J. Am. Chem. Soc. 1996, 118, 2109-2110
2109
Generalized Dipeptidomimetic Template: Solution
Phase Parallel Synthesis of Combinatorial Libraries
Dale L. Boger,*,† Christine M. Tarby,‡ Peter L. Myers,‡ and
Lynn Helena Caporale‡
The Scripps Research Institute
10666 North Torrey Pines Road
La Jolla, California 92037
Figure 1.
CombiChem, Inc., 9050 Camino Santa Fe
San Diego, California 92121
for large libraries.7 It requires functionalized solid supports and
orthogonal chemistries suitable for substrate attachment/detach-
ment, compatible spacer linkers, specialized protocols for
monitoring the individual steps of a multistep solid phase
synthesis8 including the use of attendent orthogonal capping
strategies for blocking unreacted substrate, and does not permit
the purification of resin-bound intermediates. Consequently,
an important complement to adapting solution phase chemistry
to solid phase combinatorial synthesis is the development of
protocols for solution phase combinatorial synthesis.6 Given
that solution and solid phase sample manipulation are both
convenient and easily automated, the only limitation to the
solution phase parallel synthesis of chemical or combinatorial
libraries is isolation or purification of the reaction products. If
the advantages of sample isolation attributed to solid phase
synthesis may be embodied in a solution phase synthesis, its
nonlimiting scale, expanded repertoire of chemical reactions,
direct production of soluble intermediates and final products
for assay or for purification, and the lack of required linking,
attachment/detachment, or capping strategies make solution
phase combinatorial synthesis a most attractive alternative. A
number of potential techniques are available for such purposes,
and one of the most attractive is liquid/liquid or solid/liquid
extraction. Herein, we describe a high-purity solution phase
parallel synthesis of a chemical library employing a dipeptido-
mimetic template which illustrates a simple and general isolation
and purification protocol at each step.
Compound 1 is a designed rigid template which contains a
number of important features. When fully extended, 1 contains
a rigid bicyclic core with a plane of symmetry which enables it
to function as a Gly-X mimic (Figure 1). When positions 1
and 3 are extended, the conformation mirrors that of an extended
sheet. Extension of positions 1 and 2 introduces a turn motif.
When all three positions are utilized, an interesting core
peptidomimetic which explores three-dimensional space is
produced. Its symmetrical structure contains three positions
which can be controllably functionalized with a variety of
nucleophiles and acylating agents enabling the synthesis of
libraries with three variable units (Scheme 1). As an anhydride,
the starting template is activated for the first functionalization,
which upon reaction liberates its second functionalization site
(-CO2H). As such, no orthogonal protecting groups are
required for the selective template functionalization and only
four chemical steps are required for N3 diversification. The
same released functionality (CO2H, NH) may be used for
purification of the expected products from starting materials,
reagents, and reaction byproducts by simple liquid/liquid or
solid/liquid extraction. Any alcohol, amine, thiol, or nucleophile
can be added to open the starting template anhydride. Following
functionalization of the released acid, removal of an orthogonal
protecting group on nitrogen allows an additional stage for
ReceiVed NoVember 27, 1995
Combinatorial synthesis, with its ability to rapidly produce
large numbers of diverse compounds in a cost-effective manner
in conjunction with high-throughput screening of the ever
increasing number of molecular targets, has been anticipated
to accelerate the drug discovery process.1 Initially implemented
with oligomeric peptide and nucleotide synthesis, more recent
efforts have been directed toward conventional small-molecule
synthesis. The implications of the technology are apparent both
for the production of diverse lead-generation libraries and for
the production of smaller targeted libraries for optimization
around a promising lead candidate.
A variety of methods have been utilized for the generation
of diverse chemical libraries. These include mixed, indexed,
encoded, or parallel synthesis on pins,2 beads,3 chips,4 and other
solid supports5 while solution phase synthesis has not been
widely embraced as a viable alternative.6 In part, this may be
attributed to the evolution of combinatorial synthesis from solid
phase peptide and oligonucleotide synthesis where supported
phase synthesis has emerged as the medium of choice. Syn-
thesis on a solid support offers the two important advantages
of product isolation and manipulation that remain key issues in
the generation of chemical libraries. It allows for the removal
of reactants and nonbound byproducts by simple filtration
enabling the use of excess reagents to effect high yields with
no loss of product during isolation. However, the scale of solid
phase synthesis is limited and generally restricted by the amount
of the solid support and its loading capacity, and the production
of multi-milligram quantities can be cumbersome and expensive
† The Scripps Research Institute.
‡ CombiChem, Inc.
(1) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele,
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E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J.
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(6) Panlabs have disclosed but not yet detailed a single-step parallel
synthesis of individual compounds using reliable solution chemistry, and
three groups have disclosed solution phase, single-step amide, ester, or
carbamate condensations for the preparation of library mixtures. Peterson,
J. B. In Exploiting Molecular DiVersity: Small Molecule Libraries for Drug
DiscoVery; La Jolla, CA, January 23-25, 1995. Smith, P. W.; Lai, J. Y.
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(7) For a 10000-member library (three-step synthesis at 95% yield/step)
to obtain 50 mg of each component (MW ) 500 g/mol) on Merrifield resin
with a typical loading of 1 mmol/g requires 1.166 kg of solid support )
$2449/library; on Wang resin with a loading of 0.7 mmol/g, it requires
1.666 kg of solid support ) $8331/library.
(8) Egner, B. J.; Langley, G. J.; Bradley, M. J. Org. Chem. 1995, 60,
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0002-7863/96/1518-2109$12.00/0 © 1996 American Chemical Society