A mild and selective method for the cleavage of tert-butyl esters

Article abstract of DOI:10.1016/S0040-4039(01)00980-7

A method for the cleavage of t-butyl esters using silica gel in refluxing toluene is reported. Good yields of the corresponding carboxylic acids are obtained, and the reaction is selective for t-butyl esters over t-butyl ethers and trimethylsilylethyl (TMSE) esters.

Full text of DOI:10.1016/S0040-4039(01)00980-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5163–5165
A mild and selective method for the cleavage of tert-butyl esters
Randy W. Jackson*
Department of Chemical Genomics, Celltech R&D, Inc., 1631 220th St. SE, Bothell, WA 98021, USA
Received 15 May 2001; revised 5 June 2001; accepted 6 June 2001
Abstract—A method for the cleavage of t-butyl esters using silica gel in refluxing toluene is reported. Good yields of the
corresponding carboxylic acids are obtained, and the reaction is selective for t-butyl esters over t-butyl ethers and trimethyl-
silylethyl (TMSE) esters. © 2001 Elsevier Science Ltd. All rights reserved.
Acid labile protecting groups play an important role in
organic synthesis. Among them, tert-butyl esters are
commonly employed in the synthesis of peptides, alka-
loids and other natural products and substrates of
medicinal interest.1 Removal of t-butyl esters often
involves the use of strong protic acids such as tri-
fluoroacetic and hydrochloric acid, or Lewis acids such
as ZnBr2 and silyl triflates.1–3 The harshness of these
conditions can often lead to unwanted side reactions
and decomposition of sensitive substrates. In addition,
chemoselectivity can be problematic if numerous acid-
sensitive protecting groups reside in the same molecule.
In an effort to identify a generally mild and selective
method for the deprotection of t-butyl esters a system-
atic study of acidic cleavage methods was undertaken.
Herein is reported a method using silica gel as an
efficient reagent for the cleavage of t-butyl esters
(Scheme 1).
methanol in methylene chloride, Celite® is added, and
the solution filtered through a pad of Celite®. The
solids are washed with methanol/methylene chloride,
and the filtrate concentrated to afford the product. For
scale-up purposes it is convenient to use a Dean–Stark
trap to azeotropically remove adventitious water in
order to prevent clumping of the silica gel.
The results of the deprotection reactions are shown in
Table 1. The derived carboxylic acids are obtained in
acceptably high purities and normally require no fur-
ther purification for subsequent chemical transforma-
tions.4 A variety of substrates are amenable to the
reaction conditions and good to high yields of the
carboxylic acids are obtained. Benzene is also an
acceptable solvent, however, the associated increase in
reaction times due to a lower reflux temperature makes
this a less desirable solvent. For example, refluxing a
benzene solution of 2a with SiO2 for 21 h resulted in
only 63% conversion to the acid. The enoates 3a and 4a
are stable to the reaction conditions, and the E/Z ratios
of 96/4 and 97/3, respectively, were unchanged in the
products. Also, protected amino acids and peptidic
substrates readily undergo the deprotection reaction to
afford high yields of the corresponding carboxylic
acids. Interestingly, the hydrophobic substrates tend to
require longer reaction times than the more polar
amino acid derivatives. This suggests that the rate of
the reaction is dependent upon the relative affinity of
the starting material for the silica gel, the more polar
substrates having higher affinities than the hydrophobic
ones.
The reaction of t-butyl esters with standard flash chro-
matography grade silica gel in refluxing toluene gave
high yields of the corresponding carboxylic acid. A
typical procedure is as follows.4 A solution of the ester
(0.5 mmol) and silica gel (2.5 g, 230–400 mesh) in
toluene (10 mL) is refluxed with vigorous agitation until
the starting material is consumed, typically 0.5–7 h.
Upon cooling, the solution is diluted with 10%
O
O
SiO2, toluene
reflux
R
O
R
OH
Scheme 1. General scheme for silica gel promoted cleavage of
t-butyl esters.
The chemoselectivity of the silica gel deprotection was
explored using the substrates shown in entries 4,8 and
9. Of interest was to determine whether the ester groups
could be removed in the presence of other acid labile
* Fax: +1 425 489 8019; e-mail: randy.jackson@celltechgroup.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00980-7

5164
R. W. Jackson / Tetrahedron Letters 42 (2001) 5163–5165
Table 1. Cleavage of t-butyl esters with SiO2 in refluxing toluene5

R. W. Jackson / Tetrahedron Letters 42 (2001) 5163–5165
5165
References
functionalities. As can be seen from entries 4 and 8 the
selectivity for the cleavage of t-butyl esters over t-butyl
ethers can be variable.6 After a reaction time of 1.25 h
in refluxing toluene, the fully protected serine derivative
8a was completely consumed. The product was
obtained in 84% total yield, and analysis of the 1H
NMR showed a 9/1 ratio of mono-deprotected/bis-
deprotected material. There was no evidence of Fmoc-
serine t-butyl ester in the reaction product. The
4-t-butoxycinnamate derivative 4a undergoes reaction
in a less selective manner, affording the mono- and
bis-deprotected products 4b and 4c in a ratio of 2.1/1.
In analogy to the serine derivative 8a, no evidence of
the phenol t-butyl ester was observed. Thus, the extent
of selectivity encountered in the cleavage of t-butyl
esters over t-butyl ethers appears to be substrate depen-
dent, with the rate of ester cleavage potentially being a
prime determinant.
1. (a) Green, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999; (b)
Kocienski, P. J. Protecting Groups; Thieme Medical Pub-
lishers: New York, 1994; pp. 125–128.
2. Wu, Y.-q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J.;
Hamilton, G. S. Tetrahedron Lett. 2000, 41, 2847–2849.
3. Jones, A. B.; Villalobos, A.; Linde, II, R. G.; Danishefsky,
S. J. J. Org. Chem. 1990, 55, 2786–2797.
4. Preparation of 2b: To a solution of 2a (104.6 mg, 0.50 mmol)
in toluene (10 mL) was added SiO2 (2.5 g, EM Science Silica
Gel 60, 230–400 mesh). The solution was refluxed under N2
for 7 h, cooled to ambient temperature and diluted with 20
mL of 10% methanol/methylene chloride. Celite® was
added, and the solution filtered through a pad of Celite®
under vacuum. The solids were washed with methanol/
methylene chloride, and the filtrate concentrated in vacuo.
Residual toluene was readily removed by successive concen-
trations of ethyl acetate and hexane solutions of the
product. The acid 2b was obtained as a white solid (51.6 mg,
The trimethylsilyethyl (TMSE) ester is another protect-
ing group often utilized for carboxylic acids, and a
common mode of deprotection is acid-catalyzed cleav-
age, conditions which will often result in the removal of
t-butyl esters. Entry 9 shows that TMSE esters survive
the SiO2-promoted cleavage conditions, in this case
affording the acid in 78% yield after chromatography.
The high preference for cleavage of t-butyl esters over
TMSE esters has also been observed in a structurally
non-related substrate.7 These results indicate that these
two carboxylic acid protecting groups can generally be
employed in an orthogonal protecting group strategy.8
1
68%) with H NMR and LC/MS properties identical to an
authentic sample of p-anisic acid (Aldrich Chemical Co.).
5. Products were identified by comparison with authentic
1
material or by 300 MHz H NMR and MS. The starting
materials were prepared as follows: 1a and 2a were pre-
pared via reaction of the benzoyl chloride with KOtBu in
THF; 3a and 4a were prepared via Wittig reactions of the
substituted
benzaldehyde
with
(t-butoxycarbonyl-
methylene)triphenylphosphorane in refluxing toluene; 5a
and 8a were prepared by reacting Fmoc-Cl with Phe-OtBu
and Ser(tBu)-OtBu, respectively, in methylene chloride in
the presence of N-methylmorpholine (NMM); 6a and 7a
were prepared via coupling reactions of the appropriate
Fmoc-amino acid with the corresponding amino acid (t-
butyl ester) in methylene chloride using HATU and NMM;
the synthesis of 9a will be described elsewhere.
In conclusion, it has been shown that the use of stan-
dard flash chromatography grade silica gel is a novel
alternative for the cleavage of t-butyl esters and
enhances the usefulness of this functional group. The
mild cleavage conditions broadens the synthetic appli-
cations in which protected carboxylates can be utilized,
and the moderate to high selectivity observed in the
presence of other acid-labile protecting groups extends
the utility of the t-butyl ester as an orthogonal protect-
ing group.
6. Examples of selective removal of t-butyl esters in the
presence of t-butyl ethers: (a) Makara, G. M.; Marshall, G.
R. Tetrahedron Lett. 1997, 38, 5069–5072; (b) MacPherson,
L. J.; Bayburt, E. K.; Capperelli, M. P.; Carroll, B. J.;
Goldstein, R.; Justice, M. R.; Zhu, L.; Hu, S.-i.; Melton, R.
A.; Fryer, L.; Goldberg, R. L.; Doughty, J. R.; Spirito, S.;
Blancuzzi, V.; Wilson, D.; O’Byrne, E. M.; Ganu, V.;
Parker, D. T. J. Med. Chem. 1997, 40, 2525–2532.
7. Jackson, R.W., unpublished results.
8. Examples of selective removal of t-butyl esters in the
presence of TMSE esters: (a) Schmidt, U.; Zah, M.;
Lieberknecht, A. J. Chem. Soc., Chem. Commun. 1991,
1002–1004; (b) Cassidy, M. A.; Crockett, N.; Leeper, F. J.;
Battersby, A. R. J. Chem. Soc., Perkin Trans. 1 1996,
2079–2090.
Acknowledgements
The author wishes to express his gratitude to Dr.
Nathan Ihle for helpful discussions.
.