Diversity oriented one-pot synthesis of complex macrocycles: Very large steroid-peptoid hybrids from multiple multicomponent reactions including bifunctional building blocks

Article abstract of DOI:10.1002/anie.200500019

Sixteen in one go: Up to 16 new bonds connect 12 building blocks to form 54-membered macrocycles (46-membered example shown) in a one-pot procedure combining bifunctional components with multicomponent reactions. The large rings are not made of repetitive subunits and form an ideal basis for the fast construction of libraries of chiral host molecules. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200500019

Angewandte
Chemie
Macrocycle Synthesis
Diversity Oriented One-Pot Synthesis of Complex
Macrocycles: Very Large Steroid–Peptoid
Hybrids from Multiple Multicomponent
Reactions Including Bifunctional Building
Blocks**
Ludger A. Wessjohann,* Brunhilde Voigt, and
Daniel G. Rivera
Dedicated to Professor Armin de Meijere
on the occasion of his 65th birthday
One of the most fascinating challenges in modern organic
chemistry is the design of strategies capable of providing
structurally diverse and complex molecules, which are useful
[
1]
either for the study of important biological processes or for
[
2]
the development of supra- and nanomolecular systems. The
chemical genomics approach especially has focused efforts
towards the rapid generation of molecules able to modulate
protein functions, with the hope of thereby achieving a better
understanding of the role of these molecules in many cellular
pathways as well as providing new targets for drug develop-
[
3]
ment. Frank in his recent review on chemical genomics
[
1e]
concludes:
“A general concept for the construction of
protease-resistant (protein-like) synthetics for the interfer-
ence of such (protein–protein) interactions is not yet avail-
able.” Also, in contrast to small classic enzyme inhibitors,
molecules to study protein–protein interactions are believed
to require much larger interaction surfaces with an interplay
of lipophilic and polar interaction areas. A promising solution
could be the one-pot construction of extended, highly
complex structures in which spatially separated recognition
motifs combine to achieve overall binding. For this purpose,
macrocyclic skeletons are considered to be an especially
remarkable class of target scaffolds, as they can combine
conformational preorganization with flexibility and biological
[
4]
stability.
A useful prospect has been the development of diverse
routes towards synthetic and natural-product-like macro-
[
5,6]
cycles.
chemical community so far are either of the repetitive type
for example, the homooligomeric cyclodextrins and calixar-
However, most (large) macrocycles utilized by the
(
enes) or have to be made by multistep, complex synthetic
routes, which allow the generation of a single specimen but do
not easily provide the diverse libraries required for holistic or
evolutionary approaches and activity/property screenings.
[
*] Prof. Dr. L. A. Wessjohann, Dr. B. Voigt, D. G. Rivera
Department of Bioorganic Chemistry
Leibniz Institute of Plant Biochemistry
Weinberg 3, 06120 Halle/Saale (Germany)
Fax: (+49)345-5582-1309
E-mail: wessjohann@ipb-halle.de
[
**] We are grateful to Dr. Jürgen Schmidt for the HRMS spectra and
Angela Schaks for experimental assistance. We also gratefully
acknowledge the Deutsche Forschungsgemeinschaft for financial
support (Grant GRK/894).
Angew. Chem. Int. Ed. 2005, 44, 4785 –4790
DOI: 10.1002/anie.200500019
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Communications
[
9]
Naturally occurring macrocycles are usually endowed with
variety of structurally diverse cyclic scaffolds. However, the
multicomponent reaction itself has previously not been
exploited for recognition-motif generation or, with some
exceptions,
strategies.
[
4]
unique structural complexity which, for example, enables
the disruption of protein–protein interactions or binding to
specific protein domains. Whilst diversity-oriented
approaches have been devised to create the crucial complex-
[
6,10]
as a ring-closing reaction in macrocyclization
[
7]
ity and diversity, improvements are still required for macro-
cyclization strategies to rapidly and readily access diversity
and to simultaneously introduce, for example, protein binding
motifs in a unified task in the macrocyclization step itself.
We have recently addressed this quest and devised a new
strategy for developing macrocycle diversity, in which the
proper application of multiple multicomponent macrocycli-
zations including bifunctional building blocks (MiBs) allows
rapid access to libraries of constitutionally defined peptoid-
containing macrocycles. Herein we describe the first appli-
cations of this concept for the straightforward synthesis of
very large macrocycles (up to 60-membered rings), in which
up to 4 multicomponent reactions (including the macrocycli-
zation step) incorporate 12 components in 1 pot.
A simple survey of the skeletal (peptoid-core) diversity
achieved by employing different symmetrically bifunctional-
ized (Ugi) components in a bidirectional macrocyclization is
presented in Scheme 1. The ring size of the final macrocycle
depends on the chosen combination of bifunctional building
blocks. As either endo- or exocyclic amide bonds can be
formed, higher or lower flexibility can be generated for both
the ring and the differently tethered residues. However, it is
important to note that even in the simplest double Ugi-4CR
based approach, the two Ugi-4CRs do not occur simulta-
neously because a linear macrocycle precursor is formed
initially. To understand the proper design of macrocycles, the
final cyclization step is crucial to assess the ring size (multi-
plicity) and efficiency (yield), and thereby the result of the
[
6]
[
5a,g]
The Ugi four-component reaction (Ugi-4CR) has evolved
as one of the most useful reactions in diversity-oriented
overall process.
In the case of Ugi-type reactions, the
analysis should not only be directed to the strain of the final
macrocycle but also to the cyclic precursor a-adduct, as well
as the possibly strained 1,3-ansa-like intermediate of the
Mumm rearrangement, both resulting from the various
[
8]
approaches toward drug discovery. The only by-product of
this (atom) economic process is water. Moreover, bifunctional
building blocks have been appropriately utilized to access a
Scheme 1. Skeletal diversityof the peptoid backbones that can be obtained in a multiple multicomponent macrocyclization including bifunctional
building blocks (MiBs) of the bidirectional Ugi type. *: The C!N terminus of box I runs parallel to that of box II (bidirectional peptoids), that is,
1
2
[6]
even if the same FG and FG residues are included, the boxes are not identical owing to the asymmetry of the steroid tether. **: The different
endo/exo peptoid cores available bythe MiBs. Dashed boxes indicate examples used herein.
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bifunctional building block combinations
Scheme 1; for example, aldehyde/acid
(
1
4
[6]
building blocks bridging R and R ).
With a view to applying this concept in
the work described herein, we concentrated
on a straightforward strategy towards ste-
roid–peptoid hybrid macrocycles through a
one-pot multiple Ugi-4CR of steroidal
bifunctional building blocks. Steroids com-
bine several structural features that render
them suitable architectural components in
macrocycle synthesis. They present one of
the few extended, readily available, chiral
units that can be additionally functionalized
by a large set of established procedures. The
natural stereochemical diversity and rigid
array of concave-directed differentiable
functionalities in the steroidal nucleus have
been previously used in the (target-ori-
ented) design of macrocyclic frameworks
for biomimetic and molecular recognition
Scheme 2. Synthesis of the steroidal bifunctional building blocks. a) LiAlH , THF; b) DIAD, Ph P,
4
3
MeSO H; c) NaN , DMPU; d) H , PtO ; e) HCO Et, D; f) POCl , iPr NEt; g) PCC, CH Cl ;
3
3
2
2
2
3
2
2
2
h) NH OCH CO H, Py; i) TMSCl, MeOH; j) PCC, CH Cl ; k) urea/H O , (CF CO) O; l) KOH, MeOH.
2
2
2
2
2
2
2
3
2
DIAD=diisopropylazodicarboxylate, DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone,
PCC=pyridinium chlorochromate, Py=pyridine, THF=tetrahydrofuran, TMS=trimethylsilyl.
[
11]
applications.
Scheme 2 summarizes the synthesis of
the steroidal bifunctional building blocks
from lithocholic acid (2). Synthesis of dia-
mine 3 and diisonitrile 6 proceeded by a
double Mitsunobu reaction to the corre-
sponding reduced acid, followed by azide
[
12a]
displacement,
reduction, and subsequent
[
12b]
isonitrile formation.
Steroidal dicarbox-
ylic acids are a source of additional skeletal
diversity. They are most rapidly obtained
from the 3-oxo derivative through lactone
[
13]
formation by a Baeyer–Villiger reaction
and consecutive ring-opening saponification
or alternatively by condensation with O-
(
carboxymethyl)hydroxylamine; these reac-
tions afforded the dicarboxylic acids 4 and 5,
respectively.
All multiple macrocyclizations by the
Ugi-4CR presented here were carried out
under pseudodilution conditions by adding
the diisonitrile building block at a rate of
ꢀ
1
ꢀ1
0
.1 mLh (c = 0.05 mmolmL ) to a mix-
ture of the other components. Competing
oligomerization was successfully minimized
and an almost equal mixture of head-to-
head (H-H) and head-to-tail (H-T) isomers
resulted in all cases with at least two bifunc-
[
6,14]
tional asymmetric building blocks.
Three examples, highlighted in Scheme 3,
illustrate the initial attempt to explore our
strategy. By using the diamine 3 and the
diacids 4 and 5 as counterparts of the
common diisonitrile 6 in the Ugi-4CR, two
different types of peptoid backbones are
produced, according to the considerations
summarized in Scheme 1. The diamine/dii-
sonitrile combination is characterized by an
Scheme 3. Double Ugi-4CR based macrocyclization of steroidal bifunctional building blocks (bidirec-
tional MiBs of diamine/diisonitrile and diacid/diisonitrile type). Head-to-head (H-H) and head-to-tail
(
H-T) regiomers are formed in almost equal amounts. Yields refer to the mixture; however, for clarity,
[
14]
onlythe H-T isomer is shown.
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exocyclic amide bond which shortens the tether chain but
increases the flexibility of the peptoid portion.
steroidal skeleton. An alternative third pathway, isonitrile
(imidate) induced condensation to succinic anhydride leading
to the Ugi three-component product, was not observed, but it
was also not specifically looked for, as the desired macro-
cycles were formed in typical combined yield.
Of the various components that can be varied, the oxo
component exhibits special influence on ring formation and
stereochemical complexity. Thus, macrocycles 7–10 were
isolated as almost equally distributed mixtures of diastereo-
The different outcomes in these macrocyclizations by
using different aldehydes pinpoint the importance of under-
standing the effect of a bulky aldehyde side chain on the
success and result of the overall process. In addition to pure
[
15]
mers. The Ugi approach facilitates the rapid generation of
stereochemical diversity that is much more difficult to access
in a multistep synthetic strategy, although it could also be
considered a drawback owing to the required (but often easy)
separation and difficult characterization work. Furthermore,
when isobutyraldehyde was replaced by paraformaldehyde
there was a marked increase in the macrocyclization yields,
which is probably the result of lower steric hindrance or a
significantly modified prefolding bias.
[
16]
steric effects, the favoring (or disfavoring) of double or
fourfold Ugi-4CR based macrocyclizations is dependent on
the length, flexibility, and prefolding characteristics of the
acyclic precursor. The strain and strain change of the cyclic a-
adduct are also crucial aspects which determine the formation
and further ability to rearrange to the final macrocycle. Thus,
the sterically demanding isopropyl groups might cause
significant steric strain or incorrect prefolding in the forma-
tion of the cyclic a-adduct, thereby prohibiting the formation
of the smaller macrocycle. Larger (for example, sixfold Ugi-
4CR based) macrocycles, in contrast, could not be identified
to any significant amount by ESI-FT-ICR mass spectrometry.
After reliable fourfold Ugi-4CR macrocyclizations were
established and because of the intriguing result obtained with
a diacid as the bridging building block, we extended our plan
to cover other types of peptoid tethers for the steroids. This
could be achieved with diacids that have a significant
influence either on the molecular recognition behavior or
on the internal folding of the obtained macrocycle. Tereph-
thalic and cyclopropane-1,1-dicarboxylic acids were chosen as
the counterparts, and consequently macrocycles 17–20 were
To improve the size as well as recognition-motif diversity
of the peptoid core of the macrocyclic skeleton, we set out to
design a fourfold Ugi-4CR macrocyclization by using two
equivalents of the steroidal diisonitrile 6 and another (at this
stage simpler) bifunctional building block. This complemen-
tary and direct approach, which allows manipulation of the
nature and length of the steroid bridging tethers, succeeded
for the synthesis of the fourfold macrocycles 12–16
(
Scheme 4) with ethylenediamine or succinic acid as the
simpler bifunctional building blocks. Interestingly, in the case
with succinic acid and with paraformaldehyde as the oxo
component the smaller macrocycle 14 was also formed,
although in lower yield, a result confirming that the succi-
nate-bridged double dipeptoid chain is just long enough to
span the distance between the two functional groups of the
Scheme 4. Fourfold Ugi-4CR based macrocyclization of bifunctional building blocks (MiBs of diacid/diisonitrile and diamine/diisonitrile type).
[
14,16]
A mixture of H-H and H-T isomers is observed for fourfold reactions, (i.e., not for 14).
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synthesized in a similar fashion, with paraformaldehyde as the
best oxo component for analytical purposes. Scheme 5 high-
lights the convincing results of our design. It also shows the
effect of a more strained chain on the success of the fourfold
Ugi-4CR macrocyclization versus the double reaction. With
the long and straight terephthalic acid, the double Ugi-4CR
based small macrocycle 18 was the main product, whereas the
short, kinked 1,1-cyclopropane diacid led to the formation of
the fourfold Ugi-4CR based large macrocycle 19 as the major
product; this result shows that the formation of the cyclo-
propane-bridged double dipeptoid chain is disfavored owing
to its significantly lower flexibility and shorter length to span
the steroidal moiety. At this point it should be mentioned
that, for example, a yield of 49% for isolated 19 corresponds
to an approximately 96% calculated yield for each individual
reaction/bond formed, including the macrocyclization.
Apart from the vast array of functionalities that could be
placed inside the macrocyclic cavity by altering one of the
differentiable faces of the steroidal moiety, the proven degree
of complexity and diversity accessible through this one-pot
synthetic process can be highlighted by considering four
distinct issues: 1) additional binding elements or biologically
or catalytically interesting motifs can be appended as side
chains to some of the Ugi components, 2) the macrocycliza-
tion can be performed in a template-based manner to control
the size of the cavity, 3) further skeletal diversity can be
achieved by varying the nature of the building blocks, and
example, straight or kinked, as shown above) or b) by
generating new stereogenic centers. While the first issues
are being developed in connection with ongoing projects, an
efficient access to diastereoselective Ugi reactions (4b) is the
[
17]
last problem that remains unsolved—with a few exceptions.
Supported by the possible automation of the Ugi-4CR,
[
5,6,8]
the current strategy may be extended to independently
modify the different access points of diversity generation in
a parallel (or mixed) combinatorial fashion. Moreover, the
whole system is suitable for evolutionary-based or holistic
approaches, for the generation of sets of biologically relevant
molecules or biomimetic supramolecular systems, or for any
application that requires large, constitutionally defined com-
plex molecules of a nonrepetitive or only partly repetitive
nature.
In conclusion, we have presented a very straightforward
strategy to generate a collection of chimeric peptoid macro-
cycles—here specifically with steroid moieties—of a size and
structural complexity that bears no resemblance to any
known natural product but that is potentially useful in
chemical genomics approaches, as well as for artificial
receptors for molecular recognition studies or as bottom-up
building units for nanotechnology. To our knowledge, multi-
component reactions have not so far been used to directly
form macrocycles of this size and complexity that can easily
incorporate and display chemical motifs previously identified
as suitable, for example, for anion and carbohydrate recog-
[
18]
4
) conformational diversity of the cavity can be designed
nition. We believe that no other macrocycle synthesis is
known that better combines ease, versatility, functionality,
either a) from geometrically varied building blocks (for
Scheme 5. Fourfold versus double Ugi-4CR based macrocyclizations of geometrically different bifunctional building blocks. A mixture of H-H and
[
14]
H-T isomers is observed for 17 and 19.
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size control, and speed in one pot than the process presented
here. Finally, the principal concept of MiBs should not be
limited to Ugi type multicomponent reactions only.
Schreiber, Org. Lett. 2000, 2, 709; c) S. L. Schreiber, Science
000, 287, 1964.
8] For reviews, see: a) A. Dömling, I. Ugi, Angew. Chem. 2000, 112,
300; Angew. Chem. Int. Ed. 2000, 39, 3168; b) C. Hulme, T.
[
6]
2
[
3
Nixey, Curr. Opin. Drug Discovery Dev. 2003, 6, 921; c) R. V. A.
Orru, M. de Greef, Synthesis 2003, 1471; d) L. Weber, Curr. Med.
Chem. 2002, 9, 1241; e) L. Weber, Drug Discovery Today 2002, 2,
143; f) H. Bienaymꢀ, C. Hulme, G. Oddon, P. Schmitt, Chem.
Eur. J. 2000, 6, 3321; g) C. Hulme, V. Gore, Curr. Med. Chem.
2003, 10, 51.
Experimental Section
General procedure for the Ugi-4CR based macrocyclizations: A
solution of the oxo component (2 mmol) and the amino component
(2 mmol) in MeOH (250 mL) was stirred for 1 h at room temperature.
The diacid building block (0.5 mmol) was then added and the stirring
was continued for another 30 min. A solution of diisocyanide 6
[9] B. Beck, A. Picard, E. Herdtweck, A. Dömling, Org. Lett. 2004,
6, 39, and references therein.
(0.5 mmol) in MeOH (10 mL) was added slowly to the reaction
[10] a) P. Janvier, M. Bois-Choussy, H. Bienaymꢀ, J. Zhu, Angew.
Chem. 2003, 115, 83 5;Angew. Chem. Int. Ed. 2003, 42, 811; b) A.
Failli, H. Immer, M. D. Götz, Can. J. Chem. 1979, 57, 3257.
[11] For reviews, see: a) A. P. Davis, R. P. Bonar-Law, J. K. M.
Sanders in Comprehensive Supramolecular Chemistry, Vol. 4
(Eds.: J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle),
Elsevier, Oxford, 1996, pp. 257 – 286; b) P. Wallimann, T. Marti,
A. Fꢁrer, F. Diederich, Chem. Rev. 1997, 97, 1567; c) Y. Li, J. R.
Dias, Chem. Rev. 1997, 97, 283; d) J. Tamminen, E. Kolehmai-
nen, Molecules 2001, 6, 21; e) E. Virtanen, E. Kolehmainen, Eur.
J. Org. Chem. 2004, 3385.
ꢀ1
mixture by using a syringe pump (flow rate of 0.1 mLh ). After
addition was complete, the reaction mixture was concentrated under
decreased pressure and the crude material was purified by flash
column chromatography or preparative HPLC to afford the corre-
sponding macrocycles, usually as amorphous solids.
Received: January 4, 2005
Revised: April 4, 2005
Published online: June 29, 2005
[
12] a) A. P. Davis, S. Dresen, L. J. Lawless, Tetrahedron Lett. 1997,
Keywords: combinatorial chemistry· macroc yc les ·
molecular recognition · multicomponent reactions · steroids
.
38, 4305; b) R. Obrecht, R. Herrmann, I. Ugi, Synthesis 1985,
400.
[
[
13] M. S. Cooper, H. Heaney, A. J. Newbold, W. R. Sanderson,
Synlett 1990, 533.
14] For bidirectional MiBs with at least two bifunctional asymmetric
building blocks, see ref. [6]. For simplicity reasons only the head-
to-tail (H-T) isomers are shown in all schemes. The yields refer
to the mixture of both isomers, which often cannot be
distinguished by the available structural determination techni-
ques (HRMS, NMR) prior to chromatographic separation. This
separation, however, is usually not problematic.
[
1] For reviews, see: a) G. Mitsopoulos, D. P. Walsh, Y.-T. Chang,
Curr. Opin. Chem. Biol. 2004, 8, 26; b) R. S. Lokey, Curr. Opin.
Chem. Biol. 2003, 7, 91; c) D. L. Boger, J. Desharnais, K. Capps,
Angew. Chem. 2003, 115, 4270; Angew. Chem. Int. Ed. 2003, 42,
4138; d) T. Berg, Angew. Chem. 2003, 115, 2562; Angew. Chem.
Int. Ed. 2003, 42, 2462; e) R. Frank, BIOspektrum 2002, 8, 474;
f) P. Arya, R. Joseph, D. T. H. Chou, M.-G. Baek, Angew. Chem.
[
[
15] HPLC and LC-MS spectra showed the presence of all diaster-
eomers in the mixture in close to equal amounts.
2001, 113, 351; Angew. Chem. Int. Ed. 2001, 40, 339; g) S. L.
Schreiber, Bioorg. Med. Chem. 1998, 6, 1127.
16] The double MiBs of Schemes 4 and 5 are different from those in
Scheme 3in that only one bifunctional building block is
steroidal. This results in a different multiplicity bias (disfavoring
the double MiBs) and the absence of regioisomers (H-H/H-T
isomers).
[
2] a) H.-J. Schneider, A. Yatsimirsky, Principles and Methods in
Supramolecular Chemistry, Wiley, Chichester, 2000; b) C. A.
Schalley, J. Rebek in Stimulating Concepts in Chemistry (Eds.: F.
Vögtle, S. Stooddart, M. Shibasaki), Wiley-VCH, Weinheim,
2000.
[
17] For lead references for stereoselective Ugi and Passerini
reactions, see: a) D. J. Ramꢂn, M. Yus, Angew. Chem. 2005,
[
3] For selected reports, see: a) D. Barnes-Seeman, S. B. Park, A. N.
Koehler, S. L. Schreiber, Angew. Chem. 2003, 115, 2478; Angew.
Chem. Int. Ed. 2003, 42, 2376; b) S. M. Khersonsky, D. W. Jung,
T. W. Kang, D. P. Walsh, H. S. Moon, H. Jo, E. M. Jacobson, V.
Shetty, T. A. Neubert, Y. T. Chang, J. Am. Chem. Soc. 2003, 125,
117, 1628; Angew. Chem. Int. Ed. 2005, 44, 1602; b) K. Oertel, G.
Zech, H. Kunz, Angew. Chem. 2000, 112, 1489; Angew. Chem.
Int. Ed. 2000, 39, 1431; c) H. Kunz, W. Pfrengle, J. Am. Chem.
Soc. 1988, 110, 651; d) I. Ugi, K. Offermann, Angew. Chem. 1963,
11804; c) F. G. Kuruvilla, A. F. Shamji, S. M. Sternson, P. J.
75, 917; Angew. Chem. Int. Ed. Engl. 1963, 2, 624; e) P. R.
Hergenrother, S. L. Schreiber, Nature 2002, 416, 653; d) H. E.
Pelish, N. J. Westwood, Y. Feng, T. Kirchhausen, M. D. Shair, J.
Am. Chem. Soc. 2001, 123, 6740; e) T. U. Mayer, T. M. Kapoor,
S. J. Haggarty, R. W. King, S. L. Schreiber, T. J. Mitchison,
Science 1999, 286, 971.
Andreana, C. C. Liu, S. L. Schreiber, Org. Lett. 2004, 6, 4231;
f) U. Kusebauch, B. Beck, K. Messer, E. Herdtweck, A.
Dömling, Org. Lett. 2003, 5, 4021; g) G. Cuny, R. Gamez-
Montano, J. Zhu, Tetrahedron 2004, 60, 4879; h) R. Frey, S. F.
Galbraith, S. Guelfi, C. Lamberth, M. Zeller, Synlett 2003, 1536;
i) T. Ziegler, H.-J. Kaisers, R. Schlomer, C. Koch, Tetrahedron
[
4] a) L. A. Wessjohann, E. Ruijter, D. G. Rivera, W. Brandt, Mol.
Diversity 2005, 9, 171; b) M. Feher, J. M. Schmidt, J. Chem. Inf.
Comput. Sci. 2003, 43, 218.
1999, 55, 8397; j) S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2003,
125, 7825.
[
5] a) L. A. Wessjohann, E. Ruijter, Top. Curr. Chem. 2005, 243, 13 7;
b) P. Cristau, J.-P. Vors, J. Zhu, Tetrahedron 2003, 59, 7859; c) B.
Beck, G. Larbig, B. Bejat, M. Magnin-Lachaux, A. Picard, E.
Herdtweck, A. Dömling, Org. Lett. 2003, 5, 1047; d) J. K. Sello,
P. R. Andreana, D. Lee, S. L. Schreiber, Org. Lett. 2003, 5, 4125;
e) L. A. Wessjohann, Curr. Opin. Chem. Biol. 2000, 4, 3 03 ; f) D.
Lee, J. K. Sello, S. L. Schreiber, J. Am. Chem. Soc. 1999, 121,
[
18] a) A. P. Davis, J. F. Gilmer, J. J. Perry, Angew. Chem. 1996, 108,
410; Angew. Chem. Int. Ed. Engl. 1996, 35, 1312; b) R. P. Bonar-
1
Law, A. P. Davis, B. A. Murray, Angew. Chem. 1990, 102, 1497;
Angew. Chem. Int. Ed. Engl. 1990, 29, 1407; c) K. M. Bhattarai,
R. P. Bonar-Law, A. P. Davis, B. A. Murray, J. Chem. Soc. Chem.
Commun. 1992, 752; d) A. P. Davis, R. S. Wareham, Angew.
Chem. 1999, 111, 3160; Angew. Chem. Int. Ed. 1999, 38, 2979.
10648; g) J. Blankenstein, J. Zhu, Eur. J. Org. Chem. 2005, 1949.
[
[
6] L. A. Wessjohann, E. Ruijter, Mol. Diversity 2005, 9, 159.
7] a) M. A. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48;
Angew. Chem. Int. Ed. 2004, 43, 46; b) D. Lee, J. K. Sello, S. L.
4
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Angew. Chem. Int. Ed. 2005, 44, 4785 –4790