Solid phase synthesis of 3-toluenesulfonylglutarimides

Article abstract of DOI:10.1002/jccs.200300111

A novel route for the synthesis of 3-toluenesulfonylglutarimides on a solid support is described. The cyclization step involves stepwise [3+3] strategy of Rink Amide resin bound onto an α-toluenesulfonyl group with various α,β-unsaturated esters.

Full text of DOI:10.1002/jccs.200300111

Journal of the Chinese Chemical Society, 2003, 50, 795-797
795
Communication
Solid Phase Synthesis of 3-Toluenesulfonylglutarimides
Meng-Yang Changa* (
Shui-Tein Chenb* (
), Kuo-Ging Linb (
),
) and Nein-Chen Changc* (
)
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, R.O.C.
bInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, R.O.C.
cDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.
A novel route for the synthesis of 3-toluenesulfonylglutarimides on a solid support is described. The
cyclization step involves stepwise [3+3] strategy of Rink Amide resin bound onto an a-toluenesulfonyl group
with various a,b-unsaturated esters.
Keywords: Solid-phase reaction; Stepwise [3+3] strategy; Rink Amide resin; Glutarimides; Thalid-
omide.
INTRODUCTION
Solid-phase combinatorial and parallel synthesis meth-
pared in two steps from the substitution of a-bromo t-butyl-
acetate with 4-toluenesulfinic acid sodium salt in a solution
mixture of water and 1,4-dioxane (reflux, 10 h) and the hy-
drolysis of the corresponding a-toluenesulfonyl t-butyl ester
using trifluoroacetic acid (rt, 5 h). The synthetic scheme
adopted for the solid-phase synthesis is illustrated in Scheme I.
ods have become a major tool for preparing small organic
molecule libraries to discover new lead compounds in the
pharmaceutical industry. A number of pharmaceutically use-
ful heterocyclic compounds have been prepared recently by
this solid phase methodology.1 Here, we use a solid-phase re-
action strategy to attach the a-toluenesulfonylacetic acid
onto Rink Amide resin2 for reaction with various a,b-unsatu-
rated esters having various a-substituents (R1) or b-substitu-
ents (R2) to yield diverse substituents on the 3-toluenesulfo-
nylglutarimides skeleton.
Scheme I Solid phase synthesis of 3-toluenesulfonyl-
glutarimides 1
O
O
S
1) 20% piperidine
NHFmoc
N
Tol
H
2) PyBOP, NMM,
TolSO2CH2COOH (2)
O
A
B
Glutarimides possess various biological activities,3
therefore, the synthesis of these cyclic imides have attracted
considerable attention.4-5 Glutarimides are in most cases ob-
tained by heating d-dinitriles via cyclization in an acidic solu-
tion4b or by cyclization of monoamides with acid in the pres-
ence of thionyl chloride4e or BOP.4d Due to the harsh classical
conditions, some milder methods have been proposed, such
as the condensation of a diacidic compound with amine.4a,g-i
Recently, we have developed an efficient synthesis for un-
symmetrical glutarimides with a toluenesulfonyl group at the
3-position and have proposed its applications for clinical
drugs and the mechanism of this reaction.5 These 3-toluene-
sulfonylglutarimides 1 can be prepared by known procedures
in the solution phase.5
NaH,
a,b-unsaturated ester 3a-3i
R1=H, R2=H, CH3, C10H21, (CH2)5OH,
N-Bn-piperidine-4-CH2CH2, 4-ClC6H4;
R2=H, R1=CH3, C6H5, phthalimide
CO2Et
3a-3i
R2
R1
O
O
S
O
O
Tol
O
S
Tol
O
95% TFA,
HN
N
3
4
5
2.5% H2O, 2.5% TIS
O
R2
O
R2
R1
R1
1
C
Fmoc groups on the resin A were deprotected by 20%
piperidine/DMF (rt, 20 min) to provide free amine groups on
the Rink Amide resin in DMF. The loading of a-toluene-
sulfonylacetic acid onto the resin was achieved completely in
situ with PyBOP6 and N-methylmophorine (NMM) in DMF
(0.4 M, rt, 20 min). When the synthesis of the desired resin B
with the a-toluenesulfonylacetamide group was finished, as
RESULTS AND DISCUSSION
The attached a-toluenesulfonylacetic acid 2 was pre-

796 J. Chin. Chem. Soc., Vol. 50, No. 4, 2003
Chang et al.
CONCLUSION
Table 1. Facile Annulation of Resin B with Various a,b-
Unsaturated Esters 3a-ia-b
In conclusion, we explored a facile stepwise [3+3] solid
phase strategy that is synthetically useful for constructing 4-
or 5-substituted 3-toluenesulfonylglutarimides. The proce-
dure provided an efficient improvement over existing solu-
tion-phase methods for the high-throughput combinatorial
synthesis, but the overall efficiency of this methodology only
turned out to be a quite moderate yield on a small scale. The
scale-up of the cycloaddition reaction to 0.5 mmole or greater
creates many other complex products in disproportionate ra-
tios, thus making it difficult to efficiently synthesize various
glutarimides in large quantities. This solid phase strategy was
used in a new synthetic method for thalidomide. We are cur-
rently studying the scope of this methodology for the synthe-
sis of alkaloid analogs.
No.
1
R1, R2
Yielda
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H, H
H, CH3
H, C10H21
H, (CH2)5OH
66
56
53
43
50
45
59
41
32
H, N-Bn-piperidine-4-CH2CH2
H, 4-ClC6H4
CH3, H
C6H5, H
phthalimide, H
a The yields of isolated products based on the initial loading of
the resin.
b Each product showed satisfactory 1H NMR and MS data.
determined by the ninhydrin test, deprotonation using so-
dium hydride in anhydrous THF led to the dianions interme-
diate state (rt~67 °C, 1~5 h). Stepwise [3+3] reactions of the
resulting dianions with various a,b-unsaturated esters 3 pro-
ceeded to yield diverse substituents on the a-toluenesulfo-
nylglutarimide skeleton C. Presumably, the reaction pro-
ceeded by 1,4-addition and intramolecular ring-closure to
yield the cyclized six-member glutarimide ring.
ACKNOWLEDGEMENT
The authors thank the National Science Council of the
Republic of China for financial support.
Received May 21, 2003.
Finally, cleavage of a-toluenesulfonylglutarimides 1
from the resin was carried out with 95% trifluoroacetic acid
(TFA), 2.5% triisopropylsilane (TIS) and 2.5% water (ice
bath, 1 h). As summarized in Table 1, various functional alkyl
or aryl substitutents on a-toluenesulfonylglutarimides 1 were
produced in moderate yields using this protocol. The reac-
tions yielded purified products in the range of 32~66%.7
More significantly, the stereochemistry of compounds 1 at
C-3 and C-4 retained its trans form (reactions No. 2~6) and at
the relative positions of C-3 and C-5 (reactions 7~9) main-
tained the mixed isomer forms. It is a short, simple, efficient
and reproducible solid-state approach for synthesizing vari-
ous glutarimides.
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Solid Phase Synthesis of 3-Toluenesulfonylglutarimides
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to the suspension of the resulting resin in DMF (3 mL) at rt.
After stirring 20 min the coupling was completed by negative
ninhydride test. The resin was filtered, washed with CH2Cl2,
MeOH and THF, and dried under reduced pressure. Sodium
hydride (60%, 40 mg, 1.0 mmol) was added to a suspension
of the resin in THF (10 mL) at rt for 5 min then ethyl acrylate
(50 mg, 0.5 mmol) was added. After stirring 2 h at rt, the re-
action mixture was quenched with NH4Cl(aq) solution (0.5
mL), filtered, washed with THF (2 ´ 10 mL). A 95%
TFA/2.5% TIS/2.5% water solution (10 mL) was added to
the resulting resin at ice bath temperature for 1 h. The reac-
tion mixture was then concentrated under reduced pressure.
The resulting resin was washed well with MeOH or CH2Cl2.
The filtrate was evaporated under reduced pressure and puri-
fied on silica gel (hexane/ethyl acetate = 4/1~2/1) to produce
o
product 1a (22 mg, 0.08 mmol, 66%): mp = 166-168 C;
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1
268 (M++1, 1); H NMR (400 MHz, CDCl3): d 8.06 (br s,
1H), 7.75 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 4.00
(dd, J = 3.4, 5.7 Hz, 1H), 3.18-3.10 (m, 1H), 2.86-2.81 (m,
1H), 2.70-2.64 (m, 1H), 2.45 (s, 3H), 2.40-2.32 (m, 1H); 13C
NMR (100 MHz, CDCl3): d 170.84, 164.64, 146.06, 134.74,
130.01 (2´), 129.15 (2´), 64.85, 28.47, 21.80, 18.87.
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7. Typical experimental procedure for preparation of 1a: 4-
(2¢,4¢-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin
(Rink amide resin) (loading 0.62 mmole/g, 0.2 g, 0.124
mmol) was suspended in 20% piperidine/DMF (2 ´ 3 mL).
The mixture was stirred for 20 min then filtered. The resin
was washed with DMF (2 ´ 5 mL) and this step was repeated
once. A 0.4 M NMM/DMF solution (1 mL) of acid 2 (107
mg, 0.5 mmol) and PyBOP (260 mg, 0.5 mmol) were added