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Synthesis of a versatile chiral synthon corresponding to the C(1) to C(7) segment of 14-membered macrolide antibiotics
Tetrahedron Letters,Vol.3O,No.l6,pp Printed in Great Britain
SYNTHESIS
OF
A
CORRESPONDING OF
oo40-4039/89 $3.00 Perqamon Press plc
2083-2086,1989
VERSATILE TO
14-MEMBERED
THE
CHIRAL
C(1)
to
MACROLIDE
C(7)
+ .oO
SYNTHON SEGMENT
ANTIBIOTICS
Marco Born and Chrfstoph Tamm* lnstitut fIjr Organische Chemie der Universitat St. Johanns-Ring
Abstract:
19, CH-4056 Basel, Switzerland
The synthesis of the C(1) to C(7) segment of a number of 14-membered
macroiide
antibiotics is described, starting from dimethyl 3-hydroxy-2,4-dimethylglutarate.
The use of enzymes
as catalysts in organic synthesis is still growing and can be considered
as one of the
most promising and expanding fields of organic chemistry1 . In this regard esterases such as pig liver esterase (PLE, EC 3.1.1 .l.) have shown to be very attractive. are important diesters
advantages
and racemic
development
of this enzyme.
monoesters
Stabilitiy, low cost and lack of the need of coenzymes
Our own studies on the enanfiosefective
by systematic
variation
of a refined model for the structure-activity
synthons for the construction
PLE. The chiral monoester
relationship,
of optically active compounds
A few years ago we reported the high enantioselectivity 5 obtained,
of the substrates2
of a number
of structurally
of the hydrolysis
possesses the correct stereochemistry
l4-membered
of new versatile
of the achiral dimethylester
4 by
in monensin biosynthesis,
3. This ester corresponds macrolide
of the five centres of chirality (Table).
2083
both, to the
used for the synthesis of a moiety of rifamycin
of the hydroxyester related
of meso-
such as complex natural products3.
which we previously
served as starting material for the preparation
are directed
and the preparation
and which was used by another group4 for the synthesis of a triene intermediate
C(7) segment
hydrolysis
antibiotfcs5
to the C(1) to of type 1, and
2084
1 R = various
Table:
Antibiotics
sugar units
of Type 1
_~-~____--__-_--~--~____----___--~-*
Fl2 R3 ---- _---.
____ ----
6-Deoxy-erythromycin
A and C
CH3
OH
Et
6-Deoxy-megalomycin
A
CH3
OH
Et
___--.
--__-____--
Compound
R4 __--.
I35 -_---__--__-H D-Rhodosamin
6-Deoxy-erythromydn
6
H
Et
._---. Oleandomycin
_----__II. H
--” _____ - ____--. _--____L-____.__
H
CH3 ._______,--- __------I-
Lankamycin
H __-___---__.
Z-Hydroxy-
H
AC
set-butyl
The 14-membered
macrolide antibiotics are a medicinally important group of secondary metabolites
of their activity against gram-positive the construction
bacteria. Therefore many synthetic efforts6 have been made directed to
of the structure containing ten asymmetric
centres.
Our synthesis of 3 started with the reduction of the monoester protection
of the primary
hydroxyl
chloride (TBDPhSCI), imidazole,
because
5 with BH3.(CH.-&S
group of the resulting diol 6 as the silylether
DMF), The protected hydroxyester
at 0” and subsequent
8 (tert.-butyl-diphenylsilyl
8 was isolated in 78% yield ([rr]g=
-5.6’;
2085
c = 1.5, CCl4). The well known lactone 7 was formed as a by-product obtained
et aL7 in the course of the structural
by Gerzon
synthesized 88-88.5’,
by Wakamatsu
determination
et al.8 had a mp. of 88-89’ (toluene) and [o]g=
[cx]‘~= -5.0”; c-2, MeOH; Lit.8 mp 88*, [a]D = -4.6’;
Reduction
of the protected
hydroxyester
of dihydroerythronolide -4.4”;
A and
(c = 2, MeOH) (Lit.7: mp.
MeOH).
8 with BH3(CH3)2S
at 40” afforded the monoprotected
trio1 9 in
= -3.8O; c= 2, CHCl3). Lactone 7 was also converted to 9 by a four-step sequence involving
78% yield ([a]: subsequent
(yield 15%). Lactone 7, which was
treatment
BH3+(CH3)2S.
with
KOH/MeOH;
Thus an additional
2 mol-equiv.
TBDPhSCI,
imidazole,
amount of 9% of 9 was made available. CSA, 94%,
as acetonide
desilylation
of 10 (TBAF, quant.) the resulting alcohol 11 ([cx]~= -7.1”; c = 1.39, CHCl3) was oxidized to the 12 by the method of Swern9 (yield 97%). Aldehyde
during his synthetic work on erythromycin
A, had [a$=
+5.3”;
[a]g
= -13.0”;
and
groups of 9 were
protected
aldehyde
(2,2_dimethoxypropane,
DMF; KOH/MeOH
The hydroxyl
c = 1.39, CHCt3).
12, which was obtained
by Yonemitsul
(c = 1.2, CHCl3) (Lit.tO: [&
OH COOR
_
BMS
MeOOCa”
+
fi‘ &H 7
6
4R=Me 5R=H
TBDPhSCl \
X 0
0
OH
OR
OH
OH
OR
Y”xp””
BMS
OR
MeOOC
2. TBAF 10 R = TE?DPhS 11 R-H
I
ox.
t
x
0
0 CHO
9 R = TBDPhS
o
= +5.0”, c = 1.2,
CHCl3).
MeOOC
After
8 R = TBDPhS
2086
Introduction
of the remaining
Heathcock’
two chiral centres was achieved
I. Addition of the aldehyde
THF at -78” gave the desired obtained
using the atylester
12 to a solution of the Li-enolate
hydroxyester
3 as the only product
aldol condensation
of
of 2.6-dimethylphenylpropionate
in
(yield 50%). The hydroxyester
3’ 2
from 4 in an overall yield of 30% had a mp. of 97-99” (hexane),
[cx]~=
tl.6”;
(c = 1, CCl4) and
represents a most useful chiral synthon for the construction of macrolide antibiotics.
Financial
support
of these
investigations
by the
Swiss
NationalScience
Foundation
is gratefully
acknowledged.
References 1) a) b) 2 a)
J. 6. Jones, Tetrahedron
1986, 42, 3351 and ref. cited therein.
G.M. Whitesides & C.H. Wong, Angew. Chem. 1985, 97, 617 and ref. cited therein. P, Mohr, N. Waespe-Sarcevic
& Ch. Tamm; K. Gawronska 8 J.K. Gawronski, He/v. Chim Acta 1983,
66, 2501. b)
P. Mohr, L. Rosslein & Ch. Tamm, ibid. 1987, 70, 142.
c)
T. Kuhn & Ch. Tamm; A. Riesen & M. Zehnder, Tetrahedron Lett. in press. 8 Ch. Tamm, He/v. Chim. Acta 1986, 69,621.
3)
T. Tschamber, N. Waespe-Sarcevic
4)
OS. Holmes, UC. Dyer, S. Russell, J.A. Sherringham
& J.A. Robinson,
Tetrahedron
Left. 1988,29,
6357. 5) a) b) 6) a)
W. Keller-Schierlein,
Fortschr. Chem. Org. Naturst. 1973, 30, 313
W.D. Celmer, Pure Appl. Chem. 1971, 28, 413. I. Paterson & M. Mansuri, Tetrahedron 1985, 41, 3569 and ref. cited therein
b)
I. Paterson, D.P. Laffan & D.J. Rawson, Tetrahedron
Left. 1988, 29, 1461.
c)
T. Nakata, M. Fukui & T. Oishi, Tefrahecfron Left. 1988, 29, 2219
d)
Y. Kobayashi,
e)
J. Mulzer, L. Autenrieth-Ansorge,
H. Uchiyama, H. Kanbara & F. Sate, J. Am. Chem. Sot. 1985, 107,554l H. Kirstein, T. Matsuoka & W. Munch, J. Ofg. Chem. 1987, 52,
3784. 7)
K., Gerzon, E.H. Flynn, M.V. Sigal, P.F. Wiley, R. Monahan & UC. Quarck, J. Am. Chem. Sot. 1956, 78, 6396.
8)
T. Wakamatsu, H. Nakamura, Y. Nishikimi, K. Yoshida, T. Noda & M. Taniguchi, Tetrahedron Left 1986, 27, 6071.
9)
A.J. Mancuso, S.L. Huang & D. Swern, J. Org. Chem. 1978, 43, 2480.
10)
Y. Oikawa, T. Nishi & 0. Yonemitsu, J. Chem. Sot. Perkin Trans. I1985, 19.
11)
C.H. Heathcock,
12)
The ester 3 gave correct microanalyses
MC. Pirrung, S.H. Montgomery
& J. Lampe, Tetrahedron
and spectroscopic
enantiomeric
form, which we had previously synthesized
(Received
in Germany
2 February
1989)
1981, 37, 4087.
data which corresponded (see. ref. 3).
to its
SYNTHESIS
OF
A
CORRESPONDING OF
oo40-4039/89 $3.00 Perqamon Press plc
2083-2086,1989
VERSATILE TO
14-MEMBERED
THE
CHIRAL
C(1)
to
MACROLIDE
C(7)
+ .oO
SYNTHON SEGMENT
ANTIBIOTICS
Marco Born and Chrfstoph Tamm* lnstitut fIjr Organische Chemie der Universitat St. Johanns-Ring
Abstract:
19, CH-4056 Basel, Switzerland
The synthesis of the C(1) to C(7) segment of a number of 14-membered
macroiide
antibiotics is described, starting from dimethyl 3-hydroxy-2,4-dimethylglutarate.
The use of enzymes
as catalysts in organic synthesis is still growing and can be considered
as one of the
most promising and expanding fields of organic chemistry1 . In this regard esterases such as pig liver esterase (PLE, EC 3.1.1 .l.) have shown to be very attractive. are important diesters
advantages
and racemic
development
of this enzyme.
monoesters
Stabilitiy, low cost and lack of the need of coenzymes
Our own studies on the enanfiosefective
by systematic
variation
of a refined model for the structure-activity
synthons for the construction
PLE. The chiral monoester
relationship,
of optically active compounds
A few years ago we reported the high enantioselectivity 5 obtained,
of the substrates2
of a number
of structurally
of the hydrolysis
possesses the correct stereochemistry
l4-membered
of new versatile
of the achiral dimethylester
4 by
in monensin biosynthesis,
3. This ester corresponds macrolide
of the five centres of chirality (Table).
2083
both, to the
used for the synthesis of a moiety of rifamycin
of the hydroxyester related
of meso-
such as complex natural products3.
which we previously
served as starting material for the preparation
are directed
and the preparation
and which was used by another group4 for the synthesis of a triene intermediate
C(7) segment
hydrolysis
antibiotfcs5
to the C(1) to of type 1, and
2084
1 R = various
Table:
Antibiotics
sugar units
of Type 1
_~-~____--__-_--~--~____----___--~-*
Fl2 R3 ---- _---.
____ ----
6-Deoxy-erythromycin
A and C
CH3
OH
Et
6-Deoxy-megalomycin
A
CH3
OH
Et
___--.
--__-____--
Compound
R4 __--.
I35 -_---__--__-H D-Rhodosamin
6-Deoxy-erythromydn
6
H
Et
._---. Oleandomycin
_----__II. H
--” _____ - ____--. _--____L-____.__
H
CH3 ._______,--- __------I-
Lankamycin
H __-___---__.
Z-Hydroxy-
H
AC
set-butyl
The 14-membered
macrolide antibiotics are a medicinally important group of secondary metabolites
of their activity against gram-positive the construction
bacteria. Therefore many synthetic efforts6 have been made directed to
of the structure containing ten asymmetric
centres.
Our synthesis of 3 started with the reduction of the monoester protection
of the primary
hydroxyl
chloride (TBDPhSCI), imidazole,
because
5 with BH3.(CH.-&S
group of the resulting diol 6 as the silylether
DMF), The protected hydroxyester
at 0” and subsequent
8 (tert.-butyl-diphenylsilyl
8 was isolated in 78% yield ([rr]g=
-5.6’;
2085
c = 1.5, CCl4). The well known lactone 7 was formed as a by-product obtained
et aL7 in the course of the structural
by Gerzon
synthesized 88-88.5’,
by Wakamatsu
determination
et al.8 had a mp. of 88-89’ (toluene) and [o]g=
[cx]‘~= -5.0”; c-2, MeOH; Lit.8 mp 88*, [a]D = -4.6’;
Reduction
of the protected
hydroxyester
of dihydroerythronolide -4.4”;
A and
(c = 2, MeOH) (Lit.7: mp.
MeOH).
8 with BH3(CH3)2S
at 40” afforded the monoprotected
trio1 9 in
= -3.8O; c= 2, CHCl3). Lactone 7 was also converted to 9 by a four-step sequence involving
78% yield ([a]: subsequent
(yield 15%). Lactone 7, which was
treatment
BH3+(CH3)2S.
with
KOH/MeOH;
Thus an additional
2 mol-equiv.
TBDPhSCI,
imidazole,
amount of 9% of 9 was made available. CSA, 94%,
as acetonide
desilylation
of 10 (TBAF, quant.) the resulting alcohol 11 ([cx]~= -7.1”; c = 1.39, CHCl3) was oxidized to the 12 by the method of Swern9 (yield 97%). Aldehyde
during his synthetic work on erythromycin
A, had [a$=
+5.3”;
[a]g
= -13.0”;
and
groups of 9 were
protected
aldehyde
(2,2_dimethoxypropane,
DMF; KOH/MeOH
The hydroxyl
c = 1.39, CHCt3).
12, which was obtained
by Yonemitsul
(c = 1.2, CHCl3) (Lit.tO: [&
OH COOR
_
BMS
MeOOCa”
+
fi‘ &H 7
6
4R=Me 5R=H
TBDPhSCl \
X 0
0
OH
OR
OH
OH
OR
Y”xp””
BMS
OR
MeOOC
2. TBAF 10 R = TE?DPhS 11 R-H
I
ox.
t
x
0
0 CHO
9 R = TBDPhS
o
= +5.0”, c = 1.2,
CHCl3).
MeOOC
After
8 R = TBDPhS
2086
Introduction
of the remaining
Heathcock’
two chiral centres was achieved
I. Addition of the aldehyde
THF at -78” gave the desired obtained
using the atylester
12 to a solution of the Li-enolate
hydroxyester
3 as the only product
aldol condensation
of
of 2.6-dimethylphenylpropionate
in
(yield 50%). The hydroxyester
3’ 2
from 4 in an overall yield of 30% had a mp. of 97-99” (hexane),
[cx]~=
tl.6”;
(c = 1, CCl4) and
represents a most useful chiral synthon for the construction of macrolide antibiotics.
Financial
support
of these
investigations
by the
Swiss
NationalScience
Foundation
is gratefully
acknowledged.
References 1) a) b) 2 a)
J. 6. Jones, Tetrahedron
1986, 42, 3351 and ref. cited therein.
G.M. Whitesides & C.H. Wong, Angew. Chem. 1985, 97, 617 and ref. cited therein. P, Mohr, N. Waespe-Sarcevic
& Ch. Tamm; K. Gawronska 8 J.K. Gawronski, He/v. Chim Acta 1983,
66, 2501. b)
P. Mohr, L. Rosslein & Ch. Tamm, ibid. 1987, 70, 142.
c)
T. Kuhn & Ch. Tamm; A. Riesen & M. Zehnder, Tetrahedron Lett. in press. 8 Ch. Tamm, He/v. Chim. Acta 1986, 69,621.
3)
T. Tschamber, N. Waespe-Sarcevic
4)
OS. Holmes, UC. Dyer, S. Russell, J.A. Sherringham
& J.A. Robinson,
Tetrahedron
Left. 1988,29,
6357. 5) a) b) 6) a)
W. Keller-Schierlein,
Fortschr. Chem. Org. Naturst. 1973, 30, 313
W.D. Celmer, Pure Appl. Chem. 1971, 28, 413. I. Paterson & M. Mansuri, Tetrahedron 1985, 41, 3569 and ref. cited therein
b)
I. Paterson, D.P. Laffan & D.J. Rawson, Tetrahedron
Left. 1988, 29, 1461.
c)
T. Nakata, M. Fukui & T. Oishi, Tefrahecfron Left. 1988, 29, 2219
d)
Y. Kobayashi,
e)
J. Mulzer, L. Autenrieth-Ansorge,
H. Uchiyama, H. Kanbara & F. Sate, J. Am. Chem. Sot. 1985, 107,554l H. Kirstein, T. Matsuoka & W. Munch, J. Ofg. Chem. 1987, 52,
3784. 7)
K., Gerzon, E.H. Flynn, M.V. Sigal, P.F. Wiley, R. Monahan & UC. Quarck, J. Am. Chem. Sot. 1956, 78, 6396.
8)
T. Wakamatsu, H. Nakamura, Y. Nishikimi, K. Yoshida, T. Noda & M. Taniguchi, Tetrahedron Left 1986, 27, 6071.
9)
A.J. Mancuso, S.L. Huang & D. Swern, J. Org. Chem. 1978, 43, 2480.
10)
Y. Oikawa, T. Nishi & 0. Yonemitsu, J. Chem. Sot. Perkin Trans. I1985, 19.
11)
C.H. Heathcock,
12)
The ester 3 gave correct microanalyses
MC. Pirrung, S.H. Montgomery
& J. Lampe, Tetrahedron
and spectroscopic
enantiomeric
form, which we had previously synthesized
(Received
in Germany
2 February
1989)
1981, 37, 4087.
data which corresponded (see. ref. 3).
to its