Total synthesis of the epimer at C-6′ of the miharamycin B framework

Article abstract of DOI:10.1055/s-0029-1216733

The total synthesis of the epimer at C-6′ of the core of the complex nucleoside antibiotic miharamycin B is reported. Optimization of the N-glycosylation key step involving the atypical 2-aminopurine nucleobase and a bicyclic glycosyl donor enabled to acc

Full text of DOI:10.1055/s-0029-1216733

LETTER
1269
Total Synthesis of the Epimer at C-6¢ of the Miharamycin B Framework
S
ynthesis of th
i
e
E
pim
l
er at
C
i
-6
¢
of
t
p
a
cin
B
F
rameworkMarcelo,a,c Robert Abou-Jneid,a Matthieu Sollogoub,a Jérôme Marrot,b Amélia P. Rauter,*c Yves Blériot*a
a
Institut Parisien de Chimie Moléculaire, UMR 7201, Equipe Glycochimie, UPMC Univ. Paris 06, 4 Place Jussieu, 75005 Paris, France
Fax +33(1)44275504; E-mail: yves.bleriot@upmc.fr
b
c
Institut Lavoisier, Université de Versailles-Saint-Quentin, UMR 8180, 78035 Versailles, France
Carbohydrate Chemistry Group, CQB-FCUL, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade
de Lisboa, 1749-016 Lisbon, Portugal
Fax +351(21)7500088; E-mail: aprauter@fc.ul.pt
Received 30 December 2008
7C' O2H
6'
NH
O
Abstract: The total synthesis of the epimer at C-6¢ of the core of the
complex nucleoside antibiotic miharamycin B is reported. Opti-
mization of the N-glycosylation key step involving the atypical
2-aminopurine nucleobase and a bicyclic glycosyl donor enabled to
access the N9-nucleoside in reasonable yield which was further dec-
orated. The stereochemistry at C-6¢ has been secured by X-ray crys-
tallography.
N
N
H2N
N
N
N
4'
5'
R
H
O
H2N
2'
HO
3'
N
NH2
HO
1'
O
HO
miharamycin A (1) R = OH
miharamycin B (2) R = H
Key words: antibiotics, natural products, nucleosides, total synthe-
sis
Figure 1
Complex nucleoside antibiotics are natural products that
combines the structures of nucleosides, higher monosac-
charides, peptides, and lipids.1 They are of high interest
for the organic chemists community as they display un-
usual structures and exhibit a large scope of biological ac-
tivities ranging from antiviral to antitumor properties.2
Although many structures are still under investigation
through synthetic methodologies such as amypurimycin,3
an increasing number of compounds of this class has been
obtained by total synthesis.4 We have recently reported
the full structural elucidation of miharamycin A (1) and
the total synthesis of the core of miharamycin B (2,
Figure 1).5 Miharamycins comprise a unique bicyclic sug-
ar moiety which pyranose ring is elongated at C-6, a 2-
aminopurine nucleobase linked through a b-N glycosidic
bond via its N9-position and a L-arginine or N-hydroxy-
arginine appendage connected through a peptide bond.
These two antibiotics exhibit strong activity against the
rice blast disease caused by Pyricularia oryzae6 and have
been chemically studied by several groups.7 We report
herein the synthesis of the 6R-epimer of the core of this
natural product. Regarding the configuration of mihara-
mycins at C-6¢ which has been undetermined for a long
period,8 the synthesis of this epimer is of interest for fur-
ther SAR studies.9
selective methods are available, elongation of the C-6 po-
sition of the bicyclic moiety was achieved through
vinylation of the derived aldehyde at C-6 to afford a sep-
arable mixture of diastereomeric allylic alcohols 3 and 4
in 65% yield from the primary alcohol and in 3:2 ratio in
favor of the 6S-isomer 3 which was engaged in the total
synthesis of miharamycin B. We undertook the synthesis
of the C-6¢-epimer starting from the 6R-allylic alcohol 4
using a similar strategy. Ozonolysis of compound 4 fol-
lowed by oxidation with NaClO2 afforded the correspond-
ing carboxylic acid, which was isolated as its methyl ester
5 in 65% over three steps. As the 6R-epimer of mihara-
mycin required inversion of configuration and introduc-
tion of an amine at C-6, triflation of the free secondary OH
and displacement with NaN3 provided the C-6 R-azido es-
ter 6 as a masked amino acid in 68% over two steps
(Scheme 1).
(R)
(S)
HO
BnO
HO
HO
HO
HO
BnO
ref. 5
O
O
O
O
O
+
BnO
BnO
HO
OMe
OMe
OMe
BnO
BnO
3
4
1) O3, Me2S, CH2Cl2
2) NaClO2
3) MeI, KHCO3
We started the synthesis from a precursor of the elongated
bicyclic sugar moiety of miharamycins, which was avail-
able to us. The bicyclic sugar moiety was constructed us-
ing samarium(II) iodide methodology10 through the
reductive coupling of a ketoalkyne.11 While diastereo-
(S)
(R)
CO2Me
O
CO2Me
O
1) Tf2O
N3
BnO
BnO
HO
BnO
pyridine
miharamycin B
2) NaN3
DMF
BnO
O
O
OMe
OMe
BnO
BnO
6
5
SYNLETT 2009, No. 8, pp 1269–1272
Advanced online publication: 17.04.2009
x
x.
x
x.
2
0
0
9
Scheme 1
DOI: 10.1055/s-0029-1216733; Art ID: D42608ST
© Georg Thieme Verlag Stuttgart · New York

1270
F. Marcelo et al.
LETTER
One of the key steps of this synthesis is the conversion of
the advanced azido ester 6 into a suitable glycosyl donor,
which will be engaged in the crucial N-glycosylation.
This transformation requires strongly acidic conditions to
cleave the anomeric methoxy group and, as previously ob-
served for the 6S-epimer, under these conditions, a rear-
rangement of the skeleton of the 6R-azido ester 6 was
observed leading to a ring-contracted compound that was
isolated as its peracetylated derivative 7, the structure of
which was unambiguously established by X-ray
crystallography12 (Figure 2).
CO2Me
O
CO2Me
O
CO2Me
O
TBSOTf
HO
BnO
TBSO
TBSO
BnO
BnO
BnO
BnO
pyridine
0 °C, 89%
+
BnO
O
O
O
OMe
OMe
OMe
BnO
BnO
BnO
5, 5'
8
8'
CO2Me
O
CO2Me
HO
1) H2
TBSO
AcO
AcO
10% Pd/C
40% aq HF
MeCN, 66%
O
AcO
AcO
8
2) Ac2O
O
O
pyridine
84%
OMe
OMe
AcO
AcO
9
10
1) Tf2O, py
2) NaN3, DMF
81%
CO2Me
O
N3
AcO
AcO
O
OMe
AcO
HO
11
Figure 2
CO2Me
O
CO2Me
O
1) H2
10% Pd/C
TBSO
In order to clearly demonstrate the pyranosidic structures
of our azido ester 6 and its epimer 6¢ involved in the total
synthesis of miharamycin B, and to have an alternative
scaffold displaying a different kind of hydroxyl protecting
group in order to secure the synthesis, another route to the
pyranosidic azido esters 6 and 6¢ was examined avoiding
acidic conditions. A mixture of hydroxy esters 5 and 5¢13
were protected as their separable silyl ethers 8 and 8¢ (89%
yield). Compound 8 was debenzylated with 10% Pd/C and
the hydroxy groups protected as acetates to afford triace-
tate 9 in 84% yield over two steps. Removal of the silyl
group required aqueous HF in acetonitrile as compound 9
was inert to TBAF to furnish alcohol 10. Finally, inver-
sion of the secondary alcohol via triflation and azide dis-
placement afforded the desired 6R-azido ester 11, the X-
ray structure of which was solved.14 A similar sequence
was applied to epimeric silyl ether 8¢, except the desilyla-
tion step that was achieved with TBAF in the presence of
AcOH to avoid silyl group migration, to give the 6S-azido
ester 11¢, the structure of which was also confirmed by X-
ray crystallography15 (Scheme 2, Figure 3).
TBAF, AcOH
AcO
AcO
AcO
AcO
8'
80 °C, 92%
2) Ac2O
pyridine
82%
O
O
OMe
OMe
AcO
AcO
9'
10'
1) Tf2O, py
2) NaN3, DMF
79%
CO2Me
O
N3
AcO
AcO
O
OMe
AcO
11'
Scheme 2
and 13 displaying different protecting groups (Figure 4)
were used as models and submitted to a range of aceto-
lysis conditions that screened acids (70% aq HClO4,16
TMSOTf,17 and BF3·OEt218), temperatures (–20 °C, 0 °C),
and reaction times. Furanoside formation was monitored
by careful examination of the NMR data. A small J1,2 val-
ue for the anomeric proton is indicative of a b-glucofura-
nose form which was also accompanied by a change in the
multiplicity of some of the sugar ring protons.
AcO
AcO
BnO
BnO
O
O
O
O
AcO
BnO
OMe
OMe
AcO
BnO
12
13
Figure 4
Figure 3
Unfortunately, whatever the conditions used, no improve-
ment of the pyranose/furanose ratio was detected. There-
fore, the same conditions as the one applied to the 6S-
epimer (Ac2O, concd H2SO4 5% in AcOH) were used for
The N-glycosylation step was then investigated in order to
solve the problematic acidic hydrolysis of the anomeric
substituent. To this end two bicyclic sugar derivatives 12
Synlett 2009, No. 8, 1269–1272 © Thieme Stuttgart · New York

LETTER
Synthesis of the Epimer at C-6′ of the Miharamycin B Framework
1271
the perbenzylated azido ester 6 and furnished the corre- in toluene at 85 °C. After two hours, the corresponding
sponding anomeric acetate 14 in a satisfactory 72% yield. N9-nucleoside 16 was obtained that might account for a
Noteworthy is the comparative 39% yield obtained for the reversible process involving dissociation of the nucleo-
6R-epimer emphasizing the difference of reactivity for side 15 into the nucleobase and the activated glycosyl do-
these two diastereomers. The same conditions applied to nor which then react together to form the thermodynamic
the peracetate derivative 11 only led to ring-contracted compound 16 at high temperature. Unfortunately, such
products (Scheme 3).
conditions did not work in the case of the more relevant
perbenzylated N7-nucleoside 17 leading only to decompo-
sition (Scheme 4). A similar result was also reported by
Robins in the case of furanosidic nucleosides.22
CO2Me
N3
CO2Me
O
N3
RO
Ac2O, H2SO4
O
RO
RO
OAc
RO
5% in AcOH
–20 to 0 °C
Failure of this equilibration approach prompted us to op-
timize the reaction conditions to increase the yield of the
desired N9-isomer, which is present in the natural product.
A screening of the parameters (temperature, solvent) en-
abled to select conditions which furnished the required
N9-b-nucleoside 18 as the major isomer (2:1 ratio) in 55%
yield using toluene as solvent at 85 °C for four hours with
TMSOTf as the promotor (Scheme 5, Table 1). Of note is
the use of acetonitrile as solvent at 65 °C, which exclu-
sively leads to the formation of the N7-nucleoside, a useful
result for SAR purposes. With the desired nucleoside 18
in hand, coupling with arginine was then examined and re-
quired reduction of the azide. A convenient procedure us-
ing Pd/C in the presence of Et3N cleanly reduced the azide
and concommitantly removed the chlorine atom without
affecting the benzyl ethers to furnish the 2-aminopurine
nucleoside 19. Coupling with arginine was then studied
and activation of a Z-protected arginine 2023 with isobutyl
chloroformate24 efficiently afforded the fully protected
epimer at C-6¢ of miharamycin B (21).
O
O
OMe
RO
RO
14 R = Bn
6 R = Bn
11 R = Ac
for R = Ac only ring-contracted
compounds were isolated
Scheme 3
N-Glycosylation with 2-aminopurine was then attempted
from glycosyl donor 14. N-Glycosylation was found prob-
lematic regarding the yield and the regiospecificity of the
reaction. Coupling under Vorbrüggen conditions19 with
relevant persilylated 2-aminopurine20 was unsuccessful21
using either Czernecki’s7a (SnCl4, DCE–MeCN, reflux) or
Garner’s7b (TMSOTf, DCE, reflux) procedures that
proved to work in the case of glucose peracetate to afford
the thermodynamic N9-regioisomer. Moving to the more
reactive 6-chloro-2-aminopurine using the same condi-
tions gave better results but only the kinetic N7-nucleoside
was obtained. In order to rationalize this opposite selectiv-
ity, a model N7-nucleoside 15 was treated with TMSOTf
Cl
N
RO
RO
RO
N
N
NHAc
RO
RO
RO
O
TMSOTf
O
N
N
N
7
toluene, 85 °C
N
RO
9
N
RO
Cl
NHAc
15 R = Ac
17 R = Bn
16 (31%)
decomposition
Scheme 4
Cl
N
CO2Me
O
N
N
CO2Me
O
N
OTMS
Me
N7
N
N3
N7
H2N
BnO
Cl
BnO
BnO
N9
TMS
H2, Pd/C, Et3N
N
N9
BnO
N
14
N
O
O
N
TMSOTf, toluene, 85 °C
55%
BnO
BnO
NHAc
NHAc
18 (N9/N7 = 2:1)
19
Z
ZHN
N
CO2H
O
CO2Me
Z
ZHN
N
NH
ZHN
20
N
N7
N
H
NH
ZHN
isobutyl chloroformate
O
BnO
BnO
N9
N
O
21
BnO
NHAc
Scheme 5
Synlett 2009, No. 8, 1269–1272 © Thieme Stuttgart · New York

1272
F. Marcelo et al.
LETTER
Yasuda, Y.; Niida, T.; Shomura, T. Ann. Phytopath. Soc.
Table 1 Synthesis of N9-b-Nucleoside 18 under Various Conditions
Entry Solvent
Temp (°C) Time N9/N7 Yield (%)
Japan 1968, 34, 323.
(7) (a) For synthetic efforts towards the northern moiety of
miharamycins, see: Czernecki, S.; Franco, S.; Horns, S.;
Valery, J.-M. Tetrahedron Lett. 1996, 37, 4003. (b) For
synthetic efforts towards the southern moiety of
miharamycins, see: Garner, P.; Yoo, J. U.; Saraku, R.
Tetrahedron 1992, 48, 4259.
1
2
3
4
5
6
7
MeCN
MeCN–DCE
DCE
65
85
85
85
85
110
85
3
0:1
1:9
1:3
1:3
–
58
55
41
40
3
3
(8) Seto, H.; Koyama, M.; Ogino, H.; Tsuruoka, T.; Inouye, S.;
DCE
7
Otake, N. Tetrahedron Lett. 1983, 24, 1805.
(9) Marcelo F., Silva, F. V. M.; Goulart, M.; Justino, J.; Blériot,
Y.; Rauter, A. P. in preparation.
(10) (a) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev.
2004, 104, 3371. (b) Blériot, Y.; Untersteller, E.; Fritz, B.;
Sinaÿ, P. Chem. Eur. J. 2002, 8, 240.
a
DCE
16
4
–
PhMe
3:1
2:1
33b
54
PhMe
4
(11) Fairbanks, A. J.; Sinaÿ, P. Synlett 1995, 277.
(12) CCDC 716056 contains the supplementary crystallographic
data for this structure. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.ac.uk/data _request/cif.
a Decomposition of the nucleobase and of the glycosyl donor.
b Deacetylation of the purine nucleobase was observed.
Acknowledgment
(13) Hydroxy esters 5 and 5¢ were difficult to separate and
therefore were used as a mixture.
This work was supported by the Fundação para a Ciência e Tecno-
logia (FCT, project POCI/QUI/59672/2004, Portugal). F.M. thanks
the FCT for a research grant (SFRH/BD/17775/2004).
(14) CCDC 716057 contains the supplementary crystallographic
data for this structure. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.ac.uk/data _request/cif.
(15) CCDC 695608 contains the supplementary crystallographic
data for this structure. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.ac.uk/data _request/cif.
(16) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc.
2004, 126, 9205.
References and Notes
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(17) Angibeaud, P.; Utille, J.-P. J. Chem. Soc., Perkin Trans. 1
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(3) (a) Goto, T.; Toya, Y.; Ohgi, T.; Kondo, T. Tetrahedron Lett.
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(6) (a) Tsuruoka, T.; Yumoto, H.; Ezaki, N.; Niida, T. Sci.
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(19) Vorbrüggen, H.; Hofle, G. Chem. Ber. 1981, 114, 1256.
(20) Koshkin, A. A. J. Org. Chem. 2004, 69, 3711.
(21) The lack of reactivity of 2-aminopurine has been reported by
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(22) Robins, M. J.; Zou, R.; Gou, Z.; Wnuk, S. F. J. Org. Chem.
1996, 61, 9207.
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