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Erythromycin SynthesisЧA Never-ending Story.

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Erythromycin Synthesis-A
Never-ending Story?
By Johann Mulzer*
The synthesis of the macrolide antibiotics, erythromycin
A (1) and B (2), which are highly effective against gram-positive pathogens, is probably the most extensive single project
in the history of synthetic organic chemistry."] This phenomenon is not rational as 1 and 2 are accessible in large
quantities from fermentation by the microorganism Streptomyces erythreus. It is the complexity of the molecule's structure, the plethora of stereocenters and functional groups,
and the magic of the medium ring that has fascinated about
15 large research groups worldwide for more than a decade.
All total syntheses followed the same pattern. They first
aimed at the aglycons (erythronolides A and B, 3 and 4
respectively). The final glycosidation, and with it the synthe-
tion of the natural product, today in ca. 15 steps derivatives
such as 10 and 11 can be constructed stereoisomerically pure
in gram
1, R' = OH,R 2 =
R3= O W O i H 3
3, R' = OH, R2 = R3 = H
4. R' = R2 = R3 = H
sis of 1, has been achieved only by the Woodward group.[21
The protected aglycons are formed by lactonization of the
seco acids; for example, 3 is prepared from 5-7, and 4 from
8-11. The seco acids are constructed by coupling smaller
chiral fragments that are obtained from the chiral pool, by
optical resolution, or by enantioselective synthesis.
Over the years the priorities have shifted several times.
Initially the attention focused on the seco acid fragments and
therefore on the stereocontrolled construction of the often
recurring P-hydroxycarbonyl and 1,3-diol units of 314.The
development of methods for enantio- and diastereomeric
control (acyclic stereosele~tion[~~)
proved to be unbelievably
fruitful. Whereas the first syntheses of seco acids[2*6]required cyclic intermediates and optical resolution, and often
resorted to ''relay ComPounds" recovered from the degrada[*I
/ \
In the last two years the growing number of easily accessible SecO acids shifted the attention more and more toward
the lactonization step. In general this was carried out via an
activated ester intermediate (12. Table 1). However. the formation of a 14-membered ring proved to be not straightforward ; dimerization and polymerization are significant side
reactions. The thiopyridyl activation (via the intermediates
Prof. A. J. Mulzer
Institut fur Organische Chemie
Fachbereich Chemie der Freien Universitat
Takusstrasse 3, W-1000 Berlin 33 (FRG)
Verlagsgesellschaji mbH, W-6940 Weinheim. 1991
Angew. Chem. hi.Ed. Engl. 30 (1991) No. 11
12a, b)"O1 was the standard procedure for the macrolactonization for ten years, but has now been replaced by the
Yamaguchi lactonization via the mixed anhydride 12c. Next
to activation the hydroxyl protecting groups play a central
role. They not only suppress the formation of rings of unwanted size, but may also be used to induce conformations
favorable for cyclization. Thus the 3,5-acetal or ketal unit in
5-11 locks the C2-C6 fragment of the molecule into a rigid,
linear structure, due to the diequatorial arrangement around
the 1,3-dioxane chair. In this case the 6-OH function may
remain unprotected, because it can only be lactonized after
flipping the acetonide to the diaxial conformation. The 9and 1 1 -hydroxyl groups are often protected by a cyclic acetal
(as in 5-8), which induces considerable transannular strain
by the 9'-substituent. In fact, 9'-disubstituted derivatives
such as 7 are substantially more difficult to cyclize than the
corresponding 9-monosubstituted seco acids 5,6, and 8
(Table l).[334]Moreover, the configuration at C9 is important: (9s) seco acids behave much more favorably than (9R)
The high macrolactonization yields for 10/11 (Table 1)
leave as the last aspect of the erythromycin synthesis to be
solved the 3 --* 1and 4 -+ 2 glycosations, which are indispensible for the physiological activity. As was shown early by the
Woodward group['] both the monosaccharide blocks desosamine (15) and cladinose (16),in suitably protected and
activated form, can be coupled to an almost "naked" aglycon
(14). Only the 5- and the 3-OH groups can be glycosidated and
the 5-OH group has a clear kinetic advantage over the 3-OH.
Table 1. Macrolactonization to form the 14-membered ring in the erythromycin
group x
yield in [%]
55 %
isomers.['] Many of these hitches may be avoided by the
introduction of a CC double bond in the critical region between C7 and C11 (see 9-11). At least one OH function and
its protecting group is then missing; in addition the two sp'
centers on the periphery of the ring decrease the transannular ring strain. Trisubstituted olefins display the phenomenon of allylic 1,3 strain.["] In seco acid 10 this leads to
a sickle-like curve in the carbon chain at C7-CIO. Thus
simple rotations of the rigid C1 -C6 fragments around the
C5/6 and C6/7 axes lead to an optimal conformation for
cyclization (13). The 11-OH group is out of reach of the
carboxyl function and can remain free.[71
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 11
- 1
Recently in a remarkable experiment S. K Martin and
M . Y~rnashita"~]
have broken with the accepted sequence of
lactonization followed by glycosidation. In ten steps the
diglycosidated seco acid 17 was prepared from 2 by partial
Verlagsgesellsehaft mbH, W-6940 Weinheim. 1991
0570-0833j9lj1111-1453 $3.50+.25/0
synthesis and subjected to the Yamaguchi conditions. However, the procedure afforded only small amounts of the desired macrolide 18. The major products were seven-mem-
tonization of the 6-OMe derivative of 17 (14 steps from 2)
affords exclusively the 6-OMe derivative of 18, but in only
53% yield.
Have Marrin and Yamashita solved the problem of erythromycin B synthesis? Hardly, because 1 ) the protecting
groups of 6-OMe-18 must still be removed and a mild 6-0demethylation will probably be difficult, and 2) 17 is only
partially synthesized; the necessary 3,5-differentiation for the
total synthesis will be considerably more troublesome in the
acyclic form than in the aglycon, where it occurs unaided.l21
Therefore at the moment it seems more promising to stay
with the traditional sequence and to optimize the glycosidation of 3/4 derivatives, perhaps by enzyme catalysis. After
all, the biosynthesis follows this pathway: first 4, and from
it 2.[141
German version: Angew. Chem. 103 (1991) 1482
bered lactones 19 epimeric at C2. This is not surprising because the seven-membered ring is favored and can form
readily, since the 6-OH function is not protected and also not
blocked by a 3,Sketal. As predicted, the Yamaguchi lac-
0 VCH Verlagsgesellschafr mbH.
W-6940 Wemheim, 1991
Review: I. Paterson, M. M. Mansuri, Tetrahedron 41 (1985) 3569.
R. B. Woodward et al. J. Am. Chem. SOC.103 (1981) 3210, 3213,3215.
G. Stork, S. D. Rychnovsky, J. Am. Chem. Sac. 109 (1987) 1564, 1565.
H. Tone, T. Nishi, Y. Oikawa, M. Hikota, 0.Yonemitsu, TetrahedronLeu.
28 (1987) 4569; M. Hikota, H. Tone, K. Horita, 0. Yonemitsu, Telrahedron 46 (1990) 4613.
[5] N. K. Kochetkov, A. Sviridov, M. S. Ermolenko, D. V. Yashunsky, V. S.
Borodkin, Tetrahedron 45 (1989) 5109.
[6] E. J. Corey et al., J. Am. Chem. Sac. 100 (1978) 4618.
[7] J. Mulzer, H. M. Kirstein. J. Buschmann, C. Lehmann, P. Luger, 1 Am.
Chem. Sac. 1f3 (1991) 910.
IS] J. Mulzer, P. A. Mareski, J. Buschmann, P. Luger, Synthesis 1992, in press.
[9] P . A. Bartlett, Tetrahedron 36 (1980) 1.
[lo] E. J. Corey, K. C. Nicolaou, J. Am. Chem. SOC.96 (1974) 5614; E. J. Corey,
D. J. Brunelle, Tetrahedron Lett. f976, 3409.
[ l l ] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem.
Soc. Jpn. 52 (1979) 1989.
[12] R. W. Hoffmann, Chem. Rev. 89 (1989) 1841.
(131 S. F. Martin, M. Yamashita, J Am. Chem. SOC.113 (1991) 5478.
[14] J. Staunton, Angew. Chem. 103 (1991) 1331; Angew. Chem. Int. Ed. Engl.
30 (1991) 1302.
18:19 = 1:3.4
0570-0833/9f/f111-1454 %3.50+.2SjO
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 11
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synthesis, never, ending, erythromycin, story
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