A new photocleavable linker in solid-phase chemistry for ether cleavage

Article abstract of DOI:10.1021/ol006076h

(equation presented) We have designed a new linker (1) for the solid-phase synthesis that cleaves ether bonds photolytically. the linker was prepared in nine steps and anchored to the support via an amide bond. Photocleavage is a two-step process in which

Full text of DOI:10.1021/ol006076h

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2315-2317
A New Photocleavable Linker in
Solid-Phase Chemistry for Ether
Cleavage
Ralf Glatthar and Bernd Giese*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
bernd.giese@unibas.ch
Received May 18, 2000
ABSTRACT
We have designed a new linker (1) for the solid-phase synthesis that cleaves ether bonds photolytically. The linker was prepared in nine steps
and anchored to the support via an amide bond. Photocleavage is a two-step process in which the immobilized alcohols are released by
photolytic generation of a radical that undergoes a spontaneous â-bond scission. The pivaloyl linker (1) was found to cleave off alcohols in
high yields and purities. Only traces of acid (pH ∼5.5) are necessary for an efficient cleavage.
In the past few years, interest in solid-phase synthesis has
increased dramatically due mainly to the importance of the
concept of combinatorial chemistry, a powerful tool in the
discovery of new biologically active compounds.1 The use
of photolabile linkers2 became widespread in the generation
of combinatorial libraries of organic molecules3 because this
allows a release of the library under mild conditions. This
detachment is orthogonal to acidic and basic reaction
conditions and therefore affords additional flexibility in the
synthesis on solid support.
Whereas much effort was directed toward the development
of photolabile linkers for ester cleavage,4,5 to our knowledge
the photolytic ether cleavage on solid support is unknown.6
All common linkers for ether cleavage are based on acid7 or
base lability,8 oxidative9 or reductive cleavage,10 or fluoride
(6) For a general review of alcohols achieved by cleavage from a linker,
see: (a) James I. W. Tetrahedron 1999, 4855. (b) Guillier, F.; Orain, D.;
Bradley M. Chem. ReV. 2000, 100, 2091.
(7) (a) Frechet, J. M. J.; Nuygens, L. J. Can. J. Chem. 1976, 54, 926.
Krchnak, V. S. W. A. Tetrahedron Lett. 1988, 23, 3023. (b) Kick, E. K.;
Ellman, J. A. J. Med. Chem. 1995, 38, 1427. Wallace, O. B. Tetrahedron
Lett. 1997, 38, 4939. (c) Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco,
J. A., Jr. Tetrahedron Lett. 1997, 38, 4973. Hanessian, S.; Xie, F.
Tetrahedron Lett. 1998, 39, 733. (d) Garigipati, R. S. Tetrahedron Lett.
1997, 38, 6807.
(8) (a) Kurth, M. J.; Randall, L. A. A.; Takenouchi, K. J. Org. Chem.
1996, 61, 8755. (b) Schore, N. E.; Najdi, S. D. J. Am. Chem. Soc. 1990,
112, 441. (c) Berteina, S.; De Mesmaeker, A. Tetrahedron Lett. 1998, 39,
5759.
(1) (a) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555. (b)
Ellman J. A. Acc. Chem. Res. 1996, 29, 132. (c) Broach, J. R.; Thorner, J.
Nature 1996, 384, 14. (d) Brown, R. C. D. J. Chem. Soc., Perkin Trans. 1
1988, 3293. (e) Brown, A. R.; Hermkens, P. H. H.; Ottenheijm, H. C. J.;
Rees, D. C. Synlett 1998, 817.
(2) (a) Pillai, V. N. R. Synthesis 1980, 1. (b) Lloyd-Williams, P.;
Albericio, F.; Giralt, E. Tetrahedron 1993, 49, 11065.
(3) Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele,
J. Tetrahedron 1995, 51 (30), 8135.
(9) Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco, J. A., Jr.
Tetrahedron Lett. 1997, 38, 4973.
(10) (a) Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki, M. Tetrahedron
Lett. 1996, 37, 2809. (b) Ley, S. V.; Mynett, D. M.; Koot, W.-J. Synlett
1995, 1017. (c) Tietze, L. F.; Hippe, T.; Steinmetz, A. Chem. Commun.
1998, 793.
(11) (a) Hu, Y.; Porco, J. A. J.; Labadie, J. W.; Gooding, O. W. J. Org.
Chem. 1998, 63, 4518. (b) Stranix, B. R.; Liu, H. Q.; Darling, G. D. J.
Org. Chem. 1997, 62, 6183. (c) Thompson, L. A.; Moore, F. L.; Moon, Y.;
Ellman, J. A. J. Org. Chem. 1998, 63, 2066. (d) Chan, T.-H.; Huang, W.-
Q. J. Chem. Soc., Chem. Commun. 1985, 909.
(4) (a) Rich, D. H.; Gurwara, S. K. J. Am. Chem. Soc. 1975, 97, 1575.
Renil, M.; Pillai, V. N. R. Tetrahedron Lett. 1994, 35, 3809. (b) Holmes,
C. P. J. Org. Chem. 1997, 62, 2370. Yoo, D. J.; Greenberg, M. M. J. Org.
Chem. 1995, 60, 3358. (c) Ajayagosh, A.; Pillai, V. N. R. Tetrahedron
1988, 44, 6661. (d) Ajayagosh, A.; Pillai, V. N. R. J. Org. Chem. 1987,
52, 5714. (e) Wang, S.-S. J. Org. Chem. 1976, 41, 3258. Bellof, D.; Mutter,
M. Chimia 1985, 39, 317. (f) Rock, R. S.; Chan, S. I. J. Org. Chem. 1996,
61, 1526.
(5) Peukert, S.; Giese, B. J. Org. Chem. 1998, 63, 9045.
10.1021/ol006076h CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/01/2000

sensitive silyl-oxygen bond cleavage.11 To our knowledge
all photolytical releases of alcohols occur over the indirect
way of cleaving carbonates12 or acetals.13
of 7, connecting 8 with the polymer support, and subsequent
nucleophilic epoxide opening (9 f 1, Scheme 2).14
With our newly developed linker 1, a direct photolytical
ether bond cleavage is possible. This linker is a further
development of the previous reported pivaloyl glycol linker
2 for ester cleavage.5
Scheme 2. Attachment to the Solid Support and Modificationa
The new linker 1 differs from 2 mainly in the alkyl chain
connection between the cleavage unit and the solid support.
The synthesis of linker 1 is outlined in Scheme 1.
a (a) 1. KOH, DMF, 95%; 2. DMD, acetone 94%; (b) Tenta Gel
S NH2 or PS-NHMe, DIC, DMAP, CH2Cl2; (c) KOtBu, ROH, THF,
∆ or BF3‚Et2O, ROH, toluene, ∆.
The epoxidation of 7 was performed with a dimethyldiox-
irane solution15 yielding epoxide 8 after deprotection of the
methyl ester with lithium hydroxide. Coupling of 8 with
commercially available amino support (TentaGel or poly-
styrene), conducted by standard procedures (DIC, DMAP,
CH2Cl2), yielded the pivaloyl ketone epoxy linker 9. The
anchoring proceeded with complete conversion as determined
by the Kaiser test.16 Epoxide opening with alcohols was
performed either with bases (f 1a) or acids (f 1b, 1c).
The dipeptide coupling forming 1c was conducted on solid
phase after epoxide opening of 9 with FmocSerOMe. In all
cases, the epoxide was attacked by the nucleophile regio-
selectively from the less hindered site. The tertiary hydroxyl
group proved to be stable under different reaction conditions.
The efficiency of the attachment was estimated by elementary
analysis of heteroatoms in the residue, piperidine-mediated
cleavage of a Fmoc-protecting group in connection with UV-
spectrometric analysis,17 or picric acid monitoring.18 The
attachment of ethers was additionally checked qualitatively
by gel-phase 13C NMR.19 Photolysis of the linker 1a-c with
UV light between 280 and 340 nm released alcohols 11a-c
(Scheme 3).
Scheme 1. Synthesis of the Linker Platforma
a (a) Isobutene, H2SO4, 98%; (b) methyl 4,4-dimethyl-3-oxo-
pentanoate, NaH, DMF, 78%; (c) KOH, MeOH, H2O, ∆, 99%; (d)
MeOH, pTsOH, 98%; (e) N,N-dimethylmethyleneiminium chloride,
CH3CN, pTsOH, ∆, 90%; (f) CH3I, 98%; (g) KOtBu, CH3CN, 80%.
5-Bromovaleric acid 3 was transformed via esterification with
isobutene and subsequent alkylation of methyl 4,4-dimethyl-
3-oxopentanoate to the pivaloyl ketone-substituted dicar-
bonate 4. Decarboxylation led to ketoester 5 and subsequent
Mannich addition with Eschenmoser salt to 6. Alkylation
with methyl iodide and base-induced elimination of trim-
ethylamine yielded the R,â-unsaturated pivaloyl ketone 7.
This approach (overall yield: 52%) requires chromatography
only after the alkylation (f 4) and the elimination step (f
7). The polymer-bound ethers 1 were formed by epoxidation
Scheme 3. Photolytic Cleavage of the Substrate
(12) Alsina, J.; Chiva, C.; Ortiz, M.; Rabanal, F.; Girald, E.; Albericio,
F. Tetrahedron Lett. 1997, 38, 883.
(13) (a) Rodebaugh, R.; Joshi, S.; Fraser-Reid, B.; Geysen, H. M. J. Org.
Chem. 1997, 62, 5660. (b) Dell’Aquita, D.; Imbach, J.-L.; Rayner B.
Tetrahedron Lett. 1997, 38, 5289. (c) Nicolaou, K. C.; Winssinger, N.;
Pastor, J.; DeRoose, F. J. Am. Chem. Soc. 1997, 119, 449.
(14) Beside the epoxidation, dihydroxylation of 7 with subsequent
esterification is possible, too. See also ref 5.
(15) Adam, W.; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377.
(16) Kaiser, E.; Coleacott, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1970, 34, 595.
(17) Fontenot, J. D.; Miller, J. M.; David, M. A.; Montelaro, R. C. Pept.
Res. 1991, 4, 19.
(18) Oded, A.; Houghten, R. A. Pept. Res. 1990, 3, 42.
(19) Look, G. C.; Holmes, C. P.; Chinn, J. P.; Gallop, M. A. J. Org.
Chem. 1994, 59, 7588.
The yields of the alcohols 11a-c were determined by gas
chromatography or RP-HPLC after photolysis of the sus-
2316
Org. Lett., Vol. 2, No. 15, 2000

pended resin beads 1 in quartz cells. The optical equipment
used was a 500 W Hg high-pressure lamp with cutoff filters
or a Rayonet reactor with up to 16 × 21 W lamps of a
spectral energy distribution from 370 to 250 nm with the
maximum at 300 nm. The cleavage yields are shown in Table
1.
To examine the stability of the linker toward different
reagents, resin 1a was treated under various reaction condi-
tions for 2 h. Afterward, the resins were washed, dried, and
subjected to photolysis. Yields of the photocleavage were
compared with results of the photolysis of untreated resin
1a and are given in Table 2. The linker showed good to
Table 2. Stability of the Linker toward Different Reagents
Table 1. Photolysis of the Resin-Bound Ethers 1a-c
yielda
(%)
yielda
(%)
ROH
cleavage conditions
yielda (%)
11a b
11a b
11a b
11a b
11be
11be
11be
11be
11cb
hν (300 nm), CH2Cl2,c 2 h, rt
hν (300 nm), CHCl3, 2 h, rt
hν (300 nm), THF, HCl,d 2 h, rt
hν (300 nm), MeOH, HCl,d 2 h, rt
hν (300 nm), CH2Cl2,c 2 h, rt
hν (300 nm), CHCl3, 2 h, rt
hν (300 nm), THF, HCl,d 2 h, rt
hν (300 nm), MeOH, HCl,d 2 h, rt
hν (300 nm), CH2Cl2,c 2 h, rt
78
80
51
65
68
65
59
61
61
TFA/CH2Cl2, rt
96
99
93
91
DIPEA/THF, 60 °C
DBU/toluene, 80 °C
hydrazine/THF, rt
KOtBu/THF, rt
91
89
96
97
p-TsOH/toluene, 80 °C
BF3‚Et2O/CH2Cl2, rt
LiAlH4/Et2O, rt
a Yield of photolysis compared to yield of photolysis of untreated resin.
excellent stability toward Brønsted and Lewis acids and
bases. Whereas in 2 the ester linkage was unstable toward
LiAlH4 and nucleophiles,5 the ether bond of 1 tolerated these
conditions.
a Yield determined by GC, HPLC, or UV. b Cleaved from polystyrene
resin. c Contains 0.02% 2-methyl-2-butene. d 0.001-0.01% HCl in the
corresponding solvent (pH ∼5.0-5.5). e Cleaved from TentaGel S resin.
In summary, the new linker 1 allows the photolytical
scission of ether bonds. For an efficient cleavage, a slightly
acidic medium (pH 5.0-5.5) is necessary. Because photolysis
is conducted by 300 to 340 nm light, easy handling in the
laboratory without precautions is possible. The photobyprod-
ucts are either volatile (CO and isobutene/isobutane) or inert
(resin-bound methyl ketone). Finally, the linker is compatible
with many reagents and reactions, which allows broad
application in combinatorial chemistry.
Dichloromethane, chloroform, THF, and methanol were
chosen for the photolysis study of the resin-bound ethers
1a-c (Table 1). The cleavage in dichloromethane and
chloroform led to alcohols 11a-c in 61-80% yields whereas
in THF and methanol the cleavage occurred only in 3-7%
yields (data not shown in Table 1). But addition of catalytic
amounts of HCl to the THF or methanol solutions (pH
∼5.0-5.5)20 led to an efficient cleavage also in these
solvents.21 In comparison to the cleavage conditions for acid
labile linkers,7 the slightly acidic medium used here is much
milder.22
Acknowledgment. This work was supported by the Swiss
National Science Foundation and by Novartis. The authors
thank Dr. P. Schneider (Norvartis) and Dr. J. Zimmermann
(Novartis) for valuable discussions.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1a-c, 3,
and 9 and general photolysis conditions. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) 0.001-0.01% concentrated HCl in the corresponding solvent (pH
∼5.0-5.5); 0.1 equiv of HCl relative to the ether is sufficient to catalyze
this reaction.
(21) In CH2Cl2 and CHCl3 the photolysis generated small amounts of
HCl (pH ∼4.5-5.5).
(22) For example, the release of alcohols from Rink-linker affords 1-5%
TFA in CH2Cl2. That corresponds to a pH value of 1-2.
OL006076H
Org. Lett., Vol. 2, No. 15, 2000
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