Total Synthesis of Cervinomycin A1-trimethyl Ether and Cervinomycin A2-methyl Ether

Article abstract of DOI:10.1016/S0040-4039(00)93465-8

The heptacyclic framework of cervinomycin antibiotics has been constructed through a C+EFG -> CEFG -> CDEFG -> ABCDEFG approach in which the photochemical generation of ring D was a key step.Key words: Xanthone antibiotics, Photocyclisation, Tetrahydrooxazolo<3,2-b>benzisoquinolone formation.

Full text of DOI:10.1016/S0040-4039(00)93465-8

Tetrahedron Letters, Vol.32, No.38, pp 5195-5198, 1991
Printed in Great Britain
0040-4039/91 $3.00 + .00
Pergamon Press plc
Total Synthesis of Cervinomycin Al-trimethyl Ether
and Cervinomycin A2-methyl Ether
G o v e r d h a n Mehta* and Shailesh R. Shah
School of Chemistry, University of Hyderabad, Hyderabad
- 500 134, India.
Key
Words:
Xanthone antibiotics;
photocycl isation;
tetrahydrooxazolo-
[3,2-b]benz(g)isoquinolone formation.
Abstract: The heptacyclic framework of cervinomycin antibiotics has
constructed t h r o u g h C+EFG-4~ C E F G - - ~ C D E F G A B C D E F G approach in
the photochemical generation of ring was key step.
been
w h i c h
a
~
D
a
The
cervinomycins A1
I
and A2 2a belong to
a
small but
structurally
recognisable
novel and biologically p o t e n t family of antibiotics that are
t h r o u g h
w i t h i n
the
t h e i r
conspicuous presence of xanthone and
isoquinolone
moieties
polycyclic framework.l
Ever since t h e i r
isolation 2a
from
1986,2b, c
parti-
Streptomyces
cervinomycins
cularly
cervinus sp. nov. and structure determination
in
have attracted the attention of synthetic chemists,
anaerobic
in view of their promising activity against
bacteria,
mycoplasma and some Gram-positive bacteria.2a
A synthesis of cervinomyci-
ns A 1 and A 2 has been recently reported 3a in q u i c k succession to the model
studies in the area. 3b-d Hegein, we report the synthesis of cervinomycin
Al-trimethyl e t h e r and cervinomycin A2-monomethy] ether as the culmina-
3
tion
of
our approach, 3b in w h i c h the key central ring
D
is
constructed
t h r o u g h
a photochemical electrocyclisation stratagem.
O
S
0
R
OR
R
0
0
OCH3
~
~"0 ~
~
"OCH~
. . 0 /
~
~OCH3
2 a . R -
H
I " R - H
3. R CH3
-
b.
R
-
CH3
n
For t h e a m p l i f i c a t i o n o f our e a r l i e r s t u d i e s t o w a r d s the s y n t h e s i s o f
and 2a, t h e main t a s k was t h e c o n s t r u c t i o n o f the s e n s i t i v e t e t r a h y d r o -
s e g m e n t r e p r e s e n t i n g ABC r i n g s o f the
A f t e r considerable efforts, reliable sequence leading
to the tricyclic p o r t i o n 74 was developed from the homophthalic acid deri-
1
oxazolo[3,2-b]benz(g)isoquinolone
natural products.
a
vative
45 via the keto-acid
5
and isocoumarin 6476, Scheme
i.
Attempts
5195

5196
were
the d e s i r e d W i t t i g coupling with the xanthone derived ylide 8. 3b
p r o v e d too labile for meaningful chemical manipulations and the
then made to functionalise the aromatic methyl g r o u p in
7
to
set-up
However,
regio-
7
selectivity between the two benzylic position in it c o u l d not be achieved.
Consequently,
till the end was evolved.
Dimethyl homophthaiate derivative 4b was transformed to the
through benzylic bromination to and oxidation with
a m m o n i u m dichromate. 7 W i t t i g reaction between I0 and the xanthone
furnished the stilbene derivative lla in w h i c h the trans-isomer
a
strategy in w h i c h the
A
ring construction
was
deferred
aldehyde
10
9
bis-tetrabutyl-
y l i d e
pre-
83b
dominated.
Sequential acylation and decarboxylation in the
As planned,
12a underwent smooth lactonisation to the corresponding isocoumarin 13
dicarboxylic
acid
llb led to the ketocarboxylic acid 12a.
the
keto-acid
on
exposure
photocyclisation of 13 resulted in the generation of ring
cyclic isocoumarin 144 was realised.
of ring as demonstrated in Scheme i; however, the desired reaction
2-aminoethanol to furnish the cervinomycin framework c o u l d not be realised
to
a c e t i c anhydride and catalytic perchloric
acid.
Oxidative
D
and the hexa-
The stage was set for the generation
with
A
despite many trials and variations in reaction regimen.
terisable p r o d u c t from this reaction was the ring
cervinomycins, Scheme 2.
therefore, adopted. The keto-ester 12b was photocyclised to the
clic compound 164 and this on treatment with 2-aminoethanol in
cyclised
oxazolidine
m y c i n
The only
secologue
charac-
A
154
of
An alternative route that met with success
was,
hexacy-
methanol
in
the desired fashion, possibly through an
formation and intramolecular amidation, to
intermediate
furnish cervino-
The trimethyl-ether 3 was elaborated in
1,3-
A1 trimethyl e t h e r 3. 4,8
one step 9 to the cervinomycin-A 2 methyl ether 2b, identical with the m a t e -
rial p r e p a r e d from 2a. I0
'
0
OCH3
0
OCH~
0
OCH~
•
!"
>
RO
~
V
"CH~
/
~
~
"CH5
CH3
4a.
b.
R
,=
H
5" R , -
H
_.6
R
,= CH3
6-X, yQ2 I
RO
~
V
"CH=Br
RO
H
U~
I V
V
"CH~I
0
J
9.
R
,= CH3
10.
R
=, CH3
7
S c h e m e
Yield: (i) Ac20, Py., 30"C, 10h, 73%; (ii) 10% aq. NaOH,
Ac20, HClO4(Cat.), EtOAc, 30"C, 4h, 77% from 4a; (iv) 2-aminoetha-
nol, MeOH, 30"C, 12h, 50%; (v) N-bromosuccinimide, AIBN, CCId, 2h, 60%;
(vi) [(n-CdH9)dN]2Cr207, CHCI3, 2h, 80%.
1
Reagents
(iii)
&
, lh;
,
,

5197
.o_o.O¥o
OCI-~
0
OCH3 0
, o
•
II ""~ b. R - H
'~,iv
O
~
0 RO--O
OCH30cI.~ 0
~ O C H ~ H5
OCI-~ < v
~
L
~
~
~OCHa
OCH5
~ ~
'~ ~'Of
OCH3
~
~OCHa
OCH~
(--12o. R,,, H
13
viii k._.~'" b. R - CH3
~'~~OOI"I300H'~
0
OCH~O, CH,
0
,_4
,_e
H O ~ -
0
lvl|
,OCH5
0
l
OCH3
xi
2b
(
3
-
~'0f
~
~OCH~
~
OCH5 15
Scheme
2
Reagents
aq. KOH,
aq. NaOH,
&
Yield: (i) K2CO3, 18-crown-6, THF, 30"C, 8h, quant.; (ii)
MeOH, 4h, 90%; (iii) Ac20 , DMAP, 30"C, quant.; (iv)
lh, quant.; (v) Ac20, HClO4(Cat.), CHCI 3, 24h, 75%; (vi)
20%
10%
hlf,
36h;
(zx)
AgO-
,
,
12,
BF3.Et20,
h ~ ,
6N HNO3, dioxan, 70%.
CH2C12,
10
min.,
30%; (vii)
2-aminoethanol,
CH2C12,
30"C,
85%;
CH2CI 2,
0"C, 70%; (viii) CH2N2, Et20/CH2CI2, 10"C,
I2, CH2Cl 2, 25%; (x) 2-aminoethanol, MeOH, 30"C, 72h, 40%. (xi)

5198
R e f e r e n c e s and N o t e s
i.
Other member
of the family include: (a) Lysolipin
I,
Dabler,
M.;
Keller-Schierlein, W. Helv. Chim. Acta, 1977, 60, 178. (b) Albofungin
and
M.N.;
chloroalbofungin,
Gurevich, A.I.;
Karapetyan,
M.G.;
G.I.;
Kolosov,
Popravko,
Omelchenko, V.N.; Onoprienko, V.V.; Petrenko
S.A.; Tetrahedron Lett., 1972, 1751; Onoprienko, V.V.; Kozmin, Yu P.;
Kolosov,
54885
J.;
M.N. Bioorg. Khim., 1978, 4, 1418; Chem. Abstr., 1979,
U. (c) Actinoplanones A-G, Kobayashi, K.; Nishino, C.;
Sato, S.; Mikawa, T.; Shiobara, Y.; K o d a m a , M. J.
41, 502 and 741. (d) Simaomicins and B, Lee, T.M.;
9_O0,
Ohya,
Antibiot.,
Carter,
1988,
~
G.T.; Borders, D . B . J . Chem. Soc., Chem. Commun., 1989, 1771.
(a) Omura, S.; Iwai, Y.; Hinotozawa, K.; Takahashi, Y.; Kato,
Nakagawa, A. J. Antibiot., 1982, 35, 645. (b) Omura, S.;
A.;
Nakagawa,
Antibiot., 1987, 40, 301.
(a) Kelly, T.R.; Jagoe, C.T.; Li, Q. J. Am. Chem. Soc.,
4522. (h) Mehta, G.; Venkateswarlu, Y. J. Chem. Soc., Chem.
2.
3.
J.;
Nakagawa,
Kushida, K.; Lukacs, G. J. Am. Chem. Soc., 1986, 108, 6088.
A.; Omura, S.; Kushida, K.; Shimizu, H.; Luckacs, G.
(c)
J__t.
1989,
Iii,
Commun.,
1988, 1200. (c) Rama Rao, A.V.; Reddy, K.K.; Yadav, J.S.; Singh, A.K.
Tetrahedron Lett., 1988, 3991. (d) For studies directed towards lyso-
lipin
H.-U.; Scherrer, V. Chimia, 1985, 39, 174.
All new compounds reported here gave satisfactory spectral data
analytical or mass spectral data. 7: IH NMR (500 MHz, CDCI3):
I, see, Duthaler, R.O.; Heuberger, C.; Urs H.-U. Wegmann.
Urs
4.
and
1.27
6
(3H, s), 2.35 (3H, s), 2.93 (IH, d, J=14.6Hz), 3.08 (IH, d, J=14.6Hz,
3.55 (IH, m), 3.90 (3H, s), 4.00-4.20 (3H, m), 6.62 (IH, s), 6.70
(IH, s); m/z 247 (30%, M÷), 162 (100%). 16: IH NMR (100 MHz, CDCI3):
2.24 (3H, s), 3.50 (3H, s), 3.65 (3H, s), 3.90 (2H, s), 3.98 (3H,
s), 4.01 (3H, s), 4.03 (3H, s), 4.18 (3H, s), 7.00 (IH, s), 7.40 (IH,
6
s),
560
7.62 (IH, d, J=8.5Hz), 7.66 (IH, s), 8.02 (IH, d, J=8.5Hz);
(20%, M+), 529 (100%). 3: IH NMR (400 MHz, CDCI3): 1.40
m/z
(3H,
6
s), 3.21 (IH, d, J=14.8Hz), 3.29 (IH, d, J=14.SHz), 3.67-3.70 (IH,
m
masked
4.06
by OCH 3 signals), 3.68 (3H, s), 3.70 (3H, s), 4.01
(3H, s), 4.18 (3H, s), 4.16-4.24 (3H, m), 7.00 (IH,
(3H,
s),
s),
7.32
(IH, s), 7.61 (IH, d, J=8.5Hz), 7.73 (IH, s), 8.05 (IH, d,
m/z 571 (25%, M+), 540 (100%).
J=8.5Hz);
5.
6.
Tamura, Y.; Fukata, F.; Tsugoshi, T.; Sasho, M.; Nakajima, Y.;
Y. Chem. Pharm. Bull., 1984, 3_22, 3259.
Kita,
Modi,
Tirodkar,
R.B.; Usgaonkar, R.N. Ind. J. Chem., 1972, 10, 679;
A.R.; Usgaonkar, R.N. ihid, 1979, 17b, 360.
7.
8.
Landini, D.; Rolla, F. Chem. Ind. (London), 1979, 213.
Drs. A.V. Rama Rao, J.S. Yadav and colleagues at IICT, Hyderabad have
independently
approach (accompanying
synthesised
cervinomycins
following
We thank them
a
different
for helpful
communication).
discussions and comparison of the IH NMR spectrum of 16.
Snyder, C.B.; Rapoport, H. J. Am. Chem. Soc., 1972, 94, 227.
We thank Dr. Y. Venkateswarlu, who initiated this project,
continued interest and help. This work was supported by UGC and CSIR.
9.
10.
for
his
(Received in UK 24 June 1991)