)
gave 3.59 g (81%) of white solid product; mp 149-150
°C (>98% by NMR; suitable for conversion to 1). Resub-
limation gave material having mp 150-151 °C. Char-
acterization as originally reported. (Note: 2 is unstable
toward hydrolysis and should be stored in a desiccator.)
Ga r y R. Weism a n * a n d Da vid P . Reed . A New Synthesis of
Cyclen (1,4,7,10-Tetraazacyclododecane).
Pages 5186-5187. Subsequent to publication, we
discovered that the reported reaction giving bis-amidine
cyclen precursor 2, while viable, does not involve the
intermediacy of bis-thioimido ester salt 3. Isolation and
solution NMR studies have shown that dithiooxamide is
not detectably alkylated by bromoethane under the
reaction conditions employed by us and originally de-
scribed by Wang and Bauman for the synthesis of 2,2′-
bi-2-imidazoline (Wang, J . C.; Bauman, J . E., J r. Inorg.
Chem. 1965, 4, 1613). In fact, dithiooxamide and trieth-
ylenetetraamine cleanly react in the absence of EtBr to
give 2. The sulfur-containing gaseous byproduct of the
reaction is therefore H2S, not ethanethiol as reported by
us and by Wang and Bauman. The reaction is analogous
to the direct reaction of dithiooxamide and eth-
ylenediamine to give 2,2′-biimidazoline, originally re-
ported by Forssell (Forssell, G. Chem. Ber. 1891, 24,
1846).
J O974002M
As a consequence of these observations, we have
developed a modified preparation of 2, which should be
substituted for the preparation originally reported. The
revised procedure (below) is experimentally simpler, less
expensive, and gives 2 in higher yield (81%). The overall
yield of the two-step synthesis is improved to 67%.
2,3,5,6,8,9-Hexa h yd r od iim id a zo[1,2-a :2′,1′-c]p yr a -
zin e (2). [Ca u tion : Hydrogen sulfide (toxic) is evolved.
Clifton K.-F . Sh en , Ku o-Min g Ch ien , Ch iu n -Gu n g J u o,
Gu or -R on g H er , a n d Tien -Ya u Lu h *. Chiral Bisazaful-
leroids.
Page 9242. The correct address is Republic of China,
not People’s Republic of China.
J O9740047