Solid-phase synthesis of oligoesters using a JandaJel resin

Article abstract of DOI:10.1016/S0040-4039(01)00172-1

This communication describes a general method for the solid-phase synthesis of oligomeric esters. A JandaJel resin was utilized as the solid support in conjunction with the highly acid labile Rink linker. Ester coupling reactions were performed using buff

Full text of DOI:10.1016/S0040-4039(01)00172-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2257–2259
Solid-phase synthesis of oligoesters using a JandaJel™ resin
Oliver Bru¨mmer, Bruce Clapham and Kim D. Janda*
Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology,
10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
Received 11 January 2001; accepted 30 January 2001
Abstract—This communication describes a general method for the solid-phase synthesis of oligomeric esters. A JandaJel™ resin
was utilized as the solid support in conjunction with the highly acid labile Rink linker. Ester coupling reactions were performed
using buffered reagents and the monomer was protected as its allyl ester. In this manner, ester coupling and deprotection could
be performed under essentially neutral conditions, giving rise to products in both excellent yields and purity. © 2001 Elsevier
Science Ltd. All rights reserved.
Since the seminal work of Merrifield for the solid-phase
synthesis of oligopeptides,1 polymer-supported synthe-
ses have been applied to the preparation of other
biologically relevant molecules such as oligonucleo-
tides,2 oligosaccharides3 and more recently peptido-
mimetics.4 Today, solid-phase combinatorial synthesis
is the accepted method used in the quest for com-
pounds of pharmaceutical, agricultural or material
interest.5 Oligoesters can be found in several naturally
occurring compounds including the depsipeptides vali-
nomycin,6 onchidin7 and quinomycin8 as well as the
macrodiolides pyrenophorin, vermiculin and elaphylin.9
In materials science, polyesters are among the most
versatile synthetic polymers and have found wide com-
mercial use as fibers, plastics and coatings.10 Despite
this, the chemical literature contains few examples of
the preparation of oligoesters using either conventional
solution-phase or solid-phase methodology.11
we required access to a series of discrete oligoesters type
2a–e based on the monomer 4-hydroxyphenyl acetic
acid 1 (Fig. 1). Indeed, this monomer has been utilized
in the preparation of liquid crystalline polymers.13
Efforts made to prepare these compounds proved
difficult since purification was complicated by the pres-
ence of incomplete oligoester sequences and the oli-
goesters lack of solubility. A four-step solution-phase
synthesis of a tetrameric ester was achieved in an
acceptable 35% overall yield. However, an additional
four steps of this sequence to give a hexameric product
could only be achieved in 0.4% overall yield.
In order to overcome the problems associated with the
purification and solubility of these intermediate
sequences, a solid-phase synthetic strategy was devised.
Since the desired oligoester had to be cleaved from the
resin under very mild conditions, the highly acid labile
Rink linker was utilized.14 This linker was introduced
onto chloromethyl functionalized JandaJel™ resin,
(our own high swelling alternative to Merrifield resin),15
using standard methodology.16 The dimeric ester 5 was
deemed appropriate for the elongation step and was
Our own interest in oligo esters stems from recent work
that involves ‘proof of principle’ experiments that have
demonstrated the feasibility of antibody catalyzed
degradation of such compounds.12 During these studies
n = 0, dimer 2a
n = 2, tetramer 2b
n = 4, hexamer 2c
n = 6, octamer 2d
OH HO
O
O
O
O
O
1
HO
O
OH
n
n = 8, decamer 2e
Figure 1.
* Corresponding author: Tel.: (858) 784 2515; fax: (858) 784 2595; e-mail: kdjanda@scripps.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00172-1

2258
O. Bru¨mmer et al. / Tetrahedron Letters 42 (2001) 2257–2259
OH
OH a
O
O
HO
O
3
TBDMSO
c
O
HO
1
O
O
O
b
5
O
4
HO
Scheme 1. (a) i. DBU, BnBr, CH3CN, 75%. ii. TBDMSCl, imdazole, DMF, 98%. iii. H2, Pd/C, MeOH, EtOAc, 97%. (b) DBU,
allyl bromide, CH3CN, 58%. (c) i. EDC, HOBT, DIPEA, THF, 49%. ii. TBAF, THF, 89%.
OMe
7a, R=allyl
8a, R=H
MeO
b
O
Cl
O
c
a
2a
6
O
O
O
OR
JandaJel-Rink
Scheme 2. (a) i. 5, DIPEA, CH2Cl2. ii. Ac2O, Pyr., CH2Cl2. (b) Pd(Ph3)4, PhSiH3, CH2Cl2. (c) 10% TFA, CH2Cl2.
O
O
a
b
8a
2b
O
O
O
7b
4
Scheme 3. (a) 5, DIC, DMAP, PTSA, CH2Cl2. (b) i. Pd(Ph3P)4, PhSiH3, CH2Cl2. ii. 10% TFA, CH2Cl2.
synthesized by reaction of 4-tert-butyldimethylsiloxy
phenylacetic acid 3 with allyl (4-hydroxy) phenylacetate
4 in the presence of EDC and HOBT, followed by
TBAF deprotection of the silyl group (Scheme 1).
With these results in hand, hexamer 2c, octamer 2d and
decamer 2e were synthesized by repetition of the depro-
tection and coupling steps. Hexamer 2c was obtained in
reasonable yield with good purity, moreover, this mate-
rial could be purified further using preparative TLC.
Octamer 2e and decamer 2e were also isolated in 54 and
47% yield, respectively, in good purity as estimated by
TLC analysis. Unfortunately, attempts to further purify
these materials led to decomposition of the product; in
addition, the poor solubility of these compounds pre-
cluded a more precise estimation of purity by HPLC.
Dimeric ester 5 was attached to the Rink functionalized
JandaJel™ resin 6 through the phenolic ether linkage
formed in the presence of DIPEA. This was followed
by capping of the residual hydroxyl groups with acetic
anhydride to give support bound allyl ester 7a (Scheme
2). The allyl ester protecting group was then removed
using catalytic (Ph3P)4Pd and PhSiH3 scavenger in
1
Each of the compounds were characterized using H
17
CH2Cl2 to give the support bound dimer 8a. It was
NMR and HRMS. The results for these reactions are
presented in Table 1.
anticipated that these mild and essentially neutral con-
ditions would prevent any undesirable side reactions,
indeed, cleavage of a small portion of resin using 10%
TFA/CH2Cl2 gave dimer 2a in greater than 90% purity
Table 1. Solid-phase synthesis of oligo esters
Oligo ester
% Yield (crude)
% Purity (crude)
1
as estimated by H NMR and HPLC analysis.
Tetramer, 2b
Hexamer, 2c
Octamer, 2d
Decamer 2e
79
\90a
86
ND
ND
63 (54)b
54
The esterification procedure proved more troublesome
to optimize. The standard combinations of EDC,
HOBT and DIPEA, or DCC, DMAP and 4-methyl-
morpholine gave undesirable side products in the resin
cleaved material. After much effort we found that a
mixture of (diisopropylcarbodiimide) DIC, DMAP and
PTSA18 proved to be an ideal combination giving the
desired support bound allyl ester 7b. Subsequent depro-
tection and cleavage from the resin gave tetramer 2b in
79% yield and greater than 90% purity as determined
by 1H NMR and HPLC. Since the Rink linker
employed is highly acid sensitive, the DMAP and PTSA
reagents required mixing prior to addition to the resin
(Scheme 3).19
47
a Purity estimated by 1H NMR.
b Yield after purification by TLC given in parentheses.
Conclusion
In conclusion, we have demonstrated the utility of the
JandaJel™ resins for the solid-phase synthesis of oligo-
esters. By utilizing the highly labile Rink linker,
buffered coupling reagents and neutral deprotection
conditions the desired oligoesters were isolated from the

O. Bru¨mmer et al. / Tetrahedron Letters 42 (2001) 2257–2259
2259
resin in good yield and high purity. This convenient
solid-phase methodology enabled the synthesis of com-
pounds that were previously inaccessible using conven-
tional solution-phase chemistry.
ner, A.; Dobler, M.; Mueller, H. M.; Petter, W.; Zbinden,
P.; Seebach, D. Helv. Chim. Acta 1993, 76, 2004. See also
Ref. 4.
12. Bru¨mmer, O.; Hoffman, T. Z.; Chen, D.-W.; Janda, K.
D. Chem. Commun. 2001, 19–20.
13. Pillai, C. K. S. Pure Appl. Chem. 1998, 70, 1249.
14. Rink, H. Tetrahedron Lett. 1987, 28, 3787.
Acknowledgements
15. (a) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40,
6329–6332; (b) JandaJel™ resins are commercially avail-
able from Aldrich Chemical Company.
16. Garigipati, R. S. Tetrahedron Lett. 1997, 38, 6807.
17. Thieriet, N.; Alsina, J.; Giralt, E.; Guibe´, F.; Albericio,
F. Tetrahedron Lett. 1997, 38, 7275.
We acknowledge financial support from the National
Institute of Health (GM 43858) and (GM 56154), The
Scripps Research Institute and The Skaggs Institute for
Chemical Biology.
18. Moore, J. S.; Stupp, S. I. Macromolecules 1990, 23, 65.
19. Loading of resin: JandaJel™ Rink chloride 6, (590 mg,
prepared from chloromethyl JandaJel™, 0.70 mmol g−1
Cl), allyl dimer 5 (391 mg, 1.20 mmol), CH2Cl2 15 ml and
DIPEA (163 ml, 1.2 mmol) were combined and shaken for
16 h. The resin was washed with CH2Cl2 and methanol
and dried in vacuo to give resin 7a. Residual hydroxyl
linker groups were capped by shaking a suspension of the
resin 7a in CH2Cl2 (15 ml) with acetic anhydride (470 ml,
5.0 mmol) and pyridine (360 ml, 4.5 mmol) for 30 minutes
followed by washing with CH2Cl2 and methanol.
Deprotection: Allyl ether resin 7a was suspended in
CH2Cl2 (15 ml), Pd(Ph3P)4 (63 mg, 0.06 mmol) and
PhSiH3 (615 ml, 5.0 mmol) were added and the mixture
was shaken under inert atmosphere for 2 hours. The resin
was washed with CH2Cl2, methanol and dried in vacuo to
give 8a.
References
1. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
2. Letsinger, R. L.; Mahadevan, V. J. Am. Chem. Soc. 1965,
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93, 492.
4. Kim, H.-O.; Kahn, M. Comb. Chem. High Throughput
Screening 2000, 3, 167.
5. Bunin, B. The Combinatorial Index; Academic Press: San
Diego, 1998.
6. Kuisle, O.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1999,
64, 8063.
7. Fernandez, R.; Rodriguez, J.; Quin˜oa´, E.; Riguera, R.;
Munoz, L.; Fernandez-Suarezs, M.; Debitus, C. J. Am.
Chem. Soc. 1996, 118, 11635.
8. Dell, A.; Williams, D. H.; Morris, H. R.; Smith, G. A.;
Feeney, J.; Roberts, G. C. K. J. Am. Chem. Soc. 1975,
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9. Seebach, D.; Chow, H.-F.; Jackson, R. F. W.; Sutter, M.
A.; Thaisrivongs, S.; Zimmermann, J. Liebigs Ann. Chem.
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10. (a) Stevens, M. P. Polymer Chemistry—An Introduction;
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Polymer Chemistry, 2nd Ed.; Carl-Hanser Verlag:
Munich, 1990;.
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Chim. Acta 1996, 79, 670–701; (b) Plattner, D. A.; Brun-
Cleavage procedure: Resin 8a (62 mg) was treated with
10% TFA in CH2Cl2 for 5 minutes. The resin was washed
with CH2Cl2 and methanol and the filtrate was concen-
trated in vacuo to give dimer 2a (8.1 mg). This yield was
used to calculate a resin loading of 0.46 mmol g−1
.
Ester coupling procedure: Resin 8a (295 mg) was swollen
in CH2Cl2. A solution of allyl dimer 5 (133 mg, 0.41
mmol), DMAP (61 mg, 0.50 mmol), PTSA.H2O (10 mg,
0.05 mmol) and DIC (110 ml, 0.70 mmol) in CH2Cl2 (3
ml) was added and the mixture was shaken for 5 hours.
The resin was washed with CH2Cl2 and methanol to give
7b. Deprotection and cleavage of resin 7b as described
above gave tetramer 2b as a white solid, 79%.
.
.