The asymmetric synthesis of (2S,3R)-capreomycidine

Article abstract of DOI:10.1016/S0040-4039(01)00487-7

An improved asymmetric synthesis of the guanidine-containing amino acid (2S,3R)-capreomycidine has been achieved in seven steps and 28% overall yield. The key synthetic step involved a Mannich-type reaction between a chiral glycine aluminum enolate and the benzyl-imine of 3-tert-butyldimethylsiloxy-propionaldehyde.

Full text of DOI:10.1016/S0040-4039(01)00487-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3529–3532
The asymmetric synthesis of (2S,3R)-capreomycidine
Duane E. DeMong and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 12 March 2001; revised 21 March 2001; accepted 22 March 2001
Abstract—An improved asymmetric synthesis of the guanidine-containing amino acid (2S,3R)-capreomycidine has been achieved
in seven steps and 28% overall yield. The key synthetic step involved a Mannich-type reaction between a chiral glycine aluminum
enolate and the benzyl-imine of 3-tert-butyldimethylsiloxy-propionaldehyde. © 2001 Elsevier Science Ltd. All rights reserved.
Capreomycidine 1 is a non-proteinogenic amino acid
that is a constituent of the capreomycins 2a–d and the
tuberactinomycins 3a–b (Fig. 1).1,2 These cyclic pen-
tapeptides are known for their unique tuberculostatic
properties. First discovered by Herr et al.3 in 1960, the
capreomycins have recently attracted attention due to
their demonstrated effectiveness against resistant strains
of Mycobacterium tuberculosis.4
Various derivatives of both the capreomycins and
tuberactinomycins have been made by synthetic modifi-
cations to the amino acid side chains and peptide
backbone of the intact natural product.5 This was done
in order to determine the sectors of the molecule that
are important for the expression of biological activity
and also to perhaps discover more potent synthetic
variants. Some of these derivatives have been shown to
OH
H2N
O
NH
NH
N
H
R1
O
1, (2S,3R)-capreomycidine
OH
O
O
H
N
H
N
H
N
H2N
R2
R
N
H
OH
N
H
N
H
O
HN
NH
O
NH
HN
O
H
N
H
N
H
N
H
N
NH2
NH2
O
O
O
NH
O
NH
O
O
H
H
N
H
NH
N
H
NH
2a: capreomycin IA; R1=OH, R2=β-lysine
2b: capreomycin IB; R1=H, R2=β-lysine
2c: capreomycin IIA; R1=OH, R2=Η
2d: capreomycin IIB; R1=H, R2=Η
3a: tuberactinomycin N; R=γ-hydroxy-β-lysine
3b: tuberactinomycin O; R=β-lysine
Figure 1.
* Corresponding author. E-mail: rmw@chem.colostate.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00487-7

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D. E. DeMong, R. M. Williams / Tetrahedron Letters 42 (2001) 3529–3532
be effective against other pathogens as well. The
capreomycidne moiety contained in the macrocyclic
portion of these substances has been shown to be
essential for the expression of biological activity.6
(2S,3R)-capreomycidine was lengthy and proceeded in a
low overall yield (ꢀ0.2%). With this as a backdrop, we
sought to develop a more efficient synthesis of (2S,3R)-
capreomycidine.
Total syntheses of the capreomycins as well as tuberacti-
nomycin O have been reported by Shiba et al.1,7 How-
ever, the capreomycidine moiety used in these syntheses
was obtained not synthetically, but rather semi-synthet-
ically by acid hydrolysis of the natural product.
As shown in Scheme 1, treatment of 3-(tert-butyl-
dimethylsiloxy)-propionaldehyde with benzylamine on
alumina, gave the desired imine 4 in 98% yield.12,13
Preparation of the lithium enolate of the chiral oxazinone
5 with lithium bis(trimethylsilyl)amide, followed by
transmetallation with dimethylaluminum chloride,
resulted in the formation of the corresponding aluminum
enolate.14,15 Addition of 4 to the enolate resulted in a 60%
yield of the Mannich product 6 as an inseparable mixture
of two diastereomers (3.3:1 dr by 1H NMR) both arising
from the approach of the imine to the face opposite that
of the phenyls.
Syntheses of capreomycidine and its epimer in both
racemic and optically active form have previously been
reported. Cameron and Bycroft were the first to report
a racemic synthesis of both capreomycidine and epi-
capreomycidine.8 The desired product was obtained by
elaboration of 2-aminopyrimid-4-ylacetate. Fractional
recrystallization of picrate salts of the two diastereomers
resulted in a tedious isolation of racemic capreomycidine
and racemic epi-capreomycidine. Shiba and co-workers
prepared racemic capreomycidine via a diastereoselective
aldol reaction which produced a protected version of
b-hydroxyornithine that was further elaborated to the
final product.9 Using a chloroacetylated intermediate in
this same synthesis, Shiba enzymatically resolved two
enantiomers with an acylase. This allowed for the synthe-
sis of optically pure (2S,3R)-capreomycidine.10 In a
similar manner, the synthesis of epi-capreomycidine was
also accomplished.11
The guanidinylation of Mannich product 6 proved to be
a far more challenging step than expected. Treatment of
6
with N,N%-di-tert-butoxycarbonyl-S-methylisothio-
urea and triethylamine in DMF as well as treatment of
6 with Goodman’s benzyloxycarbonyl protected triflyl-
guanidine reagent resulted in no reaction.16,17 Subjecting
6 to a combination of N,N%-di-tert-butoxycarbonyl-
thiourea, mercuric chloride and triethylamine in DMF
according to the protocol described by Kim et al., the
desired product 7 was obtained in a modest yield of 50%
as a single diastereomer (determined by 13C NMR).18 It
was then decided to determine what effect switching from
N,N%-di-tert-butoxycarbonylthiourea to the correspond-
ing N,N%-di-tert-butoxycarbonyl-S-methylisothiourea
might have on the guanidinylation yield. This approach,
also recently reported by Cammidge and co-workers,
resulted in an improved 67% yield of the desired
In order to investigate a broader array of capreomycin
derivatives for potential antituberculosis activity, it is
desirable to have an effective means of obtaining signifi-
cant quantities of a suitably protected form of (2S,3R)-
capreomycidine via synthesis rather than by degradation
of the natural product. Shiba’s synthetic approach to
BnNH2, alumina
O
NBn
CH2Cl2, 25 min., 0oC
98%
TBSO
TBSO
SMe
4
Ph
Ph
1. LHMDS
2. Me2AlCl
3.
Ph
O
Ph
O
Ph
NBn
CbzN
BocN
NHBoc
Ph
O
CbzN
O
O
TEA, HgCl2
TBSO
4
CbzN
TBSO
NBn
BocHN NBoc
O
TBSO
NHBn
THF, 1h., -78oC
60%
DMF, rt, o/n
67%
5
6
7
3.3:1 dr (1H-NMR)
Ph
Ph
OH
Ph
Ph
O
1. H2, PdCl2
115 psi, 4d.
O
H2N
O
DIAD, PPh3, THF
1.7% HF in MeCN
2h, rt, 81-91%
CbzN
CbzN
O
O
NH
2. 0.5 M HCl
reflux, 1.5h.
95%
.
2 HCl
NH
NBn
0oC 15min, rt 1h.
87%
HO
NBn
NBoc
N
H
N
Boc
NBoc
BocHN
8
1, (2S,3R)-capreomycidine
9
Scheme 1.

D. E. DeMong, R. M. Williams / Tetrahedron Letters 42 (2001) 3529–3532
3531
guanidine 7.19 Judging from the analysis of recovered
Acknowledgements
starting material, the guanidinylation only occurs with
the major diastereomer of Mannich product 6, there-
fore explaining the moderate yield and single product
from this reaction.
This work was supported by the National Science
Foundation (Grant CHE9731947). We are also grateful
to Dr. Mark Zabriskie of Oregon State University for
kindly providing an authentic specimen of (2S,3R)-
capreomycidine.
Removal of the tert-butyldimethylsilyl protecting group
from 7 with 1.7% aqueous HF in acetonitrile provided
the primary alcohol 8 in 81–91% yield. Unfortunately,
this cyclization precursor proved unstable to both acid
and base. Rapid silica gel purification using Whatman
brand silica gel gave satisfactory results. Attempted
removal of the TBS group by other means proved
unsuccessful.
References
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Using the method described by Dodd and Kozikowski,
the cyclic guanidine 9 was formed by treatment of 8
under Mitsunobu conditions in 87% yield.20 The
bicyclic compound 9 was then subjected to hydrogenol-
ysis in 3:1 THF:EtOH using PdCl2 and 115 psi hydro-
gen gas for 4 days at room temperature. Upon removal
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hydrogenation product was refluxed in 0.5 M aqueous
HCl to remove the remaining Boc group and
lyophilized to provide the di-hydrochloride salt of
capreomycidine 1 in 95% yield from 9. Neutralization
with ammonium hydroxide, followed by desalting via
Dowex 50WX2-100 cationic exchange resin (product
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acid. Spiking of this free amino acid with ammonium
acetate provided our synthetic capreomycidine in a
form that was identical to the form of the natural
capreomycidine obtained from Oregon State University
and resulted in proton and carbon spectra that matched
the natural sample. Upon synthesis of the enantiomer
of natural capreomycidine in similar yield from the
antipode of 5, the a-amines of both (2S,3R)- and
(2R,3S)-capreomycidine were protected as the corre-
sponding benzyl carbamates. Chiral HPLC analysis of
these enantiomeric carbamates showed that our syn-
thetic capreomycidine possessed an er of 99.2:0.8 (>99%
ee).21 The optical rotations of the synthetic and natural
mono-HCl salts of capreomycidine were also agreeable
(synthetic: [M]2D0=+28.2 (c=0.75, H2O); natural:
[M]2D0=+32.5 (cꢀ0.75, H2O)).22,23
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Since the desired (2S,3R)-capreomycidine was obtained
from the major diastereomer of 6, one can infer that the
major diastereomer of 6 was of the (2S,3R)-configura-
tion. This can be explained by a Zimmerman–Traxler
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E-imine.
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In summary, we have employed a novel and moderately
diastereoselective Mannich-type reaction with the chiral
glycine template 5 as a key step in the asymmetric
synthesis of (2S,3R)-capreomycidine. The synthesis
recorded here proceeds in six steps with an overall yield
of 28%. Application of this methodology to the total
synthesis of capreomycin and derivatives is currently
under study in these laboratories.
17. Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
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D. E. DeMong, R. M. Williams / Tetrahedron Letters 42 (2001) 3529–3532
20. Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994,
35, 977–980.
22. The mono-HCl salt of capreomycidine was prepared by
recrystallization of the di-HCl salt from methanol/pyri-
dine/ethanol (1st crop: 50%).
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21. Enantiomeric ratios were determined using a Daicel
Crownpak CR chiral HPLC column (pH 2 aqueous
perchloric acid, 1.6 mL/min, UV detection at 205 nm).
Retention times: (2S,3R)-capreomycidine: 21.22 min;
(2R,3S)-capreomycidine: 31.95 min.
.