Lewis acid-catalyzed cleavage of carbamate and carbonate resins

Article abstract of DOI:10.1016/S0040-4039(00)01131-X

A procedure for the preparation of amides and esters on a Merrifield resin-bound benzyloxycarbonyl equivalent has been developed. Polymer-supported carbamates react cleanly with zinc bromide and the appropriate acyl halide in the presence of triethylamine to provide their corresponding amides in high yields and purities. Cleavage of resin-bound carbonates was carried out using the similar reagent systems in the absence of triethylamine to give acetates or benzoates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01131-X

Tetrahedron Letters 41 (2000) 6619±6622
Lewis acid-catalyzed cleavage of carbamate and carbonate
resins
Wen-Ren Li,* Yu-Sheng Lin and Ying-Chih Yo
Department of Chemistry, National Central University, Chung-Li, Taiwan 32054, ROC
Received 2 June 2000; revised 27 June 2000; accepted 30 June 2000
Abstract
A procedure for the preparation of amides and esters on a Merri®eld resin-bound benzyloxycarbonyl
equivalent has been developed. Polymer-supported carbamates react cleanly with zinc bromide and the
appropriate acyl halide in the presence of triethylamine to provide their corresponding amides in high
yields and purities. Cleavage of resin-bound carbonates was carried out using the similar reagent systems in
the absence of triethylamine to give acetates or benzoates. # 2000 Elsevier Science Ltd. All rights reserved.
Combinatorial solid-phase synthesis has become the focus of intense interest as a tool for lead
discovery and optimization of new drugs,1 6 catalysts and materials.7 9 The linker strategy plays
an important part in the designing of a combinatorial library.10 This necessitates the development
of new sets of linkers that possess di€erent chemical stability and their cleavage methods in order
to apply various combinations of reaction conditions.
As we were particularly interested in the combinatorial solid-phase synthesis of radiosumin
libraries, trypsin inhibitors,11,12 we needed a linker that would be stable to dilute tri¯uoroacetic
acid treatment and allow for transformation of amines to acetates. Only a few works on
carbamate linkers13 26 and Merri®eld resin based amine linkages27,28 were reported in the
literature and their cleavage methods did not look suitable to us. Therefore, we decided to
develop a Merri®eld resin-bound linker and its cleavage method by a modi®cation of previously
developed methodology by our group for the synthesis of salmisteine derivatives.29 The linker
described in this paper is based on the benzyloxycarbonyl protection group. Benzyl carbamates
are more resistant to acid and oxidizing agent than are p-methoxybenzyl carbamates.30 Therefore,
the benzyl type of Merri®eld resin-bound carbamates should show greater stability under acidic
and oxidative conditions than those linked to Wang resin due to the absence of the electron-
donating e€ect of the p-benzyloxy group.
* Corresponding author. Fax: +886-3-427-7972; e-mail: wenrenli@rs250.ncu.edu.tw
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01131-X

6620
The Merri®eld resin-bound benzyloxycarbonyl linkages were prepared and cleaved according
to Scheme 1 and the results are summarized in Table 1. Various types of carbamates and
carbonates were linked to solid support, all leading to a mild and ecient one-pot cleavage of
resins into the amides or esters in good yields. In Table 1, benzamides for the most part were
obtained in better yields. Faster cleavage occurred with acetyl bromide as compared to benzoyl
chloride. It should be noted that benzyl esters (entries 2, 3 and 5) were stable under cleavage
conditions. No epimerization was observed when the cleavage of resin-bound carbamates was
conducted with ZnBr2/AcBr or BzCl/Et3N reagent systems. It is noteworthy that the triethyla-
mine was not necessary to drive the reaction to completion when the resin-bound carbonates were
cleaved (entries 7±9). In view of the high purity of the crude products and the simplicity of the
procedure, this reaction sequence is suitable for the combinatorial synthesis of a large number of
amides and esters on solid support.
Scheme 1.
General procedure for the attachment to p-nitrophenyl carbonate resin 1: (A) Amines: The p-
nitrophenyl carbonate resin (300 mg, 0.48 mmol) in DMF (1.9 mL) was added to the desired
substrate hydrochloride amine salt (1.44 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.88
mmol) and left to shake at room temperature for 6 h. The resin was then washed with DMF
(2 mLÂ3) and CH2Cl2 (2 mLÂ3); (B) Phenols: Same as condition A, except DIPEA was changed
to Cs2CO3 and the mixture was agitated for 24 h; (C) Aliphatic alcohol: Same as condition B,
except Cs2CO3 was changed to DMAP.
General procedure for the cleavage of resin-bound carbamates 2: The carbamate resin (200 mg,
0.32 mmol) was swelled with CH2Cl2 (1.6 mL) and treated with dry zinc(II) bromide (36 mg, 0.16
mmol) and acetyl bromide or benzoyl chloride (0.07 mL, 0.96 mmol) under an argon atmosphere.
The mixture was agitated for 24 h at room temperature, then a solution of triethylamine (0.07
mL, 0.48 mmol) in 0.38 mL CH2Cl2 was added dropwise. After the reaction was completed, the
resin was collected by ®ltration. The ®ltrate was washed with 5% NaHCO3, 5% HCl and

6621
Table 1
Synthesis of amides and esters by Lewis acid-assisted cleavage of resin-bound carbamates and carbonates 2
saturated NaCl solutions. The organic layer was dried over magnesium sulfate, concentrated, and
chromatographed on silica gel to yield the desired amides 3.
In conclusion, we have successfully developed a new cleavage strategy for Merri®eld resin-
bound benzyloxycarbonyl linkers. This new one-pot release protocol has proven to be a general
reaction for the cleavage of carbamate and carbonate resins. The carbamate and carbonate

6622
linkers are suitable for the anchoring of amines, phenols and alcohols, allowing the construction
of both peptide and organic combinatorial libraries in a bi-directional fashion. The strategy
should expand the utility of Merri®eld resin and increase the sophistication of solid-phase
synthesis. Currently, we are in the process of using this protocol in the combinatorial synthesis of
radiosumin libraries and those results will be reported in due course.
Acknowledgements
The authors are grateful to the National Science Council, ROC, for the ®nancial support (NSC
88-2113-M-008-005) of this work.
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