Studies toward stable analogues of guanofosfocins. Synthesis of the protected derivative of 8-(5a-carba-α-D-mannopyranosyloxy)purine nucleoside

Article abstract of DOI:10.1246/cl.2007.36

As a preliminary study directed towards the synthesis of a stable analogue of the guanofosfocins, a methylene analogue of the endocyclic oxygen atom in the mannose moiety, was designed. The construction of the pseudo-α-mannosyl linkage at the 8-position o

Full text of DOI:10.1246/cl.2007.36

36
Chemistry Letters Vol.36, No.1 (2007)
Studies toward Stable Analogues of Guanofosfocins. Synthesis of the Protected Derivative
of 8-(5a-Carba-ꢀ-D-mannopyranosyloxy)purine Nucleoside
Hideyuki Sugimuraꢀ and Naoya Hosogai
Faculty of Education and Human Sciences, Yokohama National University,
79-2 Tokiwadai, Hodogaya-ku, Yokohama 240-8501
(Received September 26, 2006; CL-061120; E-mail: sugimura@edhs.ynu.ac.jp)
As a preliminary study directed towards the synthesis of a
The synthesis of 5a-carbamannose from (–)-quinic acid
was established by Shing and Tang.7,8 Based on this protocol,
our synthetic strategy for the stereoselective formation of the
pseudo-ꢀ-mannopyranosyl linkage features the regioselective
substitution of the 1,2-O-cyclic sulfate derivative of 5a-carba-
ꢁ-D-mannnopyranose by a nucleophile, derived from the 8-oxo-
purine nucleoside.9
stable analogue of the guanofosfocins, a methylene analogue
of the endocyclic oxygen atom in the mannose moiety, was
designed. The construction of the pseudo-ꢀ-mannosyl linkage
at the 8-position of the purine nucleoside was accomplished by
the regioselective ring-opening substitution of the 1,2-O-cyclic
sulfate derivative of 5a-carba-mannopyranose.
The cyclohexene derivative 2 was obtained in five steps
from commercially available (–)-quinic acid (1) as described
by Shing and Tang.7,8 Treatment of the methyl ester 2 with
DIBAL-H afforded the alcohol 3, which was protected as a
Guanofosfocins are a novel family of chitin synthase inhib-
itors, isolated from the fermentation broths of Streptomyces sp.
and Trichoderma sp.1 Despite their potent inhibitory activity
against Candida albicans CHS 2, a further investigation of these
fascinating molecules has been hindered by their low stability.
In addition to their role as promising therapeutic agents against
fungous diseases, the guanofosfocins contain a highly distinctive
three component structure, a central part of which is a unique
glycosidic type bond between the 8-position of guanosine
and a D-mannose moiety. In earlier reports on the synthesis of
8-(mannopyranosyloxy)purine nucleosides, we disclosed that
three different approaches were possible for the construction
of such a glycosyl linkage.2–5 However, at the same time the
constructed glycosyl bonds were found to be easily hydrolyzed
under acidic conditions, affording 8-oxopurine nucleosides. In
contrast, an ethereal bond, for example, the 8-(cyclohexyloxy)-
purine nucleoside, was shown to be quite stable under the same
acidic conditions. Based on these findings, we designed the
carba-sugar analogues of the guanofosfocins, in which the endo-
cyclic oxygen atom of the mannose moiety is replaced by a
methylene group, as stable guanofosfocin analogues (Figure 1,
X = CH2).6 In this letter, we describe our preliminary studies
of the synthetic route to 8-(5a-carba-ꢀ-D-mannopyranosyloxy)-
purine nucleoside.
COOMe
HO COOH
i
ii
O
OTBS
HO
OH
85%
O
OH
1
2
OH
OBn
iii
iv
O
OTBS
O
OTBS
89%
74%
O
O
3
4
OBn
OH
OBn
OBn
v
vi
O
OTBS
O
OTBS
93%
87%
O
O
5"a
X
HO
1"
HO
HO
5
6
O
O
N
O
O
8
NR1
NHR2
5'
O
O
O
N
6
S
O
OH
O
vii
O
P
O
N
BnO
BnO
TBSO
BnO
5
5a
4
BnO
OH
O
P
OH
TBSO
OH OH
HO
2
88%
OH
3
1
A : X = O, R1 = Me, R2 = H
B : X = O, R1 = H, R2 = H
C : X = O, R1 = H, R2
O
OH
O
OH
OH
7
8
O
H
=
N
Scheme 1. Reagents and conditions: (i) Refs. 7 and 8; (ii)
DIBAL-H, THF, ꢁ20 to 0 ꢂC; (iii) BnBr, NaH, DMF, 0 ꢂC;
(iv) 9-BBN, THF, reflux, then H2O2 aq, NaOH aq, r.t.; (v) BnBr,
N
N
NH2
H
H
O
O
HO
5"a-carba-analogue : X = CH2
ꢂ
.
NaH, DMF, 0 C; (vi) PrSH (2 equiv.), BF3 OEt2 (0.2 equiv.),
ꢁ78 to ꢁ20 ꢂC; (vii) SOCl2, Py, CH2Cl2, 0 ꢂC, RuCl3/n-H2O,
Figure 1. Structure of guanofosfocin A–C and their carba-ana-
logues.
NaIO4, CCl4, CH3CN, H2O, r.t.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
37
NHTr
N
benzyl ether to yield the cyclohexene 4. The double bond in 4
was subjected to a stereocontrolled hydroboration–oxidation
sequence at the less hindered ꢁ-face, exclusively furnishing
the cyclohexane derivative 5. After protection of the hydroxy
group as a benzyl ether, the attempt to remove the cyclohexyli-
dene acetal in 6 under acidic conditions failed due to the simul-
taneous cleavage of the TBS group. However, selective removal
of the cyclohexylidene group was fortunately accomplished
under acetal exchange conditions. The treatment of 6 with
two equiv. of PrSH in the presence of a catalytic amount of
H
N
O
N
H2SO4–THF–H2O
(3:300:1)
TBDPSO
N
8
O
NaH
r.t., 1.3 h
50 °C, 23h
DMF,
r.t., 15 min
O
O
12
OH
BnO
BnO
TBSO
BnO
BnO
.
BF3 OEt2 afforded a good yield of the diol 7, which was con-
NHTr
N
NHTr
1"
1"
8
OH
N
2"
TBSO
verted into the cyclic sulfate 8 by the Sharpless method
(Scheme 1).10
N
N
2"
8
N
O
O
N
TBDPSO
TBDPSO
N
N
The ring-opening substitution reaction was initially ex-
plored by employing sodium phenoxide as a simple nucleophile.
Treatment of the cyclic sulfate 8 with sodium phenoxide in DMF
at 50 ꢂC for 24 h, and then under acidic conditions, furnished a
mixture two phenoxy alcohols 9 and 10 with the desired re-
gioisomer as the predominant product. The regio- and stereo-
chemical assignments were based on the 1H NMR spectral anal-
yses of the alcohol 10 and an acetate derivative 11 due to signal
overlapping in 9. H-2 in 10 resonated at ꢂ 4.24 as a triplet
(J ¼ 9:2 Hz), indicating that the C-2 phenoxy group was at
O
O
+
(2)
O
O
O
O
13
14
9%
69%
In conclusion, the ring-opening substitution of the 1,2-O-
cyclic sulfate of the 5a-carbamannopyranose derivative predom-
inately proceeded at the C-1 position, affording 8-(5a-carba-
ꢀ-D-mannopyranosyloxy)purine nucleoside in good yield. A
further investigation employing an 8-oxoguanosine derivative
as a nucleophile as well as the ring-closure reaction between
the 50-position of the nucleoside and 3-OH of the pseudo-man-
nose is currently underway.
the equatorial position. H-1 in 11 appeared at ꢂ 4.53 (J1;2
5:1 Hz), demonstrating that the C-1 phenoxy group was at the
axial position.
¼
O
O
H2SO4–THF–H2O
(3:300:1)
S
PhONa
O
This paper is dedicated to Professor Teruaki Mukaiyama on
the occasion of his 80th birthday.
BnO
BnO
O
TBSO
2
DMF, 50 °C, 24 h
r.t., 35 min
1
References and Notes
1
8
H. Katoh, M. Yamada, K. Iida, M. Aoki, Y. Itezono, M.
Nakayama, Y. Suzuki, M. Watanabe, H. Simada, H.
Fujimari, N. Nagata, S. Ohshima, J. Watanabe, J. Kamiyama,
Abstract of the 38th Symposium of the Chemistry of Natural
Products, Sendai, Japan, 1996; Chem. Abstr. 1996, 125,
322575.
OR
BnO
BnO
BnO
BnO
TBSO
1
+
OH
(1)
1
TBSO
2
2
OPh
OPh
9 (R = H)
53%
10
28%
2
3
H. Sugimura, K. Stansfield, Synlett 1998, 985.
K. Stansfield, H. Kanamori, H. Sugimura, New J. Chem.
1999, 9.
Ac2O, Py
11 (R = Ac)
As the model reaction using sodium phenoxide showed a
preferential regioselectivity, a purine nucleoside was next em-
ployed as the nucleophile. The 8-oxoadenosine derivative 12,
easily accessible from the commercially available 20,30-O-iso-
propylideneadenosine in four steps, was treated with sodium hy-
dride in DMF at r.t. for 15 min, and then added to the DMF solu-
tion of 8. After stirring at 50 ꢂC for 23 h, acid-hydrolysis afford-
ed the desirable substitution product 13 in 69% yield along with
the 9% yield of the regio isomer 14. In this case, the good regio-
selectivity observed was most likely due to the bulkiness of the
nucleophile 12 that would preferentially attack the sterically
favorable C-1 position in 8. Again, H-200 in 14 appeared at ꢂ
5.21 as a triplet (J ¼ 9:5 Hz), reflecting the doubled ax–ax cou-
plings, whereas H-100 in 13 appeared at ꢂ 5.30 as a broad singlet.
4
H. Sugimura, A. Koizumi, W. Kiyohara, Nucleosides,
Nucleotides Nucleic Acids 2003, 22, 727.
5
6
H. Sugimura, Y. Natsui, Tetrahedron Lett. 2003, 44, 4729.
Recently, a study of another type of carba-analogue of
guanofosfocins has been reported. T. G. George, P.
Szolcsanyi, S. G. Koenig, D. E. Paterson, Y. Isshiki, A.
Vasella, Helv. Chim. Acta 2004, 87, 1287.
T. K. M. Shing, Y. Tang, J. Chem. Soc., Chem. Commun.
1990, 312.
T. K. M. Shing, Y. Tang, J. Chem. Soc., Chem. Commun.
1990, 748.
7
8
9
For a recent review on the chemistry of cyclic sulfate, see:
H.-S. Byun, L. He, R. Bittman, Tetrahedron 2000, 56, 7051.
10 B. M. Kim, K. B. Sharpless, Tetrahedron Lett. 1989, 30, 655.
Published on the web (Advance View) December 2, 2006; doi:10.1246/cl.2007.36