Synthesis and properties of a new SASRIN resin derivative: SASRIN-2-pyridylthiocarbonate (SASRIN-TOPCAT) resin

Article abstract of DOI:10.1016/j.tetlet.2008.03.017

A new SASRIN resin derivative, SASRIN-TOPCAT resin, was synthesized by the reaction of SASRIN resin with 2-thiopyridyl chloroformate. The new resin can be used for the loading of alcohols and thiols under neutral conditions, and the release of alcohol from the resin is achieved by the treatment of 1% TFA in CH₂Cl₂ for 15-60 min. Compared to the other reported resins, SASRIN-TOPCAT resin is more suitable for the loading of alcohols in solid-phase organic synthesis.

Full text of DOI:10.1016/j.tetlet.2008.03.017

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2951–2955
Synthesis and properties of a new SASRIN resin derivative:
SASRIN–2-pyridylthiocarbonate (SASRIN–TOPCAT) resin
Peng Zhao, Zhen-Jun Yang, Liang-Ren Zhang, Li-He Zhang *
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
Received 2 February 2008; revised 3 March 2008; accepted 4 March 2008
Available online 8 March 2008
Abstract
A new SASRIN resin derivative, SASRIN–TOPCAT resin, was synthesized by the reaction of SASRIN resin with 2-thiopyridyl chlo-
roformate. The new resin can be used for the loading of alcohols and thiols under neutral conditions, and the release of alcohol from the
resin is achieved by the treatment of 1% TFA in CH2Cl2 for 15–60 min. Compared to the other reported resins, SASRIN–TOPCAT resin
is more suitable for the loading of alcohols in solid-phase organic synthesis.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: SASRIN resin derivative; Etherification; Solid-phase organic synthesis
Resins bearing alcohols are widely used as building
blocks in solid-phase organic synthesis (SPOS). The success
of solid-phase reactions with resin bearing alcohols has
generated a tremendous interest in expanding the applica-
tions of combinatorial synthesis.1 In general, the construc-
tion of an ether linkage of alcohols to the solid support is
more synthetically challenged. Etherification usually
requires harsh reagents and conditions, such as strong
bases and acids. However, for the synthesis of compounds
containing multi-functional or acid-sensitive groups by
SPOS, immobilization of alcohol substrates on the solid
support should be reacted under neutral conditions, and
the cleavage of the ether linkage for the release of products
from resin is preferred by using mild acidic reagents. Many
types of resin, such as Wang resin2 and dihydropyranyl
(DHP) resin,3 have been used for the alcohol loading under
mild conditions based on their acid-sensitive ether linker.
Hanessian introduced Wang-trichloroacetimidate resin4
and Wang-2-pyridylthiocarbonate (Wang-TOPCAT) resin5
for the preparation of the resin bearing alcohols under
weak acidic and neutral conditions, respectively. They also
described that alcohols could be released from Wang resin
with 1–10% TFA in CH2Cl2. However, the reports from
the same group and other research groups6 noted that
the cleavage of ether linker on Wang resin was always per-
formed under 10–95% TFA in CH2Cl2. 2-Cl–Trityl resin is
another acid-sensitive resin derivative, which has been used
widely for loading the alcohol under mild conditions, and
the cleavage of the ether linkage is completed with 1%
TFA in CH2Cl2.7 However, 2-Cl–trityl resin is very temper-
ature- and moisture-sensitive and usually stored in a refrig-
erator before use, which leads to the variable results in its
application. In addition, 2-Cl–trityl resin contains a bulky
group and can only be used to anchor the primary hydro-
xyl group. It was reported that Fmoc-threoninol(tBu)
reacted with 2-Cl–trityl resin, giving an initial loading of
1.39 mmol/g with the production of a substitution level
of 0.15 mmol/g after 22 h and only in a yield of 14.6%.8
SASRINÒ (Super Acid Sensitive Resin) resin is a very
acid-sensitive resin and was first developed by Merger
et al.9 SASRIN resin and its derivatives have been widely
used in solid-phase peptide synthesis, and the release of
the peptide from the resin can be achieved by 1% TFA in
CH2Cl2 for 10 min.10 SASRIN resin has a similar structure
*
Corresponding author. Tel.: +86 10 82801700; fax: +86 10 82802724.
E-mail address: zdszlh@bjmu.edu.cn (L.-H. Zhang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.017

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P. Zhao et al. / Tetrahedron Letters 49 (2008) 2951–2955
with Wang resin, except of an o-methoxyl group in SAS-
RIN resin. The application of SASRIN–chloride resin to
anchor thiols was described;11 however, to the best of our
knowledge, there is no report on the application of SAS-
RIN resin for loading the alcohols. For the development
of SPOS, we report here a new SASRIN resin derivative,
SASRIN–TOPCAT resin, used for the loading of various
alcohols, and the data compared to the known Wang-tri-
chloroacetimidate resin and SASRIN–chloride resin are
also discussed (Fig. 1).
The etherification of some SASRIN resin derivatives
with alcohol was investigated first. SASRIN–bromide resin
was prepared according to the literature.12 Alcohol 7 was
immobilized on it in the presence of NaH, and alcohol 7
was released from the resin by the treatment of 1% TFA
in CH2Cl2 in 84.9% yield. These results indicated that
despite the strong basic conditions for loading, the ether
linkage on SASRIN resin can be cleaved under mild condi-
tions. It promoted us to find more mild conditions for the
alcohol loading to SASRIN resin. Similar to Wang-trichlo-
roacetimidate resin, SASRIN resin reacted with CCl3CN in
the presence of DBU to give SASRIN–trichloroacetimidate
resin rapidly and completely. But in the presence of
BF3ÁEt2O as a catalyst, alcohols were anchored on SAS-
RIN–trichloroacetimidate resin only in poor yield. After
careful examination of the anchoring procedure, it was
revealed that BF3ÁEt2O could cause partial cleavage of
SASRIN–ether linkage even at 0.05 equiv (Scheme 1).
To make the etherification under mild conditions and
increase the acid sensitivity of the ether linkage on solid
support, SASRIN–2-pyridylthiocarbonate (SASRIN–
TOPCAT) resin was prepared according the procedure
for the modification of Wang resin. The synthesis of SAS-
RIN–TOPCAT resin from SASRIN resin with di-(2-pyri-
dyl)thiocarbonate under different conditions was
investigated, but SASRIN resin was transformed to SAS-
RIN–TOPCAT resin in very poor yield. It was reported
that 2-thiopyridyl chloroformate13 is a more reactive
reagent than di-(2-pyridyl)thiocarbonate. Therefore, 2-
thiopyridyl chloroformate was reacted with SASRIN resin
in the presence of DMAP to give SASRIN–TOPCAT resin
successfully. The immobilization of alcohols on SASRIN–
TOPCAT resin with AgOTf as a catalyst afforded the
moderate yields of resin bearing alcohols (Scheme 2).14
The loading of various alcohols and thiols on SASRIN–
TOPCAT resin is summarized in Table 1.
In our case, the loading of alcohols and thiols to SAS-
RIN–TOPCAT resin was completed in 1–8 h, and the
cleavage of the SASRIN–ether linkage and the release of
corresponding alcohols were completed efficiently by stir-
OMe
OMe
O
O
O
OH
OH
Cl
Wang Resin
OMe
SASRIN Resin
SASRIN-Chloride Resin
OMe
OMe
NH
O
O
O
O
Br
O
O
CCl3
S
N
SASRIN-Bromide Resin
SASRIN-Trichloroacetimidate Resin
SASRIN-TOPCAT Resin
Fig. 1. Structure of Wang resin, SASRIN resin and four SASRIN resin derivatives.
BnO
N3
a
b
O
Br
BnO
N3
O
O
OH
OMe
OMe
R7
SASRIN-Bromide resin
7
OMe
OMe
OMe
NH
CCl3
SASRIN-Trichloroacetimidate resin
c
d
O
O
O
OH
O
OR
SASRIN resin
Scheme 1. Alcohol’s immobilization on SASRIN–bromide resin and SASRIN–trichloroacetimidate resin. Reagents and conditions: (a) compound 7,
NaH, DMF; (b) 1% TFA/CH2Cl2 (5% Et3SiH was added as scavenger); (c) CCl3CN, DBU, DCM; (d) ROH, BF3ÁEt2O, DCM.

P. Zhao et al. / Tetrahedron Letters 49 (2008) 2951–2955
2953
OMe
OMe
O
O
a
b
c
O
O
Triphosgene
+
O
S
XR
N
S
Cl
N
SH
N
SASRIN-TOPCAT resin
X=O, S
Scheme 2. Preparation of SASRIN–TOPCAT resin and alcohol’s immobilization. Reagents and conditions: (a) Et3N, PhCH3, DCM; (b) SASRIN resin,
DMAP, Et3N, DCM; (c) RXH (X = O, S), AgOTf, DCM.
Table 1
Polymer-bound alcohols and thiols on SASRIN–TOPCAT resin
Alcohols
and thiols
Resins
Substitution
level (yield)
Substitution level on Wang-trichloroacetimidate
resin or SASRIN–chloride resin (yield)c
OH
O
0.33 (56.9%)a
0.45 (64.3%)c
COOAll
COOAll
FmocHN
FmocHN
FmocHN
1
2
R1
O
OH
FmocHN
0.41 (68.3%)a
0.52 (86.7%)a
N.A. (N.A.)e
R2
FmocHN
FmocHN
SH
S
0.4–0.8 (N.A.)d
3
R3
O
O
S
FmocHN
FmocHN
OtBu
SH
OtBu
0.44 (78.6%)a
N.A. (32.6%)b
N.A. (27.9%)b
0.3–0.6 (N.A.)d
N.A. (N.A.)
N.A. (N.A.)
R4
4
OH
O
O
O
BnO
BnO
BnO
BnO
OBn
OBn
OMe
OMe
5
R5
OBn
OBn
O
O
O
HO
BnO
BnO
OBn
OMe
OBn
OMe
6
R6
BnO
BnO
N3
BnO
N3
N.A. (62.6%)b
N.A. (60.2%)b
N.A. (N.A.)
N.A. (N.A.)
O
OH
7
R7
OAc
BnO
OAc
O
OH
8
R8
a
Substitution level was determined by the method of Meienhofer through spectrophotometric detection of dibenzofulvene released from SASRIN resin
aliquots and was expressed in millimole substrate per gram polystyrene.18 Yield was based on the percent of maximal theoretical substitution.
b
Yield was determined by the method reported by Hanessian and Xie.4
c
Substitution was performed on Wang-trichloroacetimidate resin and data were adapted directly from the literature.19
d
Substitution was performed on SASRIN–chloride resin and data were adapted directly from brochure of Bachem A.G.11
N.A., no data available
e

2954
P. Zhao et al. / Tetrahedron Letters 49 (2008) 2951–2955
O
O
O
b
a
Fmoc-Phe-Ser-OAll
FmocHN
C6H5
COOAll
FmocHN
BnO
COOAll
N
H
R1
9
c
b
N3
BnO
O
NHTFA
BnO
NHTFA
O
OH
R7
10
Scheme 3. Synthesis of alcohol derivatives on SASRIN–TOPCAT resin. Reagents and conditions: (a) 20% piperidine/DMF, then Fmoc-Phe-OH, DCC,
HOBT, DCM; (b) 1% TFA/CH2Cl2 (5% Et3SiH was added as scavenger); (c) SnCl2/PhSH/Et3N (1:4:5) in THF, then CF3COOEt, Et3N, MeOH.
2. Wang, S.-S. J. Am. Chem. Soc. 1973, 95, 1328–1333.
3. Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712–7713.
ring the loading resin in a solution of 1% TFA in CH2Cl2
for 15–60 min.15 To evaluate the efficiency of SASRIN–
4. Hanessian, S.; Xie, F. Tetrahedron Lett. 1998, 39, 733–736.
TOPCAT resin in solid-peptide synthesis, dipeptide
5. Hanessian, S.; Huynh, H. K. Tetrahedron Lett. 1999, 40, 671–674.
Fmoc-Phe-Ser-OAll16 and 1-N-(trifluoroacetyl)-3-(phenyl-
6. See, for examples: (a) Hanessian, S.; Xie, F. Tetrahedron Lett. 1998,
methoxy)propan-2-ol17 were also synthesized on SAS-
39, 737–740; (b) Kamal, A.; Reddy, G. S. K.; Reddy, K. L.
Tetrahedron Lett. 2001, 42, 6969–6971; (c) Hanbali, M.; Bagnard,
D.; Luu, B. Bioorg. Med. Chem. Lett. 2006, 16, 3917–3920; (d) Quan,
RIN–TOPCAT resin in 91.6% and 47.1% yield,
respectively (Scheme 3).
C.; Kurth, M. J. Org. Chem. 2004, 69, 1470–1474; (e) Yan, L. Z.;
SASRIN–TOPCAT resin has some advantages com-
Mayer, J. P. J. Org. Chem. 2003, 68, 1161–1162.
pared to the current solid supports. The first one lies on
7. Barlos, K.; Gatos, D.; Kallitsis, J.; Papaphotiu, G.; Sotiriu, P.; Y, W.;
the more acid-sensitive ether linker in SASRIN–TOPCAT
resin than the ether linker in Wang resin or the acetal linker
in dihydropyranyl (DHP) resin. Second, SASRIN–TOP-
CAT resin is stable at room temperature in a desiccator
after one month. It also exhibits the relative high loading
capability and yields for the peptide synthesis. Finally, as
shown in Table 1, SASRIN–TOPCAT resin can be used
in the loading of various alcohols or thiols substrates,
and the side reactions, such as N-alkylation, ester migra-
tion, b-elimination or epimerization were not observed.
In conclusion, a new SASRIN resin derivative, SAS-
RIN–TOPCAT resin, was synthesized and this new resin
can be used for the loading of alcohols and thiols under
neutral conditions, and the release of alcohol from the resin
is achieved by the treatment of 1% TFA in CH2Cl2 for 15–
60 min. Compared to the other reported resins, SASRIN–
TOPCAT resin is more suitable for the loading of alcohols
in solid-phase organic synthesis.
Schafer, W. Tetrahedron Lett. 1989, 30, 3943–3946.
8. Arano, Y.; Akizawa, H.; Uezono, T.; Akaji, K.; Ono, M.; Funakoshi,
S.; Koizumi, M.; Yokoyama, A.; Kiso, Y.; Saji, H. Bioconjugate
Chem. 1997, 8, 442–446.
9. Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P. Tetrahedron Lett.
1988, 29, 4005–4008.
10. See, for examples: (a) Sarantakis, D.; Bicksler, J. J. Tetrahedron Lett.
1997, 38, 7325–7328; (b) Ngu, K.; Patel, D. V. Tetrahedron Lett. 1997,
38, 973–976; (c) Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-
Kauhaluoma, J. J. Comb. Chem. 2003, 5, 826–833; (d) Raju, B.;
Kogan, T. P. Tetrahedron Lett. 1997, 38, 4965–4968.
11. Bachem product catalog No. D-2165 and D-2170. https://www.
bachem.com/bachem/bachem/joust/index.cfm?site=detail&id=7413
&action=showchildren&back=1 and https://www.bachem.com/
bachem/bachem/joust/index.cfm?site=detail&id=7414&action=show-
children&back=1.
12. Zoller, T.; Ducep, J.-B.; Hibert, M. Tetrahedron Lett. 2000, 41, 9985–
9988.
13. Corey, E. J.; Clark, D. A. Tetrahedron Lett. 1979, 31, 2875–2878.
14. Preparation of SASRIN–2-pyridylthiocarbonate resin (SASRIN–
TOPCAT resin): Starting from triphosgene (12.00 g, 40.4 mmol), 2-
thiopyridyl chloroformate was obtained according to Corey’s proce-
dure and used in situ without further purification. The flask was
rinsed with an additional volume of CH2Cl2 (20 mL) and Et3N
(3.6 mL, 25.8 mmol). SASRIN resin (2.00 g, 0.76 mmol/g) and
DMAP (170 mg, 0.14 mmol) were added at 0 °C and agitated for
24 h. The resin was washed with H2O, MeOH and CH2Cl2 succes-
sively and dried in high vacuum to give SASRIN–TOPCAT resin
(theoretical maximal substitution level 0.68 mmol/g). FT-IR (KBr
pellet) 3397, 3081, 3059, 3025, 2923, 2852, 1946, 1875, 1804, 1722
(C@O), 1612, 1587, 1508, 1494, 1451, 1420, 1373, 1333, 1288, 1197,
Acknowledgements
This work was supported by the National Natural Sci-
ence Foundation of China (90713005) and the Ministry
of Science and Technology of China (2004CB518904).
Supplementary data
1107, 1031, 907, 821, 757, 698, 665, 618, 538, 484 cmÀ1
.
15. General procedure for the loading and the cleavage of alcohols to
SASRIN–TOPCAT resin: The alcohol (3 equiv) was added to a
suspension of the resin (200 mg) in CH2Cl2 (4 mL), and AgOTf
(3 equiv) was added in one portion. After agitated for 1–8 h in dark,
the resin was quenched with pyrimidine for another 30 min and
filtered, washed with CH2Cl2, DMSO, MeOH, CH2Cl2 and dried in
high vacuum. Alcohols were cleaved by 1% TFA in CH2Cl2 (5%
Et3SiH was added as scavenger) for 15–60 min. Note: Cleavage of
thiols from SASRIN resin required more harsh acid conditions. 50%
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.03.017.
References and notes
1. Nam, N.-H.; Sardari, S.; Parang, K. J. Comb. Chem. 2003, 5, 479–
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P. Zhao et al. / Tetrahedron Letters 49 (2008) 2951–2955
2955
TFA in CH2Cl2 was recommended which had been reported by
Bachem A.G. But tert-butyl ether in compound 4 was also partially
cleaved at this acid conditions. For more detailed information, see:
http://www.bachem.com.
17. Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53, 4787–
4790.
18. Meienhofer, J.; Waki, M.; Heimer, E. P.; Lambros, T. J.; Makofske,
R. C.; Chang, C.-D. Int. J. Pep. Protein Res. 1979, 13, 35–42.
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16. Meloni, M. M.; White, P. D.; Armour, D.; Brown, R. C. D.
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