Nucleophilic substitutions on Multipin systems linked with a traceless linker

Article abstract of DOI:10.1055/s-1998-1935

The displacement of polymer-supported glucose 7 at the 6-position by azide, iodide, and acetate was achieved through a 4-hydroxybenzenesulfonate-linked Multipin system giving the corresponding glucose derivatives 8 in excellent yields. Macrocyclization of polymer-supported cyanohydrin ether 13 by displacement of the traceless sulfonate linker provided the cyclic compound 14 in moderate yield but in pure form.

Full text of DOI:10.1055/s-1998-1935

November 1998
SYNLETT
1261
TM
Nucleophilic Substitutions on Multipin Systems Linked with a Traceless Linker
Takashi Takahashi,* Satoshi Tomida, Hitoshi Inoue, and Takayuki Doi
Department of Chemical Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, JAPAN
FAX: + 81-3-5734-2884; E-mail: ttakashi@o.cc.titech.ac.jp
Received 17 August 1998
Abstract: The displacement of polymer-supported glucose 7 at the 6-
O
position by azide, iodide, and acetate was achieved through a 4-
hydroxybenzenesulfonate-linked MultipinTM system giving the
RO
9
NH2
OH
corresponding glucose derivatives
8
in excellent yields.
O
SO2
O
d
a, b
O
Macrocyclization of polymer-supported cyanohydrin ether 13 by
displacement of the traceless sulfonate linker provided the cyclic
compound 14 in moderate yield but in pure form.
BnO
BnO
Rink amide
polystyrene
crown
BnO
O
OMe
BnO
BnO
6
1
BnO
OMe
Solid-phase synthesis is gaining prominence in organic chemistry.1 The
choice of linker that connects substrates onto polymers occupies an
important place in designing a synthetic plan for small molecule library
preparation. The linker must provide stability in all reactions in the
synthesis and should be easily cleavable from the solid-support under
mild conditions ideally in each step to confirm its accomplishment.
There are many linkers that are available in the solid phase synthesis
and several traceless linkers on resins have been reported.2-8 We are
interested in a traceless linker that can be displaced with various
nucleophiles introducing new functionalities instead of original one
(Figure 1). We considered that 4-hydroxybenzenesulfonate is an
attractive linker, because a phenol can be used for attaching the linker to
a polymer and a sulfonate can be used for a leaving group in
nucleophilic reactions.7,8 We have reported that the hydroformylation of
1,1-disubstituted alkene linked with this sulfonate linker to MultipinTM
systems proceeds effectively preparing the corresponding aldehyde.9
Herein, we wish to report an efficient substitution of polymer-supported
mono-saccharide and a new cyclization method of polymer-supported
cyanohydrin ether by displacement of the traceless sulfonate linker on
MultipinTM systems.
O
4, R = Me
5, R = H
c
X
N
9
H
O
X-
BnO
BnO
O
SO2
O
BnO
OMe
O
8a, X = N3
8b, X = I
8c, X = OAc
BnO
BnO
BnO
OMe
7
Reagents and Conditions: (a) HO-(p)C6H4-SO2Cl (2), Py,
CHCl3; (b) MeO2C(CH2)9-OH (3), PPh3, DEAD, NEt3, THF; (c)
LiOH, dioxane-H2O (51% in 3 steps); (d) DIC, HOBt, DMF, 24 h.
Scheme 1
results are shown in Table 1. Azidation of 7 with sodium azide smoothly
proceeded in DMF at either 60 °C or 80 °C in 12 h providing azide 8a in
pure form (>95%) (Entries 1 and 2).17 Iodination of 7 with sodium
iodide also efficiently provided iodide 8b in DMF at 80 °C in 24 h
(Entry 6), while lower temperature and shorter reaction time gave low
conversions of the reaction (Entries 3-5). The reaction does not
effectively take place in 2-butanone, which is a good solvent in solution
phase (60 °C, 18 h, 80%) and also reported reaction on resins7 (Entries 7
and 8). The purity of the obtained 8b was >95% analyzed by HPLC.
Entry 9 and 10 show the displacement by an acetate ion. When the
crowns 7 were treated with sodium acetate in the presence of crown
ether in DMF at 80 °C, the reaction was not complete in 24 h (Entries 9
and 10). However, cesium acetate instead of sodium acetate was used
according to Nakata's procedure,18 the reaction was complete within 6 h
to give pure 8c (Entries 11 and 12). It is demonstrated that nucleophilic
additions for polymer-supported mono-saccharide by azide, iodide, and
acetate ions were optimized on crowns giving 6-substituted glucose
derivatives. This method could be used for various functionalized
saccharides and is important from the point of view of preparing an
oligosaccharide library.
4-Hydroxybenzenesulfonate Linker
O
Linker
Compound
O
S
O
O
4-Hydroxybenzenesulfonate Linker
:Nu-
Nucleophilic Addition
Compound
HO
Compound
Nu
Figure 1
Since intramolecular alkylation of cyanohydrin ethers is useful for the
formation of small-, medium-, and large-membered ring ketones,19 the
reaction on solid phase must be attractive in preparing a library of cyclic
ketones if it works using the sulfonate traceless linker.20 Cyanohydrin
ether 10 was prepared from 10-(t-butyldimethylsilyloxy)-3,7-
dimethyldeca-2,6-dienal (9)19a in three steps. Deprotection of TBS
group, followed by sulfonylation with 4-hydroxybenzensulfonyl
chloride (2) gave 11 in 46% overall yield. The phenol 11 was loaded on
trityl linked crowns 1221 to provide sulfonate-supported crowns 13 in
50% yield, which was determined by acid cleavage (10% TFA in
CH2Cl2, 1 h) of 13 from the trityl-crown. The intramolecular alkylation
of 13 in the presence of base was carried out and the results are shown in
Table 2.
Treatment of methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (1)10 with
4-hydroxybenzenesulfonyl chloride (2)11 was followed by Mitsunobu
reaction12 with methyl 10-hydroxydecanoate (3) leading to methyl ester
4, which was hydrolyzed with LiOH giving acid 5 in 51% overall yield.
Acid 5 was attached to Rink amine13 polystyrene crowns 614,15 in the
presence
of
1,3-diisopropylcarbodiimide
(DIC)
and
1-
hydroxybenzotriazole (HOBt) in DMF at 25 °C to provide mono-
saccharide-supported crowns 7 linked with the traceless sulfonate linker
at the 6-position of a glucose.16
Nucleophilic displacement of the mono-saccharide-supported crowns 7
was examined with azide, iodide, and acetate ions, respectively.7 The

1262
LETTERS
SYNLETT
Technologies Pty. Ltd. (Australia) for helpful advice and the supply of
SynphaseTM crowns.
References and Notes
(1) In Combinatorial Chemistry; Wilson, S. R.; Czarnik, A. W., Eds.;
John Wiley: New York, 1997.
(2) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60, 6006.
(3) Hobbs DeWitt, S.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.;
Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 6909.
(4) Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1997, 38, 211.
(5) Brown, A. R.; Rees, D. C.; Rankovic, Z.; Morphy, J. R. J. Am.
Chem. Soc. 1997, 119, 3288 and references cited therein.
(6) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia,
F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.;
Hamel, E. Nature 1997, 387, 268. Pernerstorfer, J.; Schuster, M.;
Blechert, S. Chem. Commun. 1997, 1949. Piscopio, A. D.; Miller,
J. F.; Koch, K. Tetrahedron Lett. 1997, 38, 7143 and references
cited therein.
(7) Hunt, J. A.; Roush, W. R., J. Am. Chem. Soc. 1996, 118, 9998.
(8) Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A.
B. Tetrahedron Lett. 1998, 39, 975. Baxter, E. W.; Rueter, J. K.;
Nortey, S. O.; Reitz, A. B. Tetrahedron Lett. 1998, 39, 979.
Zhong, H. M.; Greco, M. N.; Maryanoff, B. E. J. Org. Chem.
1997, 62, 9326.
Scheme 2
Treatment of crowns 13 with lithium hexamethyldisilazide as a base,22
the desired cyclization proceeded in THF providing 14 in 20-24% yields
(Entries 1 and 2). The isolated yield was increased up to 46% when the
reactions were carried out in refluxing dioxane (Entries 3-5).23 A mixed
solvent (toluene : dioxane = 1 : 3) did not affect the yield (Entries 6 and
7). The reaction did not proceed in the presence of non-soluble base,
such as NaH and KH (Entries 8 and 9). Although the yield is moderate,
it should be noted that the product obtained is enough pure after a
simple work-up procedure. We have already reported that 14 is easily
converted to cyclic ketone 15.19a
(9) Takahashi, T.; Ebata, S.; Doi, T. Tetrahedron Lett. 1998, 39,
1369.
(10) Tatsuta, K.; Fujimoto, K.; Kinoshita, M. Carbohyd. Res. 1977, 54,
85.
(11) Campbell, R. W.; Hill, H. W., Jr. J. Org. Chem. 1973, 38, 1047.
(12) Mitsunobu, O. Synthesis 1981, 1. Hughes, D. L. Org. React. 1992,
42, 335.
In conclusion, we have demonstrated a 4-hydroxybenzenesulfonate
linker is a useful traceless linker linked with crowns in various
substituted reactions. Displacement of mono-saccharide by azide,
iodide, and acetate ions gave 6-functionalized sugar derivatives.
Intramolecular cyanohydrin alkylation on the MultipinTM system also
provides a cyclic ketone isolated in pure form.
(13) Rink, H. Tetrahedron Lett. 1987, 28, 3787.
(14) Rink amine crowns were prepared from Fmoc-NH-Rink-
Polystyrene crowns by treatment with 20% piperidine in DMF for
20 min before use. Batch no. 491-13, Loading = 2.0 µmol per
crown, Chiron Technologies Pty. Ltd., 11 Duerdin St., Clayton,
Victoria 3168, Australia.
(15) The MultipinTM system has been successfully used in the
synthesis of a chemical library. See, Valerio, R. M.; Bray, A. M.;
Maeji, N. J. Int. J. Peptide Protein Res. 1994, 44, 158. Virgilio, A.
A.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116, 11580. Valerio, R.
M.; Bray, A. M.; Patsiouras, H. Tetrahedron Lett. 1996, 37, 3019.
Acknowledgment: This work was supported by a Grant-in-Aid for
JSPS Fellows (S.T., No. 5167) from the Ministry of Education, Science,
Sports and Culture, Japan. We gratefully acknowledge Chiron

November 1998
SYNLETT
1263
Rodebaugh, R.; Joshi, S.; Fraser-Reid, B.; Geysen, H. M. J. Org.
Lett. 1981, 22, 1359. (c) Stork, G.; Depezay, J. C.; d’Angelo, J.
Tetrahedron Lett. 1975, 389.
Chem. 1997, 62, 5660.
(20) Solid phase syntheses of cyclic compounds through C-C bond
formation. Wittig reaction; see: Nicolaou, K. C.; Pastor, J.;
Winssinger, N.; Murphy, F. J. Am. Chem. Soc. 1998, 120, 5132.
Metathesis; see: Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J.
Am. Chem. Soc. 1996, 118, 9606 and ref 6.
(16) Complete conversion was detected by a color test (negative result)
with a solution of trinitrobenzenesulfonic acid in DMF : DIEA =
10 : 1 in a few minutes.
(17) After the reaction, the crowns were washed several times and
treated under acid cleavage conditions to observe whether the
starting material is recovered. The conversion was determined by
HPLC with integration of peak area (UV, 260 nm) of the
recovered material comparing with that of an authentic sample in
a certain concentration.
(21) Trityl chloride crowns were prepared from trityl alcohol crowns
with acetyl chloride before use. HOC(Ph)2C6H4CONHCH2-
Polystyrene, Batch no. 799-19, Loading = 9.3 µmol per crown.
See ref 9.
(22) The intramolecular alkylation of trityl protected derivative of 11
in solution phase (LiHMDS, THF, 60 °C) gave the desired 10-
membered ring compound 14 in 76% yield.
(18) Shimizu, T.; Hiranuma, S.; Nakata, T. Tetrahedron Lett. 1996, 37,
6145.
(19) For intramolecular alkylation of cyanohydrin ethers: see, (a)
Takahashi, T.; Nemoto, H.; Tsuji, J. Tetrahedron Lett. 1983, 24,
2005. (b) Takahashi, T.; Nagashima, T.; Tsuji, J. Tetrahedron
(23) After the reaction, the crowns were washed several times and
treated with 10% TFA in CH2Cl2 for 20 min. None of the starting
material was observed in HPLC analyses except Entries 8 and 9.