should, ideally, be able to bind and release especially
aldehydes readily. Usually, aldehydes are immobilized to
linkers as acetals, enol ethers, or enamines.7-9 These meth-
ods, however, have the drawbacks of either inconvenient
attachment or cumbersome cleavage, apart from problems
deriving from the presence of sensitive functional groups
like, e.g., enol ethers or acetals, encountered in natural com-
pounds such as rifamycin. In contrast to these, hydrazine-
based linkers are promising alternatives.10 Commercial
tosylhydrazine resins are good scavengers but not ideal for
modifications and release.3 A few examples describing
aldehydes as the cleavage products have been reported with
polystyrene-based (Merrifield) resins.11 Lazny recently re-
ported new spacers.11a,b However, the synthetic route was
complicated by a N-N bond formation.
strates may be too close together. This is not favorable,
especially for cyclizations under solid-phase pseudodilution
conditions or when enzymatic access is required. For the
reversible linking and synthetic modification of substrates,
the monobenzylhydrazine linker 7 is preferred. To obtain
this more suitable linker, 1 was reacted with benzaldehyde
to give imine 4. Trimethyl orthoformate was used as both
solvent and dehydrating reagent for the imine formation.12
After reduction of 4 to the secondary amine, the addition of
1,4-di(bromomethyl)benzene led to the monofunctionalized
benzyl bromide 6, which was readily substituted with
hydrazine monohydrate to give the desired resin 7.
The linking of various aldehydes to 7 by hydrazone bond
formation is very straightforward. The main problem of
hydrazone-linking lies in finding suitable cleavage condition
to release the aldehydes unharmed to the solution phase.
Several research groups reported the cleavage of aldehydes
or ketones from hydrazone bonds.11 For example, Lazny used
10% TFA in THF for ketone cleavage, but this condition is
too harsh for aldehydes presenting additional sensitive
functional groups as in complex natural products.11a,b Alde-
hydes and ketones can also be released from semicarbazone
linkages in acid together with acetaldehyde or formalde-
hyde.11c,d However, the cleavage products in these cases were
always seriously contaminated by side products from form-
aldehyde or acetaldehyde.13 Some but not all of the side
products can be washed out with water, but this cleavage is
still impractical in combinatorial synthesis.
We have found that benzylhydrazine linkers reversibly link
aldehydes smoothly, allow modification reactions, and can
be produced easily. We herewith present two novel scaveng-
ing linkers (3 and 7) anchored on PEGA polymer having
hydrophilic core properties suitable for biocatalytic or large
organometallic reagents (Scheme 1). Commercial PEGA1900
Scheme 1
Although all these methods worked for our system too,
we soon noted that using acetone instead of formaldehyde
or acetaldehyde could circumvent the problems.14,15 THF was
(7) Selected examples for acetal linkers: (a) Chamoin, S.; Houldsworth,
S.; Kruse, C. G.; Bakker, W. I.; Snieckus, V. Tetrahedron Lett. 1998, 39,
4179-4182. (b) Metz, W. A.; Jones, W. D.; Ciske, F. L.; Peet, N. P. Bioorg.
Med. Chem. Lett. 1998, 8, 2399-2402. (c) Ede, N. J.; Bray, A. M.
Tetrahedron Lett. 1997, 38, 7119-7122. (d) Bertini, V.; Lucchesini, F.;
Pocci, M.; De Munno, A. Tetrahedron Lett. 1998, 39, 9263-9266. (e)
Wong, J. Y.; Leznoff, C. C. Can. J. Chem. 1973, 51, 3756-3764.
(8) Selected examples for enol ether linkers: (a) Fraley, M. E.; Rubino,
R. S. Tetrahedron Lett. 1997, 38, 3365-3368. (b) Ball, C. P.; Barrett, A.
G. M.; Commercon, A.; Compe`re, D.; Kuhn, C.; Roberts, R. S.; Smith, M.
L.; Venier, O. J. Chem. Soc., Chem. Commun. 1998, 2019-2020.
(9) Selected examples for enamine linkers: (a) Hird, N. W.; Irie, K.;
Nagai, K. Tetrahedron Lett. 1997, 38, 711-7114. (b) Crawshaw, M.; Hird,
N. W.; Irie, K.; Nagai, K. Tetrahedron Lett. 1997, 38, 7115-7118.
(10) (a) Stieber, F.; Grether, U.; Waldmann, H. Chem. Eur. J. 2003, 9,
2370-2381. (b) Kirchhoff, J. H.; Bra¨se, S.; Enders, D. J. Comb. Chem.
2001, 3, 71-77.
(1) was reacted with excess 1,4-di(bromomethyl)benzene to
obtain the dialkylation product 2. Treatment with hydrazine
monohydrate converted 2 to linker 3 with doubled loading
capacity. The increased loading is useful for scavenging
reactions. For other applications, however, the bound sub-
(11) (a) Lazny, R.; Nodzeweska, A.; Wolosewicz, K. Synthesis 2003,
2858-2864. (b) Lazny R.; Michalak, M. Synlett 2002, 1931-1934. (c) Lee,
A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907-9914.
(d) Murphy, A. M.; Dagnino, R., Jr.; Vallar, P. L.; Trippe, A. J.; Sherman,
S. L.; Lumpkin, R. H.; Tamura, S. Y.; Webb, T. R. J. Am. Chem. Soc.
1992, 114, 3156-3157.
(4) (a) Meldal, M. Tetrahedron Lett. 1992, 33, 3077-3080. (b) Rade-
mann, J.; Grotli, M.; Meldal, M.; Bock, K. J. Am. Chem. Soc. 1999, 121,
5459-5466. (c) Basso, A.; Ebert, C.; Gardossi, L.; Linda, P.; Tran Phuong,
T.; Zhu, M.; Wessjohann, L. Chem. Commun. 2004, submitted. (d) Basso,
A.; De Martin, L.; Gardossi, L.; Margetts, G.; Brazendale, I.; Bosma, A.
Y.; Ulijn, R. V.; Flitsch, S. L. Chem. Commun. 2003, 1296-1297. (e) Doeze,
R. H. P.; Maltman, B. A.; Egan, C. L.; Ulijn, R. V.; Flitsch, S. L. Angew.
Chem. 2004, 116, 3200-3203; Angew. Chem. Int. Ed. 2004, 43, 3138-
3141.
(12) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 36, 2937-2940.
(13) Poupart, M. A.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org. Chem.
1999, 64, 1356-1361.
(14) Similar hydrazone exchange reaction was described by Buchwald
for precursors of a Fischer indole synthesis: Wagaw, S.; Yang, B. H.;
Buchwald, S. J. Am. Chem. Soc. 1999, 121, 10251-10263.
(15) Acetone proved to be most useful. It is the cheapest ketone of
sufficient reactivity for the hydrazone exchange, excess is easily removed
from the product, and the resulting resin with acetone capping is still reactive
enough to allow recovery of the free solid-phase hydrazine by hydrazine
exchange if desired. Unlike with aldehydes, we saw much less (8h,i) or
mostly no unwanted reactivity and much higher enzyme compatability. Only
8j is reactive in either scavenge or cleavage.
(5) Some recent examples: (a) Barkley, A.; Arya, P. Chem. Eur. J.
2001, 7, 555-563. (b) Wu, C. W.; Sanborn, T. J.; Zuckermann, R. N.;
Barron, A. E. J. Am. Chem. Soc. 2001, 123, 2958-2963. (c) Melnyk, O.;
Fruchart, J.-S.; Grandjean, C.; Gras-Masse, H. J. Org. Chem. 2001, 66,
4153-4160. (d) Kohli, R. M.; Walsh, C. T.; Burkart, M. D. Nature 2002,
418, 658-661. (e) Pastor, J. J.; Ferna´ndez, I.; Rabanal, F.; Giralt, E. Org.
Lett. 2002, 4, 3831-3833. (f) Ulijn, R. V.; Baragana, B.; Halling, P. J.;
Flitsch, S. L. J. Am. Chem. Soc. 2002, 124, 10988-10989.
(6) St. Hilaire, P. M.; Meldal, M. Angew. Chem. 2000, 112, 1210-1228;
Angew. Chem. Int. Ed. 2000, 39, 1162-1179.
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