A ROMPGEL-supported N-hydroxysuccinimide: A host of acylations with minimal purification

Article abstract of DOI:10.1021/ol991208w

(formula presented) amides, carbamates, ureas, Weinreb amides, hydroxamic acids Yields 89-98% Purity > 95% A novel N-hydroxysuccinimide ring-opening metathesis polymer is described as a recyclable supported acyl transfer reagent. Amides, carbamates, ureas, Weinreb amides, and hydroxamic acids are all obtained in excellent yields and purities from amines with minimal purification.

Full text of DOI:10.1021/ol991208w

ORGANIC
LETTERS
2000
Vol. 2, No. 3
261-264
A ROMPGEL-Supported
N-Hydroxysuccinimide: A Host of
Acylations with Minimal Purification
,†
Anthony G. M. Barrett,* Susan M. Cramp,‡ Richard S. Roberts,† and
Frederic J. Zecri†
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London, SW7 2AY, United Kingdom, and Rhoˆne-Poulenc Agriculture Limited,
Fyfield Road, Ongar, Essex, CM5 0HW, United Kingdom
agmb@ic.ac.uk
Received November 1, 1999
ABSTRACT
A novel N-hydroxysuccinimide ring-opening metathesis polymer is described as a recyclable supported acyl transfer reagent. Amides, carbamates,
ureas, Weinreb amides, and hydroxamic acids are all obtained in excellent yields and purities from amines with minimal purification.
Polymer-supported reagents for organic synthesis are cur-
rently enjoying a renewed popularity with the emergence of
combinatorial chemistry.1,2 The current trend for automation
in synthesis is driving the need for the speed of production
and the ease of handling of large numbers of discrete
compounds, together with a need for a wide range of possible
synthetic transformations. Supported reagents are allowing
the integration of well-established solution-phase chemistry
(along with the myriad analytical techniques available) with
automation through the use of robotics.
in excess, driving reactions to completion, and both spent
and unreacted reagent are removed by simple filtration.
Supported reagents seem to offer advantages over methods
which rely on separation by physical or chemical properties
(automated chromatography, aqueous3 or fluorous-phase4
workup, acid/base-tagged reagents5) since in the context of
a diverse library, these properties are frequently nongeneral.
Most polymer-supported reagents to date have used cross-
linked polystyrene as the insoluble support due to its
commercial availability. With polystyrene, since all synthetic
modifications are invariably carried out post-polymerization,
the quality of the resin is an important consideration, since
monitoring reactions on-resin is not straightforward and
purification is generally not possible. We find an alternative
Supported reagents can be used either catalytically or used
† Imperial College of Science.
‡ Rhoˆne-Poulenc Agriculture Limited.
(1) Polymer-supported Reactions in Organic Synthesis; Hodge, P.,
Sherrington, D. C., Eds.; John Wiley & Sons: New York, 1980. Akelah,
A.; Sherrington, D. C. Chem. ReV. 1981, 81, 557. Synthesis and Separations
Using Functionalised Polymers; Sherrington, D. C., Hodge, P., Eds.; John
Wiley & Sons: New York, 1988.
(2) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18. Parlow, J.
J.; Devraj, R. V.; South, M. S. Curr. Opin. Chem. Biol. 1999, 3, 320. Hinzen,
B.; Lenz, R.; Ley, S. V. Synthesis 1998, 997. Ley, S. V.; Schucht, O.;
Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1251.
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1253. Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217.
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10.1021/ol991208w CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/07/2000

method in the use of ring-opening metathesis polymers
(ROMP). Monomer units containing all the desired func-
tionality for the reagent and a strained alkene are synthesized
in solution and are then polymerized using the Grubbs’
functional group tolerant ruthenium benzylidene catalyst 4.6
The ROM-polymers thus produced (we term these function-
alized polymers ROMPGELs7) are of excellent quality and
quantitative8 loading. We now report that acyl derivatives
of an N-hydroxysuccinimide ROMPGEL act as versatile,
recyclable, activated ester equivalents for the formation of
amides (including Weinreb amides9), carbamates, hydrox-
amic acids, and ureas from a range of acids and amines.10
azine,20 and a range of mixed anhydrides.21 An ideal resin
should possess the properties of mechanical stability, good
site accessibility, high reactivity, good selectivity, and high
loading. We find that the ROMPGEL support fulfills all of
these criteria combined with ease of synthesis and versatility
of use.
Acylation of exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-
ene-2,3-dicarboximide 1 could be achieved with either acid
chlorides (5a,b, NEt3, CH2Cl2), carboxylic acids (5c-e, DIC,
CH2Cl2), alkyl chloroformates (5f,g, NEt3, CH2Cl2), or
isocyanates (5h, CH2Cl2) to give the desired activated ester
monomers 2a-h in excellent yields. Polymerization was
carried out using the Grubbs catalyst 4 (1.5 mol %, CH2-
Cl2), terminating the reaction with ethyl vinyl ether. The
ROMPGELs 3a-h were insoluble, high-loading (between
2.1 and 3.8 mmol g-1) polymers which became slightly
swollen in a range of organic solvents (Scheme 1).22
Activated esters derived from N-hydroxysuccinimide find
widespread use as acylating agents, especially for activated
amino acids, as reagents for the introduction of carbamate
protecting groups and a range of radio-labeling, staining, and
cross-linking reagents for biological systems.11 Normally, the
N-hydroxysuccinimide byproduct is removed by precipitation
and/or chromatography. A water-soluble analogue, N-hy-
droxysulfosuccinimide,12 allows for the removal of the
byproduct and excess reagent by aqueous extraction. Alter-
natively, there are several resins that can be used, copoly-
(ethylene-N-hydroxymaleimide),13 copoly(styrene-N-hydroxy-
maleimide),14 and most recently polystyrene-supported
N-hydroxysuccinimide,15 along with a number of other acyl
transfer polymers including polymer-supported o-nitrophe-
nol,16 p-(hydroxyphenyl)sulfone,17 hydroxybenzotriazole,18
supported aminopyridinium-acyl complexes,19 hydroxytri-
Scheme 1. Synthesis of ROMPGEL Activated Esters
(6) Benzylidenebis(tricyclohexylphosphine)dichlororuthenium 4 is com-
mercially available from Fluka.
(7) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org.
Lett. 1999, 1, 579. Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S. Org.
Lett. 1999, 1, 1083.
Chromatographic separation of monomers 2c-e from N,N′-
diisopropylurea was not possible due to similar chromato-
graphic polarities; however, ROM-polymerization of the
crude mixtures gave a quantitiative yield of the ROMPGEL
and the contaminant urea could easily be removed by
washing the polymer with CH2Cl2-MeOH (9:1).
(8) The polymer loading is equal to the molarity of the monomer.
(9) Nahn, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(10) For recent uses of functionalized ROM-polymers, see; Buchmeiser,
M. R.; Wurst, K. J. Am. Chem. Soc. 1999, 121, 11101, and references
therein. Buchmeiser, M. R.; Seeber, G.; Mupa, M.; Bonn, G. K. Chem.
Mater. 1999, 11, 1533. Strong, L. E.; Kiessling, L. L. J. Am. Chem. Soc.
1999, 121, 6193. Bolm, C.; Dinter, C. L.; Seger, A.; Ho¨cker, H.; Brozio, J.
J. Org. Chem. 1999, 64, 5730. Arimoto, H.; Nishimura, K.; Kinumi, T.;
Hayakawa, I.; Uemura, D. Chem. Commun. 1999, 1361.
(11) Hermanson, G. T. Bioconjugate Techniques; Academic Press: San
Diego, 1996.
Reaction of a slight excess of ROMPGEL 3 (1.2 equiv.)
with a range of amines 6 (Figure 1), filtration, and evapora-
(12) 1-Hydroxy-2,5-dioxo-3-pyrrolidinesulfonic acid, monosodium salt.
Staros, J. V. Biochemistry 1982, 21, 3950.
(13) Laufer, D. A.; Chapman, T. M.; Marlborough, D. I.; Vaidya, V.
M.; Blout, E. R. J. Am. Chem. Soc. 1968, 90, 2696.
(14) Akiyama, M.; Narita, M.; Okawara, M. J. Polym. Sci. A1 1969, 7,
1299. Akiyama, M.; Yanagisawa, Y.; Okawara, M. J. Polym. Sci. A1 1969,
7, 1905. Akiyama, M.; Shimizu, K.; Narita, M. Tetrahedron Lett. 1970,
1015.
(15) Adamczyk, M.; Fishpaugh, J. R.; Mattingly, P. G. Tetrahedron Lett.
1999, 40, 463. Adamczyk, M.; Fishpaugh, J. R.; Mattingly, P. G. Bioorg.
Med. Chem. Lett. 1999, 9, 217.
(16) Fridkin, M.; Patchornik, A.; Katchalski, E. J. Am. Chem. Soc. 1965,
87, 4646. Fridkin, M.; Patchornik, A.; Katchalski, E. J. Am. Chem. Soc.
1966, 88, 3164. Fridkin, M.; Patchornik, A.; Katchalski, E. J. Am. Chem.
Soc. 1968, 90, 2953. Panse, G. T.; Laufer, D. A. Tetrahedron Lett. 1970,
4181. Kalir, R.; Fridkin, M.; Patchornik, A. Eur. J. Biochem. 1974, 42,
151.
(17) Wieland, T.; Birr, C. Angew. Chem., Int. Ed. Engl. 1966, 5, 310.
Marshall, D. L.; Liener, I. E. J. Org. Chem. 1970, 35, 867. Flanigan, E.;
Marshall, G. R. Tetrahedron Lett. 1970, 2403.
(18) Kalir, R.; Warshawsky, A.; Fridkin, M.; Patchornik, A. Eur. J.
Biochem. 1975, 59, 55. Mokotoff, M.; Patchornik, A. Int. J. Pept. Protein
Res. 1983, 21, 145.
(19) Shai, Y.; Jacobson, K. A.; Patchornik, A. J. Am. Chem. Soc. 1985,
107, 4249.
Figure 1. Acyl and amine units.
Org. Lett., Vol. 2, No. 3, 2000
262

tion of the solvent gave the desired products 7 in excellent
isolated yields and purities (Table 1). The ROMPGELs 3
checked whether the N-hydroxysuccinimide functionalized
polymer could be acylated post-polymerization.
Oxanorbornene monomer 1 does not undergo ROM-
polymerization, presumably due to its low solubility. Hence,
compound 1 was silylated (TBSCl, imidazole, CH2Cl2) and
the monomer polymerized as before. Desilylation (NEt3‚3HF,
then Me3SiOMe)24 gave the supported N-hydroxysuccinimide
ROMPGEL 8 (5.5 mmol g-1 loading) in quantitative yield
(Scheme 3).
Table 1. Acylation of a Range of Amines Using ROMPGELs
3a-h. Isolated Yields of Products 7 Are Quoted. All Componds
Were >95% Pure by GCMS
3a
3b
3c
3d
3e
3f
3g
3h
6A
6B
6C
6D
6E
6F
95
97
97
89
91
96
95
95
90
93
97
90
90
a
97
97
98
80b
96
98
98
96
95
95
93
a
a
a
a
95
96
a
a
a
a
97
93
a
a
a
a
95
89
a
a
a
91
98
92
a
a
a
Scheme 3. Divergent Synthesis of ROMPGEL Esters 3
6G
6H
93
98
a
a
a
a
a
a
a
a
a
a
a The reaction was not run. b Product contaminated with 20% of the N,O-
bis-acylated compound.
were selective for amines over alcohols, except when a
reactive acyl group (3c) was used. Also, amine hydrochloride
salts could be used directly in the reaction with the addition
of either solid KOH (6E) or triethylamine as a proton shuttle
and a polystyrene-supported guanidine base, P-TBD,23 as a
proton sink (6F) (Scheme 2).
ROMPGEL 8 could be acylated (RCOCl, NEt3, CH2Cl2
or RCO2H, DIC, CH2Cl2) or converted to the carbamate
(RNCO, CH2Cl2) as previously discussed.
Again, treatment of an excess of ROMPGELs 3 (1.2 equiv)
with an amine 6 gave the desired products 7 (amide or urea)
in good yield and excellent purity.25
Scheme 2. Acylation of Amines Using ROMPGEL 3
Finally, all the N-hydroxysuccinimide polymers (either
ROMPGELs 3 or 8) recovered from acylation reactions could
be recycled. Remaining acyl groups were removed (NH3,
MeOH, THF), and the recovered ROMPGEL 8 could be
reused with no loss of activity.26
In conclusion, we have demonstrated the use of a novel
support for the acylation of amines with minimal purification.
The bulk ROMPGELs produced by polymerization of
monomers 2 are suitable when multigram quantities of
acylated compounds are needed. Acylation of the N-hydroxy
ROMPGEL 8 becomes the method of choice when diverse
libraries of compounds are needed. Furthermore, the poly-
mers can be recycled and reused without any loss of yield
or purity of the final product. Further applications of
ROMPGELs will be reported in due course.
Excess triethylamine was removed along with the solvent
by evaporation. Therefore, amino acid ester hydrochloride
salts (e.g., 6F) could be used directly. There was no
observable racemization of the amino acid when used as the
acylating agent or as the amine component.
Acylation of the N-hydroxysuccinimide monomer 1 prior
to ROM-polymerization generates a polymer which is very
useful for the bulk acylation of a range of amines. We also
Acknowledgment. We thank Rhoˆne-Poulenc Agriculture
for their generous support of this project (F.J.Z.), Rhoˆne-
Poulenc Rorer, under the auspices of the TeknoMed project
(R.S.R.), GlaxoWellcome Ltd. for their endowment
(20) Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355.
(21) Ang, T. L.; Harwood, H. J. J. Macromol. Sci. Chem. A 1973, 7,
1079. Shambhu, M. B.; Digenis, G. A. Tetrahedron Lett. 1973, 1627. Martin,
G. E.; Shambhu, M. B.; Shakhshir, S. R.; Digenis, G. A. J. Org. Chem.
1978, 43, 4571.
(22) The ROMPGELs 3 obtained were sometimes soluble in dichlo-
romethane or ethyl acetate depending the nature of the acyl substituent. In
these cases, copolymerisaztion of the monomers 2 with norbornadiene (5
mol %) yielded an insoluble polymer.
(24) NEt3‚3HF complex was the reagent of choice since all byproducts
were liquids. Desilylation with tetrabutylammonium fluoride (TBAF) gave
a crystalline polymer, presumably due to ammonium salts trapped in the
resin, which led to poorer yields in subsequent acylation reactions.
(25) Amides 7cB, 7cC, 7dB, 7dC, 7eC, 7eC, and urea 7hA were
synthesized in 79-97% yield and in greater than 95% purity by GCMS.
(26) ROMPGEL 3c (1.2 equiv) was treated with amine 6A to give amide
7cA (97% yield), hydrolyzed to ROMPGEL 8, reacylated with acid chloride
5a, and used to make amide 7aA (95% yield, >95% purity). No cross
contamination was observed.
(23) Xu, W.; Mohan, R.; Morrissey, M. M. Tetrahedron Lett. 1997, 38,
7337.
Org. Lett., Vol. 2, No. 3, 2000
263

(A.G.M.B.), and the Wolfson Foundation for establishing
the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College.
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: General procedures
for the synthesis and use of ROMPGELs 3 and 8. This
OL991208W
264
Org. Lett., Vol. 2, No. 3, 2000