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Ansa macrolide synthesis preoaration of the aromatic portion of maytansine
Tetrahedron Letters
No. 9, pp 775 - 776,
ANSA
1977.
Pergamon Press.
Printed
in Great Britain.
MACROLIDE SYNTHESIS
PREPARATION OF THE AROMATIC PORTION OF MAYCANSINE
James E. Foy and Bruce Ganem *
Department of Chemistry Cornell Ithaca,
University
New York
(Received in USA 30 Deoember 1976; received Progress requires
towards the stereospecific
an efficient
route to the tetrasubstltuted 2
in these ansa macrolides. selectlon
of an appropriate
route are three features the development 8, a versatile
synthesis
which considerably
of a six-step intermediate
in UK for publication
of clinically aromatic
An unusual assemblage nitrogen protecting
14853
interesting
(“western”)
28 January 1977) maytansinoids
fragment commonly
of three different
vicinal
found
heteroatoms , the
group, and the need for a preparatively
complicate
_$_I
practical
In this letter we disclose
this objective.
route to 2-chloro-3-methoxy-5-bromomethyl-N-methylacetanilide
which satisfies
our present prerequisites
for maytansine
total syn-
thesis. 7”” N - COCH3
CH3
CH2X
Condensation 2. (mp 118-119O)
of 5-methylcyclohexane-I
in 70% yield after crystallization.
with N-chlorosuccinlmide [72%,
mp 188-89’;
,3-dfone 3 with 40% aqueous
(1 equiv)
4
Chlorination
7.00
(broad 8, lH, 775
furnishes
of 2 is best accomplished
in CH2C12 at rt, and the resulting
NMR 6 (DMSO -d8)
methylamine
NH), 2.89
chloroenaminoketone (d, 3H, J=S), 1.08
2
No. 9
776 (EI) M + 173,
(d, 3H, J=6); mass spectrum
175, ratio
3:1] oxidized
further by the addition
of
Br2 in CC14 (1 equiv) at 0’.
Cl
P ‘qRTH3
2. R, R’=H 2 R=Cl,
R’=H
3 R=Cl,
R’=Br
3.15
[64%,
CH3
mp 123-124’;
treated directly Thus the overall 3H, N-m3), 5.62,
yield of S4
2.33
However
phenol
ated _i_n
(CH31, K2C03,
6.87,
(2 singlets,
(s, 3H, Ar-CQ13),
from 3 is 85-90%
1.81
group may be effected
(EI) M+ 255,
3.95
Conversion
3H),
3.18
(s, 3H),
of 8, now available
under investigation.
4
not purified,
dehydrobromination.
4 (mp 199-200°)
yield by reaction
[ NMR (CDC13) 7.05 1.82
(ED m/e
(s, 2H),
3.18
(s, 3H, N-COCH3);
(s, 3H, 0C_H3), 3.18
C_H-Br),
rather the mixture is
Saponification
Finally oxidation
F3,
mass spectrum
6 hr reflux) to give methoxyacetanilide
in 76-80%
CH,Br),
(d, lH,
[mp 88O; NMR (CDC13) 7.00
257 ratio 3:1].
(s, 3H. N-COCA3)].
4-5 hr, sunlamp irradiation) (s,
4 is usually
6.3u;
and Ar- CH3), 1.80
each lH, Ar - H), 3.92
(reflux,
lH, NH_), 4.81
IR (CHC13) 6.1,
5 which may be isolated
CH30H,
selectively
(broad s,
from which one isomer CrYs-
at 110’ for 90 min to effect
(broad s, 6H, 0-COCH3
the corresponding
6.78
(d, 3H, p6);
anhydride/l’sOH
6 .OOu; mass spectrum
affords
4 is formed in this reaction
ratio 1:1.06:0.31]. with acetic
3
CH3
NMR (CDC13) 5.7
(d, 3H, J=5, N - CH3), 1.18
251 (M+):253:255
I
R”~-c;;&)CH3
A mixture of monochlorobromides tallizes
CH
I
(s,
IR (mull)
of 2 (K2C03,
CH30H)
or preferably
methyl-
Z. [91%; NMR (CDC13) 3H, N-Cx3),
of 2 at the aromatic
with NBS (1.1 equiv)
(2 overlapping
(s,
s, 2H),
2.38 methyl
in Ccl4
4.44
(s, 2H,
(s, 3H)].
in good overall
yield
(33%),
into maytansine
is currently
5
REFERENCES (1) S.M. Kupchan, A.R. Branfman, A.T. Sneden, A.K: Varma, R.G. Dailey Jr., Y. Komoda, Y. Nagao, J. Amer. Chem. Sot., 97, 5294 (1975). (2) For other progress reports on maytansine see (a) A. I. Meyers et. , Tetrahedron Lett. , 717 (1974), 1745 (1975), 1749 (1975); (b) E.J. Corey, M.G. Bock, j&j., 2643 (1975) (3) A.W. Crossley, N. Renouf, J. Chem. Sot 602 (1915) (4) Satisfactory elemental analysis has been obtained for this compound. (5) The authors acknowledge generous financial support from the National Institutes of Health (Grant # CA 19686) and the Eli Lilly Company.
No. 9, pp 775 - 776,
ANSA
1977.
Pergamon Press.
Printed
in Great Britain.
MACROLIDE SYNTHESIS
PREPARATION OF THE AROMATIC PORTION OF MAYCANSINE
James E. Foy and Bruce Ganem *
Department of Chemistry Cornell Ithaca,
University
New York
(Received in USA 30 Deoember 1976; received Progress requires
towards the stereospecific
an efficient
route to the tetrasubstltuted 2
in these ansa macrolides. selectlon
of an appropriate
route are three features the development 8, a versatile
synthesis
which considerably
of a six-step intermediate
in UK for publication
of clinically aromatic
An unusual assemblage nitrogen protecting
14853
interesting
(“western”)
28 January 1977) maytansinoids
fragment commonly
of three different
vicinal
found
heteroatoms , the
group, and the need for a preparatively
complicate
_$_I
practical
In this letter we disclose
this objective.
route to 2-chloro-3-methoxy-5-bromomethyl-N-methylacetanilide
which satisfies
our present prerequisites
for maytansine
total syn-
thesis. 7”” N - COCH3
CH3
CH2X
Condensation 2. (mp 118-119O)
of 5-methylcyclohexane-I
in 70% yield after crystallization.
with N-chlorosuccinlmide [72%,
mp 188-89’;
,3-dfone 3 with 40% aqueous
(1 equiv)
4
Chlorination
7.00
(broad 8, lH, 775
furnishes
of 2 is best accomplished
in CH2C12 at rt, and the resulting
NMR 6 (DMSO -d8)
methylamine
NH), 2.89
chloroenaminoketone (d, 3H, J=S), 1.08
2
No. 9
776 (EI) M + 173,
(d, 3H, J=6); mass spectrum
175, ratio
3:1] oxidized
further by the addition
of
Br2 in CC14 (1 equiv) at 0’.
Cl
P ‘qRTH3
2. R, R’=H 2 R=Cl,
R’=H
3 R=Cl,
R’=Br
3.15
[64%,
CH3
mp 123-124’;
treated directly Thus the overall 3H, N-m3), 5.62,
yield of S4
2.33
However
phenol
ated _i_n
(CH31, K2C03,
6.87,
(2 singlets,
(s, 3H, Ar-CQ13),
from 3 is 85-90%
1.81
group may be effected
(EI) M+ 255,
3.95
Conversion
3H),
3.18
(s, 3H),
of 8, now available
under investigation.
4
not purified,
dehydrobromination.
4 (mp 199-200°)
yield by reaction
[ NMR (CDC13) 7.05 1.82
(ED m/e
(s, 2H),
3.18
(s, 3H, N-COCH3);
(s, 3H, 0C_H3), 3.18
C_H-Br),
rather the mixture is
Saponification
Finally oxidation
F3,
mass spectrum
6 hr reflux) to give methoxyacetanilide
in 76-80%
CH,Br),
(d, lH,
[mp 88O; NMR (CDC13) 7.00
257 ratio 3:1].
(s, 3H. N-COCA3)].
4-5 hr, sunlamp irradiation) (s,
4 is usually
6.3u;
and Ar- CH3), 1.80
each lH, Ar - H), 3.92
(reflux,
lH, NH_), 4.81
IR (CHC13) 6.1,
5 which may be isolated
CH30H,
selectively
(broad s,
from which one isomer CrYs-
at 110’ for 90 min to effect
(broad s, 6H, 0-COCH3
the corresponding
6.78
(d, 3H, p6);
anhydride/l’sOH
6 .OOu; mass spectrum
affords
4 is formed in this reaction
ratio 1:1.06:0.31]. with acetic
3
CH3
NMR (CDC13) 5.7
(d, 3H, J=5, N - CH3), 1.18
251 (M+):253:255
I
R”~-c;;&)CH3
A mixture of monochlorobromides tallizes
CH
I
(s,
IR (mull)
of 2 (K2C03,
CH30H)
or preferably
methyl-
Z. [91%; NMR (CDC13) 3H, N-Cx3),
of 2 at the aromatic
with NBS (1.1 equiv)
(2 overlapping
(s,
s, 2H),
2.38 methyl
in Ccl4
4.44
(s, 2H,
(s, 3H)].
in good overall
yield
(33%),
into maytansine
is currently
5
REFERENCES (1) S.M. Kupchan, A.R. Branfman, A.T. Sneden, A.K: Varma, R.G. Dailey Jr., Y. Komoda, Y. Nagao, J. Amer. Chem. Sot., 97, 5294 (1975). (2) For other progress reports on maytansine see (a) A. I. Meyers et. , Tetrahedron Lett. , 717 (1974), 1745 (1975), 1749 (1975); (b) E.J. Corey, M.G. Bock, j&j., 2643 (1975) (3) A.W. Crossley, N. Renouf, J. Chem. Sot 602 (1915) (4) Satisfactory elemental analysis has been obtained for this compound. (5) The authors acknowledge generous financial support from the National Institutes of Health (Grant # CA 19686) and the Eli Lilly Company.