Traceless solid-phase synthesis of chiral 3-aryl beta-amino acid containing peptides using a side-chain-tethered beta-amino acid building block.

Article abstract of DOI:10.1021/ol9912480

[reaction: see text] A general method for the attachment of a chiral aromatic side-chain-containing beta-amino acid to a polymer support using a traceless silyl linkage strategy has been developed. Using this building block, solid-phase synthesis was carried out to obtain tripeptide analogues with the aromatic ring either unsubstituted or halogenated (Br, I) at the position of the silyl group. The building blocks could generate libraries of peptidomimetics or cyclic peptides containing beta-amino acids with nonpolar side chains.

Full text of DOI:10.1021/ol9912480

ORGANIC
LETTERS
2000
Vol. 2, No. 3
303-306
Traceless Solid-Phase Synthesis of
Chiral 3-Aryl â-Amino Acid Containing
Peptides Using a Side-Chain-Tethered
â-Amino Acid Building Block
Younghee Lee and Richard B. Silverman*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208-3113
Agman@chem.nwu.edu
Received November 12, 1999
ABSTRACT
A general method for the attachment of a chiral aromatic side-chain-containing â-amino acid to a polymer support using a traceless silyl
linkage strategy has been developed. Using this building block, solid-phase synthesis was carried out to obtain tripeptide analogues with the
aromatic ring either unsubstituted or halogenated (Br, I) at the position of the silyl group. The building blocks could generate libraries of
peptidomimetics or cyclic peptides containing â-amino acids with nonpolar side chains.
Since the introduction of the Merrifield resin,1 libraries of
peptides, nucleotides, and organic molecules have been
generated on solid supports.2 The application of combina-
torial methods and high throughput screens have been
powerful tools for the discovery of new leads and drug
candidates. Because of poor oral bioavailability and enzy-
matic degradation of linear peptides, modified peptides,
peptidomimetics, and cyclic peptides have become appealing
targets for the design of therapeutic agents with increased
pharmacological activities.3 Conventional solid-phase peptide
synthesis allows the elongation of the amino acid backbone
unidirectionally (C to N or N to C). However, attachment
of the amino acid side chain to the polymer permits chain
elongation in both directions; thus, more diverse libraries
can be prepared than with conventional methods. Further-
more, head-to-tail cyclization of peptides on the resin
provides a facile route to cyclic compounds. Because the
conventional linkers are mainly based on polar functional
groups, this method has been applicable to amino acids which
have polar side chains such as Asp, Glu (COOH), Ser, Tyr
(OH), Lys, Arg (NH2), or His (imidazole).4
Recent progress in linker technology has provided many
novel linkages to facilitate both solution- and solid-phase
reactions. Among them, a silicon-based linkage strategy to
attach aromatic and heteroaromatic compounds to solid
supports has received much attention.5 This method allows
(1) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154.
(2) (a) Scott, J. K; Smith, G. P. Science 1990, 249, 386. (b) Lam, K. S.;
Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Karzmierski, W. M.; Knapp, R.
J. Nature 1991, 354, 82. (c) Houghton, R. A.; Pinilla, C.; Blondelle, S. E.;
Appel, J, R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84. (d) Tuerk,
C.; Gold, L. Science 1990, 18, 6197. (e) Ellington, A. D.; Szostak, J. W.
Nature 1990, 346, 818. (f) Blackwell, J. K.; Weintraube, H. Science 1990,
18, 6197. (g) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555.
(3) (a) Hintermann, T.; Seebach, D. Chimia 1997, 50, 244. (b) Seebach,
D.; Abele, S.; Schreiber, J.; Martinoni, B.; Nussbaum, A. K.; Schild, H.;
Schulz, H.; Hennecke, H.; Woessner, R.; Bitsch, F. Chimia 1998, 52, 734.
(4) (a) Trzeciak, A.; Bannwarth, W. Tetrahedron Lett. 1992, 33, 4557-
4560. (b) Sabatino, G.; Chelli, M.; Mazzucco, S.; Ginanneschi, M.; Papini,
A. M. Tetrahedron Lett. 1999, 40, 809-812. (c) Rovero, P.; Quartara, L.;
Fabbri, G. Tetrahedron Lett. 1991, 32, 2639-2642. (d) Kates, S. A.; Sole,
N. A.; Johnson, C. R.; Hudson, D.; Barany, G.; Albericio, F. Tetrahedron
Lett. 1993, 34, 1549-1552. (e) Zhong, H. M.; Greco, M. N.; Maryanoff,
B. E. J. Org. Chem. 1997, 62, 9326-9330. (f) Sugiura, T.; Hamada, Y.;
Shioiri, T. Tetrahedron Lett. 1987, 28, 2251-2254.
(5) Chan, T. H. Synthesis 1979, 761-786.
10.1021/ol9912480 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/11/2000

Scheme 1. Synthesis of Polymer-Bound Chiral 3-Phenyl-â-alanine Building Blocka
a Conditions: (a) ethylene glycol, p-toluenesulfonic acid (cat.), benzene, reflux, 4 h; (b) t-BuLi, THF, -78 °C, then allylchlorodimethylsilane;
(c) acetone, p-toluenesulfonic acid (cat)., reflux, 6 h; (d) n-BuLi, THF, -78 °C, then allylchlorodimethylsilane; (e) t-BuLi, THF, -78 °C,
then DMF; (f) Ti(OPr)4, THF, reflux, 1 h; (g) methyl acetate, LDA, THF, -78 °C, then chlorotitanium triisopropoxide (2.1 equiv); (h) 4
N HCl/dioxane, MeOH, 5 min; (i) (R)-MTPACl, pyridine, CHCl3, 2 h; (j) 9-BBN, THF, 5 h, then bromopolystyrene, DMF, Pd(PPh3)4,
Na2CO3, 75 °C, 48 h; (k) 50% TFA in CH2Cl2, 5 min; (l) Br2 in CH2Cl2, 20 min.
the tethering of a substrate to the polymer at an inert site
within the molecule. Upon completion of the desired solid-
phase reactions, selective cleavage of the product at the
position of the silyl group either by protiodesilylation or ipso
substitution (with Br2 or ICl) provided hydrogen- or halide-
substituted compounds. To date, silicon-based linkages have
been employed for solid-phase syntheses of only aromatic
or heteroaromatic compounds.6
In an effort to synthesize libraries of phenylalanine-
containing molecules on a solid support, we devised an
arylsilane-based “traceless linker” strategy to attach the
aromatic side chain of phenylalanine to bromopolystyrene
and prepared phenylalanine- and halide-substituted-phenyl-
alanine-containing dipeptide analogues in high yields and
purities.7 The side-chain-tethered phenylalanine building
block may be used as a tool for the rapid synthesis of
bioactive molecules in which the bulky nonpolar aromatic
moiety plays a key role in the pharmacological effect. Using
a similar strategy, R-amino acid building blocks derived from
other aromatic rings can be constructed.
If libraries of target molecules require an aromatic side
chain as an essential element for favorable interactions with
the biological entity of interest, the R-amino acid can be
replaced with other types of multifunctional units, such as
â-amino acids. New amino acid building blocks can be
designed to generate libraries of compounds containing the
important aromatic side chain. As an example, the cyclo-â-
tetrapeptide prepared by Seebach’s group as a somatostatin
analogue was found to display significant biological activity
and affinity for human receptors.8 This result suggests that
the amino acid backbone can be replaced by other structures,
supporting peptidomimetic approaches for peptide analogues.
â-Amino acids are frequently found in natural products
and in therapeutic agents. Because of the enzymatic stability
of â-peptides in biological systems, â-amino acids have
become useful building blocks for the design of new
peptidomimetics.3 Although there are several known syn-
thetic methods for â-amino acids, such as the Arndt-Eistert
homologation of R-amino acids and catalytic hydrogenation
of 3-aminoacrylate,9 and a number of â-amino acids are
commercially available, it is highly desirable to develop
polymer-bound â-amino acid building blocks as a tool for
the rapid synthesis and high diversification of compounds.
Here we describe a synthetic route and applications of a side-
chain-tethered â-homophenylalanine as an efficient tool to
prepare â-amino acid analogues on a solid support.
Recently, a practical and highly enantioselective synthesis
of tert-butanesulfinamide was reported by the Ellman
group.10 This chiral building block was used effectively for
the asymmetric synthesis of R-branched amines11 and
â-amino acids.12 It was also found that the tert-butanesulfinyl
group acts as a Boc surrogate, which is advantageous for
solid-phase reactions. This method for â-amino acid synthesis
using tert-butanesulfinamide is generally applicable, and we
found that it was well-adapted for the asymmetric synthesis
of â-amino acid analogues with an aromatic side chain
substituted with a silyl group, which was attached to a
polymer support (Scheme 1).
304
Org. Lett., Vol. 2, No. 3, 2000

Scheme 2. Synthesis of 3-Aryl-â-alanine-Containing Tripeptides from the Polymer-Bound â-Alanine Building Block
As illustrated in Scheme 1, commercially available 4-bro-
mobenzaldehyde (2) was treated with ethylene glycol with
a catalytic amount of p-toluenesulfonic acid to afford the
1,3-dioxolane derivative of 2. Lithium-halogen exchange
of the intermediate with tert-butyllithium at -78 °C followed
by addition of allyldimethylsilyl chloride afforded 3 in an
86% yield from 2. Refluxing of 3 in acetone in the presence
of p-toluenesulfonic acid (cat) for 6 h provided 4-(allyldi-
methylsilyl)benzaldehyde (4) in an 86% yield. Alternatively,
4 was synthesized from 1,4-dibromobenzene (5) in a 67%
yield by a two-step sequence: (1) replacement of one
bromine with a silyl group and (2) replacement of the other
bromine with a formylation reaction (t-BuLi, THF, -78 °C,
then DMF). Condensation of 4 with (R)-(-)-tert-butane-
sulfinamide was performed in the presence of titanium
propoxide in refluxing THF for 1 h to give the tert-
butanesulfinyl imine 6 as an oil in a 68% yield. The titanium
enolate generated by transmetalation of lithiated methyl
acetate with ClTi(O-i-Pr)3 in THF at -78 °C was allowed
to react with 6 for 3 h to provide 7 in 79% yield. The
diastereoselectivity of 7 was determined by the analysis of
the Mosher amide 8, prepared by deprotection of the tert-
butanesulfinyl group (4 N HCl/dioxane, MeOH) followed
by subsequent derivatization of the amino group with (R)-
(-)-R-methoxy-R-(trifluoromethyl)phenylacetic acid chloride
(MTPACl).13 Analysis of both 1H NMR and 19F NMR spectra
of 8 showed less than 1% of the minor diastereomer, which
suggests that titanium enolate addition to the sulfinyl imine
6 proceeded in high stereoselectivity. Hydroboration of the
terminal olefin of 7 with 9-BBN in THF followed by in situ
Suzuki coupling14 of the borane complex with bromo-
polystryrene resin15 (Pd(PPh3)4, Na2CO3, in THF/DMF)
resulted in the polymer-bound â-amino acid derivative 9.
The loading level (0.32 mequiv/g) of 9 was determined by
mass balance of (3R)-methyl 3-amino-3-(4-bromophenyl)-
butyrate (10), which was obtained by stirring an aliquot of
resin 9 with 50% TFA in CH2Cl2 for 5 min followed by
washing and then the cleavage reaction (Br2, CH2Cl2, 20
min).
To demonstrate the suitability of building block 9 in solid-
phase synthesis, we have prepared â-amino acid containing
tripeptides 12 according to the procedure shown in Scheme
2.
Resin 9 was treated with 50% TFA in CH2Cl2 for 5 min
to deprotect the amino group, which was treated with Fmoc-
Ala-OH using standard EDC and HOBt coupling conditions
in DMF; then the Fmoc group was deprotected with 20%
piperidine in DMF for 30 min. After several washings of
the resin, benzoic acid was coupled (EDC, HOBt, TEA in
DMF) to the amine to construct the polymer-bound dipeptide
anologue 11. Hydrolysis of the ester group at the C-terminus
(6) (a) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 62, 6006. (b)
Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1997, 62, 1885-2893. (c)
Chenera, B.; Finkelstein, J. A.; Veber, D. F. J. Am. Chem. Soc. 1995, 117,
11999-12000. (d) Boehm, T. L.; Hollis Showlter, H. D. J. Org. Chem.
1996, 61, 6498-6499. (e) Woolard, F. X.; Paetsch, J.; Ellman, J. A. J.
Org. Chem. 1997, 62, 6102-6103. (f) Hu, Y.; Porco, J. A., Jr.; Labadie, J.
W.; Gooding, O. W.; Trost, B. M. J. Org. Chem. 1998, 63, 4518-4521.
(7) Lee, Y.; Silverman, R. B. J. Am. Chem. Soc. 1999, 121, 8407-8408.
(8) Gademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew. Chem.,
Int. Ed. 1999, 38, 1223-1226.
(9) (a) Matthew, J. L; Braun, C.; Guibourdenche, C.; Overhand, M.;
Seebach, D. In EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E.,
Ed.; Wiley: New York 1996; pp 105-126. (b) Cole, D, C. Tetrahedron
1994, 50, 9517. (c) Kobayashi, S.; Ishitani, H.; Ueno, M. J. J. Am. Chem.
Soc. 1998, 120, 431. (d) Ishitani, H.; Ueno, M. J.; Kobayashi, S. J. Am.
Chem. Soc. 1997, 119, 7153.
(13) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(14) Miyarura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(15) Farrall, M. J.; Frechet, J. M. J. Org. Chem. 1976, 41, 3877. The
4-bromopolystyrene resin (50-100 mesh, 1.97 mmol/g resin, produced by
copolymerization of styrene, divinylbenzene (1%), and 4-bromostyrene) used
in this study was purchased from Novabiochem Corp. (San Diego, CA).
(10) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 8011-8019.
(11) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913-9914.
(12) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12-13.
Org. Lett., Vol. 2, No. 3, 2000
305

of 11 was carried out with LiOH (5 equiv) in THF/H2O (8:
1) under refluxing conditions for 2.5 h, and the resulting
carboxylic acid was coupled with Gly-OEt under the same
conditions described above (EDC, HOBt, TEA in DMF).
Upon completion of the synthesis, cleavage of the product
with 50% TFA in CH2Cl2 at room temperature for 24 h
yielded 12a in 88% yield. Alternatively, cleavage of the
tripeptide from the resin by ipso substitution of the silyl group
with either Br2 or ICl in CH2Cl2 for 20 min afforded 12b
and 12c, respectively, in 95% yields. In all cases, the purity
of 12, as determined from the 1H NMR spectra of the crude
products, was greater than 95%. These results indicate the
potential of building block 9 for the solid-phase synthesis
of â-amino acid containing molecules and should be ap-
plicable to the generation of combinatorial libraries.
linker to facilitate maximal diversification of both the N-
and C-termini. Cleavage of the product releases the aromatic
linker moiety either with no substitution or with bromine or
iodine at the para position under mild conditions. Because
nonpolar aromatic rings play an important role as a phar-
macophore in bioactive molecules, this building block may
be used for the design of focused libraries containing a
â-amino acid with a nonpolar aromatic side chain.
Acknowledgment. We are grateful to the National
Institutes of Health (Grant No. GM49725) for financial
support of this research.
Supporting Information Available: Complete experi-
mental details and product characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, a side-chain-tethered â-amino acid building
block has been developed as a tool for solid-phase synthesis
of compounds in which the â-amino acid serves as an inert
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