Facile unmasking of dicobalt hexacarbonyl complexes of 1-cyclodecene- 3,9-diynes (Enediynes)

Full text of DOI:10.1021/jo9716035

J . Org. Chem. 1997, 62, 9379-9381
9379
the corresponding dicobalt hexacarbonyl complexes 3. As
expected, the complex 3 (X ) CH2) proved thermally
stable over extended periods and was amenable to routine
manipulation and spectroscopic analysis, which con-
firmed that both alkynes had undergone complexation.
Though methods to effect decomplexation to give 2 had
been described, we were particularly interested in mini-
mizing in situ thermal decomposition of the enediyne
product and, thus, desired a convenient method that
worked rapidly at low temperature.
F a cile Un m a sk in g of Dicoba lt
Hexa ca r bon yl Com p lexes of
1-Cyclod ecen e-3,9-d iyn es (En ed iyn es)
Graham B. J ones,* J ustin M. Wright, Teresa M. Rush,
Gary W. Plourde, II, Thomas F. Kelton,
J ude E. Mathews, Robert S. Huber, and
J ames P. Davidson
Department of Chemistry and Greenville
Hospital System-Clemson University, Laboratory of
Medicinal Chemistry, Clemson University,
Clemson, South Carolina 29634-1905
Resu lts a n d Discu ssion
Received August 28, 1997
To assay the biological effects of enediyne-derived diyls
4 effectively, it was essential for us to employ a rapid
method for unmasking of the complexes 3. Such a
method would then allow shelf-stable precursors 3 to be
converted to the enediyne immediately, allowing batch-
style bioassay methods to be employed. Due to the
thermal lability of the enediyne 2 (X ) CH2), we elected
to initially study unmasking methods using a model
compound of comparable molecular weight and, thus,
prepared and investigated the cobalt carbonyl complex
of 5-decyne, 7 (Scheme 2). The results of the decomplex-
ation study are presented in Table 1. Established
methods such as oxidative decomplexation using tri-
methylamine N-oxide,6 while effective at low tempera-
ture, required multiple equivalents to achieve quantita-
tive recovery of alkyne (Table 1, entries 1-3). Ferric
nitrate proved sluggish with multiple equivalents (Table
1, entry 4),7 and potassium nitrosodisulfonate (Fremy’s
salt) gave only moderate yields with 10 equiv of agent
(Table 1, entry 5). Ceric ammonium nitrate (CAN),
however, worked extremely well at low temperature with
1 equiv of agent (Table 1, entry 6).8 In an effort to find
a convenient system that could work quantitatively using
minimal amounts of reagent, a range of other ammonium
salts were investigated, and it was eventually discovered
that TBAF/THF could induce decomplexation (Table 1,
entries 8-13). Reactions were smooth at low tempera-
ture, giving a near-quantitative yield of product within
3 h at -10 °C (Table 1, entry 14). Given the commercial
availability of this agent as a stock solution9 and the
potential for few side reactions with its use,10 it was thus
adopted as the agent of choice for all subsequent depro-
tections. With mild and efficient methods for decom-
plexation in hand, bis(dicobalt hexacarbonyl) complexes
of the known enediynes 2 (X ) CH2, S, O) were prepared,
and TBAF/THF-induced deprotection was investigated.
As demonstrated in the model system, this method
worked extremely well at -10 °C and allowed isolation
of essentially pure enediyne following brief workup (Table
2). Half-lives of the enediynes (37 °C) were in agreement
with reported/calculated values (X ) CH2 18 h,11 X ) S
In tr od u ction
Cyclic enediynes have become increasingly important
over the past decade since the isolation of naturally
ocurring enediyne antitumor agents including calicheam-
icin (1),1 a derivative of which is currently undergoing
clinical trials for the treatment of myeloid leukemia.2 The
pharmacophore of the enediyne antibiotics is described
either by a 9- or 10-membered cyclic enediyne subgroup,
many of which show antitumor activity in their own
right.3 The origin of antitumor activity of cyclic C-10
enediynes resides in the ability of the enediyne subgroup
to undergo Bergman cyclization resulting in a reactive
1,4-diyl radical. These diyl intermediates are capable of
causing single- and double-stranded DNA breaks and
possibly protein lesions. These two events presumably
play a dominant role in the biological activity of ene-
diynes.1
The half-lives for unstrained 10-membered carbocyclic
enediynes is around 8-24 h at physiological temperature;
thus, any attempted chemical synthesis of cyclic ene-
diynes must be mindful of this thermal lability. We
recently developed a direct synthetic route to cyclic C-10
enediynes 2, based on a low-temperature carbenoid
coupling-elimination strategy, and found it desirable to
mask the product enediynes to enable handling and
manipulation at ambient temperature.4 Encouraged by
literature reports,5 we elected to protect the products as
* To whom correspondence should be addressed. Tel.: (864) 656-
1106. Fax: (864) 656-6613. E-mail: graham@clemson.edu.
(1) For reviews, see: Grissom, J . W.; Gunawardena, G. U.; Kling-
berg, D.; Huang, D. Tetrahedron 1996, 52, 6453. Nicolaou, K. C.; Smith,
A. L.; Yue, E. W. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5881.
(2) The calicheamicins: Lee, M. D.; Durr, F. E.; Hinman, L. H.;
Haman, P. R.; Ellestad, G. A. In Advances in Medicinal Chemistry;
Maryanoff, B. E., Maryanoff, C. A., Eds.; J AI Press: Greenwich, 1993;
Vol. 2.
(3) Nicolaou, K. C.; Zuccarello, G.; Riemer, C.; Estevez, V. A.; Dai,
W.-M. J . Am. Chem. Soc. 1992, 114, 7360.
(4) J ones, G. B.; Huber, R. S.; Mathews, J . E. J . Chem. Soc., Chem.
Commun. 1995, 1161.
(6) For an overview see: Davies, S. G. Organotransition Metal
Chemistry: Applications to Synthesis; Pergamon Press: Oxford, 1982.
(7) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(8) Seyferth, D.; Wehman, A. T. J . Am. Chem. Soc. 1970, 92, 5520.
Magnus, P.; Eisenbeis, S. A.; Fairhurst, R. A.; Iliadis, T.; Magnus, N.;
Parry, D. J . Am. Chem. Soc. 1997, 119, 5591.
(9) Available as a 1.0 M solution in THF from the Aldrich Chemical
Co. [cat. no. 21,614-3].
(10) Schreiber has observed a TBAF-mediated tandem desilylation-
decomplexation of the [(trimethylsilyl)alkynyl]cobalt carbonyl com-
plex: Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J . Am. Chem. Soc.
1986, 108, 3128.
(5) Nicholas, K. M.; Pettit, R. Tetrahedron Lett. 1971, 37, 3475.
Magnus, P. Tetrahedron 1994, 50, 1397.
(11) Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J .;
Kumazawa, T. J . Am. Chem. Soc. 1988, 110, 4866.
S0022-3263(97)01603-4 CCC: $14.00 © 1997 American Chemical Society

9380 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
Sch em e 1. Th er m a l Decom p osition of Un str a in ed
En ed iyn es
4 that they generate to be conducted on demand and is
expected to find application in other thermally labile
enediyne-type systems where conventional methods are
ineffective.16 Significantly, deprotection of 3, X ) CH2,
using CAN required >6 equiv of reagent at -10 °C and
required chromatographic purification of the product
(70%).
In summary, a facile method for decomplexation of
cobalt carbonyl-complexed acetylenes has been developed.
The method provides the opportunity for rapid unmask-
ing of thermally labile cyclic enediyne derivatives and
may also find application in the deprotection of other
useful substrates.7,17
Exp er im en ta l Meth od s
Unless stated otherwise, all reactions described herein were
performed in glassware that had been oven dried (140 °C/12 h)
and then flame dried prior to use. Reactions were conducted
under an atmosphere of nitrogen, with flasks sealed using dried
septa (P2O5). The tips of the cannulas were flame dried under
a stream of dry nitrogen gas prior to use. THF was distilled
immediately prior to use from sodium-benzophenone ketyl.
Methylene chloride was distilled from P2O5. Dicobalt octacar-
bonyl was obtained from Strem Chemicals. All other reagents
and solvents were commercial grade and purified according to
standard convention. Chromatography was perfomed on Brock-
mann grade I neutral alumina. Analytical TLC was performed
on glass-backed 250 µm plates visualized with anisaldehyde and
phosphomolybdic acid.
Sch em e 2. Decom p lexa tion of 5-Decyn e‚Co2(CO)6
Ta ble 1. Decom p lexa tion of Dicoba lt Hexa ca r bon yl
Com p lex 7
5-Decyn e-Dicoba lt Hexa ca r bon yl Com p lex 7. 5-Decyne
(0.97 g, 7.0 mmol) was dissolved in cold CH2Cl2 (120 mL) in a
1000 mL round-bottomed flask. The contents of the flask were
slowly cannulated into a solution of dicobalt octacarbonyl (3.00
g of 90 wt %/wt in hexane, 8.8 mmol) in CH2Cl2 (300 mL) that
had been precooled to -10 °C. The resulting solution was
allowed to stir in the dark for 12 h at -10 °C, after which time
the red liquid was filtered (under an atmosphere of nitrogen)
by cannula through a plug of neutral alumina and concentrated
in vacuo. Column chromatography (alumina, hexane eluent)
afforded 2.55 g (93% yield) of the complexed 5-decyne as a deep
red oil: 1H NMR (300 MHz, CDCl3) 2.82 (t, J ) 7.5 Hz, 4H),
1.53 (m, 8H), 0.958 (t, J ) 6.9, 6H); 13C NMR (75 MHz, CDCl3)
δ 200.4, 99.9, 33.8, 22.7, 13.8; IR (CCl4) 3412, 2970, 2025, 1472
cm-1; MS (EI) 138 (14), 95 (53), 81 (82), 67 (100), 54 (95). Anal.
Calcd for C16H18Co2O6: C, 45.31; H, 4.28. Found: C, 45.34; H,
4.33.
entry
reagents
(CH3)3NO
equiv
solvent
T (°C) % 6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
1
5
5
10
6
THF
THF
-10/4
-78/2
61
32
>99
90
(CH3)3NO
(CH3)3NO
Fe(NO3)3‚H2O
(KSO3)2NO
Ce(NH4)2(NO3)6
Ce(NH4)2(NO3)6
Bu4NHSO4
Bu4NClO4
Bu4NCl
Bu4NBr
Bu4NPF6
Bu4NF
Bu4NF
Bu4NF
CH3COCH3/THF -78/4
CH3COCH3/THF +25/12
CH3COCH3/THF -78/3
CH3COCH3/THF -78/3
CH3COCH3/THF -78/3
H2O/THF
H2O/THF
H2O/THF
H2O/THF
THF
33
>99
77
1
10
10
10
10
10
10
5
+25/12
+25/48
+25/12
+25/48
+25/12
+25/1
20
5
10
10
5
THF
THF
THF
THF
>99
>99
98
-10/3
1
1
-10/4
-78/5
Bu4NF
96
1-Cyclod ecen e-3,9-d iyn e-b is(d icob a lt h exa ca r b on yl)
Ta ble 2. TBAF /THF Decom p lexa tion of En ed iyn e
Com p lexes 3
com p lex 3, X ) CH2 was prepared from 1-cyclodecen-3,9-diyne:
4,11
1
mp 105-110 °C dec; H NMR (300 MHz, CDCl3) δ 6.35 (s,
2H), 3.24 (s, 4H), 1.89 (s, 4H); 13C NMR (75 MHz, CDCl3) δ 199.5,
125.7, 97.4, 83.8, 33.0, 29.2; IR (CCl4) 2935, 2085, 2050 cm-1
entry
X
equiv
T (°C)
% 2
.
1
2
3
4
5
6
CH2
CH2
CH2
CH2
O
2
2
10
10
2
-10/2
-78/4
93
84
>95
>95
92
3,4,7,8-Tetr a d eh yd r o-9,10-d ih yd r o-2H-oxecin e-bis(d ico-
b a lt h exa ca r b on yl) com p lex 3, X ) O was prepared from
3,4,7,8-tetradehydro-9,10-dihydro-2H-oxecine:13 mp 45-50 °C
dec; 1H NMR (300 MHz, CDCl3) δ 6.39 (q, J ) 10.5 Hz, 2H),
4.98 (s, 2H), 3.93 (t, J ) 6.54 Hz, 2H), 3.35 (t, J ) 6.51 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 199.2, 126.9, 124.9, 94.2, 92.0, 84.9,
83.0, 70.0 (d), 34.9; IR (CCl4) 3429, 2944, 2068, 1651, 1097, 519
cm-1; MS (EI) 134 (40), 104 (100), 77 (57).
-10/20 min
-78/1
-10/2
-10/2
S
2
81
22 h,12 X ) O 15 h13), confirming the utility of the
protection strategy.14,15 Since the entire deprotection
strategy can be completed in less than 30 min, it thus
allows biological evaluation of the enediynes 2 and diyls
3,4,7,8-Tet r a d eh yd r o-9,10-d ih yd r o-2H-t h iecin e-b is(d i-
coba lt h exa ca r bon yl) com p lex 3, X ) S was prepared from
3,4,7,8-tetradehydro-9,10-dihydro-2H-thiecine:12 mp 65-70 °C
dec; 1H NMR (300 MHz, CDCl3) δ 6.38 (s, 2H), 4.15 (s, 2H), 3.49
(t, J ) 6.05 Hz, 2H), 2.96 (t, J ) 6.08 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 199.1, 125.6, 94.6, 94.2, 84.3, 83.1, 33.8 (t), 29.7;
(12) Sakai, Y.; Nishiwaki, E.; Shishido, K.; Shibuya, M.; Kido, M.
Tetrahedron Lett. 1991, 32, 4363.
(13) J ones, G. B.; Kilgore, M. W.; Pollenz, R. S.; Li, A.; Mathews, J .
E.; Wright, J . M.; Huber, R. S.; Tate, P. L.; Price, T. L.; Sticca, R. P.
Bioorg. Med. Chem. Lett. 1996, 6, 1971.
(14) Enediynes 2 were incubated with 1,4-cyclohexadiene (30 equiv)
at 37 °C in benzene-d6 and formation of the corresponding tetrahy-
dronaphthalenes 5 monitored by 1H NMR.
IR (CCl4) 3447, 2034, 1651 cm-1
.
Gen er a l P r oced u r e for TBAF -THF -In d u ced Decom -
p lexa tion . Complex 3, X ) CH2 (50.0 mg, 0.0705 mmol), was
dissolved in THF (0.5 mL) and the resulting solution cooled to
-10 °C. With stirring at -10 °C, TBAF (0.705 mmol of 1.0 M
(15) Nicholas has developed an elegant decomplexation strategy
involving reduction via sodium-benzophenone ketyl followed by re-
oxidation and demonstrated its utility using cycloocta-1,5-diyne com-
plexes (Melikyan, G. G.; Khan, M. A.; Nicholas, K. M. Organometallics
1995, 14, 2170).
(16) Attempted decomplexation of the bis(cobalt carbonyl) complex
of a substituted cyclooct-3-ene-1,5-diyne using CAN and other conven-
tional reagents is reported to be problematic.15
(17) Ganesh, P.; Nicholas, K. M. J . Org. Chem. 1997, 62, 1737.

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9381
in THF) was added over 1 min. The reaction mixture was
allowed to stir for 20 min and then filtered through a plug of
neutral alumina and the plug washed with Et2O (2 × 10 mL).
The resulting ethereal solution was shaken with water (2 × 10
mL) and then dried over MgSO4, filtered through a pad of Celite,
and concentrated in vacuo to give cyclodec-3-ene-1,5-diyne (8.9
mg, 95%) as a thermally unstable oil, spectroscopically identical
with previously prepared samples:4,11 1H NMR (300 MHz,
CDCl3) δ 5.81 (s, 2H), 2.37 (m, 4H), 1.93 (pent, 4H); 13C NMR
(75 MHz, CDCl3) δ 123.2, 104.1, 82.4, 28.8, 21.6.
Acknowledgment is made to the National Institutes
of Health (R01GM57123-01), the Elsa U. Pardee Foun-
dation, and GHS-CU Biomedical Cooperative for fi-
nancial support of this work.
J O9716035