Syntheses of GM4 and GM3 Intermediates via Alkylation and Subsequent Intramolecular Glycosidation of 2-Alkoxy-2-phenylthioacetate

Article abstract of DOI:10.1021/ol990245k

(Matrix presented) We developed a new method for α-glycoside formation of sialyl conjugates based on alkylation and subsequent intramolecular glycosidation of 2-alkoxy-2-phenylthioacetate. By this method we succeeded in the syntheses of G_M4 and

Full text of DOI:10.1021/ol990245k

ORGANIC
LETTERS
1
999
Vol. 1, No. 12
885-1887
Syntheses of G and G Intermediates
via Alkylation and Subsequent
Intramolecular Glycosidation of
M4
M3
1
2-Alkoxy-2-phenylthioacetate
Takashi Takahashi,* Hirokazu Tsukamoto, and Haruo Yamada
Department of Chemical Engineering, Tokyo Institute of Technology, Meguro,
Tokyo 152-8552, Japan
ttakashi@o.cc.titech.ac.jp
Received August 23, 1999
ABSTRACT
We developed a new method for r-glycoside formation of sialyl conjugates based on alkylation and subsequent intramolecular glycosidation
of 2-alkoxy-2-phenylthioacetate. By this method we succeeded in the syntheses of GM4 and GM3 intermediates.
N-Acetylneuraminic acid (Neu5Ac; sialic acid) is located at
the nonreducing terminal position of glycoproteins, ganglio-
sides, and oligosaccharides, which are found on cell mem-
branes and in the nervous systems of various living organ-
1
isms. These sialyl conjugates play an essential role in
biological molecular recognition processes, such as cell
2
adhesion and differentiation phenomena. Recently, syntheses
of sialyl conjugates have been undertaken to elucidate their
biological properties and functions. One of the most difficult
problems in the synthesis of sialyl conjugates is the stereo-
selective glycosidation of sialic acid to afford the R-glyco-
3
sidic linkage. Here we report a new method for R-glycoside
formation of sialyl conjugates based on alkylation of sugar-
derived 2-alkoxy-2-phenylthioacetate anion 3 with bromide
4
2
and subsequent intramolecular glycosidation (Figure 1).
We also demonstrate the usefulness of this method by the
syntheses of GM4 and GM3 intermediates.
Figure 1. Retrosyntheses of GM4 and GM3 intermediates.
(
1) Gottschalk, A. Nature 1951, 167, 845.
In our key intermediate, the anion 3 can be taken as “an
anion equivalent of oxonium ion” as shown 4. The phenylthio
(2) Suzuki, Y.; Nagano, Y.; Kato, H.; Matsumoto, M.; Nerome, K.;
Nakajima, K.; Nobusawa, E. J. Biol. Chem. 1986, 261, 17057.
1
0.1021/ol990245k CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

group in 3 serves as not only a stabilizer of an enolate in
the alkylation but also as a leaving group in the glycosidation.
Stereoselective formation of the R-glycosidic linkage in the
sialic acid would result from the approach of bromide 2 from
the convex face of cis-fused lactone 3 and subsequent attack
Intramolecular glycosidation of 11a was carried out with
3i
3d
3d
various reagents (MeSOTf/DTBP, DMTST, NIS/TfOH,
3
j
and PhSOTf/DTBP ) to give 12a and 13a in 66-89%
combined yield (Scheme 2). The best stereoselectivity (4.0:
of hydroxyl group at C-6′ via intramolecular S
substitution reaction. The viability of the key intermediate
N
2-type
5
Scheme 2. Intramolecular Glycosidation of
2-Alkoxy-2-phenylthioacetates 11a and 11b and Transformation
of Glycosides 12a and 12b into Acetyl Derivatives of
N-Acetylneuraminic Acida
3
was first demonstrated in the synthesis of GM4 intermediate.
Treatment of the dibutylstannylene derivative of benzyl
,6-di-O-benzyl-â-D-galactopyranoside (5a) with tetrabu-
6
2
tylammonium bromide and isopropyl 2-chloro-2-phenyl-
thioacetate, prepared from isopropyl 2-phenylthioacetate and
N-chlorosuccinimide, gave 2-alkoxy-2-phenylthioacetates 6a
and 7a as a 5:1 mixture in 83% yield. After separation of
the diastereoisomers on silica gel, their stereochemistry was
7
determined by NOE experiments as shown in Scheme 1.
Scheme 1. Preparation and Alkylation of
2
-Alkoxy-2-phenylthioacetatesa
a
2 2
(a) PhSOTf, DTBP, MS-4A, CH Cl , 79% for 12a and 13a
(
12a:13a ) 4.0:1), 81% for 12b and 13b (12b:13b ) 2.8:1); (b)
catalytic RuCl O, NaIO O (3:3:1), 87%
for 14a, 41% for 14b; (c) (1) Tf
8-crown-6, PhMe-DMF (3:1) 80 °C and then aqueous NaHCO
3
‚H
2
4
, EtOAc-CH
3
CN-H
Cl , (2) CsOCOCF
2
2
O, Py, CH
2
2
3
,
,
1
3
MeOH, 2 steps, 70% for 15a, 50% for 15b; (d) TESCl, imidazole,
CH Cl , 64% for 16a, 36% for 16b; (e) (1) Tf O, Py, CH Cl , (2)
Bu NN , PhH, 2 steps, 80% for 17a, 75% for 17b; (f) CF CO H,
MeOH, 68% for 18a, 80% for 18b; (g) (1) 5% Pd-CaCO , H
EtOH, (2) Ac O, Py, catalytic DMAP, CH Cl , 2 steps, 68% for
9a, 83% for 19b; (h) DBU, CH Cl , 50% for 19a and 63% for
9b.
2
2
2
2
2
4
3
3
2
3
2
,
2
2
2
a
(
a)Bu
NBr, reflux, 83% for 6a and 7a (6a:7a ) 5.0:1), 63% for 6b
and 7b (6b:7b ) 2.9:1); (b) CBr , PPh , CH Cl , and then ethyl
2 2
SnO,PhMe,reflux,andthen3equivof(PhS)ClCHCO iPr,
1
1
2
2
Bu
4
4
3
2
2
vinyl ether, 80%; (c) 6a or 6b, LDA, THF-HMPA, 80% for 10a,
8% for 10b; (d) catalytic PPTS, EtOH, 76% for 11a, 77% for
1b.
6
1
1
2
) was obtained when phenylsulfenyl triflate (PhSOTf) and
,6-di-tert-butylpyridine (DTBP) were used as an activator
for the phenylthio group. When only PhSOTf was used, the
stereoselectivity was lowered to 2.0:1. However, the stere-
ochemistry of each compound could not be determined at
this stage, so the major compound 12a was transformed into
the acetyl derivative of N-acetylneuraminic acid 19a.
Bromide 9 is obtained by selective bromination of the
primary alcohol in 8 and protection of the allylic alcohol
with ethyl vinyl ether in 80% yield.
4
Alkylation of 9 with 2-alkoxy-2-phenylthioacetate 6a was
carried out as follows. After treatment of 6a with LDA in
THF at -78 °C followed by addition of bromide 9 and
HMPA, the reaction mixture was stirred at -40 °C for 30
min to give alkylated product 10a in 80% yield. Removal
of the ethoxyethyl group gave alcohol 11a as a single
diastereomer whose stereogenic center was determined by
NOE between the 4′-vinyl proton and the proton at C-4 of
Dihydroxylation of the olefin in 12a with RuCl
3
‚H
2
O-
9
NaIO
4
1
afforded diol 14a as a single diastereomer in 70%
0
yield. Inversion of configuration of the 4′,5′-diol in 14a,
11
according to Sato’s procedure, gave diol 15a in 70% yield.
Selective protection of an equatorial hydroxyl group with a
triethylsilyl group afforded alcohol 16a in 64% yield.
Transformation of an axial hydroxyl group into triflate and
subsequent treatment with tetrabutylammonium azide intro-
duced an azido group at C-5′ with inversion of configuration.
8
galactoside. This showed that electrophile 9 was attacked
from the convex face of 6a.
1886
Org. Lett., Vol. 1, No. 12, 1999

Removal of the 8′,9′-O-isopropylidene protecting group, the
′-O-methoxymethyl group, and the 4′-O-triethylsilyl group
in 17a was achieved with trifluoroacetic acid in methanol
to give 18a in 68% yield. Reduction of the azide group to
amine followed by acetylation of the amine and all hydroxyl
groups afforded 19a in 68% yield from 18a. Spectral data
7
1
13
D
([R] , IR, H NMR, C NMR, and MS) of 19a were in good
(
3) (a) Okamoto, K.; Goto, T. Tetrahedron 1990, 46, 5835. (b) DeNinno,
agreement with those of an authentic sample obtained by
M. P. Synthesis 1991, 583. (c) Ito, Y.; Gaudino, J. J.; Paulson, J. C. Pure
Appl. Chem. 1993, 65, 753. (d) Hasegawa, A.; Nagahama, T.; Ohki, H.;
Hotta, K.; Ishida, H.; Kiso, M. J. Carbohydr. Chem. 1991, 10, 493. (e)
Marra, A.; Sinay, P. Carbohydr. Res. 1990, 195, 303. (f) Birberg, W.; Lohn,
H. Tetrahedron Lett. 1991, 32, 7453. (g) Birberg, W.; Lohn, H. Tetrahedron
Lett. 1991, 32, 7457. (h) Lohn, H.; Stenvall, K. Tetrahedron Lett. 1992,
6b,c,1212-13
DBU treatment of R-glycoside 20a.
We confirmed
that the major glycoside 12a in the intramolecular glycosi-
dation was the desired R-glycoside.
In addition, we applied this method to the synthesis of
the GM3 intermediate by employing benzyl 2,3,6-tri-O-
benzyl-O-[2,6-di-O-benzyl-â-D-galactopyranosyl]-â-D-glu-
3
3, 115. (i) Liebe, B.; Kunz, H. Tetrahedron Lett. 1994, 35, 8777. (j)
Martichonok, V.; Whitesides, G. M. J. Org. Chem. 1996, 61, 1702. (k)
Martin, T. J.; Schmidt, R. R. Tetrahedron Lett. 1992, 33, 6123. (l) Kondo,
S.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem. Soc. 1992, 114, 8748. (m)
Sim, M. M.; Kondo, H.; Wong, C.-H. J. Am. Chem. Soc. 1993, 115, 2260.
1
3
copyranoside (5b) as the starting compound.
Alkylation and subsequent intramolecular glycosidation of
(
n) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 6221. (o) Ito, Y.; Ogawa,
2
-alkoxy-2-phenylthioacetate are useful for construction of
T. Tetrahedron 1990, 46, 89. (p) Wang, Z.-G.; Zhang, X.-F.; Ito, Y.;
Nakahara, Y.; Ogawa, T. Bioorg. Med. Chem. 1996, 4, 1901. (q) Kononov,
L. O.; Ito, Y.; Ogawa, T. Tetrahedron Lett. 1997, 38, 1599. (r) Kondo, T.;
Abe, H.; Goto, T. Chem. Lett. 1988, 1657. (s) Ercegovic, T.; Magnusson,
G. J. Chem. Soc., Chem. Commun. 1994, 831. (t) Ercegovic, T.; Magnusson,
G. J. Org. Chem. 1995, 60, 3378. (u) Martichonok, V.; Whitesides, G. M.
Carbohydr. Res. 1997, 302, 123. (v) Martichonok, V.; Whitesides, G. M.
J. Am. Chem. Soc. 1996, 118, 8187. (w) Castro-Palomino, J. C.; Tsvetkov,
Y. E.; Schmidt, R. R. J. Am. Chem. Soc. 1998, 120, 5434.
the R-glycoside linkage of N-acetylneuraminic acid. GM4
intermediate 19a is an important compound for the synthesis
of many gangliosides. Furthermore, the R-glycosides 12a and
12b are efficient intermediates for various derivatives of sialic
acid. Further studies on the syntheses of N-acetylneuraminic
acid conjugates utilizing 2-alkoxy-2-phenylthioacetate are
underway in our laboratory.
(4) Bromide 2 was previously used in the synthesis of N-acetylneuraminic
acid via alkylation of 2-alkoxy-2-cyanoacetate anion in our laboratory.
Takahashi, T.; Tsukamoto, H.; Kurosaki, M.; Yamada, H. Synlett 1997,
Supporting Information Available: Experimental pro-
cedures for preparation of compounds 6, 10, 11, and 12 and
characterization data for 6, 7, 10, 11, 12, 13, and 19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
065.
(5) (a) Mukaiyama, T.; Sugaya, T.; Marui, S.; Nakatsuka, T. Chem. Lett.
1
982, 1555. (b) Hindsgaul, O.; McAuliffe, J. C. J. Org. Chem. 1997, 62,
1
234. (c) McAuliffe, J. C.; Hindsgaul, O. Synlett 1998, 307.
(
6) (a) Liptak, A.; Janossy, L.; Imre, J.; Nanashi, P. Acta Chim. Acad.
Sci. Hung. 1979, 101, 81. (b) Ogawa, T.; Sugimoto, M. Carbohydr. Res.
985, 135, C5. (c) Numata, M.; Sugimoto, M.; Koike, K.; Ogawa, T.
Carbohydr. Res. 1987, 163, 209.
7) 12% NOE for 6a, 7% NOE for 7a, 4% NOE for 6b, and 6% NOE
for 7b were observed.
1
OL990245K
(
(11) (a) Sato, K.; Yoshitomo, A. Chem. Lett. 1995, 39. (b) Sato, K.;
Yoshitomo, A.; Takai, Y. Bull. Chem. Soc. Jpn. 1997, 70, 885.
(12) Marra, A.; Sinay, P. Gazz. Chim. Ital. 1987, 117, 563.
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K.; Sugimoto, M.; Sato, S.; Ito, Y.; Nakahara, Y.; Ogawa, T. Carbohydr.
Res. 1987, 163, 189.
(
(
8) 5% NOE for 11a and 3% NOE for 11b were observed.
9) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H. F.;
Jiang, Q. Chem. Eur. J. 1996, 2, 50.
10) Stereochemisrty of 14a was determined with coupling constants (8.1
Hz) between 5′-H and 6′-H of diacetylated compound of 14a.
(
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