Efficient synthesis of the core structure of muraymycin and caprazamycin nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction

Article abstract of DOI:10.1016/j.tetasy.2010.03.037

The reaction of protected uridine 5′-aldehydes with sulfur ylides has been reinvestigated. Further transformation of the resulting epoxide product provided a compound of which a single crystal for X-ray diffraction was obtained. As a consequence from the elucidated structure, the stereochemical configuration of the epoxide furnished by the sulfur ylide reaction was revised. Based on these results, an efficient synthesis of the core structure of the naturally occurring muraymycin and caprazamycin nucleoside antibiotics was developed.

Full text of DOI:10.1016/j.tetasy.2010.03.037

Tetrahedron: Asymmetry 21 (2010) 763–766
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of the core structure of muraymycin and caprazamycin
nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction
Anatol P. Spork a, Stefan Koppermann a, Birger Dittrich b, Regine Herbst-Irmer b, Christian Ducho a,
*
a Georg-August-University Göttingen, Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Tammannstr. 2, 37077 Göttingen, Germany
b Georg-August-University Göttingen, Department of Chemistry, Institute of Inorganic Chemistry, Tammannstr. 4, 37077 Göttingen, Germany
a r t i c l e i n f o
a b s t r a c t
The reaction of protected uridine 50-aldehydes with sulfur ylides has been reinvestigated. Further trans-
formation of the resulting epoxide product provided a compound of which a single crystal for X-ray dif-
fraction was obtained. As a consequence from the elucidated structure, the stereochemical configuration
of the epoxide furnished by the sulfur ylide reaction was revised. Based on these results, an efficient syn-
thesis of the core structure of the naturally occurring muraymycin and caprazamycin nucleoside antibi-
otics was developed.
Article history:
Received 8 March 2010
Accepted 31 March 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Due to the emerging resistances of bacterial strains towards
established antibiotics, there is a particular need for the develop-
ment of novel antimicrobial agents.1 Nucleoside antibiotics
represent a class of antibacterially active natural products bear-
ing unique nucleoside core structures. These antibiotics inhibit
the bacterial membrane protein translocase I (MraY), a key
enzyme in the intracellular stages of peptidoglycan biosynthe-
sis.2,3 Nucleoside antibiotics should therefore be considered as
attractive lead structures for drug development, thus making
the facile synthesis of their structural key motifs an important
objective.
The original assignment of the stereochemical configuration of
the epoxides obtained by the aforementioned sulfur ylide reaction
was based on a model compound and computational investiga-
tions.8,10 We reacted the protected uridine 50-aldehyde 4a with
the sulfur ylide derived from sulfonium salt 5 to give diastereomer-
ically pure epoxide 6a as the sole epoxide product in 60% yield.9
Nucleophilic ring-opening of 6a with amine 79 provided the
protected nucleosyl amino acid 8 in 52% yield (Scheme 1). As
expected,8–12 the ring-opening reaction of epoxy ester 6a occurred
in a perfectly regio- and diastereoselective SN2-type manner, as
proven by rigorous 2D NMR analyses, and no other product was
observed. In contrast to any other similar derivative we had previ-
ously synthesised via this strategy, amino alcohol 8 could be crys-
tallised from benzene, and single crystals suitable for X-ray
diffraction were obtained.
Muraymycin (e.g., muraymycin A1 1)4 and caprazamycin anti-
biotics (e.g., caprazamycin A 2)5 represent two subclasses of nucle-
oside antibiotics with identical (50S,60S)-configured nucleosidic
core moieties 3 (Fig. 1). So far, only one practical synthesis of this
nucleosyl amino acid scaffold based on a Sharpless aminohydroxy-
lation strategy has been reported.6 An aldol approach for the con-
struction of the nucleoside moiety has also been described,7 but it
suffers from a lack of stereocontrol and from moderate yields. In
contrast, the reaction of sulfur ylides with suitably protected uri-
dine 50-aldehydes was reported to occur with high diastereoselec-
tivity and to provide epoxides leading to biologically active 50-epi
muraymycin analogues.7,8 We have recently described an
improved version of this approach for the convergent synthesis
of muraymycin analogues.9
However, the X-ray crystal structure of 813–16 (Fig. 2) revealed
that the original stereochemical assignment of the epoxide pro-
vided by Sarabia et al. (50S,60R)8,10 could not be correct. In contrast,
the formal stereochemistry of the epoxide moiety of 6a had to be
(50R,60S), as shown in Scheme 1, in order to provide the ring-open-
ing product 8 with the proven (50S,60R)-configuration.17
It was then investigated if the stereochemical outcome of the
sulfur ylide reaction might differ depending on various structural
features of the reactants. We have demonstrated before that the
transformation of uridine 50-aldehydes 4a and 4b into epoxides
6a,b and 9a,b provides identical product stereochemistry regard-
less of the sulfur ylide employed. The sulfur ylides derived from
the tert-butyl ester sulfonium salt 5 and from Sarabia’s originally
used indoline amide sulfonium salt 108,10 were tested, and further
conversion of epoxides 9a,b obtained from the latter reaction into
* Corresponding author. Tel.: +49 (0)551 39 3285; fax: +49 (0)551 39 9660.
E-mail address: cducho@gwdg.de (C. Ducho).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.037

764
A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
O
O
N
O
N
HOOC
O
NH
NH
NH
OR1
N
N
HO
O
HO
O
O
O
N
O
O
O
O
6'
5'
6'
5'
R2
R4
O
OH
O
H
N
H
N
O
O
9
HN
O
N
H
H2N
O
HO
N
H
R3O
O
O
O
O
O
OH OH
OH OH
OH OH
HN
1
2
3
HN
N
H
O
NH
NH2
H2N
H2N
R4
O
OH
O
O
OH OH
R1
=
R2
=
R3
=
=
N
MeO
11
OMe
OH
O
OMe
Figure 1. Structures of muraymycin and caprazamycin antibiotics, exemplified by muraymycin A1 1 and caprazamycin A 2, and their common nucleoside core structure 3.
their corresponding tert-butyl esters gave 6a and 6b, respectively
(Scheme 2).9 Furthermore, epoxide 6a obtained without N-3-PMB
protection of the uracil moiety could be transformed into epoxide
6b by alkylation with PMB chloride (75% yield). The epoxide 6b
furnished from this reaction was found to be identical both spec-
troscopically (NMR) and chromatographically (HPLC) to the prod-
uct isolated from the aforementioned sulfur ylide reaction with 5
(Scheme 2). Thus, the stereochemical course of the sulfur ylide
reaction was completely independent not only of the sulfur ylide
employed, but also of the presence or absence of nucleobase pro-
tection. Finally, the potential influence of the protecting groups
at 20-OH and 30-OH of the ribose moiety was studied. Epoxide 9b
was treated with tetra-n-butyl ammonium azide to give the ring-
opening product 11 in 68% yield. The TBDMS groups of 11 were
then cleaved under acidic conditions, providing product 12 in
90% yield; an isopropylidene group was subsequently introduced
to afford derivative 13 in 37% yield (reaction not optimised). How-
ever, the corresponding material obtained from the previously de-
scribed sulfur ylide reaction of uridine 50-aldehyde 14 with 10,8
followed by ring-opening with tetra-n-butyl ammonium azide
(53% yield over two steps), was found to be identical by means
of rigorous NMR and HPLC analyses (Scheme 2). It was therefore
concluded that the protecting group pattern at the ribose moiety
had no influence on the stereochemical outcome of the sulfur ylide
transformation.
All epoxide products obtained from the sulfur ylide reaction dis-
played the stereochemical configuration proven for 6a. Hence,
Sarabia’s ribose derivative originally employed for the wrong con-
figurational assignment10 might have been an unsuitable model
compound for this transformation or the assignment was other-
wise flawed.
O
With respect to the corrected stereochemistry, it was then
investigated if the sulfur ylide reaction could be applied to the syn-
thesis of nucleoside-building blocks with potential use for the
preparation of muraymycins or caprazamycins. Besides the appar-
ent potential to open the epoxide products from the sulfur ylide
reaction with nitrogen nucleophiles in order to obtain (60R)-config-
Br
O
N
S
O
N
O
5
NH
NH
5, NaH, THF,
then 4a, CH2Cl2
O
O
O
O
O
O
5'
O
O
6'
60 %
TBDMSO
OTBDMS
TBDMSO
OTBDMS
4a
6a
Cl
H
N
NH3
O
CbzHN
O
NH
7
O
O
O
7, DIPEA,
N
O
MeOH
6'
5'
CbzHN
OH
O
N
H
N
H
52 %
TBDMSO
OTBDMS
8
5',6'-configuration proven by
X-ray crystal structure analysis
Previous configurational
Corrected assignment of 6a
assignment of 6a:[8,10]
based on the stereochemistry of 8:
O
O
NH
NH
O
O
N
O
N
O
O
O
O
5'
O
5'
O
O
6'
6'
Figure 2. X-ray crystal structure of compound 8 (ORTEP plot with 50% probability
ellipsoids; one of four main molecules with identical absolute configuration in the
asymmetric unit); only hydrogen atoms at stereogenic centres are displayed
(green).
TBDMSO
OTBDMS
TBDMSO
OTBDMS
Scheme 1. Sulfur ylide reaction of 4a with 5, further transformation of the resulting
epoxide 6a into 8 and correction of the stereochemistry of 6a.

A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
765
O
Br
S
O
N
O
N
O
N
O
N
1) 10, NaOH,
O
CH2Cl2, H2O
R
O
R
O
5
N
N
NP MB
O
NPMB
O
NN3,
2) Bu4
N
O
5, NaH, THF,
then 4, CH2Cl2
O
amberlyst 15,
acetone
O
OH
O
O
O
O
N3
O
O
O
53 % (over
2 steps)
TBDMSO
OTBDMS
TBDMSO
OTBDMS
O
O
O
O
4a: R = H
6a: R = H
PMB-Cl,
KHMDS,
DMF
4b: R = PMB
14
13
75 %
6b: R = PMB
O
10, NaOH,
CH2Cl2,
H2O
Me2CH(O Me )2,
acetone, BSA
Cl
S
37 %
O
N
4 steps
10
O
O
R
N
NPMB
NPMB
9b, Bu4NN3,
amberlyst 15,
acetone
N
O
N
O
O
N
O
N
O
N
O
O
AcCl, MeOH
90 %
OH
O
OH
O
N
N3
N3
O
68 %
TBDMSO
OTBDMS
TBDMSO
OTBDMS
OH OH
9a: R = H
11
12
9b: R = PMB
Scheme 2. Syntheses to investigate the influence of structural features of the reactants on the stereochemical outcome of the sulfur ylide reaction.
O
N
O
N
O
N
NPMB
O
NPMB
O
NPMB
Bu4NN3,
various
solvents
NaBr,
amberlyst 15,
acetone
N
O
N
O
O
O
+
O
OH
O
OH
O
N
11
Br
N3
O
85 %
TBDMSO
OTBDMS
TBDMSO
OTBDMS
TBDMSO
OTBDMS
9b
15
17
LevOH, DIC,
DMAP, CH2Cl2
82 %
O
O
O
NPMB
NPMB
NPMB
H2 (1bar),
10 % Pd/C,
MeOH
1) Bu4NN3, DMF
2) N2 H4 HOAc,
DMF, MeOH
N
O
N
O
N
O
N
O
N
O
N
O
OH
O
OLev
O
OH
N3
Br
H2N
O
93 %
92 %
(one-pot)
TBDMSO
OTBDMS
TBDMSO
OTBDMS
TBDMSO
OTBDMS
17
16
18
Scheme 3. Conversion of epoxide 9b obtained via the sulfur ylide approach into the protected nucleoside-building block 18.
ured muraymycin or caprazamycin analogues, it was also desired
to conceive a synthesis of the natural product-like nucleoside unit
via this route. Epoxide 9b was therefore reacted with sodium bro-
mide in the presence of amberlyst™ 158 to give bromohydrin 15 in
85% yield (Scheme 3). It was envisaged to convert 15 into the cor-
responding azide by simple SN2 nucleophilic displacement at C-60.
However, this reaction was non-trivial due to the apparent refor-
mation of epoxide 9b under the reaction conditions, giving rise
to significant amounts of 11 as a by-product. Several attempts to
overcome this limitation, particularly by changing the solvent,
were unsuccessful. Hence, a protecting group was introduced at
the 50-hydroxy moiety in order to avoid epoxide reformation. Lev-
ulinyl (Lev) protection furnished 16 in 82% yield. Employing a con-
venient one-pot sequence of treatment with tetra-n-butyl
ammonium azide and levulinyl deprotection using hydrazine ace-
tate, the desired product 17 could then be obtained in 93% yield.
The subsequent reduction of the azide moiety furnished amine
18 in 92% yield (Scheme 3). The protected nucleosyl amino acid
18 is a suitable building block for the synthesis of muraymycins,
caprazamycins and analogues thereof as the aminoacylated alkyl
side chain can be easily introduced via reductive amination.7
3. Conclusion
In conclusion, we have reinvestigated and revised the stereo-
chemical outcome of the previously described reaction of uridine
50-aldehydes with sulfur ylides.8–10 It was reported before to em-
ploy this transformation to synthesise biologically active 50-epi
analogues of muraymycin nucleoside antibiotics, which is not fea-

766
A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
7. Yamashita, A.; Norton, E.; Petersen, P. J.; Rasmussen, B. A.; Singh, G.; Yang, Y.;
Mansour, T. S.; Ho, D. M. Bioorg. Med. Chem. Lett. 2003, 13, 3345–3350.
8. Sarabia, F.; Martín-Ortiz, L. Tetrahedron 2005, 61, 11850–11865.
9. Spork, A. P.; Koppermann, S.; Ducho, C. Synlett 2009, 2503–2507.
10. Sarabia, F.; Martín-Ortiz, L.; López-Herrera, F. J. Org. Lett. 2003, 5, 3927–3930.
11. Valpuesta, M.; Durante, P.; López-Herrera, F. J. Tetrahedron Lett. 1995, 36, 4681–
4684.
sible with respect to the corrected stereochemistry of the epoxide
products obtained from the sulfur ylide reaction. In contrast, we
developed an efficient synthesis of the nucleoside core structure
of both muraymycin and caprazamycin antibiotics based on the
sulfur ylide-epoxide strategy (60% overall yield over five steps from
protected uridine 50-aldehyde 4b). Although this novel route is
slightly longer than the previously described Sharpless aminohydr-
oxylation approach,6 it is completely stereocontrolled, and avoids
the use of toxic heavy metals and expensive chiral ligands, thus
potentially enabling the synthesis of the protected nucleoside-
building block on a multi-gram scale.
12. Azzena, F.; Crotti, P.; Favero, L.; Pineschi, M. Tetrahedron 1995, 51, 13409–
13422.
13. The crystal structure determination of 8 was not without challenges. Although
sufficiently large and transparent rectangular crystals could be grown by
solvent evaporation with ease, the fact that the co-crystallising solvent led to
crystal decay within seconds required low-temperature crystal-mounting
conditions. Furthermore, the crystals investigated by us were composed of
twin domains, so that for data integration two orientation matrices were
required (Bruker (2001). SAINT. Bruker AXS Inc., Madison, WI). The crystal
lattice appeared to be of higher metric symmetry than was the case
(orthorhombic rather than monoclinic) leading to additional twinning by
pseudo-merohedry. There were four domains of potentially overlapping
reflections. A more detailed description of the twinning in connection with
the determination of the Flack-parameter will be given elsewhere. In spite of
the twinning, determination of the Flack-parameter (0.04 0.02),14 which was
crucial for arriving at the conclusions reported, was possible. Full
crystallographic data for this structure have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 770311. These data can be obtained free of charge on
application to CCDC, 12, Union Road, Cambridge, CB2 1EZ; fax +44
(1223)336033; or email: deposit@ccdc.cam.ac.uk.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG, SFB 803
‘Functionality controlled by organization in and between mem-
branes’) and the Fonds der Chemischen Industrie (FCI) for financial
support. Donation of laboratory equipment by the BASF SE is grate-
fully acknowledged.
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Mittl, P. R. E. Structure 1999, 7, 55–63). The asymmetric unit consists of four
main molecules with identical absolute configuration, which are accompanied
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molecules.
17. It should be noted that the descriptor of the stereocenter at C-50 formally
changes from (R) to (S) upon reaction with the nitrogen nucleophile at C-60 due
to altered priorities.