The asymmetric synthesis of erythromycin B

Full text of DOI:10.1021/ja963575y

J. Am. Chem. Soc. 1997, 119, 3193-3194
3193
Scheme 1
The Asymmetric Synthesis of Erythromycin B
Stephen F. Martin,* Tsuneaki Hida,1 Philip R. Kym,2
Michael Loft, and Anne Hodgson
Department of Chemistry and Biochemistry
The UniVersity of Texas, Austin, Texas 78712
ReceiVed October 15, 1996
The macrolide antibiotics erythromycins A (1) and B (2),
which owe their antibiotic activity to their ability to inhibit
ribosomal-dependent protein biosynthesis,3 have been the objects
of numerous synthetic investigations.4 However, despite these
efforts and a variety of elegant investigations and approaches,
there is but a single total synthesis of erythromycin A (1) by
previous work in our laboratory,9 we surmised that protection
of the C(6) alcohol had to remain in place until after macro-
lactonization of the seco-acid derivative at which time selective
deprotection under basic or neutral conditions would be required;
the dimethyl-tert-butylsilyl (TBS) group emerged as a reasonable
choice. Formation of the 14-membered lactone is favored by
incorporating the C(3) and C5) hydroxyl groups in a cyclic
array.4 To minimize unnecessary manipulations, we decided
that the protecting group for the C(5) alcohol should be easily
modified for cyclization with a free C(3) hydroxyl function;
consequently, the p-methoxybenzyl group (PMB) was selected.10
Protection for the C(3) hydroxyl group had to be reasonably
robust, but yet removable under mild conditions that left other
protecting groups intact. The TBS group was then selected in
anticipation that it could be selectively removed in the presence
of the more hindered TBS group on the C(6) hydroxy group to
enable chain extension at C(3). This analysis led to 7 as the
initial goal of the synthesis.
Thus, a cyclic p-methoxybenzylidene acetal was first formed
involving the primary and secondary alcohol groups at C(3)
and C(5) of 4, and the remaining tertiary hydroxyl group at
C(6) was silylated to give 6 (Scheme 1).11 Reductive cleavage
of the acetal moiety in 6 with BH3-THF in the presence of
AlCl3 effected the selective release of the less hindered primary
hydroxyl group that was then reprotected to give 7 in 73%
overall yield from 4. It is noteworthy that hydride reduction
of the acetal in the tertiary alcohol 5 proceeded in the opposite
regiochemical sense to give a vicinal diol in which the C(3)
primary hydroxyl group was protected as a p-methoxybenzyl
ether. The altered mode of acetal cleavage in 5 presumably
arises from preferential complexation of the Lewis acid with
the tertiary alcohol at C(6) prior to coordination with and
activation of the proximal oxygen at C(5), which is more
hindered, whereas activation of the less hindered acetal oxygen
is observed for 6.
Woodward5 and a formal total synthesis of 1 reported subse-
quently by Oishi.6 Tatsuta has since described an alternate
glycosylation strategy for preparing 1 from naturally-derived
9(S)-dihydroerythronolide A.7 We now report a concise and
highly efficient route to the erythromycin antibiotics that has
resulted in the first asymmetric synthesis of erythromycin B.
The point of embarkation for the total synthesis of erythro-
mycin B (2) was the differential protection of the three hydroxyl
groups of the known trihydroxy ketal 4, which we had
previously prepared in 32% overall yield and seven steps from
2-ethylfuran.8 The criteria applied to selecting the specific
hydroxyl protecting groups was crucial to the eventual success
of the synthesis and hence merit brief discussion: Based upon
(1) On leave from Takeda Chemical Industries, Ltd.
(2) American Cancer Society Postdoctoral Fellow, 1994-1996.
(3) Macrolide Antibiotics; Omura, S., Ed.; Academic Press: Orlando,
FL, 1984.
(4) For leading references and representative synthetic approaches, see:
(a) Corey, E. J.; Hopkins, P. B.; Kim, S.; Yoo, S.; Nambiar, K. P.; Falck,
J. R. J. Am. Chem. Soc. 1979, 101, 7131. (b) Masamune, S.; Hirama, M.;
Mori, S.; Ali, S. A.; Garvey, D. S. J. Am. Chem. Soc. 1981, 103, 1568. (c)
Bernet, B.; Bishop, P. M.; Caron, M.; Kawamata, T.; Roy, B. L.; Ruest,
L.; Sauve´, G.; Soucy, P.; Deslongchamps, P. Can. J. Chem. 1985, 63, 2810,
2814, 2818. (d) Stork, G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987,
109, 1564, 1565. (e) Chamberlin, A. R.; Dezube, M.; Reich, S. H.; Sall, D.
J. J. Am. Chem. Soc. 1989, 111, 6247. (f) Paterson, I.; Rawson, D. J.
Tetrahedron Lett. 1989, 30, 7463. (g) Nakata, M.; Arai, M.; Tomooka, K.;
Ohsawa, N.; Kinoshita, M. Bull. Chem. Soc. Jpn. 1989, 62, 2618. (h) Hikota,
M.; Tone, H.; Horita, K.; Yonemitsu, O. J. Org. Chem. 1990, 55, 7. (i)
Myles, D. C.; Danishefsky, S. J.; Schulte, G. J. Org. Chem. 1990, 55, 1636.
(j) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. Tetrahedron 1990, 46,
4613. (k) Sviridov, A. F.; Borodkin, V. S.; Ermolenko, M. S.; Yashunsky,
D. V.; Kochetkov, N. K. Tetrahedron 1991, 47, 2291, 2317. (l) Mulzer, J.;
Mareski, P. A.; Buschmann, J.; Luger, P. Synthesis 1992, 215. (m) Stu¨rmer,
R.; Ritter, K.; Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1993, 32,
101. (n) Evans, D. A.; Kim, A. S. Tetrahedron Lett. 1997, 38, 53.
(5) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward,
D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C.
H.; Cheˆnevert, R. B.; Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D. G.;
Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J.
A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki,
K.; Lee, V. J.; Leutert, T.; Malchenko, S.; Martens, J.; Matthews, R. S.;
Ong, B. S.; Press, J. B.; Rajan Babu, T. V.; Rousseau, G.; Sauter, H. M.;
Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda,
Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.; Wade, P. A.; Williams,
R. M.; Wong, H. N.-C. J. Am. Chem. Soc. 1981, 103, 3210, 3213, 3215.
(6) Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett. 1988, 29, 2219,
2223.
Deprotection of the thio ketal using mercury(II) perchlorate
in the presence of calcium carbonate to give the ketone 8 then
set the stage for the stereoselective aldol reaction that would
complete construction of the C(3)-C(15) segment of the
macrolide backbone. In the event, reaction of 8 with lithium
hexamethyldisilazide generated an enolate that added to the
aldehyde 98 to give 10 with excellent syn and anti Felkin-Anh
stereoselectivity (>40:1). A comparison of this and several
related aldol reactions4b,k,8,12 suggests that the diastereofacial
selectivities in such processes may be affected by subtle
differences in substitution on the enolate that are more than five
atoms from the reacting center.13
With 10 in hand, it remained to add a propionate group to
C(3) and incorporate the cyclic protecting groups between the
(9) Martin, S. F.; Yamashita, M. J. Am. Chem. Soc. 1991, 113, 5478.
(10) Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24,
4037.
(11) The structure assigned to each compound was in accord with its
spectral (1H and 13C NMR, IR, MS) characteristics. Analytical samples of
new compounds were obtained by distillation, recrystallization, flash
chromatography, or preparative HPLC and gave satisfactory identification
by high-resolution mass spectrometry. All yields are based on isolated,
purified materials.
(7) Toshima, K.; Nozaki, Y.; Mukaiyama, S.; Tamai, T.; Nakata, M.;
Tatsuta, K.; Kinoshita, M. J. Am. Chem. Soc. 1995, 117, 3717.
(8) Martin, S. F.; Lee, W.-C.; Pacofsky, G. J.; Gist, R. P.; Mulhern, T.
A. J. Am. Chem. Soc. 1994, 116, 4674.
(12) Martin, S. F.; Lee, W.-C. Tetrahedron Lett. 1993, 34, 2711.
S0002-7863(96)03575-5 CCC: $14.00 © 1997 American Chemical Society

3194 J. Am. Chem. Soc., Vol. 119, No. 13, 1997
Communications to the Editor
Scheme 2
Scheme 3
C(3)-C(5) and C(9)-C(11) alcohol pairs to give a seco-acid
derivative of erythromycin B that would undergo macrolacton-
ization. Thus, reduction of the hydroxy ketone with Me4NBH-
(OAc)3 proceeded stereoselectively (9:1) to give an intermediate
C(9)-C(11) anti diol14 that was protected as a cyclic mesitylene
acetal (Mes) to provide 11 (Scheme 2). Selective deprotection
of the primary hydroxyl followed by oxidation with the Dess-
Martin periodinane15 then gave the aldehyde 12. Reaction of
12 with tri-n-butylcrotylstannane in the presence of boron
trifluoride etherate delivered a separable mixture (percent yield
ratio of 69:6:12:6) of all four possible diastereomeric homoal-
lylic alcohols in which the major, and desired, product was the
syn-isomer arising from nucleophilic attack according to the
Felkin-Anh model. The free hydroxyl group at C(3) of the
major adduct was then incorporated into a p-methoxyphenyl
(PMP) acetal by oxidative cyclization10 to give 13. Oxidative
cleavage of the carbon-carbon double bond in 13 followed by
removal of the C(13) hydroxyl protecting group by hydro-
genolysis, the selectivity of which was critically dependent upon
solvent, furnished the seco-acid derivative 14.
copper(II) oxide in acetonitrile provided 21 in 40% yield (65%
based upon recovered 19).17
Selective hydrolysis of the mesitylene acetal in 21 followed
by fluoride-induced removal of the silyl protecting group on
the L-cladinose moiety then gave the tetraol 22. Oxidation of
22 with 1 equiv of the Dess-Martin periodinane reagent
proceeded exclusiVely at the C(9) hydroxyl group; subsequent
removal of the methyl carbonate moiety from the desosamine
residue then delivered erythromycin B (2). The synthetic
erythromycin B, which was thus obtained in only 30 chemical
steps from commercially available 2-ethylfuran (3), was identical
1
to a natural sample by comparison of TLC, H and 13C NMR,
Macrolactonization of the conformationally constrained seco-
acid 14 according to the Yamaguchi protocol proceeded with
high efficiency to give the erythronolide B derivative 15
(Scheme 3).16 Deprotection of the C(6) tertiary hydroxyl group
then proceeded smoothly to give 16. On the other hand,
selective removal of the p-methoxybenzylidene acetal from the
hydroxyl groups at C(3) and C(5) proved somewhat trouble-
some. Hydrogenolysis was unselective, and under the best
conditions identified thus far for hydrolytic removal of this
protecting group, the desired triol 17 could be isolated in 70%
yield (84% based upon recovered 16). However, starting
material 16 (17%) together with 9(S)-dihydroerythronolide (7%)
were also recovered from the reaction.
It now remained to append the D-desosamine and L-cladinose
residues to 17. Thus, reaction of 17 with the pyrimidyl
thioglycoside 18 in the presence of silver triflate according to
a slight modification of the precedent set forth by Tatsuta7
furnished 19 as a single isomer. Introducing a protected
L-cladinose moiety onto 19 by the Woodward protocol,5 in
which lead(II) perchlorate was used to activate the glycosyl
donor, failed in our hands, but we discovered that treating 19
with 20 in the presence of a mixture of copper(II) triflate and
and HRMS. The unusual ability of the Dess-Martin reagent
to selectively oxidize secondary alcohols, even in the presence
of unprotected tertiary amines, based on slight variations in their
steric environments, is virtually unprecedented and warrants
further investigation.18 In this context, we also discovered that
9(S)-dihydroerythromycin B (23) itself may be selectively
oxidized to give 2 by using a stoichiometric amount of the
Dess-Martin reagent. The scope of selective oxidations of
sterically-differentiated secondary alcohols using the Dess-
Martin reagent is currently being examined, and these results
will be reported in due course.
Acknowledgment. We thank the National Institutes of Health (GM
31077) and the Robert A. Welch Foundation for their generous support
of this research. We are grateful to Dr. Paul A. Lartey (Abbott
Laboratories) for generous gifts of erythromycins A and B, and we
thank Drs. Erica Kraynack and Philippe Breton for conducting ancillary
glycosylation studies.
Supporting Information Available: Complete characterization (1H
and 13C NMR and IR spectra and mass spectral data) for all new
compounds (9 pages). See any current masthead page for ordering
and Internet access instructions.
(13) For a leading reference to double stereodifferentiating aldol reactions,
see: Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem.
Soc. 1995, 117, 9073.
(14) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(16) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. See also refs 4h,j.
JA963575Y
(17) The corresponding â-anomer was also isolated in 10% yield (17%
based upon recovered starting material).
(18) Oxidation of the N-oxide derivative of 9(S)-dihydroerythromycin
with bromine in the presence of bis(tri-n-butyl)tin oxide was recently
reported to proceed selectively at the C(9) hydroxyl group.7