An efficient regioselective and diastereoselective synthesis of the epoxy-quinol functionality as building block for the Manumycin antibiotics by the sequence of photooxygenation, reduction and Weitz-Scheffer epoxidation

Article abstract of DOI:10.1055/s-2002-20481

The photooxygenation of the acetanilide 2 affords the hydroperoxide 3, which by titanium-tetraisopropoxide-catalyzed reduction with dimethyl sulfide gives the corresponding quinol 4. Regioselective and diastereoselective Weitz-Scheffer epoxidation of the latter by tert-butyl hydroperoxide (TBHP) and DBU as base catalyst leads to the cis-epoxy quinol 1, the essential functionality in Manumycin antibiotics.

Full text of DOI:10.1055/s-2002-20481

510
LETTER
An Efficient Regioselective and Diastereoselective Synthesis of the Epoxy-
quinol Functionality as Building Block for the Manumycin Antibiotics by the
Sequence of Photooxygenation, Reduction and Weitz–Scheffer Epoxidation
S
ynthesis of the Epoxy-Q
a
uinol Fun
l
c
tional
d
a
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
b
Department of Chemistry, Atatürk University, 25240 Erzurum, Turkey
E-mail: hkilic@atauni.edu.tr
Received 5 November 2001
use in cancer chemotherapy.7 However, in view of the
metabolic instability of these natural products, it would
seem that their potential as drugs should be limited; none-
theless, it has been established that the structurally related
Abstract: The photooxygenation of the acetanilide 2 affords the
hydroperoxide 3, which by titanium-tetraisopropoxide-catalyzed
reduction with dimethyl sulfide gives the corresponding quinol 4.
Regioselective and diastereoselective Weitz–Scheffer epoxidation
of the latter by tert-butyl hydroperoxide (TBHP) and DBU as base product LL-C10037 8,9 without side chains possesses po-
catalyst leads to the cis-epoxy quinol 1, the essential functionality
in Manumycin antibiotics.
tent antitumor properties. The latter observation suggests
that the complex side chains are not essential and, conse-
Key words: photooxygenation, quinol, Weitz–Scheffer epoxida-
tion, diastereoselectivity, regioselectivity
quently, it should be worthwhile to prepare such simpli-
fied manumycin analogues, which might display useful
biological activity. For the purpose of structure-activity
studies, an efficient and versatile synthesis of manumycin
The antibacterial manumycin A (Scheme 1) was first iso- derivatives was desirable.
lated from Streptomyces parvulus in 1963 and since then
These natural products possess a central epoxy-quinol
a family of structurally related antibiotics has been ob-
tained from the Streptomyces species.1,2 More recently,
alisamycin3 and asukamycin4 and others5 have been char-
acterized. The manumycin natural products possess a
wide range of bioactivity, in addition to their established
antibacterial properties.6
functionality, with polyunsaturated side chains linked to
the C-5 position and the amino substituent. This unit is
thought to originate from 3-amino-4-hydroxybenzoic acid
through a biosynthetic pathway with a building block
from the TCA cycle.10a,b A consequence of this synthetic
pathway is the syn orientation of the epoxide (relative to
the hydroxy group), a feature that is common to most
manumycins. In the present work, we describe a conve-
nient diastereoselective synthesis of the racemic epoxy-
quinol cis-1, in which we have employed an effective se-
quence of photooxygenation, reduction, and Weitz–
Scheffer epoxidation (Scheme 2).
H
N
O
H
N
O
O
O
O
O
OH
O
OH
Manumycin A
Asukamycin
3
3
O
OH
HN
OH
HN
H
O
N
O
O
O
OH
O
O
O
NHAc
NHAc
NHAc
NHAc
CH3
a
b
d
O
OH
CH3
HOO CH3
HO
HO
rac-cis-1
CH3
2
3
4
H
O
O
H
O
N
NHAc
N
CH3
O
c
O
O
O
O
OH
3
OH
HO
rac-cis-1
CH3
O
O
OH
Alisamycin
NHAc
LL-C10037α
HN
O
AcO CH3
4a
Scheme 1
Scheme 2 Reagents: (a) O2, TPP, h , acetone/CH2Cl2, –25 °C, 2 d,
62% yield; (b) Me2S (1.2 equiv), Ti(O-i-Pr)4 (5 mol%), CH2Cl2,
20 °C, 1 h, 4 Å molecular sieves, 83% yield; (c) Ac2O, pyridine,
CH2Cl2, 20 °C, 5 d, 67% yield (relative to converted material, conver-
sion ca. 60%); (d) TBHP (1.2 equiv), DBU, CH2Cl2, 20 °C, 3 d, 78%
yield.
The significant discovery is that manumycins act as selec-
tive inhibitors of ras farnesyl transferase and might be of
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0510,0512,ftx,en;G22501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of the Epoxy-quinol Functionality
511
For the synthesis of the epoxy-quinol cis-1, we selected as Scheme 3. The more electrophilic, unfunctionalized
starting material the known acetanilide 2 with the hydroxy enone C=C double bond is attacked regioselectively.
functionality and methyl substituent.11 TPP-sensitized
photooxygenation of the acetanilide 2 at –25 °C resulted
in the hydroperoxide 3 (Scheme 1, step a). After column
chromatography on silica gel, the hydroperoxide 3 was
isolated in 62% yield.12 The use of the tetra-n-butyl am-
monium fluoride, claimed as catalyst for the photooxy-
genation of phenolic substrates,13 is unnecessary; in fact,
it caused a low yield of impure hydroperoxide 3. The IR,
1H NMR and 13C NMR spectral data substantiate the
structure assignment. The IR exhibited the characteristic
hydroperoxide band at 3340 cm–1 and a strong, highly
Ac
Ac
N
H
O
N
H
O
CH3
O
CH3
O
H
H
O
tBuO
O
O
tBu
rac-cis-1
Scheme 3
The present synthetic strategy is concise, convenient and
of well defined regioselectivity as well as diastereoselec-
tivity. Moreover, the reported for the preparation of manu-
mycin-type epoxy quinols employs readily available
phenolic starting materials. The efficiency of this protocol
should provide a variety of epoxy quinol derivatives for
the structure-activity studies with ras farnesyl transferase
of such manumycin analogues.
1
conjugated carbonyl absorption at 1654 cm–1. In the H
NMR spectrum, the olefinic protons display an AB pat-
tern at = 7.08–6.27 ppm, as required by the , -unsatur-
ated enone functionality, of which the olefinic proton
proximate to the methyl group is further split into a dou-
blet by the vinylic proton next to the acetamide group
through W coupling. The 13C NMR spectrum possesses
the two expected carbonyl resonances at = 180.2 and
163.4 ppm, which confirm the presence of the conjugated
enone and amide functionalities.
Acknowledgement
This work was supported by the DFG (SBF 347 ‘Selektive Reaktio-
The reduction of the hydroperoxide 3 with dimethyl sul- nen Metall-aktivierter Moleküle’) and the Fonds der Chemischen
fide,14 catalyzed by titanium tetraisopropoxide, gave the
Industrie.
desired quinol 4 (Scheme 1, step b) in high yield.15 The
proposed structure for the quinol 4 is based on spectral
and analytic data. For further structural proof, quinol 4
H. K. thanks the Technical and Scientific Council of Turkey (TU-
BITAK) and DFG for a fellowship to conduct this work in Würz-
burg.
was converted to the corresponding acetate 4a, whose as-
References
signment is consistent with its spectral and analytic data
(Scheme 1, step c). Thus, in an efficient two-step se-
quence, the hydroxyl and enone functionalities were con-
veniently introduced in the acetanilide 2.
(1) Buzzetti, F.; Gaümann, E.; Hütter, R.; Keller-Schierlein, W.;
Neipp, L.; Prelog, V.; Zähner, H. Pharm. Acta. Helv. 1963,
38, 871.
(2) Schöder, K.; Zeeck, A. Tetrahedron Lett. 1973, 4995.
(3) MacDonald, G.; Alcaraz, L.; Lewis, J. N.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 5433.
(4) Cho, H.; Sattler, I.; Beale, J. M.; Zeeck, A.; Floss, H. G. J.
Org. Chem. 1993, 58, 7925.
(5) Taylor, R. J. K.; Alcaraz, L.; Kapfer-Eyer, I.; MacDonald,
G.; Wei, X.; Lewis, N. Synthesis 1998, 775.
(6) Sattler, I.; Thiericke, R.; Zeeck, A. Nat. Prod. Rep. 1998, 15,
221.
The Weitz–Scheffer epoxidation of the quinol 4 with t-bu-
tyl hydroperoxide (TBHP) and catalytic amounts of DBU
as base afforded the racemic epoxide cis-1 (relative to the
hydroxy group) in 78% yield (Scheme 1, step d).16 Fortu-
nately, the Weitz–Scheffer epoxidation of the quinol 4
gave only a single diastereomer, namely cis-1 and no oth-
er products. In contrast, the use of hydrogen peroxide in-
stead of t-butyl hydroperoxide as oxygen source resulted
in a low yield of the quinol 4.
(7) Hara, M.; Han, M. Poc. Natl. Acad. Sci. USA 1995, 92, 3333.
(8) Kapfer, I.; Lewis, N. J.; MacDonald, G.; Taylor, R. J. K.
Tetrahedron Lett. 1996, 37, 2101.
The structural assignment of the cis-1 epoxide rests main-
ly on its 1H and 13C NMR spectra. The olefinic proton oc-
curs as a doublet at = 7.38 (J = 2.7 Hz) ppm, the epoxide
protons display an AB pattern at = 3.68–3.53 ppm, in
which the low-field portion is further coupled to the ole-
finic proton proximate to the acetamide group.17 NOE ex-
periments confirmed the cis configuration. The 13C NMR
spectrum consists of four sp2 carbon and five sp3 carbon
signals, in support of the assigned structure for the epoxy-
quinol cis-1. Evidently, the hydroxy-directing effect18 op-
erates efficiently in the Weitz–Scheffer epoxidation to af-
ford exclusively the cis-configured epoxide 1. A hydrogen
bond between the quinol hydroxy group and the tert-butyl
hydroperoxide anion directs the delivery of the oxygen
atom to the dienone face towards which the hydroxy
group points, as shown in the transition structure of
(9) Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 1549.
(10) (a) Kim, C.-G.; Kirshning, A.; Bergon, P.; Zhou, P.; Su, E.;
Sauerbrei, B.; Ning, S.; Ahn, Y.; Breuer, M.; Leistner, E.;
Floss, H. G. J. Am. Chem. Soc. 1996, 118, 7486. (b) Hu, Y.;
Melville, C. R.; Gould, S. R.; Floss, H. G. J. Am. Chem. Soc.
1997, 119, 4301.
(11) Parmar, V. S.; Prasad, A. K.; Tyagi, O. D.; Gupta, S.; Sinha,
R.; Gupta, S.; Aprajita, C.; Shakil, N. A. Ind. J. Chem. 1992,
31B, 903.
(12) Procedure for the Preparation of N-(3-Hydroperoxy-3-
methyl-6-oxocyclohexa-1,4-dienyl)-acetamide(3): A
sample of the acetanilide 2 (1.0 g, 6.0 mmol) and meso-
tetraphenylporphine (TPP, 50 mg) in acetone:methylene
chloride (7:3; 80 mL) was irradiated for 2 d at –25 °C with a
400-W sodium lamp, while a gentle stream of dry oxygen
gas was allowed to pass through the solution. After removal
of the solvent (ca. 10 °C, 15 Torr), the mixture was
Synlett 2002, No. 3, 510–512 ISSN 0936-5214 © Thieme Stuttgart · New York

512
W. Adam et al.
LETTER
chromatographed on silica gel (100 g) with
1. Anal. Calcd for C9H11NO3 (181.1): C, 59.66; H, 6.12; N,
7.73. Found: C, 59.25; H, 6.14; N, 7.67. Selected data for
4a: 1H NMR (250 MHz, CDCl3): = 8.00 (br s, 1 H), 7.68
(d, J = 3.0 Hz, 1 H), 6.95 (dd, J = 10.0, 3.0 Hz, 1 H), 6.26 (d,
J = 10 Hz, 1 H), 2.10 (s, 3 H), 2.00 (s, 3 H), 1.54 (s, 3 H); 13C
NMR (63 MHz, CDCl3): = 179.6, 169.5, 169.1, 152.1,
131.2, 128.2, 125.3, 74.7, 26.9, 24.6, 21.3; IR (KBr): 3352,
2980, 1734, 1695, 1657, 1516, 1400, 1368, 1341, 1240, 1099
cm–1. Anal. Calcd for C11H13NO4 (223.1): C, 59.19; H, 5.87;
N, 6.27. Found: C, 59.14; H, 5.78; N, 6.16.
EtOAc:petroleum ether (40–50 °C) (1:1) as eluent to remove
TPP as the first fraction. Further elution gave the title
compound (0.74 g, 62%) as a white solid. Recrystallization
from EtOAc:CH2Cl2 gave colorless plates, mp 125–
126 °C(dec); 1H NMR (250 MHz, CD3COCD3): = 11.05
(br s, 1 H), 8.45 (br s, 1 H), 7.67 (d, J = 3.0 Hz, 1 H), 7.08
(dd, J = 10.0, 3.0 Hz, 1 H), 6.27 (d, J = 10 Hz, 1 H), 2.16 (s,
3 H), 1.41 (s, 3 H); 13C NMR (63 MHz, CD3COCD3):
=
180.2, 163.4, 153.3, 133.0, 128.8, 127.3, 78.9, 23.8, 23.3; IR
(KBr): 3340, 3164, 2846, 1654, 1646, 1532, 1396, 1343,
1242, 1136, 1060 cm–1. Anal. Calcd for C9H11NO4 (197.1):
C, 54.82; H, 5.62; N, 7.10. Found: C, 55.16; H, 5.77; N, 7.11.
(16) Procedure for the Preparation of cis-N-(5-Hydroxy-5-
methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)-
acetamide (cis-1): To a magnetically stirred solution of the
quinol 4 (0.34 g, 1.87 mmol) in CH2Cl2 (30 mL) at r.t. (ca.
20 °C) were added anhyd tert-butylhydroperoxide (TBHP)
(2.24 mmol; 0.56 mL, ca. 4.0 M in dichloroethane) and one
drop of DBU. The resulting mixture was stirred at r.t. (ca.
20 °C) for 3 d, the solvent was removed (10 °C, 10 Torr),
and the mixture was chromatographed on silica gel (40 g), by
eluting with a 4:1 mixture of EtOAc:petroleum ether (40–
50 °C). The first fraction consisted of unreacted TBHP;
further elution gave the quinol epoxide cis-1 (0.29 g, 78%)
as a white solid. On recrystallization from CH2Cl2:EtOAc
(1:1) colorless needless were obtained, mp 185–186 °C. 1H
NMR (250 MHz, CD3COCD3): = 8.19 (br s, 1 H), 7.38 (d,
J = 2.7 Hz, 1 H), 4.71 (br s, 1 H), 3.68 (dd, J = 4.0, 2.7 Hz,
1 H), 3.53 (d, J = 4.0 Hz, 1 H), 2.09 (s, 3 H), 1.46 (s, 3 H);
13C NMR (63 MHz, CD3COCD3): = 189.5, 169.5, 130.7,
128.0, 68.2, 58.6, 53.0, 27.4, 23.7; IR (KBr): 3361, 3268,
3002, 1698, 1650, 1542, 1373, 1260, 1125, 1097, 1032, 931
cm–1. Anal. Calcd for C9H11NO4 (197.1): C, 54.82; H, 5.62;
N, 7.10. Found: C, 54.73; H, 5.55; N, 7.03.
(13) Wasserman, H. H.; Pickett, J. E. Tetrahedron 1985, 41,
2155.
(14) Adam, W.; Balc , M.; K l ç, H. J. Org. Chem. 2000, 65,
5926.
(15) Procedure for the Preparation of N-(3-Hydroxy-3-
methyl-6-oxocyclohexa-1,4-dienyl)-acetamide(4): To a
magnetically stirred solution of the hydroperoxide 3 (0.50 g,
2.53 mmol) and 4 Å molecular sieves (2 g) in methylene
chloride (75 mL) at 10 °C were added dimethyl sulfide (0.19
g, 3.0 mmol) and titanium tetraisopropoxide (36.0 mg, 0.12
mmol). After 1 h of stirring, the reaction was stopped by the
addition of water (50 L), and the solids were removed by
filtration. The solvent was evaporated (ca. 15 °C, 15 Torr),
the residue was loaded on a short silica gel column (30 g),
and eluted with a 4:1 mixture of EtOAc:petroleum ether (40–
50 °C) to afford the title compound (0.38 g, 83%) as a
colorless oil. Crystallization from a mixture of
EtOAc:petroleum ether gave colorless needles, mp 104–
105 °C; 1H NMR (250 MHz, CD3COCD3): = 8.58 (br s, 1
H,), 7.95 (d, J = 3.0 Hz, 1 H), 7.27 (dd, J = 10.0, 3.0 Hz, 1
H), 6.33 (d, J = 10 Hz, 1 H), 4.87 (br s, 1 H), 2.36 (s, 3 H),
1.68 (s, 3 H); 13C NMR (63 MHz, CD3COCD3): = 180.2,
169.3, 155.7, 132.1, 130.5, 124.3, 67.5, 27.9, 23.8; IR (KBr):
3277, 2966, 1655, 1611, 1533, 1383, 1234, 1092, 1054 cm–
(17) Alcaraz, L.; MacDonald, G.; Ragot, J. P.; Lewis, N.; Taylor,
R. J. K. J. Org. Chem. 1998, 63, 3526.
(18) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307. (b) Evarts, J. B.; Fuchs, P. L.; Fuchs, P. L.
Jr. Tetrahedron Lett. 1999, 40, 2703.
Synlett 2002, No. 3, 510–512 ISSN 0936-5214 © Thieme Stuttgart · New York