Synthesis of 4-demethoxyadriamycinone utilizing ruthenium-catalyzed oxidation of allyl acetates

Article abstract of DOI:10.1016/S0040-4039(01)00428-2

A new method for the construction of the side chain of anti-cancer drugs adriamycins is demonstrated by the synthesis of 4-demethoxyadriamycinone. The key step is the ruthenium-catalyzed oxidation of allyl acetates to the corresponding α-hydroxyketones.

Full text of DOI:10.1016/S0040-4039(01)00428-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3343–3346
Synthesis of 4-demethoxyadriamycinone utilizing
ruthenium-catalyzed oxidation of allyl acetates
Torsten Hottop, Hans-Ju¨rgen Gutke and Shun-Ichi Murahashi*
Department of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3, Machikaneyama, Toyonaka,
Osaka 560-8531, Japan
Received 14 February 2001; revised 7 March 2001; accepted 9 March 2001
Abstract—A new method for the construction of the side chain of anti-cancer drugs adriamycins is demonstrated by the synthesis
of 4-demethoxyadriamycinone. The key step is the ruthenium-catalyzed oxidation of allyl acetates to the corresponding
a-hydroxyketones. © 2001 Elsevier Science Ltd. All rights reserved.
Anthracyclines are of extreme importance in chemical
anti-cancer therapy; daunomycin (1a) and adriamycin
(1b) provide a broad range of activity towards different
types of tumors, and hence many methods for synthesis
of natural and non-natural anthracyclines have been
reported.1 Among modified anthracyclines, 4-
demethoxyanthracyclines2 such as idarubicin (1c)3 and
annamycin (1d)4 are of interest because of higher
potency, particularly in the latter case of strongly
decreased cardiotoxicity and activity against some nor-
mally anthracyclin-resistant cancer cell lines. Introduc-
tion of a functional group of a-ketol to the A ring
would be the most important problem involved in the
synthesis of aglycons of anthracyclines.
presence of triethylamine in THF gave the diacetate 4
(mp 118°C) (88%). Addition of vinyl magnesium bro-
mide to a solution of 4 in THF gave no desired product
due to enolization; however, in the presence of cerium
chloride the reaction occurred smoothly under the strict
reaction conditions.8 Thus, use of dry CeCl3 is crucial.9
Quenching the reaction mixture with acetic anhydride
at −78°C, the acetate 5 (mp 108°C) was obtained in
62% yield after recrystallization. Treatment of 5 with a
catalytic amount of PdCl2(MeCN)2 in toluene gave the
rearranged allyl acetate 6 (97%).10 The oxidation of 6
with peracetic acid in acetonitrile/water (1:1) in the
presence of a ruthenium chloride catalyst afforded a
mixture of diastereomers (7+8) (1:7).11 The desired cis
isomer 8 (mp 138°C) was isolated in 60% yield.12 Trans-
formation of 8 to the benzoquinone 9 was quite
difficult. The best result was obtained upon treatment
with zinc dust in methanol, followed by oxidation of
We wish to report synthesis of 4-demethoxyadriamy-
cinone based on a process which includes ruthenium-
catalyzed oxidation of trisubstituted alkenes to the
corresponding a-ketols.5 The reported method for
introduction of the a-ketol group is limited to the
hydration of tertiary propargyl alcohol with an excess
of environmentally destructive mercury oxide under
strongly acidic conditions.6
O
OH
O
HO
R2
R1
O
OH OR
First, we examined synthesis of a-ketol quinone (9) as
shown in Scheme 1. Diels–Alder reaction of benzo-
quinone with diene 2 in THF,7 followed by hydrolysis
with a 0.1 M HCl solution gave the adduct 3. Acetyla-
tion of 3 upon treatment with acetic anhydride in the
O
1a) R1 = OMe, R2 = H
1b) R1 = OMe, R2 =OH
1c) R1 = H, R2 = H
Me
HO
R =
R =
NH2
HO
O
Keywords: 4-demethoxyadriamycinone; anthracyclinone; a-ketol;
ruthenium-catalyzed oxidation.
* Corresponding author. Tel.: +81-6-6850-6220; fax: +81-6-6850-6224;
e-mail: mura@chem.es.osaka-u.ac.jp
Me
HO
1d) R1 = H, R2 = OH
I
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00428-2

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T. Hottop et al. / Tetrahedron Letters 42 (2001) 3343–3346
OAc
O
O
OAc
OSiMe3
+
O
O
c
a
OAc
b
OtBu
OAc OtBu
OtBu
OAc OtBu
O
O
4
5
2
3
g
d
OAc
O
OAc
OAc
O
HO
O
HO
OAc
e
OAc
+
OAc
OAc
OAc OtBu
OAc OtBu
OAc OtBu
O
OtBu
8
10
7
6
d
f
O
O
O
O
O
HO
OAc
e
OAc
OtBu
11
OtBu
9
Scheme 1. Reagents: (a) i. THF, rt, 4 h; ii. 0.1 M HCl, THF, rt, 15 min, 74%. (b) Ac2O, NEt3, THF, 45°C, 5 h, 88%. (c) i.
CH2ꢀCHMgBr, CeCl3, THF, 1 h, −78°C; ii. Ac2O, −78°C to rt, 1 h, 62%. (d) PdCl2(MeCN)2 cat., toluene, rt, 97% for 6, 98% for
11. (e) CH3CO3H, RuCl3 cat., MeCN/H2O, 60% for 8, 30% for 9. (f) i. Zn, MeOH, rt, 24 h; ii. CAN, MeCN/H2O, 0°C, 15 min,
47%. (g) i. NaBH4, THF/H2O, 0°C, 38 h. ii. CAN, MeCN/H2O, 0°C, 74%, 1 h.
the intermediate hydroquinone with CAN (47%).13 The
low yield is due to the high lability of 9. An alternative
method for the synthesis of 9 is as follows. Removal of
the acetyl groups of 5 upon treatment with NaBH4 in
water/THF followed by oxidation with CAN gave 10
(74%), which underwent allylic rearrangement to give
11 as a quite stable yellow solid (mp 115°C) in 98%
yield. However, the ruthenium-catalyzed oxidation of
11 gave the unstable 9 in low yield.
We examined a route which includes a coupling reac-
tion of the CD ring as shown in Scheme 2. A solution
of the compound 12 was treated with sodium hydride,
to which was added a solution of 10 at −40°C accord-
ing to the procedure of Kita et al.14 Stirring at room
temperature for an additional 3 h was necessary to
allow the extrusion of carbon dioxide of 12. The desired
yellow tetracycle 14 (mp 168–173°C), in which the
acetyl group at O-5 of 13 was shifted to O-6, could be
OAc
O
OH
O
O
O
OH
O
OAc
OAc
12
b
O
10
a
OAc O
OtBu
OAc OtBu
13
14
O
OH
O
O
OH
O
O
OH
HO
HO
OAc
c
d
1d
OAc
OH
OAc OtBu
15
O
OAc OtBu
O
OH OH
O
16
17
Scheme 2. (a) NaH, THF, −40°C to rt, 3 h, 70%. (b) PdCl2(MeCN)2 cat., toluene, rt, 24 h, 99%. (c) RuCl3 cat., CH3CO3H,
MeCN/CH2Cl2/H2O, rt, 24 h, 60%. (d) 1.2 M HCl, i-PrOH, reflux, 2 h, 50%.

T. Hottop et al. / Tetrahedron Letters 42 (2001) 3343–3346
3345
obtained in 70% yield as a single product.15 Such
migration of the acyl group takes place readily
because of higher thermodynamic stability of the
naphthacenedione 14 in comparison with its tautomer
13.16 The palladium-catalyzed allylic rearrangement of
14 gave the allyl acetate 15 (mp 187–189°C) in 99%
yield.17 Oxidation of 15 with CH3CO3H in the pres-
ence of RuCl3 catalyst in a mixture of water, acetoni-
trile and dichloromethane (1:1:1) afforded 16 (mp
209–213°C) in 60% yield after crystallization.18 The
relative configuration between the t-BuO group at C-
7 and the OH group at C-9 of 16 was determined to
be trans using NOESY experiments. The stereochem-
istry is also deduced by measuring the width of the
7-H proton signal at half height; a very broad signal
(18.3 Hz) indicates trans configuration.19 Strong tem-
perature dependence of the shift of this peak also
indicates an intramolecular hydrogen bonding with
the OH group at C-9, which is only possible for the
trans isomer. The presence of an acetoxy group at
C-5 in the compound 6 seems to affect the stereo-
chemistry of the oxidation products 8, making them
cis because of the attractive interaction of the acetoxy
group with the ruthenium, while the oxidation of 15
affords trans-16. Deprotection and epimerization at
C-7 was readily achieved in one step by heating 16
with diluted hydrochloric acid in isopropanol/water to
yield 4-demethoxyadriamycinone (17), which showed
the same spectroscopic data to those reported.20,21
Conventional treatment of 17, including oxyiodination
5. Murahashi, S.-I.; Saito, T.; Hanaoka, H.; Murakami,
Y.; Naota, T.; Kumobayashi, H.; Akutagawa, S. J.
Org. Chem. 1993, 58, 2929.
6. (a) Kende, A. S.; Curran, D. P.; Tsay, Y.; Mills, J. E.
Tetrahedron Lett. 1977, 3537; (b) Gupta, R. C.; Har-
land, P. A.; Stoodley, R. J. Tetrahedron 1984, 40, 4657.
7. Potman, R. P.; Janssen, N. J. M. L.; Scheeren, J. W.;
Nivard, R. J. F. J. Org. Chem. 1984, 49, 3628.
8. Dimitrov, V.; Bratovanov, S.; Simova, S.; Kostova, K.
Tetrahedron Lett. 1994, 35, 6713.
9. Cerium chloride heptahydrate was dried in a Schlenk
flask under vacuum (0.1 Torr) for 24 h at 70°C, for 24
h at 80°C, for 48 h at 90°C, for 12 h at 100°C, for 12
h at 120°C and finally for 100 h at 140–145°C.
10. A NOESY experiment confirmed the configuration at
the double bond of 6. The ratio of the isomers was
91:7.
11. A NOESY experiment with the minor oxidation
product 7 proved indirectly the configuration of the
major product 8.
12. Selected data for 8. Mp 138°C; 1H NMR (CDCl3) l
7.03 (d, J=10 Hz, 1H), 7.01 (d, J=10 Hz, 1H), 5.23
(d, J=18 Hz, 1H), 5.06 (d, J=18 Hz, 1H), 4.91 (dd,
J=4 and 3 Hz, 1H), 3.48 (s(br), 1H), 3.31 (d, J=15
Hz, 1H), 2.67 (d, J=15 Hz, 1H), 2.58 (dd, J=15 and 3
Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 1.85
(ddd, J=15, 4, and 1 Hz, 1H), 1.17 (s, 9H).
13. Selected data for 9. Mp 126–131°C; 1H NMR (CDCl3)
l 6.76 (d, J=13 Hz, 1H), 6.72 (d, J=13 Hz, 1H), 5.17
(d, J=17 Hz, 1H), 4.98 (d, J=17 Hz, 1H), 4.97, (t,
J=5 Hz, 1H), 3.64 (s(br), 1H), 3.08 (d, J=19 Hz, 1H),
2.57 (d, J=19 Hz, 1H), 2.32 (dd, J=14 and 5 Hz, 1H),
2.17 (s, 3H), 2.08 (ddd, J=14, 5, and 1 Hz, 1H), 1.24
(s, 9H).
with
L-rhamnal diacetate in the presence of N-iodo-
succinimide, gave 1d, where resolution of the racemic
aglycon 17 took place to furnish the optically pure
(7S,9S)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-a-L-
mannopyranosyl)adriamycinone (1d) and its 7R,9R
14. Fujioka, H.; Yamamoto, H.; Annoura, H.; Maeda, H.;
Kita, Y. Chem. Pharm. Bull. 1992, 40, 32.
isomer.3
15. Selected data for 14. Mp 168–173°C (decomp.); 1H
NMR (CDCl3) l 13.53 (s, 1H), 8.23 (m, 2H), 7.76 (m,
2H), 6.16 (dd, J=17 and 11 Hz, 1H), 5.17 (d, J=17
Hz, 1H), 5.14 (d, J=11 Hz, 1H), 4.94 (s(br), 1H), 3.48
(d, J=18 Hz, 1H), 3.40 (d, J=18 Hz, 1H), 2.97 (d,
J=16 Hz, 1H), 2.54, (s, 3H), 2.04 (dd, J=16 and 4
Hz, 1H), 2.00 (s, 3H), 1.31 (s, 9H).
Our present approach using ruthenium-catalyzed oxi-
dation of alkenes to the corresponding a-ketols can
be also applied to the synthesis of other anthracy-
clinones.
References
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NMR (CDCl3) l 8.23 (m, 2H), 7.76 (m, 2H), 5.77 (t,
J=7 Hz, 1H), 5.01 (s(br), 1H), 4.68 (d, J=20 Hz, 1H),
4.64 (d, J=20 Hz, 1H), 3.81 (d, J=20 Hz, 1H), 3.68
(d, J=20 Hz, 1H), 3.04 (dd, J=16 and 2 Hz, 1H), 2.55
(s, 3H), 2.23 (d, J=16 Hz, 1H), 2.06 (s, 3H), 1.25 (s,
9H).
18. Preparation of 16: To a mixture of 30 ml of acetoni-
trile, 30 ml of dichloromethane and 30 ml of water was
added 450 mg (0.914 mmol) of 15 and ruthenium
trichloride (10 mg, about 0.048 mmol) at room temper-
ature, together with peracetic acid (30% solution in
ethyl acetate, 2 equiv.). The mixture was stirred for 12
h. After 4 and then 8 h another 2 equiv. of peracetic
acid was added. Mp 209–213 (decomp.); 1H NMR
(CDCl3) l 13.42 (s, 1H), 8.23 (m, 2H), 7.76 (m, 2H),

3346
T. Hottop et al. / Tetrahedron Letters 42 (2001) 3343–3346
5.26 (d, J=17 Hz, 1H), 5.09 (d, J=17 Hz, 1H), 5.02 (m,
20. Selected data for 17. Mp 140–150°C (decomp.); 1H
NMR (CDCl3) l 13.58 (s, 1H), 13.26 (s, 1H), 8.26–
8.45 (m, 2H), 7.76–7.98 (m, 2H), 5.38 (d(br), J=2
Hz, 1H), 3.30 (dd, J=19 and 2 Hz, 1H), 3.01 (d, J=19
Hz, 1H), 2.42 (d, J=15 Hz, 1H), 2.19 (dd, J=15 and 5
Hz, 1H).
1H), 3.50 (s(br), 1H), 3.34 (d, J=16 Hz, 1H), 3.28 (d,
J=16 Hz, 1H), 2.66 (dd, J=15 and 4 Hz, 1 H), 2.54 (s,
3H), 2.18 (s, 3H), 1.88 (dd, J=15 and 4 Hz, 1H), 1.22 (s,
9 H). Anal. calcd for C28H28O8: C, 64.14; H, 5.38. Found:
C, 64.12; H, 5.31.
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.
.