Synthesis of enediyne model compounds possessing a cyanohydrin moiety as a triggering device

Article abstract of DOI:10.1016/S0040-4039(02)01529-0

Development of enediyne model compounds possessing a cyanohydrin moiety is described. These model compounds generate enyne-allenylketones efficiently under mild basic conditions and the resulting biradicals showed potent DNA cleaving abilities.

Full text of DOI:10.1016/S0040-4039(02)01529-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6779–6781
Synthesis of enediyne model compounds possessing a cyanohydrin
moiety as a triggering device
Ichiro Suzuki,* Yuko Tsuchiya, Akira Shigenaga, Hisao Nemoto and Masayuki Shibuya
Faculty of Pharmaceutical Sciences, University of Tokushima, Sho-machi 1-78, Tokushima 770-8505, Japan
Received 7 June 2002; revised 17 July 2002; accepted 19 July 2002
Abstract—Development of enediyne model compounds possessing a cyanohydrin moiety is described. These model compounds
generate enyne–allenylketones efficiently under mild basic conditions and the resulting biradicals showed potent DNA cleaving
abilities. © 2002 Elsevier Science Ltd. All rights reserved.
After the discovery of the potent antitumor antibiotics
neocarzinostatin and related compounds which possess
a cyclic enediyne structure and cycloaromatize to afford
reactive biradicals, a great deal of effort has been made
in the synthesis and design of analogs of these com-
pounds that act in a similar mode.1 In these studies,
Myers–Saito type cycloaromatization seemed to receive
much less attention than Masamune–Bergman type
cyclization, probably because of the complicated reac-
tivity of the resulting a,3-didehydrotoluene biradical.
The a,3-didehydrotoluene biradical is considered to be
a singlet biradical having a considerable ionic character
due to the partial conjugation between two SOMOs.2
This ionic character would be enhanced in protic media
reducing DNA damaging abilities of the biradicals.2c,3
To develop artificial anticancer drugs, a molecular
design for controlling the reactivity of this biradical has
to be exploited.
The targeting new models 5, 6 and 4c were synthesized
in the manner shown in Scheme 2. The enediyne 4c has
a possibility to develop enediyne prodrugs possessing a
biologically removable protecting group. The starting
dibromide 1 was prepared according to the procedure
reported by Myers et al.5 Sonogashira type Pd-cata-
lyzed cross coupling of 1 with methylpropargylether,
and subsequent reduction gave enyne 2. The
methoxymethyl ether of 2 served as a common precur-
sor for the enediyne models. Alkynes 7, 8 and 9 were
prepared by the propargylation of corresponding
cyanohydrins and these alkynes were coupled with
ether 3 in the presence of Pd-catalyst. The resulting
enediynes 4a and 4b were treated with p-TsOH in
MeOH and gave cyanohydrins 5 and 6. These enediy-
nes decomposed gradually at room temperature, and so
were used without further purification. Since the
enediyne 4c, which was prepared from 3 and 9, was
stable enough to be purified with silica gel column
chromatography, we used 4c for DNA-cleaving studies.
Previously, we demonstrated that enediyne models
bearing an electron-withdrawing group on the allene
terminus indicated enhanced DNA cleaving abilities.4
According to this concept, we designed new enediyne
models containing a cyanohydrin moiety which afford
reactive allenylketones in basic conditions and finally
generate DNA damaging biradicals (Scheme 1).
The reactions of enediyne 5 and 6 with Et3N (1.2
equiv.) in the presence of 50 equiv. of 1,4-cyclohexadi-
ene (1,4-CHD) as a hydrogen donor in methanol at
37°C afforded the cycloaromatized products 10 and the
adduct 11, respectively, as shown in Table 1. The
R'
CN
OH
R
R
R
R
COR'
COR'
O
R'
R''
R''
R''
R''
Scheme 1.
Keywords: diynes; enynes; radicals; ionization; cyanohydrins; DNA.
* Corresponding author. Tel.: +81 88 633 9534; fax: +81 88 633 9505; e-mail: isuzuki@ph2.tokushima-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01529-0

6780
I. Suzuki et al. / Tetrahedron Letters 43 (2002) 6779–6781
Br
Br
EtO2C
Br
Br
MOMO
HO
(iii)
(i), (ii)
OMe
OMe
1
2
3
OH
CN
OEE
CN
(iv)
(vii)
MOMO
CN
MOMO
MOMO
MOMO
CN
OMe
OMe
4a
4b
5
OH
CN
OEE
CN
(vii)
(v)
MOMO
Ph
Ph
OMe
OMe
O
6
OMe
OR3
R2
(vi)
CN
Ph
O
R1
OMe
7: R1= R2 = CN, R3 = EE
8: R1 = Ph, R2 = CN, R3 = EE
9: R1 = Ph, R2 = CN,
4c
R3 = 2-Methoxyacetyl
Scheme 2. Reagents and conditions: (i) Pd(PPh3)4, CuI, DIEA, MeOCH2CꢀCH/DMF, 0°C, 65%; (ii) DIBALH/THF, −78°C, 98%;
(iii) MOMCl, DIEA/CH2Cl2, reflux, 93%; (iv) 7, Pd(PPh3)4, CuI, nPrNH2/toluene, 60°C, 33%; (v) 8, Pd(PPh3)4, CuI, nPrNH2/tol-
uene, 60°C, 34%; (vi) 9, Pd(PPh3)4, CuI, Et2NH/toluene, 60°C, 74%; (vii) p-TsOH/MeOH, rt.
adduct 11 was converted to 12 by catalytic hydrogena-
tion and the structure was confirmed. These results
indicate that the base-promoted deprotonation of
cyanohydrin gave the allenylketone and the facile
cycloaromatization of enyne–allenylketone proceeded
via a biradical cyclization pathway. An intermediate
corresponding to ketoenediyne and allenylketones
could not be detected with TLC or by H NMR during
each reaction. No products produced by the ionic reac-
tion between the biradical and solvent MeOH were
1
Table 1. Results of cycloaromatization reactions of enediyne models 4c, 5 and 6
OR1
R
R
Et3N
R
MOMO
COR
OMe
MOMO
O
MOMO
O
MOMO
CN
MeOH,
OMe
OMe
OMe
4c: R = Ph, R1= COCH2OMe; 5: R = CN, R1= H; 6: R = Ph, R1= H
Additive
MOMO
COR
OMe
+
MOMO
COR
OMe
MOMO
COR
OMe
10a: R = OMe
10b: R = Ph
12a: R = OMe
12b: R = Ph
11a: R = OMe
11b: R = Ph
H2, Pd/C
COR
MOMO
COR
OMe
Non-additive MOMO
COR
OMe
+
+
MOMO
O
OMe
14: R = Ph
10a: R = OMe
10b: R = Ph
13: R = Ph
Entry
Enediyne
Time
Additive
Products
1
2
3
4
5
5
5
6
6
1 h
1 h
B5 min
B5 min
35 min
CHDa
–
10a, 7%; 11a, 31%
Complex mixture
10b, 36%; 11b, 31%
10b, 14%; 13, 12%; 14: 6%
10b, 20%; 11b, 19%
CHDa
–
4c
CHDa
a 50 equiv. of 1,4-cyclohexadiene was used.

I. Suzuki et al. / Tetrahedron Letters 43 (2002) 6779–6781
6781
(-)
COPh
O
MOMO
MOMO
MOMO
COPh
OMe
Ph
OMe
13
O
(+)
15
14
16r: Biradical
16i: Zwitterion
ene type reaction
O
MOMO
Ph
MOMO
COPh
OMe
OMe
MeO
17
Scheme 3.
detected. When the enediyne 4c bearing a protected
cyanohydrin moiety was treated with Et3N in MeOH,
removal of the methoxyacetyl group and subsequent
cycloaromatization gave a similar result to the reaction
of 6. While the cycloaromatization of 5 gave a complex
mixture, 6 afforded 10, 13 and 14 in the absence of a
hydrogen donor.
mechanism via a biradical pathway. Studies for devel-
opment of compounds having a biologically removable
protecting group on a cyanohydrin moiety is now on
going.
Acknowledgements
The formation of 13 and 14 should be explained as
shown in Scheme 3. The biradical 16r formed via
1,5-hydrogen shift of 15 is assumed to have the stable
zwitterionic mesomer 16i.6 Both biradical 16r and zwit-
terion 16i can give 13 by recombination or ionic
cyclization. Mechanistically, the formation of 14 can be
rationalized by considering the participation of solvent
MeOH in the course of the reaction, but it is also
possible that zwitterionic mesomer 17 participates in
the reaction, and this should not be ignored.
This work was supported by a research grant from
Faculty of Pharmaceutical Sciences, The University of
Tokushima and Grant-in-Aid for Scientific Research
(No. 13771334) from the Ministry of Education, Sports
and Culture, Japan.
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DNA strand cleavage by the synthetic enediyne 4c was
estimated on agarose gels by conversion of covalently
closed circular DNA (Form I) to open circular DNA
(Form II) and the results were summarized in Table 2.
In a basic buffer solution, 4c showed potent DNA-
cleaving abilities, as was expected. This result is consis-
tent with the base-promoted deprotection–cyclo-
aromatization reaction mechanisms mentioned above.
In summary, we developed enediyne model compounds
which cycloaromatize by a base-promoted triggering
Table 2. pH dependence of DNA cleavage by enediyne 4c
Entry
pH
DNA cleavage (%)a
1
2
3
4
5
5
6
7
8
9
1193
1594
3291
4993
4694
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a Col E1 DNA (12.5 mg/ml) was incubated for 12 h at 37°C with
enediyne 4c (1 mM) in pH 5, 6, 7, 8 and 9 phosphate buffers, and
analyzed by electropholysis (1% agarose gel, ethidium bromide
staining). Results presented are mean value+SD of three runs. A
Control reaction mixture without the addition of any drug was
incubated and the mean value of three runs was used as the
background to be subtracted from the obtained values.