Total syntheses of (±) cervinomycins A1 and A2

Article abstract of DOI:10.1016/S0040-4039(00)93466-X

Regiocontrolled total syntheses of cervinomycins A₁ (1) and A₂ (2_have been achieved from easily accessible 6-acetyl-2-bromo-1,4,-dimethoxynaphthalene (4).

Full text of DOI:10.1016/S0040-4039(00)93466-X

Tetrahedron Letters, Vol.32, No.38, pp 5199-5202, 1991
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0040-4039/91 $3.00 + .00
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Total Syntheses of (+) Cervinomycins A 1 and A 2
A V Rama Ran*, 3 S Yadav, K Kishta Reddy and Velaparthi Upender
Indian Institute of Chemical Technology, Hyclerabad 200 007, India
Abstract:
Regiocontrolled total syntheses of cervinomycins AI (I) and A7 (2) have been
achieved
from easily accessible
6-acetyl-2-bromo-1,4-dimefhoxynaphthalene
(~).
Cervinomycins L A! (I) and A2 (2) belong to a small but growing family2 of antibiotics,
all of which possess xanthone and isoquinoJone moieties juxtaposed angularly in a polycyclic
aromatic framework. The triacetyl cervinomycin A2 (3) is being developed3 as a drug because
of its potent antianaerobic activity against several bacteria. Owing to their skeletal novelty
and potent activity, several groups%5 have attempted their syntheses. However only one
total synthesis6 has appeared so far. Herein, we report
for the total syntheses of cervinomycins A l (1) and A2 (2).
a regiocontrolled, elegant approach
Our synthetic technology is based on the retrosynthetic protocol which dictates that
we deviate from the bridging of isoquinolone (ABC fragment) and xanthone (E~G fragment)
moieties by photocyclisation (Scheme l). This will not rule out the preferred5a possibility
0
~
. ~ O M e
ocH3
0
OR
12
!
R-- R1 .-H
RI-H, Ring E quinone
_3 R= RI= AC
17 RI=CH3, Ring Equinone
~
,
,
~
O
R OR
OR
0
0
OMe
OMe
Scheme
4
5199

5200
of coupling at para to -OH group of the
C ring. Hence our strategy centres around the key
intermediate t) constituting DE ring) which will allow us to regioselectively build the xanthone
and isoquinolone moieties on it.
An expedient approach to the synthesis of key intermediate 12 with the BCDE ring
unit) from 6-acetyl-2-bromo-l)O-dimethoxynaphthalene (~)7 is illustrated in Scheme II. Our
plan relies upon the strategically placed bromine and acetyl functionalities in /~ providing
access to regiocontrolled introduction of xanthone and the C ring of cervinomycin respectively.
Thus) compound /~ was first converted to 2-bromo-l,t~-dimethoxy-6-naphthyl acetone
step sequence. The ketone 5 was then olefinated with Ph3P=CHCO2Et and the resulting
cis/trans mixture was hydrogenated to provide the ester 6. The ester was hydrolysed to
give the acid 7) which on treatment with PPE furnished9 the angular keto compound as
sole product. The ester functionality at the -position of the keto group was introduced by
5 by
a
3
6
g
treatment of g with NaH/diethyl carbonate followed by aromatization of the C ring to produce
the substituted phenanthrene 9.
Scheme II
OMe
a.b,c
~
d.ef
ONe Br
!
- - - - , - . -
Br
" ~ , ~ y ~ B r
6
7
R= Et
R=H
OMe
8
OMe
5
.CO2Et
~F~O CO2Et
ON,
ON,,
II
I
- -
Jl
I
oMe
m
9
OMe
10
OMe
11
OMe
R~agents & Conditions-
(a) Thallium(Ill)nitrate trihydrate 8 (I eq), 2:2;I MeOH;Dioxane;HCIO., 0-25°C, 1 h, 85%; (b)
•
,
q .
aq.KOH (2 eq), MeOH, 25°C, 12 h) 98%; (c) 2.1 eq of MeLl m ether soin, 0-25°C, I h, 65%;
(d) PhaP=CHCO?Et (2 eq)) toluene, reflux, 36 h) 91% (e) H3) PtO2, EtOH,
I atm; (f) KOH
(2 eq)/EtOH, 25°C) 8 h; (g) Excess PPE) CHCIa) 25°C, 30 h'~ over all yield from 6 52%; (h)
Nail (2.1 eq), diethyl carbonate, THF, reflux, 16" h, 75%; (i) C5H~NHBr~(I eq) AcOH, 25°C,
I
h, 95% (j) DBU (2 eq)) CH?CI?) 25°C, I0 h, 65%; (k) K3CO~ (3 eq))'DMS (2 eq), acetone,
reflux, I0 ha 85%; (I) LDA "(2.~ eq), N-methoxy-N-methy'lace'{amide (2.5 eq), THF) -78°C)
I.5 ha 74%; (m) NaBHh (0.5 eq), K~CO4. (I eq), MeQH, 25°C, 30 min, 80%; (n) (NH4)2Ce(NO3)6
(2 eq), CH3CN, H20) 2'5°C, 15 min)-9596.
We next turned our attention to elaborate 9 to the desired quinone 12. Thus) the methyl
ether of the 9 was converted to the keto compound lO using N-methoxy-N-methylacetamide I0.
Reduction of the ketone I0 by NaBH4 resulted in the formation of lactone II. As anticipated,

5201
the displacement of the bromine in II by phenoxide ion proved difficult and hence lactone
11
II was converted to the quinone 12 by oxidative demethylation
With the key synthon 12 in hand, we then proceeded to build the xanthone unit by
reacting quinone 12 with methyl 2-hydroxy-%5-dimethoxybenzoate 12 in the presence of anhy-
drous K2CO3 in DMF. The resultant quinone 13 was then converted to the pentacyclic methyl
ether I$ (Scheme Ill).
S c h e m e III
o o
o ..o
v
y
- o - v
c.3
O
OMe
f
I
•, ~ 0
~ o M e C O 2 M e
0
N
0
~
O
M
e
II
1
OMe
0
O
M"]
e
.]OMe[ .0"
,d._•_e..ff4==.
~
OCH3
g
OCH3
~ . /
is
" - ~ ~O / "-,,~--OCH3
~
~ " ~O /
~
~OCH3
OMe
OMe
l_s
-Reagents & Conditions-
(a) aq. NagSgOa; K g C O x ( 5 ~(:I), DMS (# eq), acetone, reflux, 6 h; (b) aq. KOH (1.5 eq), EtOH,
25°C, 10 h~; "(c)~ Exc%ss ~PPE ~, CHCI3, 25°C, 36 h, over all yield from 13 62%; (d) aq. KOH
(1.5 eq), EtOH, 25°C, 8 h (e) CHgNg, ether; (f) PCC (1.2 eq), CH?CIo, 25°C, 15 h, over all
yield from 14 90%; (g) H2NCH2CH2OR (2 eq), K2CO3 (1.5 eq), MeOl-l~ 2~°C, 36 h, 82%.
We then addressed the key annulation of the oxazolidine ring to give the final skeleton
#
which proved to be more difficult than anticipated. Our earlier experience to form oxazolidine
ring on isocoumarin which often furnished side product in a varied amount, was also substanti-
ated by Kelly6. This prompted us to look for an alternative method. The mechanism of the
S c h e m e IV
o/",t'o.. 1
o
Me
-"
: 0
H o ~ N H 2
K2CO3
- MeOH
15
16

5202
reaction came as
a redressal to choose methyl keto ester as depicted in the Scheme IV as
requisite precursor for building oxazolidine ring. Hence, our attempt on methyl keto ester
14
15 with ethanolamine which involves initial protection of keto group
and subsequent intra-
molecular amidation onto ester, turned out to be successful, furnishing the desired oxazolidine
16.
As a final step, chemoselective oxidative demethylation II of E ring in 16 was achieved
by ceric ammonium nitrate/aq. CH3CN to give 17 in 95% yield. After several unsuccessful
attempts, Et3N:BCI3 (in dichloromethane, at 0°C 15 rain, 85°/6) was found to be an optimum
reagent 15 for deprotecting the methoxyl group of ring C, thereby furnishing cervinomycin-A2
(2). This, on reduction with NaBH4 yielded cervinomycin A I (I). The NMR and IR spectra
of these synthetic materials were superimposable with those of natural cervinomycins16
We are indebted to Prof Omura (3apan) for providing the authentic samples of cervino-
mycin A I and A2.
REFERENCES
I.
a) S. Omura, A. Nakagawa, K. Kushida, G. Lukacs, 3. Am. Chem. Soc, 1986, log,
6088; b) S. Omura, A. Nakagawa, K. Kushida, H. Shimizu, G. Lukacs, 3. Antibiot.,
1987, t~0, 301.
2.
G.T. Carter, 3.A. Nietsche, D.R. Williams, D.B. Borders, 3. Antibiot., 1990, 5, .500
and references cited therein.
A. Nakagawa, Y. Iwai, H. Shimizu, S. Omura, 3. Antibiot., 1986, 39, 1636.
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a) G. Mehta, Y. Venkateswarlu, 3.C.S. Chem. Comm., 1988, 1200; b) K.A. Parkar,
S.M. Ruder, 3. Am. Chem. Soc, 1989, III, 59t~8; c) R.O. Dutualer, C. Henberger,
V.H.-U. Wegmann, V. SeherreG Chimia, 1985, 59, 17t+.
3.
t+.
5.
6.
7.
8.
9.
T.R. KeJly, C. 3agoe, Q. Li, 3. Arn. Chem. Soc., 1989, III, 4522.
U. Lauk~ P. Skrabal, H. Zollinger, Helv. Chim. Acta., 1983, 66, 157t+.
A. McKillop, M.P. Swann, E.C. Taylor, 3. Am. Chem. Soc., 1971, 93, t+919.
a) W.S. Johnson, Org. React., 19t#b 2, llt~; b) I. Agranat, Y.S. Shih, Synthesis, 197%
865 and referenced cited therein.
I0.
11.
12.
a) C.N. Lewis, P.L. Spargo, 3. Staunton, Synthesis, 1986, 9t~t+; b) S. Nahm~ S.M. Weinreb,
Tetrahedron Lett., 1981, 22, 3815.
P. 3acob (III), P.S. Callery, A.T. Shulgin, N. Castagnoli 3r., 3. Org. Chem., 1976, ¢1,
3627.
Prepared from Asaranaldehyde (Fluka) by oxidation (NaCIO?, NHgSO~H), esterification
(CHgN9) and selective mono demethylation to obtain the procr'uct in'B`5% yield.
For'~irr3ilar cyclisation with PPA, see: G. Metz, Synthesis, 1972, 612.
a) E.P. Goldberg, H.R. Naee, 3. Am. Chem. Soc., 1955, 77, 3.59; b) P.A. laureut, Bull.
Soc. Chim Fr., 1967, 67, 7782.
13.
It+.
15.
16.
Prepared by addition of BCI3(I eq) in CH2Cl^/containing Et3N (1.1 eq).
m
Prof
G Mehta and Mr S R Sha'h have inffependently
synthesased compound 1`5 by a
different strategy and converted to Cervinomycin trimethyl ether by our approach.
IICT Communication No. 2762
(Received in UK 25 June 1991)