Diverging DOS strategy using an allene-containing tryptophan scaffold and a library design that maximizes biologically relevant chemical space while minimizing the number of compounds

Article abstract of DOI:10.1021/co100052s

A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a m

Full text of DOI:10.1021/co100052s

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Diverging DOS Strategy Using an Allene-Containing Tryptophan
Scaffold and a Library Design that Maximizes Biologically Relevant
Chemical Space While Minimizing the Number of Compounds
Thomas O. Painter,† Lirong Wang,‡ Supriyo Majumder,† Xiang-Qun Xie,*,‡ and Kay M. Brummond*,†
†Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
‡Department of Pharmaceutical Sciences, School of Pharmacy, Drug Discovery Institute, Department of Computational Biology,
University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S Supporting Information
b
ABSTRACT: A diverging diversity-oriented synthesis (DOS)
strategy using an allene-containing tryptophan as a key starting
material was investigated. An allene-yne substituted derivative
of tryptophan 12 gave indolylmethylazabicyclooctadiene 17
when subjected to a microwave-assisted allenic [2 þ 2]
cycloaddition reaction. This same tryptophan-derived precur-
sor afforded an indolylmethyldihydrocyclopentapyridinone 14
when subjected to a rhodium(I)-catalyzed cyclocarbonylation
reaction and an indolylmethylpyrrolidinocyclopentenones 16
when reacted with molybdenum hexacarbonyl. Construction
of allenic tetrahydro-β-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization
afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-β-carboline, followed by a
microwave-assisted allenic [2 þ 2] cycloaddition reaction, provided tetrahydrocyclobutaindoloquinolizinones 24 and the
tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used
as templates for the construction of a virtual library of 11 748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes.
Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at
the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D)
fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327 000
compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from
the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space
defined by these compounds and will be synthesized and screened for biological activity.
KEYWORDS: thermal [2 þ 2] cycloaddition, allene, allene-yne, cyclocarbonylation, cycloisomerization, microwave-assisted,
Pictet-Spengler, rhodium(I)-catalyzed, tetrahydro-β-carboline, tryptophan, virtual library, Pauson-Khand, BCUT, Tanimoto,
MLSMR, chemical space
’ INTRODUCTION
approach can be time intensive for a variety of reasons, such as
understanding the wide range of chemistries employed during
substrate preparation. Alternatively, a reagent-based approach
utilizes a common intermediate that when subjected to a variety
of reaction conditions or reagents, affords different scaffolds.6
The challenge associated with the reagent-based approach, espe-
cially when operating under transition metal catalysis conditions,
is that small structural changes in a precursor can render an
otherwise high yielding reaction, unsuccessful.
Chemical synthesis of complex organic molecules has recently
undergone some revolutionary transformations, including the emer-
ging area of diversity-oriented synthesis (DOS); the synthesis of a
diverse set of small molecules for the identification of new ligands for
a variety of biological targets.1 The DOS synthetic strategy is used to
access structurally unique compounds and employs a combination
of building block-, appendage-, stereochemical-, and skeletal-
diversity.2 Of these, skeletal diversity is the most challenging to
achieve3 and, at the same time, is considered the most powerful
because it provides molecularly distinct scaffolds that occupy
separate regions of chemical space.4
In 2004, one of the authors reported a reagent-based approach
to skeletal diversity whereby an allene-yne was subjected to three
Skeletal diversity is commonly achieved by a substrate-based
approach that employs a common set of reagents to elaborate
functionally and structurally unique precursors.5 A substrate-based
Received: November 2, 2010
Revised:
January 3, 2011
Published: February 18, 2011
r
2011 American Chemical Society
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Scheme 1. Diverging DOS Strategy for an Allene-Containing Tryptophan
Scheme 2. Synthesis, Cyclocarbonylation, and Carbocyclization Reactions of Allene-ynes 12a-c
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Table 1. Pictet-Spengler Reaction Affording Allenic
Tetrahydro-β-Carbolines 20a-c
Scheme 3. Synthesis of Tetrahydroindolizinoindoles
entry
R
product
solvent reaction time yield (%)
dr
cyclocarbonylation reaction to give 3 under the standard condi-
tions were not successful. The details for accessing these
skeletally unique compounds are delineated within.
1
2
3
H
20a{1,2,0} CH3OH
p-C6H4F 20b{1,5,0} CH2Cl2
n-Pr 20c{1,9,0} CH2Cl2
5 h
71
70
68
N/A
2.5 h
50 min
2: 1
2: 1
different transition metal catalysts to afford three unique scaffolds.7
This overall strategy was likened to nature’s construction of the
carbon skeletons of secondary metabolites from unsaturated
substrates such as farnesyl pyrophosphate. The power of this
reagent-based approach as a DOS strategy has subsequently been
demonstrated by the preparation of multiple libraries of com-
pounds possessing scaffolds and compounds with interesting
biological activity.8
The work described herein is an extension of this diversifica-
tion strategy with a focus on the cyclocarbonylation and carbo-
cyclization reactions of allene or alkyne groups attached to an
indole nucleus.9 The indole nucleus was selected as an ideal
starting point because of its presence in many naturally occurring,
bioactive molecules.10 Furthermore, the cyclocarbonylation and
carbocyclization reactions described within offer a novel ap-
proach to the preparation of terpene indole alkaloids.11 Under-
scoring the importance of this class of compounds is the recent
discovery of a β-carboline-containing compound from a library
of 12 000 natural products and synthetic compounds, possessing
nanomolar activity against Plasmodium falciparum.12
The diversification protocol delineated within (Scheme 1),
involves functionalization of the conformationally mobile indolyl-
aminopentadienoate 1 with an alkyne followed by: (1) a Rh(I)-
catalyzed cyclocarbonylation reaction,13 (2) a thermal [2 þ 2]
cycloaddition reaction,14 or (3) a molybdenum mediated
Pauson-Khand-type reaction15 to give 2, 6, and 4, respectively.
The Ag(I)-catalyzed cycloisomerization reaction of 1 to give 8 was
not performed since a library of structurally similar compounds
has already been prepared in our laboratories.16 Alternatively, a
conformationally locked tetrahydro-β-carboline can be gener-
ated by subjecting deprotected 1 to a Pictet-Spengler reaction.
This allene-containing tetrahydro-β-carboline can then be
subjected to a Ag(I)-catalyzed cycloisomerization reaction
to give9.17,18 Alternatively, functionalization of the allene-containing
tetrahydro-β-carboline with an alkyne and reaction with moly-
bdenum hexacarbonyl gives the Pauson-Khand product 5;
reaction of the same allene-yne to the thermal [2 þ 2] cycloaddi-
tion reaction gives 7. Attempts to effect the Rh(I)-catalyzed
’ RESULTS AND DISCUSSION
Methodology Development. To obtain the requisite allene-
yne for the indolylmethyl-containing scaffolds 2, 4, and 6,
tryptophan was benzoyl protected and then converted to corre-
sponding propargyl ester using dicyclohexylcarbodiimide and
N,N-dimethylaminopyridine in 84% yield over two steps. The
Boc group was then appended to the indolyl nitrogen to afford
10 in 88% yield.19 Propargyl ester 10 was subjected to triphenyl-
phosphine, carbon tetrachloride, and triethylamine to effect a
dehydrative Claisen rearrangement followed by treatment with
methanol and triethylamine to provide allenic amino-ester 11 in
67% yield.20 Allene-ynes 12a-c were then obtained via reaction
of 11 with propargyl bromides 13a-c in the presence of sodium
hydride in DMF in 45-78% yield (Scheme 2).
Next, the allene-ynes were subjected to the cyclocarbonylation
reaction conditions. Reaction of allene-ynes 12a-c with 5 mol %
rhodium biscarbonylchloride dimer [Rh(CO)2Cl]2 under one
atmosphere of carbon monoxide at 50 °C in DCE for 1-2 h
afforded 84%, 88%, and 70% yields of 14a, 14b, and 14c,
respectively (Scheme 2). Attempts to effect the cyclocarbonyla-
tion in the absence of the Boc-protecting group afforded only
products resulting from decomposition and no recovered start-
ing material. However, it was subsequently shown that the Boc
group could be removed from 14b by heating in DMSO at
180 °C for 10 min to give 15 in 78% yield.
The molybdenum-mediated cyclocarbonylation of 12c was
previously demonstrated in our group;21 the yield and diastereos-
electivity for the formation of 16c are shown in Scheme 2. To
determine whether the groups on the terminus of the alkyne
affected the yield or the diastereoselectivity of the cyclocarbonyla-
tion reaction, substrates 12a-b were reacted molybdenum hex-
acarbonyl and DMSO in toluene to afford R-alkylidene
cyclopentenones 16a-b (Scheme 2). Unfortunately, the cyclo-
carbonylation of the aryl- and alkyl-substituted alkynes (12a-b)
afforded the major diastereomersof16a and 16b inaboutthesame
yield as terminal alkyne 12c, 43-50% yield. There was only a
marginal increase in the diastereoslectivity observed for the
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Scheme 4. Synthesis, Cyclocarbonylation, and Carbocyclization of Allene-yne 23a{1,2,37}
Scheme 5. Library Scaffold Assignment
reaction of 12b. The diastereomeric ratios were determined by the
1H NMR of the crude sample, and the major diastereomer was
separated via column chromatography. The stereochemical assign-
ments were made by analogy to compounds reported previously.
Next, we were interested in examining the thermal [2 þ 2]
cycloaddition of the tryptophan-substituted allene-ynes. Heating
allene-yne 12a and 12b at 225 °C under microwave irradiation
for 7-10 min afforded bicyclo[4.2.0]octa-1,6-dienes 17a{1,0,29}
and 17b{1,0,37} in 45% and 50% yields, respectively; with the
Boc-group removed during these high reaction temperatures
(Scheme 2). Structurally similar terminal alkynes have previously
been shown to decompose under these reaction conditions; thus,
substrate 12c was not subjected to the thermal cycloaddition.
Conformationally constrained compounds have a number of
advantages over flexible ones, including the orientation of func-
tional groups in very specific ways that can allow for more rapid
determination of the pharmacophore conformation. Thus strat-
egies to inhibit the conformational mobility of allene-ynes 12 were
considered. Emerging as an interesting option was an allene
containing tetrahydro-β-carboline via a Pictet-Spenger reaction.
Interestingly, no examples of a Pictet-Spengler reaction per-
formed in the presence of an allene could be identified in the
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Chart 1. (A) Indole Building Blocks, (B) Aldehyde Building Blocks, and (C) Alkyne Building Blocks
literature, probably because of the strong acids and elevated
reaction temperatures typically required for the cyclization.22 We
reasoned that hydrolysis of the allene of 19 during the Pictet-
Spengler reaction could be avoided if the reaction was performed at
ambient temperature and in the presence of an organic acid and
molecular sieves.
Preparation of the Pictet-Spengler precursor 19 was accom-
plished from benzamide protected tryptophan 18 via the same
strategy as that described for the synthesis of allene 11 (see
Supporting Information). Removal of the benzoyl-protecting
group of the R-allenic amino-ester 18 with Meerwein’s reagent
provides amine 19 in 59% yield (Table 1).20,23 With amine 19 in
hand, we investigated the cyclization reaction via Pictet-Spengler
reaction conditions. Amine 19 was subjected to aqueous
formaldehyde and trifluoroacetic acid in the presence of 4 Å
molecular sieves in methanol at room temperature to afford
allene-containing tetrahydro-β-carboline 20a{1,2,0} in 71%
yield (Table 1, entry 1). Reaction of 19 with p-fluorobenzalde-
hyde under similar conditions in CH2Cl2 gave 20b{1,5,0} in 70%
yield as a 2:1 trans/cis isomeric mixture (Table 1, entry 2). React-
ing 19 with n-butanal under the same conditions gave tetrahydro-
β-carboline 20c{1,9,0} in 68% yield, also as a 2:1 trans/cis
isomeric mixture (Table 1, entry 3). The trans-isomer was deter-
mined to be the major product based upon calculations of the
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Figure 1. 3D Chemistry-space matrix plots of a virtual library of 11 748 compounds constructed from scaffolds 1-6 (scaffold 1 = purple dots, scaffold 2 =
blue dots, scaffold 3 = cyan dots, scaffold 4 = green dots, scaffold 5= yellow dots, scaffold 6 = light orange dots) and the 327 000þ compound MLSMR
(gray dots) by Sybyl diversity analysis based on the BCUT metrics calculation. The new compounds clearly fill voids in chemical space when compared to
the MLSMR database.
products of the subsequent allenic cycloisomerization reaction
(see Supporting Information).24,25
Table 2. 2D Fingerprint Similarity Results for Comparison of
the Derivatives of Six Scaffolds with the MLSMR Compounds
Allene-containing tetrahydro-β-carbolines 20a-b were next
subjected to a Ag(I)-catalyzed cycloisomerization reaction
(Scheme 3).22 Reaction of tetrahydro-β-carboline derivative
20a{1,2,0} with 20 mol % silver nitrate in acetone in a vial
wrapped in aluminum foil for 18 h afforded 21a{1,2,0} in 56%
yield. Treatment of a 2:1 trans/cis mixture of tetrahydro-β-
carboline 20b{1,5,0} to the same conditions gave 21b{1,5,0} in
72% yield as a 2:1 trans/cis isomeric mixture (Scheme 3).
Equilibration of the 2:1 trans/cis isomeric mixture of 21b{1,5,0}
to a 1:4 trans/cis isomeric mixture was accomplished by via reac-
tion of a solution of 21b{1,5,0} in CDCl3 to 2.5 equiv of TFA for
2.5 h in quantitative yield (see Supporting Information). The
isomers were separated via column chromatography on silica gel
and characterized. Because of the lack of diastereocontrol observed
in the silver-catalyzed cyclization of 21b, the cyclization of 21c
was not examined.
With a more conformationally constrained allene-containing
β-carboline in hand, functionalization with an alkyne group
was examined. Reacting tetrahydro-β-carboline 20a{1,2,0} with
2-butynoic acid (22) and isobutyl chloroformate at room tem-
perature for 18 h afforded allene-yne 23a{1,2,37} in 72% yield
after flash chromatography (Scheme 4). Reacting 20b{1,5,0} or
20c{1,9,0} under similar conditions afforded no product even
after refluxing in THF; suggesting that the steric bulk surround-
ing the N-2 position of tetrahydro-β-carbolines impedes this
condensation reaction.
scaffold
mean Tc (stdev)
% compounds < Tc 0.75
Tc max.
1
2
3
4
5
6
0.66 (0.02)
0.74 (0.03)
0.64 (0.02)
0.73 (0.03)
0.67 (0.02)
0.67 (0.02)
100
61.5
100
79.7
100
100
0.73
0.85
0.71
0.80
0.74
0.73
yield (Scheme 4). Attempts to effect a Rh(I)-catalyzed cyclocar-
bonylation reaction of 23a{1,2,37} afforded an unidentifiable
brown precipitate. However, protecting the nitrogen on the
indole 23a with a Boc group to give 25 enabled the reaction of
propiolamide 25 in presence of molybdenum hexacarbonyl and
DMSO in toluene affording the desired R-alkylidene cyclopen-
tenone 26 in 73% yield as a 1:1 mixture of diastereomers
(Scheme 4). Interestingly, the Rh(I)-catalyzed cyclocarbonyla-
tion reaction of 25 afforded a 45% yield of a ∼1:3 mixture of
regioisomeric products with the major product being the R-
alkylidene cyclopentenone 26, the same product that was
obtained for the molybdenum-mediated process. The minor
product was the desired 4-alkylidene cyclopentenone, resulting
from the reaction with the distal double bond of the allene. We
have observed regioselective discrepancies on occasion in our lab,
and it nearly always involves precursors with coordinating
heteroatoms near the reacting alkyne or allene. The low yield
of this reaction is attributed to the long reaction times (15 h).
The scope and limitation studies described above support the
premise that the allene and allene-yne containing tryptophans
With allene-yne 23a{1,2,37} in hand, we proceeded with the
allenic [2 þ 2] cycloaddition reaction. Heating a DMF solution
of 23a{1,2,37} in the microwave at 225 °C for 7 min afforded
tetrahydrocyclobutaindoloquinolizinone 24{1,2,37} in a 39%
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Figure 2. 3D chemical space comparison plot of the 53 representative compounds (red dots) vs the 11 748 compound virtual combinatorial library built
from six scaffolds (color coded).
provide entry into a multiple skeletally unique scaffolds. Below
we have delineated a virtual library development exemplifying
the uniqueness of these scaffolds and its occupation of new
chemical space when compared to the compounds in the NIH
molecular repository.
generate 528 compounds of the scaffold 4 and 2244 compounds
of each of the scaffolds 1, 2, 3, 5, and 6 for a total of 11 748
compounds.
A diversity analysis was performed using a combination of cell
partition based chemistry space matrix computations using BCUT
(Burden (B) CAS (C) Pearlman at the University of Texas
(UT)) metrics and Tanimoto coefficient (Tc) similarity calcula-
tions using two-dimensional (2D) fingerprints.27 NIH Molecular
Libraries Small Molecule Repository (MLSMR) collects samples
for high throughput biological screening and distributes them to
the NIH Molecular Libraries Probe Production Center Network.
As our group is in this network, we applied 3D chemistry space
BCUT metrics calculations to analyze the structural diversity of
the virtual library and to determine whether the virtual library
contributes chemical diversity value to the existing MLSMR
library. The calculations showed that compounds found within
this virtual library fill new chemical space or void regions when
compared to the 327 000þ compounds from the NIH small
molecule repository (MLSMR).28 The BCUT matrix consid-
ers physical properties including atomic Gasteiger-Huckel
charges, polarizabilities, H-bond donor (HBD), and H-bond
acceptor (HBA) descriptors. These four descriptors correspond
to electrostatic, dispersion, and H-bonding modes of the im-
portant bimolecular interactions. For the three-dimensional plot
shown in Figure 1, we selected the three molecular property
descriptors that gave the most diverse representation of our
library of compounds when compared to the MLSMR. Each
scaffold is color-coded and each dot represents a compound in
the chemistry space matrix. All compounds from the scaffolds
occupy the void regions except for scaffold 4 that is imbedded
among the gray regions of MLSMR chemical space (Figure 1).
A pairwise similarity comparison was also performed for each
core to evaluate the similarity properties of the new virtual library
versus the entire MLSMR database by using a 2D fingerprint
Tanimoto coefficient (Tc) calculation. In this step, the most
similar compound in the MLSMR database was identified for
each individual molecule in the virtual library and the correspond-
ing Tanimoto coefficient (Tc) value of these two compounds was
Virtual Library Development and Diversity Analysis. With
the synthetic methodology for the synthesis of six molecularly
distinct scaffolds in place, a large virtual library composed of
these scaffolds was created and data-mining methods were used
to identify which and how many compounds should be synthe-
sized to provide a representative subset of the chemical space.
The ultimate goal of the data-mining task was to maximize
biologically relevant chemical space with the minimum number
of compounds in an effort to optimize resources. The com-
pounds in the virtual library were assembled from commercially
available building blocks from Aldrich and because very few
tryptophan, propiolic acid, and propargyl bromide derivatives
were commercially available, indoles and alkynes were used for
the virtual library design. This substitution is plausible based
upon the known syntheses of tryptophan derivatives from
indoles and serine,26 propiolic acids from alkynes and carbon
dioxide, and propargyl bromides from alcohols derived from
alkynes and formaldehyde. The library consists of scaffolds 1-6
provided by the synthetic methodology (Scheme 5).
The Aldrich chemical database was mined for commercially
available indoles, aldehydes, and alkynes using a generic substructure
search. The structures were downloaded as SD files and converted
into a Microsoft Excel format, and the undesired reactants were
filtered out manually. For example, compounds possessing
isotopes or incompatible reactive functionalities were removed
from the database; although compounds containing reactive
functional groups that we deemed could be easily protected
were left in the list to give the best representation of potentially
accessible chemical space. The aldehyde database was further
refined by imposing a molecular weight constraint of <250. The
complete database consisted of 44 indoles (Chart 1A), 12 aldehydes
(Chart 1B), and 51 alkynes (Chart 1C). Next, the virtual library
was constructed using the Legion package of Sybyl 8.0 to
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RESEARCH ARTICLE
recorded. The compound similarity results shown in Table 2
indicated that all the compounds derived from scaffolds 1, 3, 5,
and 6 have Tc values less than 0.75 and, none of the compounds in
the virtual library have Tc value larger than 0.8, when compared to
the compounds in the MLSMR database; all six scaffolds have a
mean Tc value well below 0.75 (0.63, 0.74, 0.64, 0.73, 0.67, and
0.67 for scaffolds 1-6, respectively). Moreover, the largest Tc
value is 0.71 for compounds derived from scaffold 3, which means
none of these compounds has Tc score more than 0.71 when
compared with any of the MLSMR compounds.
Because synthesis of a compound subset from this virtual
library of 11 748 compounds is the final goal of these calculations,
fifty-three representative compounds were extracted from the
library by cell-based diverse subset selection using the DVS
package of Sybyl 8.0. This subset consisted of nine compounds
from scaffold 1, seven compounds from scaffold 2, thirteen
compounds from scaffold 3, seven compounds from scaffold 4,
five compounds from scaffold 5, and twelve compounds from
scaffold 6. For comparison purposes, this fifty-three compound
subset has been highlighted within the overall virtual library
(Figure 2).
Methodology for the synthesis of six tryptophan-derived
scaffolds has been developed using the Pictet-Spengler, metal-
catalyzed allenic cyclocarbonylation, microwave-assisted allenic
[2 þ 2] cycloaddition, and Ag(I)-catalyzed allenic cycloiso-
merization reactions. The scaffolds were used as the basis for a
virtual library possessing 11 748 compounds that occupies new
regions of chemical space when compared to the MLSMR using
the BCUT metrics and 2-D fingerprint analysis methods. A
subset of fifty-three compounds was selected to represent
chemical space within the entire virtual library with the aid of
the DVS package of Sybyl 8.0, molecular weight filtering, and
manual selection of synthetically feasible building blocks. This
approach to library synthesis should aid in future endeavors to fill
chemical space and expedite the generation of compound
diversity. The synthesis of and biological evaluation of these
fifty-three compounds will be reported in due course.
(3) A scaffold analysis of the 24 million compounds in the Chemical
Abstracts (CAS) database reveals that half of the compounds can be
described by a mere 143 molecular frameworks, see: Lipkus, A. H.; Yuan,
Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F., III; Schenck, R. J.; Trippe,
A. J. Structural Diversity of Organic Chemistry. A Scaffold Analysis of the
CAS Registry. J. Org. Chem. 2008, 73, 4443–4451.
(4) When screening libraries of compounds for biological activity,
increasing the occupation of distinct chemical space increases the
likelihood of finding biological activity for a wider range of biological
targets, see: Sauer, W. H. B.; Schwarz, M. K. Molecular Shape Diversity
of Combinatorial Libraries: A Prerequisite for Broad Bioactivity. J. Chem.
Inf. Comput. Sci. 2003, 43, 987–1003.
(5) For recent work demonstrating the rapid preparation of over
eighty distinct scaffolds, see: Morton, D.; Leach, S.; Cordier, C.;
Warriner, S.; Nelson, A. Synthesis of Natural-Product-Like Molecules
with Over Eighty Distinct Scaffolds. Angew. Chem., Int. Ed. 2009, 48,
104–109.
(6) For a recent review of this build/couple/pair strategy, see:
Nielsen, T. E.; Schreiber, S. L. Towards the Optimal Screening Collec-
tion: A Synthesis Strategy. Angew. Chem., Int. Ed. 2008, 47, 48–56.
(7) Brummond, K. M.; Mitasev, B. Allenes and Transition Metals: A
Diverging Approach to Heterocycles. Org. Lett. 2004, 6, 2245–2248.
(8) For an example of a library generated using this diverging DOS
strategy, see: Werner, S.; Iyer, P. S.; Fodor, M. D.; Coleman, C. M.;
Twining, L. A.; Mitasev, B.; Brummond, K. M. Solution-Phase Synthesis
of a Tricyclic Pyrrole-2-Carboxamide Discovery Library Applying a
Stetter-Paal-Knorr Reaction Sequence. J. Comb. Chem. 2006, 8,
368–380.
(9) Carbocyclization approaches using alkene and enyne metathesis
to prepare functionalized heterocycles is common, but less so for other
transition metal catalyzed processes. For a leading references, see: Ben-
Othman, R.; Othman, M.; Coste, S.; Decroix, B. One-Pot Enyne
Metathesis/Diels-Alder Reaction for the Construction of Highly
Functionalized Novel Polycyclic Aza-Compounds. Tetrahedron 2008,
64, 559.
(10) For a recent review of indole-containing natural products:
Kawasaki, T.; Higuchi, K. Simple Indole Alkaloids and Those with
Nonrearranged Monoterpenoid Unit. Nat. Prod. Rep. 2005, 22, 761.
(11) O’Connor, S. E.; Maresh, J. Chemistry and Biology of Mono-
terpene Indole Alkaloid Biosynthesis. Nat. Prod. Rep. 2006, 23, 532.
(12) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.;
Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.;
Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana,
S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.;
Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.;
Winzeler, E. A.; Diangana, T. T. Spiroindolones, A Potent Compound
Class for the Treatment of Malaria. Science 2010, 329, 1175–1180.
(13) For leading references, see: Brummond, K. M.; Davis, M.;
Huang, C. Rh(I)-Catalyzed Cyclocarbonylation of Allenol Esters to
Prepare Acetoxy 4-Alkylidene Cyclopent-3-en-2-ones. J. Org. Chem.
2009, 74, 8314–8320.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimentals procedures and
b
characterization data are provided for all new compounds,
computational studies supporting the stereochemical assignment
of compound 21b are discussed, and compound selection charts
for the virtual library of fifty-three compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Chen, D.; Brummond, K. M. Microwave-Assisted Intramole-
cular [2 þ 2] Allenic Cycloaddition Reaction for the Rapid Assembly
of Bicyclo[4.2.0]octa-1,6-dienes and Bicyclo[5.2.0]nona-1,7-dienes.
Org. Lett. 2005, 7, 3473–3475. Brummond, K. M.; Tantillo, D. J.
Differentiating Mechanistic Possibilities for the Thermal Intramolecular
[2 þ 2] Cycloaddition of Allene-ynes. J. Am. Chem. Soc. 2010, 132,
11952–11966.
(15) Brummond, K. M.; Wan, H.; Kent, J. L. An Intramolecular
Allenic [2 þ 2 þ 1] Cycloaddition. J. Org. Chem. 1998, 63, 6535.
(16) For the design and synthesis of a 3,4-dehydroproline amide
discovery library, see: Werner, S.; Kasi, D.; Brummond, K. M. Design
and Synthesis of a 3,4-Dehydroproline Amide Discovery Library.
J. Comb. Chem. 2007, 9, 677–683 and PubChem SID #’s 8143029-
8143143.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: kbrummon@pitt.edu. (K.M.B.) or xix15@pitt.edu (X.Q.X).
Funding Sources
We would like to thank the NIGMS P50GM067082 for generous
funding.
’ REFERENCES
(1) Tan, D. S. Diversity-Oriented Synthesis: Exploring the
Intersections Between Chemistry and Biology. Nat. Chem. Biol.
2005, 1, 74–84.
(2) Dandapani, S.; Marcaurelle, L. A. Current Strategies for Diversity-
Oriented Synthesis. Curr. Opin. Chem. Biol. 2010, 14, 362–370.
(17) (a) Dieter, R. K.; Yu, H. Synthesis of 3-Pyrrolines, Annulated
3-Pyrrolines, and Pyrroles from R-Amino Allenes. Org. Lett. 2001, 3,
3855–3858. (b) Dieter, R. K.; Chen, N.; Yu, H.; Nice, L. E.; Gore, V. K.
173
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RESEARCH ARTICLE
Reaction of R-(N-Carbamoyl)alkylcuprates with Propargyl Substrates:
Synthetic Route to R-Amino Allenes and Δ3-Pyrrolines. J. Org. Chem.
2005, 70, 2109–2119. (c) Dieter, R. K.; Chen, N.; Gore, V. K. Reaction
of R-(N-Carbamoyl)alkylcuprates with Enantioenriched Propargyl
Electrophiles: Synthesis of Enantioenriched 3-Pyrrolines. J. Org. Chem.
2006, 71, 8755–8760. (d) Mitasev, B.; Brummond, K. M. Synthesis of
Functionalized Δ3-Pyrrolines via a Ag(I)-Catalyzed Cyclization of
Amino Acid Derived Allenes. Synlett 2006, 3100–3104.
(18) For a review on the silver-catalyzed allenic cycloisomerization
reaction please see: Alvarez-Corral, M.; Munoz-Dorado, M.; Rodriguez-
Garcia, I. Chem. Rev. 2008, 108, 3174–3198.
(19) Franzꢀen, H; Grehn, L.; Ragnarsson, U. Synthesis, Properties,
and Use of Nin-Boc-Tryptophan Derivatives. J. Chem. Soc., Chem.
Commun. 1984, 1699–1700.
(20) Castelhano, A.; Horne, S.; Taylor, G.; Billedeu, R.; Krantz, A.
Synthesis of R-Amino Acids with β,γ-Unsaturated Side Chains. Tetra-
hedron 1988, 44, 5451–5466.
(21) Brummond, K. M.; Curran, D. P.; Mitasev, B.; Fischer, S.
Heterocyclic R-Alkylidene Cyclopentenones Obtained via a Pauson-
Khand Reaction of Amino Acid Derived Allenynes. A Scope and
Limitation Study Directed Toward the Preparation of a Tricyclic Pyrrole
Library. J. Org. Chem. 2005, 70, 1745–1753.
(22) For a review of the Pictet-Spengler reaction please, see: Cox,
E. D.; Cook, J. M. The Pictet-Spengler Condensation: A New Direc-
tion for an Old Reaction. Chem. Rev. 1995, 95, 1797–1842.
(23) Brummond, K. M.; Painter, T. O.; Probst, D. A.; Mitasev, B.
Rhodium(I)-Catalyzed Allenic Carbocyclization Reaction Affording
δ- and ε-Lactams. Org. Lett. 2007, 9, 347–349.
(24) Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. Stereospecific
Synthesis of Trans-1,3-Disubstituted-1,2,3,4-Tetrahydro-β-Carbolines.
J. Org. Chem. 1981, 46, 164–168.
(25) Casnati, G.; Dossena, A.; Pochini, A. Electrophilic Substitution
in Indoles: Direct Attack at the 2-Position of 3-Alkylindoles. Tetrahedron
Lett. 1972, 5277.
(26) For a selected example, see: Blaser, G.; Sanderson, J. M.;
Batsanov, A. S.; Howard, J. A. K. The Facile Synthesis of a Series of
Trytophan Derivatives. Tetrahedron Lett. 2008, 49, 2795–2798.
(27) Xie, X.-Q. C.; Chen, J. Z. Data Mining a Small Molecule Drug
Screening Representative Subset from NIH PubChem. J. Chem. Inf.
Model. 2008, 48, 465–475.
(28) Of the databases that our compounds could be compared to,
the NIH Molecular Repository was selected because this will be the
physical location of the compounds. NIH Molecular Repository
(http://mlsmr.glpg.com/MLSMR_HomePage).
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