WANG RESIN

Wang Resin
OH
O

(commonly used linker in solid-phase peptide and small molecule

synthesis)
Solubility: swollen to gel-phase in many organic solvents, not in
H2 O or alcohols.
Form Supplied in: polystyrene beads, typically 1% cross-linked,
0.1 mm diameter, loading 1 mmol g1 of OH; widely available.
Purity: solid-phase resins often contain trapped impurites; several
swell and shrink cycles by washing with a sequence of solvents in decreasing polarity, e.g. DMF, dichloromethane, and
methanol is recommended before use.
Handling, Storage, and Precaution: in the dried state, cross-linked
polystyrene beads are indefinitely stable.

Linker Synthesis. In 1963, R. B. Merrifield reported1 the

pioneering synthesis of a tetrapeptide immobilized on crosslinked chloromethylated polystyrene (now also known as Merrifield resin). This marked the beginning of solid-phase organic
synthesis, which rapidly gained popularity for the synthesis of
peptides and nucleotides. More recently, these techniques were
extended to the preparation of small molecules, particularly in
combinatorial chemistry. In all these applications, the advantage
of solid-phase synthesis lies in the ability to work up reactions
by simple filtration of the immobilized product away from all
reagents or by-products in solution.
Peptide release from Merrifields original resin required the use
of HF, and much effort has been devoted to alternatives. This
is achieved by incorporating a linker2 between the polymer
matrix and the point of compound attachment, which can then
be cleaved under milder conditions. At least in some solid-phase
reactions, the increased distance from the polymer matrix also
has a beneficial effect on the microenvironment where reactions
occur, and increased yields are noted with linkers. The most popular solid-phase linker is the Wang linker reported3 by Su-Sun Wang
in 1973, usually referred to as the Wang resin and sometimes as
HMP (hydroxymethylphenoxy) resin. An optimized preparation4
(eq 1) was later described by Merrrifield.
Why is the Wang resin so widely used? Compared to the base
Merrifield resin, the Wang linkers additional p-phenoxy substituent results in greater acid lability, thus avoiding the need for
HF and enabling product cleavage with TFA. For peptide synthesis, this led to the Fmoc/t-Bu approach5 where the amine is Fmoc
protected, and side-chain functional groups masked with groups
such as t-Bu which are globally removed during TFA resin cleavage. The resins popularity means that it is commercially available
with a high loading from various manufacturers at a relatively inexpensive cost (it can also be prepared more cheaply from the
Merrifield resin, eq 1). At the same time, the resin is compatible

with a wide variety of reactions and is significantly more robust

than more acid-labile resins such as the Rink and trityl resins. For
these reasons, the Wang linker is often the first resin that is evaluated when developing a new solid-phase synthesis. In addition to
the classical Wang resin (eq 1), the Wang linker is also widely used
with TentaGel-type resins, in which a polyethylene glycol (PEG)
spacer is attached to polystyrene before addition of the linker. In
this case, the PEG results in substantial differences in polymer
properties, enabling the use of hydrophilic solvents for reactions.
3 equiv

OH
HO

Cl
Merrifield
resin

3 equiv NaOMe
DMAC, 50 C, 8 h
98%

OH
(1)

O
Wang (or HMP) resin

Compound Attachment. The Wang resin was originally

developed for the attachment of carboxylic acids, typically
with a carbodiimide-activating agent (eq 2). Other acylating agents include symmetrical anhydrides with catalytic
DMAP, mixed anhydrides with 2,6-dichlorobenzoyl chloride,6
N-carboxyanhydrides,7 and carboxylic acid activation by
1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole8
(MSNT)
and 1-methylimidazole. Alternatively, alcohol activation by
Mitsunobo reaction9 is also practised.
OH
O

RCO2H
DIC, DMAP
DMF

O
O

(2)

Besides carboxylic acids, several other functional groups can be

directly attached to the Wang resin. A synthesis10 of H-phosphonates (eq 3) uses a phosphorylating agent. Phenolic compounds11
as well as others with acidic hydrogens are readily immobilized under Mitsunobu conditions. An example,12 (eq 4) with Nhydroxyphthalimide provides an entry to hydroxamic acids after
hydrazinolysis and acylation.
O
1.

OH
O

Cl

O
P

2. NaHCO3, Et3N
O

P
O
H
O

(3)

Avoid Skin Contact with All Reagents

WANG RESIN
O

(catalytic BF3 .Et2 O) to give the corresponding solid-phase ether.

The Wang aldehyde, conveniently prepared by ParikhDoering
oxidation of the Wang resin, has found use in the immobilization
of amines20 by reductive alkylation and diols21 by 1,3-dioxane or
1,3-dioxolane formation.

HO N
O
PPh3, DEAD
3 equiv each

OH
O

THF

O
(4)

Derivatization of the Wang resin into chloroformate equivalents

such as the p-nitrophenylcarbonate,13 the imidazolylcarbamate,14
the succinimidylcarbonate,15 and the 2-pyridylthiocarbonate16
produces further versatility in functional group attachment (eq 5).
These resins are useful for the immobilization of oxygen, nitrogen, and sulfur nucleophiles which can subsequently be released
under the usual TFA cleavage conditions. In the case of amines,
the intermediate carbamate has also been accessed17 by reaction
of the Wang resin with isocyanates generated in situ by Curtius
rearrangement.

Chemical Stability. The Wang resin has been successfully

employed in a vast number of solid-phase syntheses of peptides
and small molecules. The linker is compatible with basic (including organolithiums) and reducing conditions as well as reactive
intermediates such as organic radicals. Given the electron-rich
nature of the linker, strongly electrophilic or oxidizing reagents
can be troublesome if the immobilized substrate does not react
at a significantly faster rate. While the Wang resin is designed
to be acid-cleavable and will not withstand high concentrations
of protic or strong Lewis acids, less acidic conditions are tolerated. In Wangs original3 peptide synthesis, N-2-(p-biphenyl)
isopropyloxycarbonyl (Bpoc) amino acids were coupled to the
resin and deprotected with 0.5% TFA within minutes at each cycle, while solid-phase adaptations of the PictetSpengler reaction
(eq 7) and Biginelli condensation (eq 8) also illustrate the use of
substoichiometric amounts of acid.
O
O

O
O

NH2

RNuH

N
H

O
O

O
O

Nu

R
(5)

1. 4 equiv PhCHO
5% TFA, CH2Cl2, 24 h
2. 95% TFA cleavage
85% mass recovery
90% HPLC purity

(7)

HO
HN

N
H

O
N
NO2 , N

X=O

,O N

, S

O
O

Additional electrophilic versions of the Wang linker are the

bromide18 and trichloroacetimidate19 (eq 6). The bromide can be
displaced by carboxylates and nitrogen nucleophiles, while the
trichloroacetimidate reacts with alcohols under mild conditions
OH

1. 3 equiv PhCHO, 3 equiv H2N(CO)NH2

0.2 equiv HCl, dioxane, 18 h
2. 50% TFA cleavage
81% yield

HO

NH
N
H

PPh3Br2 or
NBS, Me2S

CCl3CN
DBU

NH
Br
O

O
O

A list of General Abbreviations appears on the front Endpapers

CCl3 (6)

(8)

Compound Cleavage. Compound release from the Wang resin

is classically accomplished by TFA treatment, the p-phenoxy substituent serving to accelerate the reaction compared to the base
Merrifield resin (eq 9). In peptide synthesis, 95% TFA is commonly employed, also resulting in global removal of side-chain
protecting groups. Both resin and side-chain cleavage reactions
produce carbocationic species that can react with electron-rich
amino acids. To avoid this undesirable side-reaction, nucleophilic
scavengers are often added together with TFA. Popular choices

WANG RESIN

include water, thioanisole, and triethylsilane. In small molecule

synthesis, TFA concentrations ranging from 1% to neat have been
reported, depending on the nature of the functional group to be
cleaved and its sensitivity to acid. When developing a new solidphase route, testing of several TFA concentrations with and without scavengers is recommended to determine the optimal conditions. Besides protic acids, the cleavage of esters by Lewis
acids such as AlCl3 22 is also documented. If the functional group
released after cleavage is unstable under acidic conditions, it is
important to realize that further reactions can occur. For example,
when resin-bound -ketoesters are subjected23 to TFA cleavage,
the products are methyl ketones arising from decarboxylation of
the intermediate -ketoacid.
X
O

TFA

H
X
R

O
+

RXH

(9)

Many other nonacidic routes for compound release have been

developed for specific functional groups. In the case of esters, nucleophilic hydrolysis to give the free acid has been accomplished24
with bis(tributyltin)oxide. Transesterification to afford the methyl
ester can be carried out with sodium methoxide or more mildly
with methanol in the presence of DBU/LiBr25 or Et3 N/catalytic
KCN.26 Such reactions, however, are better documented with the
less electron-rich Merrifield resin. Aminolysis of Wang esters
have the potential to yield diversified amides upon cleavage, but
the reaction needs to be promoted by strong Lewis acids such as
AlCl3 27 or the prior formation of the dimethylaluminumamide.28
With carbonyl containing functional groups at the point of attachment, LiAlH4 effects reductive cleavage, for example providing29
N-methylamines from carbamates. The nonacidic cleavage of immobilized ethers can be accomplished30 by benzylic oxidation of
the Wang linker with DDQ. When secondary amines are attached
to the Wang resin, von Braun reaction with acid chlorides results31
in acylative cleavage and formation of the tertiary amide.
R3
O

O
N

O
O

Bu4NOH

R2

THF, MeOH

R1
O
R3
N R2 (10)

the resulting cyclization serves to cleave the product off the resin.
Such protocols are not unique to the Wang resin and fall beyond
the scope of this article. An illustrative example32 (eq 10) features
a Claisen-like condensation to yield tetramic acids.
Related Reagents. HMBA Resin; Merrifield Resin; Rink
Resin.

1. Merrifield, R. B., J. Am. Chem. Soc. 1963, 85, 2149.

2. (a) Guillier, F.; Orain, D.; Bradley, M., Chem. Rev. 2000, 100, 2091. (b)
James, I. W., Tetrahedron 1999, 55, 4855.
3. Wang, S. S., J. Am. Chem. Soc. 1973, 95, 1328.
4. Lu, G. S.; Mojsov, S.; Tam, J. P.; Merrifield, R. B., J. Org. Chem. 1981,
46, 3433.
5. Fmoc Solid Phase Peptide Synthesis, Chan, W. C.; White, P. D., Eds.;
Oxford University: Oxford, 2000.
6. Sieber, P., Tetrahedron Lett. 1987, 28, 6147.
7. Swain, P. A.; Anderson, B. L.; Fuller, W. D.; Naider, F.; Goodman, M.,
React. Polym. 1994, 22, 155.
8. Blankemeyer-Menge, B.; Nimtz, M.; Frank, R., Tetrahedron Lett. 1990,
31, 1701.
9. Barbaste, M.; Rolland-Fulcrand, V.; Roumestant, M. L.; Viallefont, P.;
Martinez, J., Tetrahedron Lett. 1998, 39, 6287.
10. Zhang, C.; Mjalli, A. M. M., Tetrahedron Lett. 1996, 37, 5457.
11. Richter, L. S.; Gadek, T. R., Tetrahedron Lett. 1994, 35, 4705.
12. Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M., Tetrahedron Lett.
1996, 37, 8045.
13. Dixit, D. M.; Leznoff, C. C., Israel, J. Chem. 1978, 17, 248.
14. Hauske, J. R.; Dorff, P., Tetrahedron Lett. 1995, 36, 1589.
15. Alsina, J.; Rabanal, F.; Chiva, C.; Giralt, E.; Albericio, F., Tetrahedron
1998, 54, 10125.
16. Hanessian, S.; Huynh, H. K., Tetrahedron Lett. 1999, 40, 671.
17. Sunami, S.; Sagara, T.; Ohkubo, M.; Morishima, H., Tetrahedron Lett.
1999, 40, 1721.
18. (a) Ngu, K.; Patel, D. V., Tetrahedron Lett. 1997, 38, 973. (b) Zoller, T.;
Ducep, J. B.; Hibert, M., Tetrahedron Lett. 2000, 41, 9985.
19. Hanessian, S.; Xie, F., Tetrahedron Lett. 1998, 39, 733.
20. Swayze, E. E., Tetrahedron Lett. 1997, 38, 8465.
21. Hanessian, S.; Huynh, H. K., Synlett 1999, 102.
22. Barn, D. R.; Morphy, J. R.; Rees, D. C., Tetrahedron Lett. 1997, 38,
6335.
23. Kulkarni, B. A.; Ganesan, A., J. Comb. Chem. 1999, 1, 373.
24. Salomon, C. J.; Mata, E. G.; Mascaretti, O. A., J. Chem. Soc., Perkin
Trans. 1 1996, 995.
25. Seebach, D.; Thaler, A.; Blaser, D.; Ko, S. Y., Helv. Chim. Acta 1991,
74, 1102.
26. Kuster, G. J.; Scheeren, H. W., Tetrahedron Lett. 1998, 39, 3613.
27. Barn, D. R.; Morphy, J. R.; Rees, D. C., Tetrahedron Lett. 1996, 37,
3213.
28. Ley, S. V.; Mynett, D. M.; Koot, W. J., Synlett 1995, 1017.
29. Ho, C. Y.; Kukla, M. J., Tetrahedron Lett. 1997, 38, 2799.
30. Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco, J. A., Jr., Tetrahedron
Lett. 1997, 38, 4973.
31. Miller, M. W.; Vice, S. F.; McCombie, S. W., Tetrahedron Lett. 1998,
39, 3429.
32. Kulkarni, B. A.; Ganesan, A., Tetrahedron Lett. 1998, 39, 4369.

HO
R1

Finally, cyclative cleavage or cyclorelease represents an

alternative strategy for cleavage. Here, the point of resin attachment is attacked by another functional group intramolecularly and

A. Ganesan
University of Southampton, Southampton, UK

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