Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans

Article abstract of DOI:10.1021/ja002033k

Herein we report a novel strategy for the design and construction of natural and natural product-like libraries based on the principle of privileged structures, a term originally introduced to describe structural motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugural template for the construction of natural product-like libraries via this strategy. Initially, a novel solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that relies on the use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated through the construction of six focused combinatorial libraries designed around natural and designed molecules of recent biological interest.

Full text of DOI:10.1021/ja002033k

J. Am. Chem. Soc. 2000, 122, 9939-9953
9939
Natural Product-like Combinatorial Libraries Based on Privileged
Structures. 1. General Principles and Solid-Phase Synthesis of
Benzopyrans
K. C. Nicolaou,* J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S. Barluenga, and
H. J. Mitchell
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
and Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe,
La Jolla, California 92093
ReceiVed June 7, 2000
Abstract: Herein we report a novel strategy for the design and construction of natural and natural product-
like libraries based on the principle of priVileged structures, a term originally introduced to describe structural
motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged
structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as
an inaugural template for the construction of natural product-like libraries via this strategy. Initially, a novel
solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that
relies on the use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and
cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated
through the construction of six focused combinatorial libraries designed around natural and designed molecules
of recent biological interest.
Introduction
libraries of natural product analogues and natural product-like
compounds.6 Many of these libraries attempt to emulate the
structural characteristics observed in natural products but, at
the same time, provide more rapid access to larger collections
of products that possess greater diversity and incorporate
optimized physical and pharmacological properties into their
structures. A number of different strategies have emerged for
making these libraries with the earliest efforts focused on the
immobilization of complex natural product skeletons (usually
derived from either semisynthesis or total synthesis) onto solid
support to be used as scaffolds which are derivatized and cleaved
to provide focused libraries. Examples of this approach include
the construction of small libraries based upon the natural
products yohimbine,7 paclitaxel,8 sarcodictyins,9 and vancomy-
cin.10 In a related approach, the convergent total synthesis of
several natural products has been achieved on solid support,
and the use of multicomponent building block pools in these
Natural products play important roles in both drug discovery
and chemical biology. In fact, many approved therapeutics as
well as drug candidates are derived from natural sources.1
Additionally, natural products have been extensively used to
elucidate complex cellular mechanisms, including signal trans-
duction and cell cycle regulation leading to the identification
of important targets for therapeutic intervention.2 As a result
of recent advances in biology, there is now an increased demand
for new natural product-like small molecules. Specifically, the
fields of genomics and proteomics promise the rapid identifica-
tion of large numbers of gene products for which small molecule
modulators will be of both biological and medicinal interest.3
Moreover, the combination of cell biology and high throughput
technology has led to the development of various cellular assays
in which small molecule libraries can be used to efficiently
identify and help study previously unknown macromolecular
targets.4
(4) For examples, see: (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S.
J.; King, R. W.; Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971-
974. (b) Silverman, L.; Campbell, R.; Broach, J. R. Curr. Opin. Chem.
Biol. 1998, 2, 397-403.
(5) For discussion, see: (a) Cordell, G. A.; Shin, Y. G. Pure Appl. Chem.
1999, 71, 1089-1094. (b) Corley, D. G.; Durley, R. C. J. Nat. Prod. 1994,
57, 1484-1490. (c) Cordell, G. A. Phytochemistry 1995, 40, 1585-1612.
(6) (a) Watson, C. Angew. Chem., Int. Ed. 1999, 38, 1903-1908. (b)
Bertels, S.; Frormann, S.; Jas, G.; Bindseil, K. U. Drug DiscoVery Nat.
1999, 72-105. (c) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127-
1152.
Despite the increased need for new natural products, their
isolation and structure elucidation still remain a highly labor-
intensive process.5 As an alternative, chemists are now enlisting
the tools of solid-phase combinatorial synthesis to construct
* Address correspondence to this author at The Scripps Research Institute.
(1) For reviews, see: (a) Cragg, G. M.; Newman, D. J.; Snader, K. M.
J. Nat. Prod. 1997, 60, 52-60. (b) Shu, Y.-Z. J. Nat. Prod. 1998, 61, 1053-
1071.
(2) For reviews, see: (a) Hinterding, K.; Alonso-D´ıaz, D.; Waldmann,
H. Angew. Chem., Int. Ed. 1998, 37, 688-749. (b) Hung, D. T.; Jamison,
T. F.; Schreiber, S. L. Chem. Biol. 1996, 3, 623-639.
(3) (a) Lenz, G. R.; Nash, H. M.; Jindal, S. Drug DiscoVery Today 2000,
5, 145-156. (b) Razvi, E. S.; Leytes, L. J. Mod. Drug DiscoVery 2000,
41-42. (c) Rosamond, J.; Allsop, A. Science 2000, 287, 1973-1976. (d)
Garrett, M. D.; Workman, P. Eur. J. Cancer 1999, 35, 2010-2030. (e)
Barry, C. E.; Slayden, R. A.; Sampson, A. E.; Lee, R. E. Biochem.
Pharmacol. 1999, 59, 221-231.
(7) Atuegbu, A.; Maclean, D.; Nguyen, C.; Gordon, E. M.; Jacobs, J.
W. Bioorg. Med. Chem. 1996, 4, 1097-1106.
(8) Xiao, X.-Y.; Parandoosh, Z.; Nova, M. P. J. Org. Chem. 1997, 62,
6029-6033.
(9) (a) Nicolaou, K. C.; Winssinger, N.; Vourloumis, D.; Ohshima, T.;
Kim, S.; Pfefferkorn, J.; Xu, J. Y.; Li, T. J. Am. Chem. Soc. 1998, 120,
10814-10826. (b) For a review, see: Nicolaou, K. C.; Pfefferkorn, J.; Xu,
J.; Winssinger, N.; Oshima, T.; Kim, S.; Hosokawa, S.; Vourloumis, D.;
van Delft, F.; Li, T. Chem. Pharm. Bull. 1999, 47, 1199-1213.
10.1021/ja002033k CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/30/2000

9940 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
syntheses has resulted in the production of libraries as demon-
strated for the prostaglandins,11 epothilones,12 muscones,13 (S)-
zearalenone,14 and HPE.15 To achieve the construction of larger
(nontarget directed) libraries, Schreiber et al. has described
several diversity-oriented solid-phase synthetic strategies used
to create libraries of complex structures for screening in various
chemical genetic applications.16 More recently, a solid-phase
combinatorial construction of carpanone-like libraries using a
biosynthesis inspired reaction sequence was reported by Shair.17
Finally, while not a chemical strategy per se, various genetic
recombination techniques have been used to re-engineer mi-
croorganisms to synthesize “unnatural” natural products, espe-
cially in the area of polyketide biosynthesis.18
We now introduce a strategy for the construction of natural
product-like libraries using the concept of priVileged structures,
a term first proposed by Evans et al. to describe select structural
types (originally benzodiazepines and benzazepines) that bind
to multiple, unrelated classes of protein receptors as high affinity
ligands.19 These privileged structures are typically rigid, poly-
cyclic heteroatomic systems capable of orienting varied sub-
stituent patterns in a well-defined three-dimensional space.20 The
tendencies of derivatives of these privileged structures to exhibit
binding affinity toward various receptors and enzymes has made
them attractive scaffolds for discovery libraries, particularly in
cases when there is only limited structural information available
about the target.19 The utility of this approach is readily evident
by the numerous libraries which are designed and constructed
on such scaffolds.21,22
Figure 1. Overall strategy for the design, synthesis, and application
of natural product-like combinatorial libraries based upon privileged
structures.
for either unknown or recently discovered biological targets.
We were particularly intrigued by the possibility that using
scaffolds of natural origin, which presumably have undergone
evolutionary selection over time, might confer favorable bio-
activities and bioavailabilities to library members. Thus, we
sought to identify privileged structural subunits found in
biologically active natural products and use them as templates
for the construction of libraries. Our generalized strategy is
outlined in Figure 1. Accordingly, after identification of a motif,
a suitable solid-phase methodology would be developed for the
efficient loading, functionalization, and cleavage of compounds
based on the structure of interest. The preliminary testing and
refinement of this method is proposed to be accomplished
through the solid-phase synthesis of various natural products
and small demonstration libraries of analogues. It was reasoned
that using focused libraries as a synthetic testing ground for
the solid-phase chemistry will have a 3-fold advantage in that
it (a) requires the testing of a wide variety of reactions in
situations where the cleavage products could be carefully
analyzed to determine reaction reliability, (b) would provide
access to libraries focused around several natural products of
current biological interest, thereby facilitating structure activity
studies of these molecules, and (c) should create a collection
of several hundred unique compounds that can be added to the
larger, anticipated libraries to enhance overall diversity. Comple-
tion of these smaller libraries is expected to provide a basis set
of solid-phase reactions amenable to the template of interest,
and from this pool it would be possible to select several reaction
sequences useful for the construction of a larger, more diverse
natural product-like library. This latter effort might also require
additional reaction validation as well as an appropriate high
throughput encoding strategy such that cleavage of the members
of this large library would result in a collection of spatially
distinct compounds in a suitable format for biological screening
as suggested in Figure 1.
Given the success of privileged structures in medicinal
chemistry, we envisioned a similar application of this concept
to the construction of natural product-like libraries, especially
since the principal use of such libraries is to discover ligands
(10) (a) Xu, R.; Greiveldinger, G.; Marenus, L. E.; Cooper, A.; Ellman,
J. A. J. Am. Chem. Soc. 1999, 121, 4898-4899. (b) Nicolaou, K. C.;
Winssinger, N.; Hughes, R.; Smethurst, C.; Cho, S. Y. Angew. Chem., Int.
Ed. 2000, 39, 1984-1989.
(11) (a) Lee, K. J.; Angulo, A.; Ghazal, P.; Janda, K. D. Org. Lett. 1999,
1, 1859-1862. (b) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119,
8724-8725. (c) Dragoli, D. R.; Thompson, L. A.; O’Brien, J.; Ellman, J.
A. J. Comb. Chem. 1999, 1, 534-539. (d) Thompson, L. A.; Moore, F. L.;
Moon, Y.-C.; Ellman, J. A. J. Org. Chem. 1998, 63, 2066-2067.
(12) (a) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia,
F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E.
Nature 1997, 387, 268-272. (b) Nicolaou, K. C.; Vourloumis, D.; Li, T.;
Pastor, J.; Winssinger, N.; He, Y.; Ninkovic, S.; Sarabia, F.; Vallberg, H.;
Roschangar, F.; King, N. P.; Finlay, M. R. V.; Giannakakou, P.; Verdier-
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(c) For a review see: Nicolaou, K. C.; Roschangar, F.; Vourloumis, D.
Angew. Chem., Int. Ed. 1998, 37, 2014-2045.
(13) Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F. J. Am. Chem.
Soc. 1998, 120, 5132-5133.
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Chem., Int. Ed. 1998, 37, 2534-2537.
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Chem. Soc. 1997, 119, 449-450.
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Schreiber, S. L. J. Am. Chem. Soc. 1999, 121, 9073-9087. (b) Lee, D.;
Sello, J. K.; Schreiber, S. L. J. Am. Chem. Soc. 1999, 121, 10648-10649.
(c) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-712.
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D. J. Am. Chem. Soc. 2000, 122, 422-423.
To demonstrate these principles, in this and the following
articles, we detail the construction of a 10 000-membered natural
product-like library based on the 2,2-dimethylbenzopyran
template, a structural motif found in numerous natural products.
In this paper, we outline our rationale for selecting the
benzopyran as a privileged structure and then describe the
(18) For a review, see: (a) Khosla, C. Chemtracts 1998, 11, 1-15. (b)
Hertweck, C. Chem. BioChem. 2000, 1, 103-106.
(19) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
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A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-2246.
(20) The term priVileged structure has been suggested to also include
the following: benzamidines, biphenyltetrazoles, spiropiperidines, indoles,
and benzylpiperidines. See: Mason, J. S.; Morize, I.; Menard, P. R.; Cheney,
D. L.; Hulme, C.; Labaudiniere, R. F. J. Med. Chem. 1999, 42, 3251-
3264 and references therein.
(21) For reviews of recent libraries, see: (a) Dolle, R. E.; Nelson, K. H.
J. Comb. Chem. 1999, 1, 235-282. (b) Andres, C. J.; Denhart, D. J.;
Deshpande, M. S.; Gillman, K. W. Comb. Chem. High Throughput
Screening 1999, 2, 191-210 and references therein.
(22) For an example of computational library design using privileged
substructures, see: Lewell, X. Q.; Judd, D.; Watson, S.; Hann, M. J. J.
Chem. Inf. Comput. Sci. 1998, 38, 511-522.

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9941
development of solid-phase chemistry for its construction
through a unique cycloloading strategy.23 The versatility and
reliability of this cycloloading strategy is subsequently refined
through the solid-phase synthesis of six small combinatorial
libraries and various other natural and designed benzopyran-
type molecules of recent medicinal interest. The following paper
describes the application of this chemistry to the construction
of a 10 000-membered natural product-like library paying
particular attention to diversity assessment, quality control, use
of a new encoding technology, and biological applications.24
The final paper of this series describes a practical parallel
solution phase approach for the diversity enhancement of these
benzopyran libraries through the introduction of additional
functionality on the pyran ring of the template.25
may be capable of interacting with a variety of cellular targets.
In addition, the fact that many of the structures are active in
cell-based assays suggested that derivatives of the benzopyran
unit remain sufficiently lipophilic to cross cell membranes, a
key feature of any biologically relevant small molecule library.26
These generalizations were corroborated by the fact that a variety
of designed pharmaceutical ligands containing the motif have
recently been disclosed, including compounds 40-44 (Figure
2); furthermore, a topographical analysis of structures of known
therapeutics identified the benzopyran moiety as a preferential
framework for drug design.28 A final, more subtle, advantage
to the use of the 2,2-dimethylbenzopyran template is that the
olefin of the pyran ring constitutes a latent site of diversity. In
other words, while this olefin will not be modified in the primary
library, one could envision a range of subsequent modifications
that could be used to either increase library diversity or enhance
the properties of a particular lead structure. Such pyran olefins
are readily modified by hydrogenation, epoxidation, dihydroxy-
lation, and aminohydroxylation giving rise to a large number
of biologically active structures,27 prominent examples of which
include the ATP-dependent potassium channel activator cro-
makalim70 (45, Figure 3), the anti-HIV agent suksdorfin71 (46,
Figure 3), and the antineoplastic natural product â-lapachone72
(47). The molecular diversity implementations of these modi-
Results and Discussion
Selection of the Benzopyran as a Privileged Structure.
From the outset, we were aware that ultimate success of these
efforts was contingent on the proper choice of a privileged
natural product motif to be used as a library template. In
deliberating, we required a structure that was found as a subunit
in a large number of natural products with diverse biological
activities, and this template needed to accommodate the instal-
lation of a maximum degree of diversity via solid-phase split-
and-pool synthesis. Furthermore, the scaffold should contain
one or more rigid ring systems such that substituents would be
presented to potential binding targets in a well-defined fashion.
Finally, we required that the template be sufficiently lipophilic
to ensure good cell membrane penetration, and that the majority
of final library members be of less than 500 molecular weight.26
A search of chemical abstracts revealed the 2,2-dimethyl-
2H-benzopyran moiety to be present in more than 4000
compounds including natural products and designed structures.27
The relatively high incidence of this benzopyran unit (and its
derivatives, vide infra) in natural products is partially attributable
to the numerous prenylation and cyclization reactions in many
polyketide biosynthesis pathways. Representative members of
these natural products are illustrated in Figure 2 along with their
reported biological activities. Examining the characteristics of
compounds 1-44 (Figure 2) reveals their diverse structural
properties, and more importantly, their wide ranging biological
actions, suggesting that derivatives of this benzopyran motif
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9942 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
Figure 2. Selected examples of benzopyran containing natural products and pharmaceutical ligands along with reported biological activities.
fications and a unique parallel solution-phase strategy for
introducing them into the current benzopyran libraries are
discussed in the third paper of this series.25
Development of Solid-Phase Chemistry. When considering
a solid-phase method to load, derivatize, and cleave the
benzopyran motif, we were particularly interested in developing

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9943
Scheme 1. Proposed Solid-Phase Loading, Elaboration, and
Cleavage of 2,2-Dimethylbenzopyran.a
Figure 3. Selected examples of biologically active benzopyrans in
which the pyran olefin has been modified.
a strategy whereby the loading and/or cleavage step(s) would
contribute to the complexity of the target structure.73 The
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446.
scaffold and also eliminates the issue of residual functionality
in the target structure resulting from the linker. Well-suited to
this application was a polystyrene-based selenenyl bromide resin
recently developed in our laboratories74a which is capable of
loading substrates through electrophilic cyclization reactions.75
Thus, one could envision (as outlined in Scheme 1) the loading
of an o-prenylated phenol (48, Scheme 1) through a prece-
dented76 6-endo-trig cyclization to give resin-bound benzo-
pyrans (50) linked to the resin through a selenoether. Such resin-
bound scaffolds could then be elaborated (see Scheme 2) to a
variety of natural and designed structures using the functionality
of the aromatic ring. Such elaborations may include, but are
not limited to, annulations, condensations, aryl/vinyl couplings,
glycosidations, and organometallic additions as illustrated in
Scheme 2. Subsequently, the desired benzopyran derivative can
be released from solid support by oxidation of the selenide to
the corresponding selenoxide which undergoes spontaneous syn-
elimination at 25 °C. Besides its efficiency and chemical
robustness (see Table 2), linking of the pyran ring offers the
added advantage that all four positions of the aromatic ring (i.e.
R1-R,4 structure 50 of Scheme 1) remain available for instal-
(59) Tanaka, T.; Koike, K.; Mitsunaga, K.; Narita, K.; Takano, S.;
Kamioka, A.; Sase, E.; Ouyang, Y.; Ohmoto, T. Phytochemistry 1995, 40,
1787-1790.
(60) Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Kuoh, C.-S. Phytochemistry
1999, 52, 523-527.
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334.
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1298.
(63) De la Fuente, G.; Reina, M.; Timon, I. Phytochemistry 1991, 30,
2677-2684.
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tochemistry 1994, 36, 1073-1076.
(65) Daele, V.; Paul, G. H.; Marie, J. P. R.; Laerhoven, V.; Carolus, W.
J. WO-A 9412494 [Chem. Abstr. 1994, 121, 99834].
(66) Soll, R. M.; Dollings, P. J.; Mitchell, R. D.; Hafner, D. A. Eur. J.
Med. Chem. 1994, 29, 223-232.
(67) Mackenzie, A. R.; Monaghan, S. M., Pfizer Research and Develop-
ment Co., WO-A 9420491 [Chem. Abstr. 1994, 123, 55885].
(68) Gutterer, B.; Flockerzi, D.; Amschler, H.; Ulrich, W.-R.; Bar, T.;
Martin, T.; Hatzelmann, A.; Boss, H.; Beume, R.; Hafner, D.; Kley, H.-P.,
Byk Gulden Lomberg Chemische Fabrik Gmbh, Germany, European Patent
Application EP 96-111557 19960718 [Chem. Abstr. 1998, 128, 140610].
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T., Japan Kokai Tokkyo Koho, Japanese Patent JP 11209366 [Chem. Abstr.
1999, 131, 129903].
(74) (a) Nicolaou, K. C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem.
Commun. 1998, 1947-1948. For preparation of related selenium-based
resins, see: (b) Ruhland, T.; Andersen, K.; Pedersen, H. J. Org. Chem.
1998, 63, 9204-9211. (c) Fujita, K.; Watanabe, K.; Oishi, A.; Ikeda, Y.;
Taguchi, Y. Synlett 1999, 11, 1760-1761. (d) Russell, H. E.; Luke, R. W.
A.; Bradley, M. Tetrahedron Lett. 2000, 41, 5287-5290.
(75) (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Kim, S.; Kessabi,
J. Org. Lett. 1999, 5, 807-810. (b) Nicolaou, K. C.; Roecker, A. J.;
Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 2966-2967.
(76) For solution phase precedent of selenium-mediated 6-exo-trig
cyclizations of ortho-prenylated phenols and related systems, see: (a) Clive,
D. L. J.; Chittattu, G.; Curtis, N. J.; Kiel, W. A.; Wong, C. K. J. Chem.
Soc., Chem. Commun. 1977, 725-727. (b) Anzeveno, P. B. J. Org. Chem.
1979, 44, 2578-2580. (c) Nicolaou, K. C.; Lysenko, Z. J. Am. Chem. Soc.
1977, 99, 3185-3187.
(70) Ashwood, V. A.; Buckingham, R. E.; Cassidy, F.; Evans, J. M.;
Faruk, E. A.; Hamilton, T. C.; Nash, D. J.; Stemp, G.; Willcocks, K. J.
Med. Chem. 1986, 29, 2194-2201.
(71) Lee, T. T.-Y.; Kashiwada, Y.; Huang, L.; Snider, J.; Cosentino, M.;
Lee, K.-H. Bioorg. Med. Chem. 1994, 2, 1051-1056.
(72) (a) Wuerzberger, S. M.; Pink, J. J.; Planchon, S. M.; Byers, K. L.;
Bornmann, W. G.; Boothman, D. A. Cancer Res. 1998, 58, 1876-1885.
(b) Li, C. D.; Li, Y.-Z.; Pinto, A. V.; Pardee, A. B. Proc. Natl. Acad. Sci.
U.S.A. 1999, 96, 13369-13374.
(73) (a) For a review, see: van Maarseveen, J. H. Comb. Chem. High
Throughput Screening 1998, 1, 185-214.

9944 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
Table 1. Loading and Cleavage of 2,2-Dimethylbenzopyransa
Scheme 2. Potential Reaction Pathways Leading to
Structurally Diverse Derivatives of Resin-Bound
Benzopyrans
entry phenol prepb
R1
R2
R3
R4
purityc (%)
1
2
3
4
5
6
7
8
9
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
A
A
A
A
A
A
A
A
C
A
D
C
C
A
D
C
C
C
C
C
C
C
C
C
C
D
A
D
A
A
C
C
C
C
C
C
B
B
B
B
B
B
B
B
B
B
B
OH
H
H
OH
H
H
OMe
OMe
H
H
OH
H
H
H
OH
H
H
CN
H
H
H
H
H
H
H
OH
H
OMe CHO
Me
H
H
H
OMe CHO
H
H
CHO
Br
H
H
H
H
OH
H
H
H
H
H
H
Ac
Ac
Ac
H
CO2Me
CO2Me OH
CO2Me
CO2Me
CO2H
H
CN
CN
H
H
NO2
H
CHO
CHO
CHO
H
H
H
H
H
H
OH
OMe
H
H
H
H
H
Ac
H
H
OH
OMe
H
H
H
95
95
95
95
95
95
95
95
95
95
95
- - -
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
95
- - -
- - -
90
90
95
95
95
95
95
95
95
95
95
OH
OH
OH
H
OMe
H
H
OH
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
H
H
H
H
H
H
H
H
CN
H
H
NO2 Me
H
H
OH
OH
OH
OH
H
H
H
OMe
H
CN
H
H
H
H
H
CHO
CHO
CHO
CHO
H
OMe
OMe
OEt
H
lation of diversity elements. This contrasts, for example, with
the use of a more traditional linking strategy whereby the tether
would likely be attached directly to the aromatic ring through
either a phenol or aniline group. The disadvantage of the latter
approach is that it (a) would remove a position of diversity on
the aromatic ring (since one position is committed to the linker)
and (b) would constrain all products to possessing either a
phenolic or an amino group at that position.
98
99
H
OMe
H
H
Br
H
CHO OMe
H
H
H
H
Br
H
OH
H
H
H
H
I
CHO
OMe
H
H
H
Br
H
Br
OMe
H
H
H
100
101
102
103
104
105
106
107
108
109
110
111
H
In practice, the requisite selenenyl bromide resin (64, Scheme
3) was prepared74a from commercial polystyrene (1% DVB
cross-linked, 100-200 mesh) via standard lithiation77 followed
by treatment with dimethyl diselenide to give methyl selenide
62, a conjugate whose oxidation with bromine in CHCl3 afforded
ionic species 63. Upon heating in ethanol, 63 fragmented
providing desired selenenyl bromide resin 64 as a dark red
polymer with swelling properties similar to typical cross-linked
polystyrene. To date, well over a kilogram of this resin has been
prepared in our laboratories with loadings ranging from 0.5 to
1.75 mmol/g (as controlled by the stoichiometry of the dimethyl
diselenide reagent). After some experimentation, it was deter-
mined that a functionalization of 1.1 mmol/g was best suited
for most synthetic applications and was thus employed for all
further studies.
As shown in Table 1, a large number of o-prenylated phenols
were prepared (see Supporting Information) and subsequently
tested in the described cycloloading reaction. In a typical loading
experiment, a suspension of selenenyl bromide resin 64 in CH2-
Cl2 at 25 °C was treated with a solution containing 2.0 equiv
of o-prenylated phenol. Rapid resin decolorization was typically
observed in under 5 min, presumably signifying consumption
of the selenenyl bromide functionality. After 20 min, the resin
was filtered, washed, and dried under vacuum. The success of
H
H
Br
I
H
H
H
Br
Me
H
H
I
H
H
H
I
a Loading conditions: 1.0 equiv of selenenyl bromide resin (1.1
mmol/g), 2.0 equiv of phenol, CH2Cl2, 0 f 25 °C, 20 min. b See
Supporting Information for Methods A-D used in the preparation of
phenolic substrates c Purity was estimated by integration of 1H NMR
signals of crude oxidative cleavage product.
each loading was determined by cleaving the reaction product
via oxidation of the phenylseleno group to the corresponding
selenoxide (H2O2, THF, 25 °C, 20 min) followed by syn-
elimination and concomitant release of the product. Typically,
a dilute solution of methyl sulfide in THF was then added to
the reaction vessel to quench any remaining oxidant and the
resulting solution was concentrated in vacuo.78 All cleavage
products were then analyzed by 1H NMR spectroscopy and mass
spectrometry (MS) to determine estimated purity. Loading
proceeded smoothly in all cases except for phenols 76, 99, and
100 (Table 1).79 While the number of scaffolds prepared and
tested considerably exceeds the actual number required for
construction of most libraries, we sought to demonstrate, by
these studies, the generality of this loading strategy and its
(77) Farall, J. M.; Fre´chet, J. M. J. J. Org. Chem. 1976, 41, 3877-3882.

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9945
Scheme 3. Preparation of Selenium Functionalized Resin
(64)a
correlates strongly with reduction in the activity of an ornithine
decarboxylase (ODC), an enzyme involved in the biosynthesis
of polyamine growth factors.80 Since ODC activity is unregu-
lated in various cancer cells, blocking its activity holds
promising chemotherapeutic and chemopreventive possibilities.81
Separately, the bis-benzopyran-containing paratocarpin A (148,
Scheme 4) has been reported to inhibit tumor invasion activity
in the MCF-7/6 breast cancer cell line.82 In light of these
intriguing activities, we targeted these four natural products (18,
131, 134, and 148) and their analogues as illustrated in Scheme
4. Hence, benzopyrans (112) bearing a methyl ketone substituent
were condensed with various benzaldehydes (119-126) to
produce, presumably, the â-hydroxy ketone adducts which were
prone to spontaneous elimination to give resin-bound chalcones
113.83 Chalcones containing a THP protected phenol were
treated with TsOH to reveal the free phenol, and subsequently,
all products were cleaved from the resin by treatment with
hydrogen peroxide in THF. As shown, application of this
reaction sequence to scaffolds 116-118 and aldehydes 119-
129 resulted in the formation of lonchocarpin (131), 4-hydroxy-
lonchocarpin (134), 4-hydroxy-3-methoxylonchocarpin (18), and
paratocarpin A (148) in 91, 82, 57, and 85% overall yields,
respectively, along with 22 analogues in yields ranging from
25 to 90%.
tolerance to almost all aromatic functionality (R1-R4) without
necessitating any nonproductive protecting group manipulations.
Moreover, ready access to an array of scaffolds facilitated our
reaction development studies, and it convincingly illustrates how
this selenium-based linking strategy comprises a powerful tool
for future combinatorial chemistry investigations of almost any
natural product of the 2,2-dimethylbenzopyran family.
Solid-Phase Synthesis of Benzopyran Natural Products
and Focused Libraries Thereof. With a large set of function-
alized, resin-bound benzopyran platforms in hand, we were
positioned to begin testing reaction pathways leading to various
structural types of interest. At the same time, we were also
interested in evaluating the stability of the selenium tether under
a variety of chemical and physical conditions. In the context of
these efforts, we targeted several benzopyran-containing prod-
ucts, including chalcones, pyranocoumarins, chromene glyco-
sides, stilbenoids, polycyclic steroid biosynthesis inhibitors,
N-heterocycles, and pyranoflavones.
The first of these libraries centered on a family of benzopyran-
containing chalcones with important biological activities. Specif-
ically, lonchocarpin (131, Scheme 4), 4-hydroxylonchocarpin
(134), and 4-hydroxy-3-methoxylonchocarpin (18), all isolated
from Cube´ resin, have been shown to interrupt mitochondrial
electron transport by inhibition of NADH:ubiquinone oxi-
doreductase (Complex I).45 Interestingly, it has recently been
shown that inhibition of NADH:ubiquinone oxidoreductase
The second natural product-based library is outlined in
Scheme 5, which demonstrates the construction of linear and
angular pyranocoumarins similar to the natural products xan-
thyletin (207, Figure 4), xanthoxyletin (208, Figure 4), and
seselin (6, Figure 4). These three coumarins and their derivatives
have been the focus of numerous biological investigations and
they are reported to exhibit cytotoxic, anti-viral, and anti-platelet
aggregation activities among others.34,84 As illustrated, four
major reaction pathways were developed to facilitate the
split-and-pool combinatorial construction of these and other
coumarin-type structures. Individual library members were
identified by radiofrequency encoding using IRORI tags and
MacroKan technologies.85-87 All four reaction pathways
commenced from resin-bound benzopyrans (155, Scheme 5)
possessing an o-hydroxy aldehyde functionality. Treatment of
these scaffolds with aryl, alkyl, or alkoxy â-ketoesters (173-
177 and 180-186) in the presence of piperidine (EtCN, 95 °C)
resulted in Knoevanagel condensation and concomitant trans-
esterification to provide lactones of type 156 or 157, respec-
tively.88 Moreover, treatment of scaffold 155 with substituted
phenyl acetic acids (187-190) in the presence of DCC and
4-DMAP at 180 °C in DMSO resulted in the formation of 2-aryl
(78) Quenching with methyl sulfide proved most practical when cleaving
large numbers of compounds simultaneously since the reagent can be
conveniently added as a THF solution to all reaction vessels. After 10 min
the resin can be removed and the filtrate concentrated directly to provide
the desired benzopyran cleavage product. Given the volatility of methyl
sulfide, any excess was removed during evaporation leaving only the desired
cleavage product and a trace amount of DMSO (produced by oxidation of
Me2S). This residual DMSO is inconsequential since most samples are
directly dissolved in DMSO for biological screening. As described in the
following paper, it is this facile cleaving operation which greatly facilitated
the use of automation in synthesizing the 10 000-membered library.25
Incidentally, for individual cleavages of larger amounts of resin, one can
also employ a standard aqueous workup using sodium sulfite to quench
the residual oxidant (see Experimental Procedures in the Supporting
Information for the details of both protocols).
(80) Rowlands, J. C.; Casida, J. E. Pharmacol. Toxicol. 1998, 83, 214-
219.
(81) Seiler, N.; Atanassov, C. L.; Raul, F. Int. J. Oncol. 1998, 13, 993-
1006.
(82) Parmar, V. S.; Bracke, M. E.; Philippe, J.; Wengel, J.; Jain, S. C.;
Olsen, C. E.; Bisht, K. S.; Sharma, N. K.; Courtens, A.; Sharma, S. K.;
Vennekens, K.; Van Marck, V.; Singh, S. K.; Kumar, N.; Kumar, A.;
Malhotra, S.; Kumar, R.; Rajwanshi, V. K.; Jain, R.; Mareel, M. M. Bioorg.
Med. Chem. 1997, 5, 1609-1619.
(83) Hollinshead, S. P. Tetrahedron Lett. 1996, 37, 9157-9160.
(84) For examples, see: (a) Magiatis, P.; Melliou, E.; Skaltsounis, A.-
L.; Mitaku, S.; Le´once, S.; Renard, P.; Pierre´, A.; Atassi, G. J. Nat. Prod.
1998, 61, 982-986. (b) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; Lee, K.-
H. J. Med. Chem. 1999, 42, 2662-2672.
(79) While loading failures were rare, they occurred for two specific
substituent patterns, namely when electron-withdrawing groups [EWG] were
situated either adjacent to the prenyl group [Case 1] or adjacent to the
phenolic group participating in the cyclization reaction [Case 2]. In these
cases, the desired scaffolds typically were loaded with the EWG masked.
(85) (a) Nicolaou, K. C.; Xiao, X.-Y.; Parandoosh, Z.; Senyei, A.; Nova,
M. P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2289-2291. (b) Moran, E.
J.; Sarshar, S.; Cargill, J. F.; Shahbaz, M. J. M.; Lio, A.; Mjalli, A. M. M.;
Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 10787-10788.
(86) A full discussion of the IRORI encoding and sorting technologies
employed in these libraries is provided in the following paper.25
(87) We thank Mr. Rick Brown of Discovery Partners International (DPI)
for a generous gift of IRORI MacroKans (K.C.N. is an advisor of DPI).

9946 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
Scheme 4. Parallel Solid-Phase Synthesis of Chalcone Natural Products (18, 131, 134, and 148) and Analogues Thereofa,b
coumarins89 of type 159, while condensation of scaffold 155
with stabilized Wittig reagents (171 and 172) at 165 °C in N,N-
diethylaniline afforded coumarins of type 160.90 At this stage,
structures containing no further functionality were cleaved under
standard conditions to provide benzopyrans of type 162-165.
In one of the two remaining cases, the protected phenol of 156
was liberated (TsOH) and alkylated with halides R3X (178 and
179) before being oxidatively cleaved. In the other case,
structures of type 157 containing an alkyl ester moiety were
hydrolyzed [LiOH, THF:H2O (20:1), 50 °C, 12 h] to provide
the free acid 161. Unfortunately, all attempts to effect coupling
of this carboxylic acid (161) with either alcohols or amines were
hampered by poor conversion, and as such the free acid itself
was simply cleaved. Selected application of these reaction
pathways to scaffolds 166-170 using the illustrated building
blocks resulted in the construction of a 37-membered coumarin
library, as shown in Figure 4, which included the natural
products seselin (6), xanthyletin (207), and xanthoxyletin (208).
The third library was constructed based on a chromene
glycoside (245, Scheme 6) isolated from Ageratum conyzoides.52
Our interest in achieving the synthesis of carbohydrate-contain-
ing structures stems from the propensity of sugars to improve
the solubility and cellular targeting of small organic molecules,
thereby making them attractive combinatorial building blocks.91
Hence, the trichloroacetimidates of three sugars, D-glucose (231),
D-xylose (235), and L-rhamnose (239), were prepared by a three-
step procedure consisting of peracetylation (Ac2O, Et3N,
4-DMAP), removal of the anomeric acetate (n-BuNH2, THF,
25 °C), and formation of the trichloroacetimidates (Cl3CCN,
DBU, 0 °C) to afford 234, 238, and 242, respectively, as
illustrated in Scheme 7.92 Using IRORI radiofrequency tagging
and MacroKans, three phenol-containing scaffolds (243, 244,
and 251) were simultaneously coupled with each sugar. These
couplings were accomplished by treatment of a suspension of
the phenolic scaffolds, trichloroacetimidates, and 4 Å molecular
sieves with BF3‚Et2O at -40 °C and allowing the reactions to
warm to 0 °C over 12 h. The resulting resin-bound chromene
glycosides were then deprotected (228 f 229) [NaOMe, THF:
MeOH (5:1), 24 h] and cleaved under standard oxidative
conditions. Analysis of the cleavage products by 1H NMR
spectroscopy demonstrated that the couplings proceeded with
complete stereoselectivity for the â-glycosides in all cases
typically with purities of better than 90%. Encouraged by the
facility and selectivity of these glycosidations, we next targeted
a more complex carbohydrate containing benzopyran, namely
macrophylloside heptaacetate (263, Scheme 7), the parent of
which is a chromene glycoside isolated from Gentiana macro-
phylla.54 Hence, the phenol of 255 was first methylated (MeI,
NaH, DMF, 35 °C, 88%) and the methyl ester of the resulting
product (256) was hydrolyzed to reveal the requisite free
(88) (a) Yang, J.-R.; Langmuir, M. E. J. Heterocycl. Chem. 1991, 28,
1177-1180. (b) Besson, T.; Coudert, G.; Guillaumet, G. J. Heterocycl.
Chem. 1991, 28, 1517-1523.
(89) Hans, N.; Singhi, M.; Sharma, V.; Grover, S. K. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1996, 35B, 1159-1162.
(90) Ishii, H.; Kenmotsu, K.; Doepke, W.; Harayama, T. Chem. Pharm.
Bull. 1992, 40, 1770-1772.
(91) For discussion, see: Hecht, S. M. Bioorganic Chemistry: Carbo-
hydrates; Oxford Press: New York, 1999.
(92) (a) For D-glucose, see: Schmidt, R. R.; Michel, J. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 731-733. (b) For D-xylose, see: Mori, M.; Ito, Y.;
Ogawa, T. Carbohydr. Res. 1990, 195, 199-224. (c) For L-rhamnose, see:
Kere´kga´rto´, J.; Agoston, K.; Batta, G.; Szurmai, Z. Carbohydr. Res. 1997,
297, 153-161.

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9947
Scheme 5. Radiofrequency Encoded Split-and-Pool Synthesis of Linear and Angular Pyranocoumarinsa-c
carboxylic acid 257 ready for the first coupling reaction. In the
event, treatment of carboxylic acid 257 and trichloroacetimidate
25893 with BF3‚Et2O at -40 °C and then warming to 0 °C over
12 h resulted in smooth coupling to produce â-glycoside 259
(91%), which underwent selective deprotection upon treatment
with HF‚py to afford 260 in 89% yield. The second coupling
between resin-bound substrate 260 and trichloroacetimidate 261
(prepared as shown in Scheme 6) proceeded under similar
conditions affording 262 in 57% yield as a single anomer.
Finally, the disaccharide was cleaved from the resin to afford
heptaacetylated macrophylloside (263) in 18% isolated yield
over six steps based on 255.
As a fourth combinatorial application of this linking strategy,
we undertook the synthesis of a recently reported aldosterone
biosynthesis inhibitor66 (41, Scheme 8) and various analogues
of it, again using radiofrequency encoded split-and-pool tech-
niques. The synthesis commenced with a halogen-metal
exchange94 of resin-bound aryl bromide 264 by treatment with
excess n-BuLi at -78 °C and warming to 0 °C, after which
time it was cooled to -78 °C and various aldehydes (271-
275) were added. The reaction mixture was then warmed to 25
°C and stirred for 12 h (99% yield for the case of aldehyde
271). The resulting benzhydrols (266) were then subjected to a
standard Mitsunobu reaction (DEAD, Ph3P, THF, 25 °C) with
various imidazole derivatives (276-280) (85% yield for the case
(93) Mayer, T. G.; Kratzer, B.; Schmidt, R. R. Angew. Chem., Int. Ed.
1980, 9, 731-732.
(94) Ding, C. Z. Synth. Commun. 1996, 26, 4267-4273.

9948 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
Figure 4. Linear and angular pyranocoumarin natural products (6, 207, and 208) and analogues generated from Scheme 5.
of aldehyde 272, amine 276).66 At this juncture, those structures
derived from aldehydes other than 272 were oxidatively cleaved
to provide structures of type 268, whereas those derived from
aldehyde 272 were deprotected (TsOH, THF:MeOH (9:1), 25
°C) to reveal a phenolic group at the C-3 position (100% yield
for the case of aldehyde 272 and amine 276). The liberated
phenol was then reacted with one of two benzyl alcohols (281
or 282) under Mitsunobu conditions, to furnish derivatives of
type 269 which were cleaved to afford the previously reported
compound (41, 75% overall yield based on 264) and various
structural analogues.
In a fifth library, we targeted a recently disclosed phosphodi-
esterase IV inhibitor (43, Figure 1 and Scheme 9) with a unique
cyano-stilbenoid structure.68 As outlined along the top of
Scheme 9, these structures can be readily accessed by condensa-
tion of a resin-bound benzaldehyde with a substituted phenyl-
acetonitrile. Unfortunately, the required aldehyde to synthesize
phosphodiesterase inhibitor 43 failed to load as previously
described.79 We circumvented this difficulty through loading
of the corresponding aryl bromide (303) followed by conversion
to the desired aldehyde 304 through a halogen metal exchange94
and quenching with DMF in 99% yield. Newly constructed
scaffold 304 along with scaffolds 305 and 306 were then con-
densed with three heterocyclic phenylacetonitriles (300-302)
in a parallel fashion, and the resulting stilbenoids were cleaved
to afford the previously reported phosphodiesterase IV inhibitor
43 (72% overall yield) as well as several structural analogues.
In our sixth and final library, we continued to address the
issue of installing N-heterocyclic functionality onto the ben-
zopyran template. Specifically, we were interested in the
synthesis of tetrazole structures similar to those found in
potassium channel activator 42 (Figure 2).67 Such tetrazoles are
readily constructed from the corresponding aryl nitriles. Hence,
a series of five nitrile-containing scaffolds (320-324, Scheme
10) were prepared and encoded for split-and-pool synthesis.
Initially, all compounds were pooled and condensed with
azidotrimethyltin (toluene, 100 °C, 12 h) to provide the
corresponding stannylated tetrazoles.95 The secondary nitrogens
of these tetrazoles were liberated by washing with aqueous
trifluoroacetic acid (TFA) and subsequently alkylated with
various alkyl halides (325-330).96 Finally, the resin-bound
tetrazoles were cleaved under oxidative conditions to afford a
series of substituted tetrazoles (331-366, Scheme 10).
To further evaluate the versatility of this selenium linking
strategy and our ability to access other benzopyran-containing
structures of interest, we undertook the solid-phase target-
directed synthesis of several molecules as outlined in Scheme
11. In the first example, bromobenzopyran 264 was converted
to the corresponding tri-n-butylstannane 367 through a halogen-
metal exchange followed by quenching with n-Bu3SnCl.94 Tri-
n-butylstannane 367 was then reacted with several aryl iodides
under palladium(0)-catalyzed coupling conditions97 to afford
structures 368 and 369 which were subsequently cleaved to
give compounds 370 (90%) and 371 (85%). Interestingly,
while these electron-deficient aryl iodides coupled quite ef-
fectively, attempts to employ either unsubstituted or electron-
rich aryl iodides resulted in low yields of the desired coupling
products.
A second example focused on the construction of benzofuran
376 (Scheme 11) through a Sonogashira/Castro-Stevens bis-
coupling strategy.98 In the first event, aryl iodide 372 was
coupled to (trimethylsilyl)acetylene in the presence of PdCl2 at
50 °C.99 The resulting alkyne was then deprotected with
(95) Duncia, J. V.; Pierce, M. E.; Santella, J. B., III J. Org. Chem. 1991,
56, 2395-2400.
(96) O’Brien, P. M.; Sliskovic, D. R.; Picard, J. A.; Lee, H. T.; Purchase,
C. F., II; Roth, B. D.; White, A. D.; Anderson, M.; Mueller, S. B.; Bocan,
T.; Bousley, R.; Hamelehle, K. L.; Homan, R.; Lee, P.; Krause, B. R.;
Reindal, J. F.; Stanfield, R. L.; Turluck, D. J. Med. Chem. 1996, 39, 2354-
2366.
(97) Farina, V.; Hauck, S. I. Synlett 1991, 157-159.
(98) Chauder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V. Angew.
Chem., Int. Ed. 1999, 38, 1435-1438.

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9949
Scheme 6. Radiofrequency Encoded Split-and-Pool Synthesis of Chromene Glycoside Isolated from Ageratum conyzoides (245)
and Analogues Thereofa,b
Scheme 7. Solid-Phase Synthesis of Peracetyl Macrophylloside D (263)a
TBAFand subsequently coupled to 2-iodophenol under Pd-
(OAc)2(Ph3P)2 catalysis.100 Finally, the coupling product was
cleaved under oxidative conditions to provide furan 376 in 52%
yield over four steps based on 372.
In the third example, acetophenone 116 (Scheme 11) was
converted to pyrazole 380 by initial conversion to the corre-
sponding â-dicarbonyl system via enolate formation with
LHMDS followed by quenching with benzoyl cyanide to afford
377 in 87% yield. Condensation of 377 with hydrazine hydrate
in the presence of a catalytic amount of acetic acid gave resin-
bound pyrazole 378 in 87% yield.101 This pyrazole was then
alkylated with MeI to furnish 379 and cleaved to give pyrazole
380 in 58% overall yield based on 116.102
(99) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(100) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313-
(101) Siddiqui, A. U.; Rao, U. M.; Srinivas, M.; Siddiqui, A. H. Org.
Proc. Proc. Int. 1992, 24, 355-358.
3315.

9950 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
Scheme 8. Synthesis of Aldosterone Biosynthesis Inhibitor 41 and Selected Analogues Thereofa
Scheme 9. Solid-Phase Parallel Synthesis of Phosphodiesterase Inhibitor 43 and Analogues Thereofa,b
A fourth example involved conversion of benzoic acid 381
into oxazole 384 (Scheme 11). Hence, alkylation of 381 was
effected by treatment with R-bromo acetophenone and DBU in
DMF at 80 °C to afford 382 in quantitative yield. Heterocycle
formation was accomplished by treatment of 382 with acetamide
and BF3‚Et2O in xylenes at 140 °C to give 383 (55% yield)

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9951
Scheme 10. Radiofrequency Encoded Split-and-Pool Synthesis of the Substituted Tetrazole Librarya
Table 2. Reaction Conditions Under Which Selenium Tether Is
(same conditions as in Scheme 4) to give chalcone 385, which
was subsequently treated with elemental iodine in DMSO at
180 °C for 30 min and then cleaved to afford flavone 387 in
27% overall yield from 117.104 In a final example, the previously
synthesized seselin (6) was reconstructed in an attempt to test
the stability of the linking approach to the highly practical
Grubbs olefin metathesis reaction. Hence, aldehyde scaffold 166
(Scheme 11) was transformed to styrene 388 by treatment with
Ph3PdCH2 in 100% yield. The phenolic group of 388 was then
acylated with acryloyl chloride to provide 389 which was treated
with Cl2Cy2RudCHPh to effect the ring closing metathesis
reaction.105 Finally, coumarin 390 was cleaved to provide seselin
(6) in 77% overall yield from 166.
Stablea
temperature
Lewis acids
Bro¨nsted acids
from -78 to 195 °C
SnCl4, BF3‚OEt2, ZnCl2, SnCl2
HCl, AcOH, TFA (aq), TsOH, PPTS
organometallics RMgX, RLi, R2CuLi, Wittig
reducing agents NaBH4, NaCNBH3, BH3‚THF, DIBAL,
LiBH4, LiAl(O-tBu)3H, SnCl2‚2H2O
bases
LDA, LHMDS, NaHMDS, NaH, K2CO3, Cs2CO3,
pyridine, piperidine, i-Pr2NEt, Et3N, LiOH (aq),
NaOH (aq), NaOMe, KOEt, KOt-Bu
electrophiles
miscellaneous
R-X, RC(O)X, [RC(O)]2O, RCHO
Pd reagents, DCC, SOCl2, COCl2, DEAD, Ph3P,
TBAF, HF‚py, Cl2Cy2RudCHPh
CH2Cl2, THF, DMF, C6H6, MeC6H5, DMSO,
N,N-diethylaniline, mesitylene, MeCN, EtCN
solvents
a During the current and related synthetic studies in these laboratories,
the above listed reagents and conditions were found to be compatible
with the selenoether linking strategy.
Conclusion
In conclusion, we have described the rational selection of a
benzopyran-based privileged structure for use in the construction
of natural product-like libraries and the development of general
strategies for its construction and diversification. A novel
cycloloading protocol has been developed for the efficient
which was cleaved to afford oxazole 384 in 42% yield over
three steps based on 381.103
Pyranoflavone 387 (Scheme 11) was constructed next from
methyl ketone 117 by condensation with 4-(t-Bu)-benzaldehyde
(102) Inspection of 1H NMR spectrum of 373 after cleavage revealed
that the product was a 1:1 mixture of regioisomers.
(103) Huang, W.; Pei, J.; Chen, B.; Pei, W.; Ye, X. Tetrahedron 1996,
52, 10131-10136.
(104) Tan, W.; Li, W.-D.; Huang, C.; Li, X.; Xing, Y. Synth. Commun.
1999, 29, 3369-3377.
(105) Nicolaou, K. C.; Rodr´ıguez, R. M.; Mitchell, H. J.; van Delft, F.
L. Angew. Chem., Int. Ed. 1998, 37, 1874-1876.

9952 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Nicolaou et al.
Scheme 11. Synthesis of Miscellaneous Benzopyran Containing Structuresa
loading, elaboration, and cleavage of this general template. The
fidelity of the devised method was validated under various
reaction conditions through the parallel and split-and-pool
synthesis of several small organic molecule libraries. As shown
in Table 2, these synthetic efforts have confirmed the robustness
of our selenoether tether under a range of reaction conditions,
as required for the successful synthesis of diverse natural
product-like libraries. In fact, it is arguable whether other
conventional linkers could withstand this array of reaction
conditions, and yet still be cleaved under such facile conditions
as those employed in the present case.106 In the following paper,
we describe the application of the chemistry and principles
developed in this phase of the program to the construction of a
(106) For a recent review of linkers, see: Guiller, F.; Orain, D.; Bradley,
M. Chem. ReV. 2000, 100, 2091-2157.

Combinatorial Libraries Based on PriVileged Structures
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 9953
10 000-membered library of biologically relevant, natural
product-like compounds.24
Boehringer-Ingelheim, Glaxo, Hoffmann-La Roche, DuPont,
Merck, Novartis, Pfizer, and Schering Plough.
Acknowledgment. Financial support for this work was
provided by The Skaggs Institute for Chemical Biology and
National Institutes of Health (U.S.A.), fellowships from the
Department of Defense (to J.P.), the American Chemical Society
Division of Medicinal Chemistry (sponsored by Parke-Davis,
Hoescht Marion Roussel, Abbott, Wyeth Ayerst, and Bristol
Myers Squibb) (to J.P.), and the Ministerio de Educacion y
Cultura, Spain (to S.B.), and grants from Amgen, Bayer AG,
Supporting Information Available: Experimental proce-
dures for resin and library preparation, tabulated 1H NMR and
1
MS data for all library members, and representative H NMR
spectra of crude cleavage products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA002033K