[259796-15-1]F  · (C8H7NO4)n  · (181.15)

(polymeric acyl transfer reagent for activated carboxylic acids, chloroformates and isocyanates in amine acylation and related reactions)

Alternate Name: ROMPGEL-N-hydroxysuccinimide.

Solubility: soluble in DMF, DMSO; insoluble in H2O, most organic solvents.

Form Supplied in: gray granular solid.

Analysis of Reagent Purity: the purity of the precursor polymer is verified by 1H NMR. IR confirms complete desilylation of the product.

Preparative Methods: see text.1

Purification: stirring in methanolic ammonia in THF overnight followed by filtration, sequential washing with H2O, THF, CH2Cl2 and diethyl ether and drying at 40 °C and 20 mmHg.

Handling, Storage, and Precautions: stable to air, light and heat.

Peptide Bond Formation

This polymeric reagent bears the same functionality and follows the same reactivity as N-hydroxysuccinimide (HOSu), namely as an acyl transfer reagent. The reagent can be prepared by ring-opening metathesis polymerization (ROMP) of the TBS-protected ether (1) using benzylidenebis(tricyclohexylphosphine)dichlororuthenium2 (Grubbs' catalyst) (2), followed by removal of the silyl group, optimally with triethylamine trihydrofluoride,3 precipitating the granular polymer (1).1

Once formed, the hydroxy functionality can be derivatized to give activated esters, either by using an acid chloride and triethylamine as base (2), or with a carboxylic acid and using 1,3-dicyclohexylcarbodiimide (DCC) as the coupling reagent (3). The polymer is purified by washing away the solution-based reagents with excess solvent. The polymer can also be converted to an activated carbonate (chloroformate and triethylamine as base, 4), or to an activated carbamate by reaction with an isocyanate (5).

The stable esters (4) can be reacted with a range of nucleophiles, with acyl transfer. Traditional usage of HOSu involves at least an aqueous wash to remove the polar succinimide and, more often, further chromatographic purification of the product. Reaction of an amine nucleophile with 1.3 equiv of a ROMPGEL-N-hydroxysuccinimide-supported ester is sufficient to give essentially quantitative conversion to the product. Here, since both the remaining unreacted activated ester and the N-hydroxysuccinimide by-product are bound in the polymer matrix, both can be removed by a single filtration. Evaporation of the solvent gives essentially pure product in excellent isolated yields. Amines can be effectively acylated in this way (6). Polystyrene-supported ortho-nitrophenol4 and polystyrene-supported N-hydroxybenzotriazole5 are other examples of polymer-supported acyl transfer reagents.

Amine hydrochloride salts can also be acylated directly, employing triethylamine as an HCl shuttle and the strong base polystyrene-supported triazabicyclo[3.3.0]decane6 (P-TBD) as the HCl sink (7). Amino acid esters are acylated with minimal (<1%) racemization.

ROMPGEL-N-hydroxysuccinimide can also be used to form carbamates (8) and ureas (9).

For bulk acylation purposes (where the same acyl group is to be transferred to a range of nucleophiles), it is more convenient to acylate the monomer (5) and to polymerize this derivative directly. Low molecular weight monomers may lead to liquid ROM-polymers, so between 5-30 mol % norbornadienene (NBD) can be added, forming cross-links7 between neighboring linear chains and giving the required insoluble polymer gel (4)1,8 (10).

Hydroxylamine (released from the hydrochloride salt in situ by adding solid potassium hydroxide) is cleanly acylated and with a single filtration and evaporation gives hydroxamic acids (11). Replacing hydroxylamine with N,O-dimethylhydroxylamine gives the corresponding Weinreb amides.9

Amidoximes can also be acylated, initially on oxygen. If the reaction is carried out in the presence of P-TBD, dehydrative cyclization occurs to give the corresponding 1,2,4-oxadiazoles in good-to-excellent yield and essentially pure, after a single filtration and evaporation (12).8

In general, ROMPGEL-supported esters react only with amine nucleophiles. For electron-poor acyl groups, however, some O-acylation can be observed (13).1

Finally, the polymer can be recycled after use by washing with methanolic ammonia to remove any remaining acyl group. Re-acylation and subsequent reaction give the new product in >95% purity with no sign of the remnant acyl group being incorporated (14).1

Related Reagents.

N-hydroxysuccinimide; N-hydroxybenzotriazole; polystyrene-supported N-hydroxybenzotriazole.

1. Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zécri, F. J., Org. Lett. 2000, 2, 261.
2. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H., Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
3. McClinton, M. A., Aldrichimica Acta 1995, 28, 31.
4. Fridkin, M.; Patchornik, A.; Katchalski, E., J. Am. Chem. Soc. 1965, 87, 4646.
5. Kalir, R.; Warshawsky, A.; Fridkin, M.; Patchornik, A., Eur. J. Biochem. 1975, 59, 55.
6. Xu, W.; Mohan, R.; Morrissey, M. M., Tetrahedron Lett. 1997, 38, 7337.
7. Höcker, H.; Reif, L.; Thu, C. T., Makromol. Chem. Suppl. 1984, 6, 331.
8. Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zécri, F. J., Comb. Chem. High Throughput Screening 2000, 3, 131.
9. Nahm, S.; Weinreb, S. M., Tetrahedron Lett. 1981, 22, 3815.

Anthony G. M. Barrett

Imperial College, London, UK

Richard S. Roberts

Syngenta, Jealott's Hill, Berkshire, UK

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.