Asymmetric synthesis of (2S,3R)-capreomycidine and the total synthesis of capreomycin IB

Article abstract of DOI:10.1021/ja0351241

A 27 step total synthesis of the tuberculostatic macrocyclic peptide antibiotic capreomycin IB has been accomplished. The synthesis features the use of an enolate-aldimine condensation between a chiral glycine aluminum enolate and the benzyl imine of 3-tert-butyldimethylsiloxy-propanal as a means of preparing the cyclic guanidine amino acid (2S,3R)-capreomycidine. Additionally, a Hofmann rearrangement was exacted on a late-stage pentapeptide in order to transform an asparagine residue into a diaminopropanoic acid residue.

Full text of DOI:10.1021/ja0351241

Published on Web 06/20/2003
Asymmetric Synthesis of (2S,3R)-Capreomycidine and the
Total Synthesis of Capreomycin IB
Duane E. DeMong and Robert M. Williams*
Contribution from the Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523
Received March 12, 2003; E-mail: rmw@lamar.colostate.edu
Abstract: A 27 step total synthesis of the tuberculostatic macrocyclic peptide antibiotic capreomycin IB
has been accomplished. The synthesis features the use of an enolate-aldimine condensation between a
chiral glycine aluminum enolate and the benzyl imine of 3-tert-butyldimethylsiloxy-propanal as a means of
preparing the cyclic guanidine amino acid (2S,3R)-capreomycidine. Additionally, a Hofmann rearrangement
was exacted on a late-stage pentapeptide in order to transform an asparagine residue into a diaminopro-
panoic acid residue.
Introduction
The tuberculostatic cyclic peptide antibiotics capreomycins
IA, IB, IIA, and IIB (1a-d) were isolated from Streptomyces
capreolus by Herr and co-workers at Eli Lilly in 1959 (Figure
1).1 An original structural proposal for capreomycin IB made
by Bycroft et al.2 was later corrected by Shiba and co-workers
who completed the first total syntheses of capreomycins IA and
IB.3 The capreomycins all contain two diaminopropanoic acid
residues, the R,â-unsaturated amino acid ureido-dehydroalanine
and the intriguing cyclic guanidino amino acid (2S,3R)-cap-
reomycidine (2). Capreomycins IA and IIA both contain serine
in the cyclic peptide structure (R1 ) OH), while capreomycins
IB and IIB contain alanine (R1 ) H). Additionally, the IA and
IB forms contain a pendant â-lysine (3) group, while the IIA
and IIB forms are devoid of this substituent.
The capreomycins, which have enjoyed clinical utility for
many years, have been the subject of renewed interest recently
due to their effectiveness against multidrug-resistant strains of
Mycobacterium tuberculosis.4 This is of particular importance
to individuals with compromised immune systems who are
especially susceptible to these infections.5 The capreomycins
are thought to have the same mode of action as the structurally
similar peptide antibiotic viomycin (aka tuberactinomycin B).6
It has been proposed that capreomycin inhibits protein biosyn-
thesis in prokaryotes in two ways: (1) inhibition of the trans-
location of peptidyl tRNA and (2) inhibition of the dissociation
Figure 1. Structures of the capreomycins.
of the ribosomal subunits. Various structural analogues of the
capreomycins have been prepared semisynthetically, and some
of these agents have been shown to have broad-spectrum
antimicrobial activity unlike that of capreomycin itself.7
One of the key constituents of the capreomycins and the
related tuberactinomycins is the cyclic guanidine-containing
(6) (a) Tanaka, N.; Igusa, S. J. Antibiot. 1968, 21, 239-240. (b) Yamada, T.;
Teshima, T.; Shiba, T. Antimicrob. Agents Chemother. 1981, 20, 834-
836. (c) Liou, Y.-F.; Tanaka, N. Biochem. Biophys. Res. Commun. 1976,
71, 477-483. (d) Modolell, J.; Va´zquez, D. Eur. J. Biochem. 1977, 81,
491-497. (e) Yamada, T.; Mizugichi, Y.; Nierhaus, K. H.; Wittmann, H.
G. Nature 1978, 275, 460-461. (f) Yamada, T.; Masuda, K.; Mizuguchi,
Y.; Suga, K. Antimicrob. Agents Chemother. 1976, 9, 817-823.
(7) (a) Yamada, T.; Yamanouchi, T.; Ono, Y.; Nagata, A.; Wakamiya, T.;
Teshima, T.; Shiba, T. J. Antibiot. 1983, 36, 1729-1734. (b) Wakamiya,
T.; Shiba, T. J. Antibiot. 1983, 36, 197-199. (c) Dirlam, J. P.; Belton, A.
M.; Birsner, N. C.; Brooks, R. R.; Chang, S.-P.; Chandrasekaran, R. Y.;
Clancy, J.; Cronin, B. J.; Dirlam, B. P.; Finegan, S. M.; Froshauer, S. A.;
Girard, A. E.; Hayashi, S. F.; Howe, R. J.; Kane, J. C.; Kamicker, B. J.;
Kaufman, S. A.; Kolosko, N. L.; LeMay, M. A.; Linde, R. G., II; Lyssikatos,
J. P.; MacLelland, C. P.; Magee, T. V.; Massa, M. A.; Miller, S. A.; Minich,
M. L.; Perry, D. A.; Petitpas, J. W.; Reese, C. P.; Seibel, S. B.; Su, W.-G.;
Sweeney, K. T.; Whipple, D. A.; Yang, B. V. Bioorg. Med. Chem. Lett.
1997, 7, 1139-1144. (d) Lyssikatos, J. P.; Chang, S.-P.; Clancy, J.; Dirlam,
J. P.; Finegan, S. M.; Girard, A. E.; Hayashi, S. F.; Larson, D. P.; Lee, A.
S.; Linde, R. G., II; MacLelland, C. P.; Petitpas, J. W.; Seibel, S. B.; Vu,
C. B. Bioorg. Med. Chem. Lett. 1997, 7, 1145-1148. (e) Linde, R. G., II;
Birsner, N. C.; Chandrasekaran, R. Y.; Clancy, J.; Howe, R. J.; Lyssikatos,
J. P.; MacLelland, C. P.; Magee, T. V.; Petitpas, J. W.; Rainville, J. P.;
Su, W.-G.; Vu, C. B.; Whipple, D. A. Bioorg. Med. Chem. Lett. 1997, 7,
1149-1152.
(1) Herr, E. B.; Haney, M. E.; Pittenger, G. E.; Higgens, C. E. Proc. Ind. Acad.
Sci. 1960, 69, 134.
(2) Bycroft, B. W.; Cameron, D.; Croft, L. R.; Hassanali-Walji, A.; Johnson,
A. W.; Webb, T. Nature 1971, 231, 301-302.
(3) (a) Shiba, T.; Nomoto, S.; Teshima, T.; Wakamiya, T. Tetrahedron Lett.
1976, 17, 3907-3910. (b) Nomoto, S.; Teshima, T.; Wakamiya, T.; Shiba,
T. J. Antibiot. 1977, 30, 955-959. (c) Nomoto, S.; Teshima, T.; Wakamiya,
T.; Shiba, T. Tetrahedron 1978, 34, 921-927.
(4) (a) Rastogi, N.; Labrousse, V.; Seng Goh, K. Curr. Microbiol. 1996, 33,
167-175. (b) Heifets, L.; Lindholm-Levy, P. Antimicrob. Agents Chemo-
ther. 1989, 33, 1298-1301. (c) Heifets, L. Antimicrob. Agents Chemother.
1988, 32, 1131-1136.
(5) Bloch, A. B.; Cauthen, G. M.; Onorato, I. M.; Kenneth, G.; Dansbury, G.;
Kelly, G. D.; Driver, C. R.; Snider, D. E. JAMA, J. Am. Med. Assoc. 1994,
271, 665-671.
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A R T I C L E S
DeMong and Williams
Scheme 2. Completion of (2S,3R)-Capreomycidine
Scheme 1. Enolate-Aldimine Reaction
amino acid capreomycidine. Cameron and Bycroft reported the
first synthesis of racemic capreomycidine (2) in 1971.8 Subse-
quently, Shiba et al. reported both a racemic and an enantiose-
lective synthesis of 2.8 Shiba’s approach to enantiomerically
pure (2S,3R)-capreomycidine was accomplished in 14 steps and
an overall yield of 0.14%. Recently, Zabriskie and co-workers
completed a 13C-labeled synthesis of 2 that was developed for
biosynthetic studies.9 Our objectives were to develop a more
efficient synthesis of this distinctive amino acid which could
be seamlessly incorporated into an efficient total synthesis of
capreomycin IB and congeners. In addition, the unique structural
motifs present in the capreomycins and their interesting biologi-
cal activity render this family of antimicrobial agents attractive
targets for total synthesis. Herein, we report a concise total
synthesis of capreomycin IB that is suitable for the preparation
of analogues not readily accessible semisynthetically from
natural material.
â-carbon (1H NMR). Attempts to improve the selectivity of this
transformation by employing diverse enolate motifs with the
analogous p-methoxybenzyl imine resulted in either no reaction
or significantly lower yield and/or selectivity when compared
with the aluminum enolate (see Supporting Information). By
changing the imine nitrogen substituent in a similar system, it
was found that the use of a benzhydryl imine rather than a
benzyl imine resulted in a significant improvement in the
diastereoselectivity (6.5:1 vs 3.3:1) but a lower yield (22%).12
Attempts to guanidinylate this Mannich product were unsuc-
cessful, presumably due to the added steric hindrance of the
benzhydryl group. Although not further pursued in the synthesis
of capreomycidine, the result leaves open the possibility for
additional optimization of this methodology.
In our initial report, guanidinylation of Mannich product 6
was accomplished with triethylamine, mercuric chloride, and
N,N′-di-tert-butoxycarbonyl-S-methyl isothiourea.10 After our
communication of these results, we found that silver triflate
could be substituted for mercuric chloride, providing an
improved 75% yield of 7 (Scheme 2). The use of silver triflate
provided a significantly cleaner reaction profile and had the
added benefit of eliminating the need for difficult to remove
mercury salts. The completion of the synthesis of capreomy-
cidine was accomplished by the method previously described.
With the completion of the synthesis of (2S,3R)-capreomy-
cidine, our attention was turned to the total synthesis of cap-
Results and Discussion
The synthesis of capreomycin IB began with our investiga-
tions into a concise synthesis of the cyclic guanidino amino
acid (2S,3R)-capreomycidine (2).10 We envisioned that 2 could
be accessed via a novel enolate-aldimine reaction between
chiral glycinate (-)-5 and benzyl imine 4 (Scheme 1).
Imine 4 was prepared in 98% yield by treatment of 3-tert-
butyldimethylsiloxy-propanal with benzylamine on alumina.11
Initial attempts to exact a condensation of imine 4 with the boron
enolate of (-)-5 resulted in a less than 20% yield of a stable
boron-chelate product that proved recalcitrant to transformation
into 6. As previously described, formation of the lithium enolate
of (-)-5 with lithium hexamethyldisilazide at -78 °C was
followed by transmetalation with dimethylaluminum chloride
to provide the requisite aluminum enolate. Addition of imine 4
resulted in a 50-60% yield of Mannich products 6a and 6b as
an inseparable 3.3:1 mixture of diastereomers epimeric at the
(12) The results mentioned were observed with the 3-(p-methoxy)benzyloxy-
propanaldimine:
(8) (a) Bycroft, B. W.; Cameron, D.; Johnson, A. W. J. Chem. Soc. C 1971,
3040-3047. (b) Wakamiya, T.; Mizuno, K.; Ukita, T.; Teshima, T.; Shiba,
T. Bull. Chem. Soc. Jpn. 1978, 51, 850-854. (c) Shiba, T.; Ukita, T.;
Mizuno, K.; Teshima, T.; Wakamiya, T. Tetrahedron Lett. 1977, 18, 2681-
2684.
(9) Jackson, M. D.; Gould, S. J.; Zabriskie, T. M. J. Org. Chem. 2002, 67,
2934-2941.
(10) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001, 42, 3529-3532.
(11) Texier-Boullet, F. Synthesis 1985, 679-681.
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Synthesis of (2S,3R)-Capreomycidine and Capreomycin IB
A R T I C L E S
Scheme 4. Preparation of DAPA-â-lysine Dipeptide
Scheme 3. Preparation of the Diethylacetal of R-R-Formylglycine
Scheme 5. Tripeptide Formation
reomycin IB. In his synthetic work with both the capreomycins
and structurally similar tuberactinomycins, Shiba showed that
the enamidourea functionality could be accessed from the
diethylacetal of R-formylglycine.13 Previous preparations of
acetals of R-formylglycine have all been carried out in racemic
form.14 It was our goal to prepare an enantiomerically pure form
of R-formylglycine dimethylacetal such that both diastereomeric
linear peptides (constituted with each antipode of the R-formyl-
glycine) could be prepared and the macrocyclization propensities
of the two species independently assessed.
In this work previously described from our laboratory, the
preparation of R-R-formylglycine dimethylacetal was accom-
plished in two steps from (+)-5.15 The resulting amino acid
can be either amine- or carboxyl-protected and incorporated into
peptides. While epimerization appeared to be minimal when
coupling N-protected forms of R-R-formylglycine dimethyl-
acetal, attempts to incorporate the methyl ester hydrochloride
salt of R-R-formylglycine dimethylacetal into peptide coupling
sequences resulted in a significant amount of epimerization.
Furthermore, when attempting to hydrolyze the dimethylacetal
after incorporation into a cyclic peptide, it was found that even
after several hours at reflux in 2 N HCl in acetone (conditions
used to cleave Shiba’s diethylacetal after only 10 min), some
of the dimethylacetal still remained. The unexpected difference
in the acid lability of the methyl- and ethylacetals mandated
the employment of the more labile diethylacetal.
We thus adapted the titanium enolate chemistry to the
synthesis of enantiomerically pure R-formylglycine diethylacetal
11 (Scheme 3). Formation of the titanium enolate of (+)-5 was
followed by addition of triethylorthoformate to provide an 85%
yield of diethylacetal 10. Hydrogenolysis of 10 provided clean
conversion to R-R-formylglycine diethylacetal (11). Addition-
ally, exposure of 11 to refluxing EtOH‚HCl afforded the ethyl
ester hydrochloride salt 12, which was used crude in subsequent
peptide couplings.
The suitably protected diaminopropanoic acid 13 was prepared
from an oxidative Hofmann rearrangement of N-CBz-asparagine
using previously published methodology.16,17 Coupling of 13
with the previously reported N-hydroxysuccinimidyl ester of
bis(tert-butoxycarbonyl)-â-lysine18 14 in the presence of N-
methylmorpholine provided dipeptide 15 in 92% yield.
Hydrolysis of the methyl ester present in 15 provided a
quanititative yield of carboxylic acid 16 (Scheme 5). Coupling
of 16 with the previously described R-R-formylglycine diethyl-
acetal ethyl ester hydrochloride salt 12 with EDCI, HOBt, and
NMM provided the desired tripeptide 17 in 91% yield.
Unfortunately, the coupling reaction resulted in an inseparable
2.6:1 mixture of epimers at the R-formylglycine diethylacetal
center. This was an unexpected result due to the fact that for-
mation of the Mosher’s amide of the R-R-formylglycine dimeth-
ylacetal methyl ester hydrochloride salt resulted in no epimer-
ization. Since pyridine was used in the Mosher’s amide for-
(16) (a) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 0, 266-268. (b)
Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 6571-6573.
(c) Zhang, L.-h.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997,
62, 6918-6920. (d) Webber, S. E.; Okano, K.; Little, T. L.; Reich, S. H.;
Xin, Y.; Fuhrman, S. A.; Matthews, D. A.; Love, R. A.; Hendrickson, T.
F.; Patick, A. K.; Meador, J. W., III; Ferre, R. A.; Brown, E. L.; Ford, C.
E.; Binford, S. L.; Worland, S. T. J. Med. Chem., 1998, 41, 2786-2805.
(e) Chhabra, S. R.; Mahajan, A.; Chan, W. C. Tetrahedron Lett. 1999, 40,
4905-4908. (f) Chhabra, S. R.; Mahajan, A.; Chan, W. C. J. Org. Chem.
2002, 67, 4017-4029.
The synthesis of capreomycin IB began with the preparation
of the diaminopropanoic acid-â-lysine dipeptide (Scheme 4).
(13) (a) Teshima, T.; Nomoto, S.; Wakamiya, T.; Shiba, T. Tetrahedron Lett.
1976, 17, 2343-2346. (b) Nomoto, S.; Shiba, T. Bull. Chem. Soc. Jpn.
1979, 52, 1709-1715.
(17) For other approaches to orthogonally protected diaminopropanoic acid,
see: (a) Mokotoff, M.; Logue, L. W. J. Med. Chem. 1981, 24, 554-559.
(b) Maryanoff, B. E.; Greco, M. N.; Zhang, H. C.; Andrade-Gordon, P.;
Kauffman, J. A.; Nicolaou, K. C.; Liu, A.; Brungs, P. H. J. Am. Chem.
Soc. 1995, 117, 1225-1239. (c) Xue, C. B.; Roderick, J.; Jackson, S.;
Rafalski, M.; Rockwell, A.; Mousa, S.; Olson, R. E.; DeGrado, W. F.
Bioorg. Med. Chem. 1997, 5, 693-705. (d) Osterkamp, F.; Ziemer, B.;
Koert, U.; Wiesner, M.; Raddatz, P.; Goodman, S. L. Chem.sEur. J. 2000,
6, 666-683.
(14) (a) Dudley, K. H.; Bius, D. L.; Johnson, D. J. Heterocycl. Chem. 1973,
10, 935-941. (b) Swaminathan, S.; Singh, A. K.; Li, W.-S.; Venit, J. J.;
Natalie, K. J., Jr.; Simpson, J. H.; Weaver, R. E.; Silverberg, L. J.
Tetrahedron Lett. 1998, 39, 4769-4772. (c) Ramer, S. E.; Moore, R. N.;
Vederas, J. C. Can. J. Chem. 1986, 64, 706-713. (d) Clarke, Johnson,
Robinson, Eds. The Chemistry of Penicilin; Princeton University Press:
Princeton, NJ, 1949. (e) Doyle, T. W.; Belleau, B.; Luh, B.-Y.; Carrado,
F. F.; Cunningham, M. P. Can. J. Chem. 1977, 55, 468-483. (f) Dekhane,
M.; Dodd, R. H. Tetrahedron 1994, 50, 6299-6306.
(18) Wakamiya, T.; Uratani, H.; Teshima, T.; Shiba, T. Bull. Chem. Soc. Jpn.
1975, 48, 2401-2402.
(15) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2002, 43, 2355-2357.
9
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A R T I C L E S
DeMong and Williams
Scheme 6. Pentapeptide Formation
Scheme 7. Completion of Capreomycin IB
mation rather than NMM, it is likely that the increased basicity
of NMM is responsible for the epimerization. Although this
was an undesired result, it proved practical to complete the
capreomycin IB synthesis with this material. Removal of the
benzyloxycarbonyl group was accomplished with hydrogen in
the presence of Pearlman’s catalyst to provide a 99% yield of
amine 18 which was used immediately in the subsequent coup-
ling reaction in order to avoid a possible N,N-acyl migration.
In an attempt to make our approach to capreomycin IB as
convergent as possible, the previously reported dipeptide frag-
ment of asparagine and alanine (19) was prepared.19 Coupling
of tripeptide 18 and 19 with diisopropylcarbodiimide and HOBt
resulted in an 88% yield of pentapeptide 20 (Scheme 6). We
decided to incorporate the asparagine residue into pentapeptide
20 as a “masked” form of the second diaminopropanoic acid
residue. Our hope was that the primary amide could, via a
chemoselective Hofmann rearrangement, be transformed into a
primary amine, which would be ready to couple with a suitably
protected capreomycidine species.20 The major reason for this
endeavor was to attempt to avoid an undesired series of
protection and deprotection steps that would be required if we
were to incorporate the diaminopropanoic acid residue directly.
To that end, Hofmann rearrangement of 20 with bis(trifluoro-
acetoxy)iodosobenzene and pyridine provided an 88% yield of
the primary amine 21.
reomycidine (22), which was used crude in the subsequent
coupling reaction. Coupling of 22 with pentapeptide 21 re-
sulted in an 89% yield of the desired linear hexapeptide 23.
The CBz group of 23 was removed by hydrogenolysis in the
presence of 10% palladium on carbon. Cleavage of the ethyl
ester was accomplished with 1 N LiOH in ethanol. The crude
amino acid was then desalted with a Waters C18 Sep-Pak
cartridge.
It was at this point that it became necessary to prepare a
suitably protected form of capreomycidine for incorporation into
the peptide. After extensive investigation of protecting group
strategies for this amino acid, it was found that the protection
of the R-amine of 2 with a benzyl carbamate was the most
effective and straightforward approach (Scheme 7). Treatment
of the crude dihydrochloride salt of 2 with benzylchlorofor-
mate and aqueous sodium hydroxide provided NR-CBz-cap-
Treatment of the desalted amino acid with EDCI and HOAt
resulted in a 20% yield (3 steps) of the macrocycle 24 as a
single diastereomer. The 20% combined yield observed in the
deprotections and subsequent macrocyclization is owed, in part,
to the multiple silica gel purifications required to obtain pure
macrocycle. Additionally, the isolation of a single diastereomer
from the macrocyclization suggests that one of the diastereomers
cyclizes more efficiently than the other, leading also to a
decrease in reaction yield. That being the case, however, the
result does compare similarly to the yield observed by Shiba in
their capreomycin IB macrocylization (23%, four steps). Using
conditions previously developed by Shiba, removal of the Boc
groups was achieved by exposure to 99% formic acid. After
(19) (a) Onoprienko, V. V.; Yelin, E. A.; Miroshnikov, A. I. Russ. J. Bioorg.
Chem. 2000, 26, 361-368. (b) Sano, S.; Kawanishi, S. J. Am. Chem. Soc.
1975, 97, 3480-3484.
(20) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett, J. K.;
Boutin, R. H. J. Org. Chem. 1984, 49, 4272-4276. (b) Boutin, R. H.;
Loudon, G. M. J. Org. Chem. 1984, 49, 4277-4284.
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Synthesis of (2S,3R)-Capreomycidine and Capreomycin IB
A R T I C L E S
removal of the formic acid, the residue was dissolved in 1:1
acetone:2 N HCl and refluxed for 10 min to cleave the
diethylacetal. Upon cooling of the reaction mixture to room
temp, an excess of urea was added and the resulting solution
was stirred overnight. Evaporation of the solvent and addition
of absolute ethanol resulted in precipitation of capreomycin IB
(2S,3R)-capreomycidine, in which a novel aluminum enolate-
aldimine reaction with a chiral glycinate was utilized. Finally,
the use of an asparagine residue as a “masked” form of diami-
nopropanoic acid allowed for a significant decrease in the num-
ber of protection and deprotection steps required to complete
the synthesis. Efforts to utilize this synthetic approach to prepare
novel congeners of the capreomycins as potential agents for
treatment of MDR-tuberculosis is under study in these labora-
tories.
1
(1b) (50-60%) as a white solid, which matched by H NMR,
optical rotation, and TLC with the natural product. Additionally,
mixing of the synthetic capreomycin IB with an approximately
1:1 mixture of natural capreomycins IA and IB resulted in an
increase in intensity of all 1H NMR resonances associated with
capreomycin IB.
Acknowledgment. This work was supported by the National
Science Foundation (Grant CHE0202827). We thank Dr. Mark
Zabriskie of Oregon State University for kindly providing an
Conclusion
authentic specimen of (2S,3R)-capreomycidine and 1H and 13
C
spectra for capreomycin IB.
In summary, a concise total synthesis of capreomycin IB has
been accomplished. The synthesis was completed in 27 total
steps (14 steps in the longest linear sequence) and an overall
yield of 2% from (-)-5. It is significant to compare this to
Shiba’s total synthesis that required 45 total steps (19 steps in
the longest linear sequence) and proceeded in 0.008% overall
yield. Our approach featured the asymmetric synthesis of
Supporting Information Available: Full experimental details
and characterization (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0351241
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