Application of a catalytic asymmetric povarov reaction using chiral ureas to the synthesis of a tetrahydroquinoline library

Article abstract of DOI:10.1021/co300098v

A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery.

Full text of DOI:10.1021/co300098v

Research Article
pubs.acs.org/acscombsci
Application of a Catalytic Asymmetric Povarov Reaction using Chiral
Ureas to the Synthesis of a Tetrahydroquinoline Library
Baudouin Gerard,†,§ Morgan Welzel O’Shea,†,§ Etienne Donckele,† Sarathy Kesavan,†,§
Lakshmi B. Akella,†,§ Hao Xu,‡ Eric N. Jacobsen,‡ and Lisa A. Marcaurelle*,†,§
†Chemical Biology Platform, The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142,
United States
‡Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
S
* Supporting Information
ABSTRACT: A 2328-membered library of 2,3,4-trisubstituted tetrahy-
droquinolines was produced using a combination of solution- and solid-
phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was
prepared via an asymmetric Povarov reaction using cooperative catalysis
to generate three contiguous stereogenic centers. A matrix of 4
stereoisomers of the THQ scaffold was prepared to enable the
development of stereo/structure−activity relationships (SSAR) upon
biological testing. A sparse matrix design strategy was employed to select
library members to be synthesized with the goal of generating a diverse
collection of tetrahydroquinolines with physicochemical properties
suitable for downstream discovery.
KEYWORDS: Povarov reaction, chiral urea, tetrahydroquinoline, asymmetric, solid-phase
for loading onto solid support and 2) chemical handles for
introducing appendage diversity. With these features in mind,
we began by selecting the imino Diels−Alder partners for the
asymmetric Povarov reaction. Use of an imine glyoxolate 5,
obtained from condensation of aniline 6 and ethyl glyoxolate 7,
as the 4-π component,6 was attractive for a number of reasons
(Scheme 2). The use of glyoxolate ester derivatives would
provide a low molecular weight scaffold bearing a functional
handle for loading the products onto solid supports. In
addition, the primary products of the Povarov reaction (8)
contain an epimerizable stereogenic center that could allow
further diversification of the scaffold. Finally, excellent enantio-
and diastereoselectivities have been demonstrated in the urea-
catalyzed asymmetric Povarov reaction of glyoxylate imines.3a
Various substituted anilines (4-methoxycarbonyl 6a, 4-((tert-
butyldimethylsilyl)oxy) 6b, 4-bromo 6c) were evaluated as
imine precursors in the Povarov reaction with dihydrofuran as a
model dienophile. The imine generated from 6a was unstable
and resulted in a low yield on large scale in the Povarov
reaction. Meanwhile, reactions of 6b were found to be poorly
reproducible and became problematic with future protecting
group manipulations. In contrast, 6c offered good reactivity and
reproducibility in the imine formation on large scale.
Furthermore, the aryl bromide could be used as a diversity
INTRODUCTION
■
The acid-catalyzed [4 + 2] cycloaddition of N-aryl imines and
electron-rich olefins, known as the Povarov reaction,1 is a
powerful method for the synthesis of tetrahydroquinolines
(THQ), a commonly occurring motif in a variety of natural
products and biologically active compounds (Figure 1).2 Up to
three contiguous stereocenters can be generated simultaneously
in the Povarov reaction, and enantioselective catalytic variants
of this reaction have been identified recently.3 As part of our
ongoing efforts to develop new methods for producing
collections of stereochemically and skeletally diverse small
molecules,4,5 we were interested in applying the chiral urea (1)/
Brønsted acid cocatalyzed asymmetric Povarov reaction3a
(Scheme 1) to the synthesis of a THQ-based library.
At the outset of the project we faced three synthetic
challenges in the production of a diverse THQ-based library:
(1) adaptation of the asymmetric Povarov reaction conditions
to multigram scale, (2) development of a practical strategy for
accessing a matrix of stereoisomers, and (3) optimization of
solid-phase diversification reactions. In this paper, we describe
successful solutions to these challenges in the context of the
large-scale synthesis of a collection of stereoisomeric THQ
scaffolds as well as the solid-phase production of a 2328-
membered THQ library.
RESULTS AND DISCUSSION
■
Received: August 23, 2012
Revised: October 3, 2012
Published: October 22, 2012
Scaffold Design. In designing a THQ scaffold for library
synthesis, we required two key features: 1) a primary alcohol
© 2012 American Chemical Society
621
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
Figure 1. Examples of natural products and biologically active compounds featuring a tetrahydroquinoline core.
Scheme 1. Asymmetric Cocatalysis of the Povarov Reaction Using a Brønsted Acid and a Chiral Urea
was observed based on the nature of the protecting group. For
example, the nosylated pyrrole 10a proved unreactive during
the Povarov reaction mostly due to poor solubility in toluene at
low temperatures (−60 °C) (entry 1). Meanwhile, use of Boc-
protected pyrrole 10b led to an overall decrease in yield (38%)
and diastereoselectivity (from 9:1 to 7:3 dr) (entry 2).
However, it was found that Fmoc and Cbz carbamates, 10c
and 10d gave more suitable results with up to 80% isolated
yield of the corresponding cycloadduct and with good levels of
diastereoselectivity (9:1 dr) and enantioselectivity (up to 93:7
er). Thus, dienophile 10c and 10d were selected for the scale
up of the THQ scaffolds for library production.
Scheme 2. Retrosynthesis of THQ Scaffold 8
Large-Scale Reaction Optimization. Having selected 5c
as diene and 10c and 10d as dienophiles, we next evaluated the
optimization for the asymmetric Povarov reaction on multigram
scale to achieve high yield and optimal levels of enantio- and
diasteroselectivity suitable for library production. In preliminary
studies, we found that the manner in which the imine was
generated was a critical parameter for obtaining consistent
results on large scale.11 The imine formed in situ was found to
be extremely sensitive to nucleophilic attack with an excess of
aniline leading to side product formation.12 A practical
procedure was developed involving formation of the imine
via slow addition of aniline 6c into glyoxolate 7 in toluene at 0
°C, followed by isolation of the crude imine via solvent removal
in vacuo.7
site on solid phase for cross coupling reactions.7 It was found
that the Povarov adduct could be recrystallized and thus
confirming the absolute configuration of the cycloaddition
product with endo stereochemistry.8
With the diene in hand, we moved on to study the dienophile
partner 9. We focused on dienophiles featuring a handle for
solid-phase diversification, and those which showed good
reactivity while retaining high levels of enantio- and
diastereoselectivity in the Povarov reaction. As noted in
previous reports, 2,3-dihydropyrrole derivative 10 is a versatile
dienophile for the Povarov reaction.3a,9,10 We conducted a
study (Table 1) to determine the most suitable protecting
group for the pyrrole nitrogen under Povarov reaction
conditions. As expected, a noticeable difference in reactivity
Initially, when employing previously described conditions for
the Povarov reaction3a (4 mol % of urea catalyst 1, 2 mol % of
ortho-nitrobenzenesulfonic acid (NBSA) as the Brønsted acid in
toluene at −60 °C in presence of 5 Å MS, 1 mmol scale), we
observed formation of the desired product 11 with good
622
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
Table 1. Screening of Dienophiles for the Asymmetric Povarov Reaction
a
b
c
entry
R
product
dr
er
yield of 11 (%)
1
2
3
4
Ns, 10a
11a/12a
11b/12b
11c/12c
11d/12d
NR
32
Boc, 10b
Cbz, 10c
Fmoc, 10d
7:3
9:1
9:1
95:5
93:7
84:16
58
80
a
b
Diastereoisomeric ratio (dr) was measured by UPLC with UV detection at 210 nm on the crude reaction mixture. Enantiomeric ratio (er) was
c
measured by SFC with UV detection at 210 nm after chromatography separation of the major diastereoisomer. Isolated yield of 11 after silica gel
chromatography.
Table 2. Large Scale Reaction Optimization
a
b
c
entry
R
acid
acid (mol %)
cat. (mol %)
scale (mmol)
product
dr
er
yield of 11 (%)
1
2
3
4
5
6
Cbz, 10c
Cbz, 10c
Cbz, 10c
Cbz, 10c
Cbz, 10c
Fmoc, 10d
NBSA
NBSA
PTSA
PTSA
PTSA
PTSA
2
2
2
1
1
1
4
4
4
2
2
2
1
25
39
39
67
35
11c/12c
11c/12c
11c/12c
11c/12c
11c/12c
11d/12d
90:10
90:10
90:10
89:11
91:9
90:10
93:7
40
58
61
58
65
89
92:8
89:11
88:12
84:16
90:10
a
b
Diastereoisomeric ratio (dr) was measured by UPLCwith UV detection at 210 nm on the crude reaction mixture. Enantiomeric ratio (er) was
c
measured by SFC with UV detection at 210 nm after chromatography separation of the major diastereoisomer. Isolated yield of 11 after silica gel
chromatography.
Scheme 3. Solution-Phase Synthesis of Library Scaffolds
623
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
Figure 2. Matrix of four stereoisomers for the NH and NMe THQ scaffolds.
Table 3. Solid-Phase Suzuki Feasibility Studies
a
a
a
entry
SM
catalyst
base
T (°C)
solvent
EtOH
product
conv (%)
SM (%)
byproduct (%)
1
2
3
4
5
6
20
20
20
20
20
21
PdCl2(PPh2)3
TEA
60
60
60
60
rt
22
22
22
22
22
23
60
70
12
5
18
25
13
27
0
Pd(dba)2, P(t-Bu)3
PEPPSI
K3PO4
CsCO3
K3PO4
K3PO4
K3PO4
PhMe
1,4 dioxane
PhMe
78
9
Pd(dba)2, S-Phos
Buchwald precatalyst
Buchwald precatalyst
73
0
THF
100
100
0
rt
THF
0
0
a
Conversion was measured by UPLC with UV detection at 210 nm.
enantio- (9:1 er) and diastereoselectivity (9:1 dr) albeit in
modest yield (40%) (Table 2, entry 1). We hypothesized that
residual amount of water from the Brønsted acid may hydrolyze
the water-sensitive imine 5c10,13 and, therefore, affect the
overall isolated yield of 11 on large scale. After studying the
effect of other Brønsted acids in the Povarov reaction, we found
that the use of anhydrous p-toluenesulfonic acid (PTSA)14 gave
comparable results (yield and enantio- and diastereoselectivity)
to NBSA (Table 2, entries 2 and 3). Anhydrous PTSA was
found to be easy to use and could be stored for several weeks at
room temperature in a desiccator. Thus, for practical reasons
we decided to use PTSA for the remainder of our optimization
experiments. This modification enable us to conduct the
asymmetric Povarov reaction on large scale with up to 66 mmol
of 5 (17 g) in presence of 10c as the dienophile to give
moderate yield and good enantiomeric ratio (65%, 88:12 er,
entry 5). Similar yield and enantioselectivity of 11d was
obtained when 10d was used as dienophile in the Povarov
reaction. In addition, 11d could be easily purified via
crystallization to give almost enantiomeric pure material.
Gratifyingly, we observed no erosion of reactivity when using
lower catalyst and Brønsted acid loading (2 mol % of urea
catalyst and 1 mol % of PTSA (entries 3 and 4)). Similar results
were obtained in the Povarov reaction when the enantiomer of
the urea catalyst 1 was employed.15
Epimerization Studies. To obtain stereochemical diversity,
a practical method to epimerize the stereogenic center adjacent
to the ester was sought to convert the endo diastereomer 11c
into the thermodynamically favored exo diastereoisomer 12c.
Although there was precedent for a similar epimerization
strategy via the corresponding aldehyde in the synthesis of the
natural product martinelline,16 we were hoping to develop a
624
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
Chart 1. Building Blocks for Amine Capping
synthetic sequence to access 12c directly and on large scale.
After extensive screening of epimerization conditions,17 it was
found that treatment with 0.1 M solution of sodium methoxide
in methanol at 60 °C afforded the desired epimer as the methyl
ester (14c) in 70% yield (Scheme 3). The endo methyl ester
13c that was recovered after purification could be resubjected
to the same conditions to provide 14c in 90% overall yield over
two cycles.
Library Scaffold Preparation. For solid-phase library
production, a protecting group manipulation was required to
replace the incompatible Cbz group with Fmoc. To streamline
the preparation of the final cores, we decided to utilize Fmoc-
pyrrole 10d as the dienophile to generate endo diaster-
eoisomers and Cbz-pyrrole 10c to generate the remaining exo
diastereoisomers. After Povarov cycloaddition using Fmoc-
pyrrole 10d with either 1 or its enantiomer, cycloadduct 11d
was reduced using LiBH4 to afford the corresponding primary
625
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
Chart 2. Building Block for Cross Coupling
Scheme 4. Solid-Phase Synthesis of THQ Library on SynPhase Lanterns
alcohol 15d (Scheme 3).18 Scaffold 15d could be easily
recrystallized in a 9:1 mixture of benzene and dichloromethane
to give enantioenriched compounds with excellent enantiose-
lectivity (99:1 er). After epimerization of 11c to 14c, the exo
Fmoc protected diastereoisomer was obtained via a stepwise
processes involving (1) ester reduction using LiBH4 and (2)
protecting group exchange from the incompatible Cbz to Fmoc
to afford 16d. Recrystallization of 16d afforded enrichment of
enantiopure compound up to 97:3 er.
During initial feasibility studies, it was found that the THQ
aniline had limited reactivity upon treatment with various
electrophiles, such as acyl chlorides and sulfonyl chlorides, thus
restricting its use as diversity site for solid-phase production.
However, it was found that the aniline could be alkylated by
reductive amination with a limited number of aldehydes.
Formaldehyde was found to be the most reactive among the
aldehydes tested. Scaffolds 15d and 16d were therefore
methylated via reductive amination with excellent yields (90−
95%) to give 17d and 18d. This strategy allowed us to generate
eight different scaffolds, including both enantiomers of the NH
and NMe endo and exo cores (Figure 2).
Solid-Phase Feasibility Studies. With the NH and NMe
THQ-scaffolds in hand, we turned our attention to the
development of solid-phase methods for the introduction of
building blocks at the two diversity sites: (1) the secondary
amine and (2) the aryl bromide. Solid-phase feasibility studies
were conducted on SynPhase Lanterns (vide infra). Amine
capping at the first diversity site for both the NH and NMe
sublibraries involved screening with a variety of electrophiles,
including isocyanates, sulfonyl chlorides, aldehydes, and acids.
Bis-capping was observed with the use of isocyanates in the
presence of the free aniline and therefore removed from the
design of the NH sublibrary. While isocyanates performed well
for the NMe sublibrary, the use of aldehydes was problematic
resulting in significant decomposition during reductive
alkylation conditions. Therefore, aldehydes were removed
626
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
Figure 3. Purity analysis for THQ library (UPLC analysis with UV detection at 210 nm). Library members are displayed as blocks of 4 stereoisomers
(see legend) for both the NH and NMe sublibraries. Reagents used for solid-phase diversification are shown on the x- and y-axes. (See Charts 1 and
2 for detailed list of reagents).
from the NMe sublibrary design. Acids and sulfonyl chlorides
performed well for both sublibraries.
phase were attempted using 3-methoxybenzene boronic acid 19
and sulfonamides 20 and 21 as a model (Table 3, entry 1).
Moderate conversion to the desired product was observed in
addition to the formation of a significant amount of unknown
byproducts,19 possibly due to a rapid protodeboronation step20
versus a slow oxidative insertion step. A variety of other
conditions were screened including multiple ligands (P(t-Bu)3,
PEPPSI 26,21 S-Phos 24, Pd catalyst (PdCl2(PPh3)2), Pd-
(dba)2), bases (TEA, K3PO4, Cs2CO3) and solvents (EtOH,
Next, the feasibility of Pd-mediated cross coupling reactions
at the aryl bromide was investigated. Both Sonogashira and
Suzuki cross couplings were explored. Initial screenings of the
Sonogashira cross coupling led to poor conversion and
produced a significant amount of side products. Therefore,
we decided to focus solely on the Suzuki cross coupling for
production purposes. Traditional Suzuki conditions on solid
627
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
publication from the Buchwald lab highlights the use of X-Phos
ligand in a preformed catalyst.22 The use of such a precatalyst
was reported to increase the rate of boronic acid coupling
versus its decomposition due to the use of milder reaction
condition. Upon treatment with the Buchwald precatalyst 27 at
room temperature, we were delighted to find formation of the
desired cross coupling product in high conversion without the
formation of undesired side products for both NH and NMe
sublibraries (entries 5 and 6).
Table 4. Property Analysis for the THQ Library
b
b
NH scaffold
(n = 1)
NMe scaffold
(n = 1)
NH library NMe library
(n = 1100)
a
property
(n = 1252)
MW
283
1.4
44
1
297
1.9
36
1
420
2.9
73
433
3.4
65
ALogP
TPSA
rot. bonds
HBA
3.9
4.4
3.7
4.2
1.3
3
3
HBD
3
2
2.0
With this information in hand, a sparse matrix design strategy
for each sublibrary was implemented to select library members
to be synthesized. First, a virtual library was constructed for
both sublibraries using all possible building block combinations
at R1 (amine) and R2 (aryl bromide) using a master list of
reagents (R1 = sulfonyl chlorides, isocyanates, acids, and
aldehydes; R2 = boronic acids).23 This resulted in ∼2400
compounds per stereoisomer. Physicochemical property filters
were then applied to eliminate building block combinations
that led to products with undesirable properties. Property filters
included the following: MW ≤ 500, ALogP −1 to 5, H-bond
acceptors + donors ≤10, rotatable bonds ≤10 and TPSA ≤
140. A total of 274 compounds per scaffold for the NH
sublibrary and 310 compounds per scaffold for the NMe
sublibrary were selected from the remaining set using chemical
similarity principles, maximizing diversity but retaining near
neighbors for built-in SAR.22 The reagents selected for library
production are shown below (Charts 1 and 2). The same set of
reagents was used for each stereoisomer thereby maintaining
the ability to generate SSAR for each building block
combination.
a
b
Physicochemical properties listed as mean values. Property analysis
of bare scaffolds, where R1 and R2 = H.
Solid-Phase Library Production. With the solid-phase
feasibility studies complete, we turned our attention to library
production. Immobilization of the scaffold onto solid support
was achieved via activation of the SynPhase Lanterns (L-series)
with triflic acid followed by treatment with scaffolds 15−18 in
the presence of excess 2,6-luditine (Scheme 4).24 The average
loading levels obtained were 17.0 μmol/Lantern for the NH
sublibrary and 13.3 μmol/Lantern for the NMe sublibrary.
Removal of the Fmoc protecting group under standard
conditions followed by capping with the appropriate electro-
philic building blocks for NH and NMe sublibraries yielded
compounds 12{1−42} and 13{8−54}. Subsequent Pd-
mediated cross coupling utilizing the Suzuki reaction afforded
compounds 14{1−42, 1−14} and 15{8−54, 1−14}. Once the
reaction sequence was complete, the Lanterns were subjected
to an aqueous sodium cyanide wash (1:1 1.0 M NaCN in
water/THF solution) to remove any residual Pd. Release of the
final compounds (16{1−42, 1−14} and 17{8−54, 1−14})
from solid support was achieved via treatment with HF/
pyridine. All library products were analyzed by ultraperform-
ance liquid chromatography, and compound purity was
assessed by UV detection at 210 nm. The average purity of
the THQ NH library (1088 compounds) was 78%, with 71% of
the library being >75% pure, while the average purity of the
THQ NMe library (1240 compounds) was 75%, with 68% of
the library being >75% pure. A full purity analysis is provided in
Figure 3. Of note, certain nitrogen containing building blocks
proved problematic during the amine capping for the NH
sublibrary, including acids 12, 24, 29 and 30, while the trans-1-
propenylboronic acid (1) generally did not perform well for
either sublibrary.
Figure 4. Molecular weight (MW) and ALogP distribution for THQ-
library members.
Figure 5. Multifusion similarity map comparing the THQ library (n =
2328) to the 2011 MLSMR (n = 335834). The reference set
(MLSMR) is not shown on the map (see text for details).
PhMe, 1,4-dioxane, THF) in an attempt to increase the rate of
oxidative insertion and potentially limit formation of side
products without success (Table 3, entries 1−4). A recent
Library Analysis. Analysis of the THQ library (Table 4 and
Figure 4) reveals that the calculated physicochemical property
628
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
profile for the compound set is within the intended range for
the library design (vide supra). Meanwhile, the structural
diversity of the THQ library was analyzed in comparison to the
NIH Molecular Library Repository (MLSMR) as we intended
to submit a subset of these compounds to the collection at the
time of the analysis. We employed multifusion similarity (MFS)
maps for the comparison of each collection using extended
connectivity fingerprints (ECFP_4) for molecular representa-
tion and Tanimoto coefficient (Tc) as the similarity measure.25
In this method, each molecule in the test set (THQ library, n =
2328) is compared to every molecule in the reference set (2011
MLSMR, n = 335834), and the largest similarity score and the
mean similarity score to the reference set is obtained. The
resulting mean similarity (x-axis) and maximum similarity (y-
axis) values are plotted in two dimensions as a scatter plot
facilitating the visual characterization and comparison. Figure 5
shows the MFS map comparing the THQ library to the
MLSMR. Each data point in the map depicts a compound from
the test set and its location was influenced by the reference set.
(The reference compounds themselves do not appear on the
plot.) The maxium mean similarity of the THQ library is 0.13
(Tc) indicative of the overall structural diversity with the
respect to the MLSMR reference set. Furthermore, there are no
compounds with maximal similarity equal or greater than 0.57
(Tc) in the MLSMR, illustrating that these compounds
represent regions of unoccupied chemical space within this
collection.
ACKNOWLEDGMENTS
■
The authors would like to thank Stephen Johnston and Anita
Vrcic for compound management and analytical support.
REFERENCES
■
(1) Kouznetsov, V. V. Recent synthetic developments in a powerful
imino Diels−Alder reaction (Povarov reaction): Application to the
synthesis of N-polyhetereocycles and related alkaloids. Tetrahedron
2009, 65, 2721−2750.
(2) (a) Leeson, P. D; Carling, R. W.; Moore, K. W.; Moseley, A. M.;
Smith, J. D.; Stevenson, G.; Chan, T.; Baker, R.; Foster, A. C.;
Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Hoogsteen, K.. 4-Amido-
2-carboxytetrahydroquinolines. Structure−activity relationships for
antagonism at the glycine site of the NMDA receptor. J. Med. Chem.
1992, 35, 1954−1968. (b) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj,
R. P.; Lough, A. J. A three-component coupling protocol for the
synthesis of substituted hexahydropyrrolo[3,2-c]quinolines. Chem.
Commun. 1999, 7, 651−652. (c) Takamura, M.; Funabashi, K.;
Kanai, M.; Shibasaki, M. Catalytic enantioselective reissert-type
reaction: Development and application to the synthesis of a potent
NMDA receptor antagonist (−)-L-689,560 using a solid-supported
catalyst. J. Am. Chem. Soc. 2001, 123, 6801−6808. (d) Witherup, K.
M.; Ransom, R. W.; Graham, A. C.; Bernad, A. M.; Salvatore, M. J.;
Lumma, W. C.; Anderson, P. S.; Pitzenberger, S, M.; Vargatt, S. L.
Martinelline and Martinellic acid, Novel g-protein-linked receptor
antagonists from the tropical plant Martinella iquitosensis (Bignonia-
ceae). J. Am. Chem. Soc. 1995, 117, 6682−6685. (e) Kumar, A.;
Srivastava, S.; Gupta, G.; Chaturvedi, V.; Sinha, S.; Srivastava, R.
Natural product inspired diversity oriented synthesis of tetrahydro-
quinoline scaffolds as antitubercular agent. ACS Comb. Sci. 2011, 13,
65−71. (f) Schiemann, K.; Finsinger, D.; Zenke, F.; Amendt, C.;
Knochel, T.; Bruge, D.; Buchstaller, H.-P.; Emde, U.; Stahle, W.;
Anzali, S. The discovery and optimization of hexahydro-2H-pyrano-
[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the
mitotic kinesin-5. Bioorg. Med. Chem. Lett. 2010, 20, 1491−1495.
(g) Sridharan, V.; Suryavanshi, P, A.; Menendez, J. C. Advances in the
chemistry of tetrahydroquinolines. Chem. Rev. 2011, 111, 7157−7259.
(h) Demont, E. H.; Garton, N. S.; Gosmini, R. L. M.; Hayhow, T. G.
C.; Seal. J.; Wilson, D. M.; Woodrow, M. D. Tetrahydroquinolines
derivatives and their pharmaceutical use. Europe Patent PCT Int. Appl.
WO2011054841A1, 2011.
(3) (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Asymmetric cooperative catalysis of strong Brønsted acid−promoted
reactions using chiral ureas. Science 2010, 327, 986−990. (b) Ishitani,
S.; Kobayashi, S. Catalytic asymmetric aza-Diels−Alder reactions using
a chiral Lanthanide Lewis acid. Enantioselective synthesis of
tetrahydroquinoline derivatives using a catalytic amount of a chiral
source. Tetrahedron Lett. 1996, 37, 7357−7360. (c) Akiyama, T.;
Morita, H.; Fuchibe, K. Chiral Brønsted acid-catalyzed inverse
electron-demand aza-Diels−Alder reaction. J. Am. Chem. Soc. 2006,
128, 13070−13071. (d) Liu, H.; Dagousset; Masson, G.; Retailleau, P.;
Zhu, J. P. Chiral Brønsted acid-catalyzed enantioselective three-
component Povarov reaction. J. Am. Chem. Soc. 2009, 131, 4598−
4599. (e) Xie, M.; Liu, X.; Zhu, Y.; Zhao, X.; Xia, Y.; Lin, L.; Feng, X.
Asymmetric synthesis of tetrahydroquinolines with quaternary stereo-
centers through the Povarov reaction. Chem.Eur. J. 2011, 17,
13800−13805. (f) Ren, L.; Lei, T.; Ye, J.-X.; Gong, L-Z Step-
economical synthesis of tetrahydroquinolines by asymmetric relay
CONCLUSIONS
■
In summary, a 2328-membered library of tetrahydroquinolines
was successfully prepared using the asymmetric Brønsted acid/
urea-catayzed Povarov reaction3a as a key step. Adaptation of
the Povarov reaction for large scale synthesis led to the use of
anhydrous PTSA as the Brønsted acid in place of NBSA and
optimization of the imie formation step. These modifications
enabled the large scale (>5 g) preparation of 4 stereoisomers of
two THQ scaffolds with two functional handles for solid-phase
diversification. In silico library design followed by production
on SynPhase Lanterns afforded a diverse library of function-
alized tetrahydroquinolines with properties suitable for down-
stream discovery.
ASSOCIATED CONTENT
* Supporting Information
Additional data and figures. This material is available free of
■
S
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lisa_marcaurelle@h3biomedicine.com.
■
Present Address
§H3 Biomedicine Inc., 300 Technology Square, Cambridge,
Massachusetts 02139, United States
Funding
catalytic Friedlander condensation/transfer hydrogenation. Angew.
̈
Chem., Int. Ed. 2012, 51, 771−774. (g) Tan, H. R.; Ng, F, H.;
Chang, J.; Wang, J. Highly enantioselective assembly of functionalized
tetrahydroquinolines with creation of an all-carbon quaternary center.
Chem.Eur. J. 2012, 18, 3865−3870. (h) He, L.; Bekkaye, M.;
Retailleau, P.; Masson, G. Chiral phosphoric acid catalyzed inverse-
electron-demand aza-Diels-Alder reaction of isoeugenol derivatives.
Org. Lett. 2012, 14, 3158−3161.
This work was funded in part by the NIGMS-sponsored Center
of Excellence in Chemical Methodology and Library Develop-
ment (Broad Institute CMLD; P50 GM069721), as well as the
NIH Genomics Based Drug Discovery U54 grants Discovery
Pipeline RL1CA133834 (administratively linked to NIH grants
RL1HG004671, RL1GM084437, and UL1DE019585).
Notes
(4) (a) Schreiber, S. L. Target-oriented and diversity-oriented organic
synthesis in drug discovery. Science 2000, 287, 1964−1969. (b) Burke,
The authors declare no competing financial interest.
629
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630

ACS Combinatorial Science
Research Article
M. D.; Schreiber, S. L. A planning strategy for diversity-oriented
synthesis. Angew. Chem., Int. Ed. 2004, 43, 46−58. (c) Nielsen, T. E.;
Schreiber, S. L. Toward the optimal screening collection: A synthesis
strategy. Angew. Chem., Int. Ed. 2007, 74, 48−56.
(19) The molecular weight of the observed byproduct corresponded
to phosphine (PR3) incorporation as judged by LCMS.
(20) (a) Kuivila, H. G.; Reuwer, J. F.; Mangravite, J. A. Electrophilic
displacement reactions. XVI. Metal ion catalysis in the protodeboro-
nation of areneboronic Acids. J. Am. Chem. Soc. 1964, 86, 2666−2670.
(b) Clapham, K. M..; Batsanov, A. S.; Bryce, M. R.; Tarbit, B.
Trifluoromethyl-substituted pyridyl- and pyrazolylboronic acids and
esters: Synthesis and SuzukiMiyaura cross-coupling reactions. Org.
Biomol. Chem. 2009, 7, 2155−2161. (c) Clapham, K. M.; Batsanov, A.
S.; Greenwood, R. D. R.; Bryce, M. R.; Smith, A. E.; Tarbit, B.
Functionalized heteroarylpyridazines and pyridazin-3(2H)-one deriv-
ativesvia palladium-catalyzed cross-coupling methodology. J. Org.
Chem. 2008, 73, 2176−2181.
(21) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass,
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. D. Easily prepared air-
and moisture-stable Pd−NHC (NHCN-heterocyclic carbene)
complexes: A reliable, user-friendly, highly active palladium precatalyst
for the Suzuki−Miyaura reaction. Chem.Eur. J. 2006, 12, 4743−
4748.
(22) Kinzel, T.; Zhang, Y.; Buchwald, S. L. A new palladium
precatalyst allows for the fast Suzuki-Miyaura coupling reactions of
unstable polyfluorophenyl and 2-heteroaryl boronic acids. J. Am. Chem.
Soc. 2010, 132 (40), 14073−14075.
(23) For further details on the selection of reagents for master list,
see: Akella, L. B.; Marcaurelle, L. A. Application of a sparse matrix
design strategy to the synthesis of DOS libraries. ACS. Comb. Sci.
2011, 13, 357−364.
(24) Ryba, T. D.; Depew, K, M.; Marcaurelle, L. A. Large scale
preparation of silicon-functionalized SynPhase polystyrene Lanterns
for solid-phase synthesis. J. Comb. Chem. 2009, 11, 110−116.
(25) (a) Medina-Franco, J. L.; Maggiora, G. M.; Giulianotti, M. A.;
Pinilla, C.; Houghten, R. A. A similarity-based data-fusion approach to
the visual characterization and comparison of compound databases.
Chem. Biol. Drug Des. 2007, 70, 393−412. (b) Medina-Franco, J. L.;
Martinez-Mayorga, K.; Giulianotti, M. A.; Houghten, R. A.; Pinilla, C.
Visualization of the chemical space in drug discovery. Curr. Comput.-
Aided Drug Des. 2008, 4, 322−333.
(5) (a) Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.;
Gerard, B.; Kesavan, S.; Lee, M. D., IV; Liu, H.; Lowe, J. T.; Marie, J-.
C.; Mulrooney, C. A.; Pandya, B. A.; Rowley, A.; Ryba, T. D.; Suh, B-.
C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross, N. T.; Zhang, Y-. L.;
Fass, D. M.; Reis, S. A.; Zhao, W-. Z.; Haggarty, S. J.; Palmer, M.;
Foley, M. A. An aldol-based build/couple/pair strategy for the
synthesis of medium- and large-sized rings: Discovery of macrocyclic
histone deacetylase inhibitors. J. Am. Chem. Soc. 2010, 132, 16962−
16976. (b) Gerard, B.; Duvall, J. R.; Lowe, J. R.; Murillo, T.; Wei, J.;
Akella, L. B.; Marcaurelle, L. A. Synthesis of a stereochemically diverse
library of medium-sized lactams and sultams via SNAr cyclo-
etherification. ACS. Comb. Sci. 2011, 13, 365−374.
(6) For references on the use of imine glyoxolate in Povarov reaction,
see: (a) Alves, J. M.; Azoia, N. G.; Fortes, G, A. Regio- and stereo-
selective aza-Diels−Alder reaction of ethyl glyoxylate 4-methoxyphe-
nylimine with 1,3-dienes in the presence of BF3·Et2O. Evidence for a
non-concerted mechanism. Tetrahedron 2007, 63, 727−734. (b) Her-
mitage, S.; Howard, J. A. K.; Jay, D.; Pritchard, R. G.; Probert, M. R.;
Whiting, A. Mechanistic studies on the formal aza-Diels−Alder
reactions of N-aryl imines: Evidence for the non-concertedness
under Lewis-acid catalysed conditions. Org. Biomol. Chem. 2004, 2,
2451−2460. (c) Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M.;
Lucchini, V. Synthesis and cycloaddition reactions of ethyl glyoxylate
imines. Synthesis of substituted furo-[3,2-c]quinolines and 7H-
indeno[2,1-c]quinolines. J. Heterocycl. Chem. 1988, 25, 1831−1835.
(7) Tester, S. A.; Mata, E. G. Prospect of metal-catalyzed C−C
forming cross-coupling reactions in modern solid-phase organic
synthesis. J. Comb. Chem. 2008, 10, 487−497.
(8) See Supporting Information for further details.
(9) For references on the use of dihydropyrrole as dienophile in the
Povarov reaction, see: Hadden, M.; Nieuwenhuyen, M.; Potts, D.;
Stevenson, P. J.; Thompson, N. Synthesis and reactivity of
hexahydropyrroloquinolines. Tetrahedron 2001, 57, 5615−5624.
(10) For reference on synthesis of dihydropyrrole protected
carbamate, see: (a) Marais, W.; Holzapfel, C. W. On a facile synthesis
of melatonin and other related indoles. Syn. Commun. 1998, 28, 3681−
3691. (b) Kraus, G. A.; Neuenschwander, K. Facile synthesis of N-acyl-
2-pyrrolines. J. Org. Chem. 1981, 46, 4791−4792.
(11) Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M. Synthesis
and cycloaddition reactions of ethyl glyoxylate imines. Synthesis of
substituted furo-[3,2-c]quinolines and 7H-indeno[2,1-c]quinolines. J.
Heterocycl. Chem. 1988, 25, 1831−1835.
(12) This side product was identified as the aminal adduct.
(13) NBSA is commercially available only as the hydrate (containing
x molecules of water). To remove residual amounts of water, NBSA
was dissolved in a minimum amount of dry THF and azeotroped with
toluene. This sequence was repeated three times until a dark brown
viscous oil was obtained. The light sensitive oil was dried under high
vacuum over CaCl2 and stored in the dark.
(14) p-Toluenesulfonic acid was dehydrated by azeotropic distillation
with toluene using a Dean−Stark apparatus. The residue was then
crystallized from benzene.
(15) The SSS enantiomer urea catalyst was obtained from Astatech,
Inc.
(16) Xia, C.; Heng., L.; Ma, D. Total synthesis of ( )-martinelline.
Tetrahedron Lett. 2002, 43, 9405−9409.
(17) Keenan, T. P.; Yaeger, D.; Holt, D. A. Tetrahedron: Asymmetry
1999, 10, 4331−4341.
(18) (a) Khadem, S.; Joseph, R.; Rastegar, M.; Leek, D. M.;
Oudatchin, K. A.; Arya, P. Solution- and solid-phase approach to
tetrahydroquinoline-derived polycyclics having a 10-membered ring. J.
Comb. Chem 2004, 6, 724−734. (b) Guo, F.; Chang, B. H.; Rizzo, C. J.
An N1-hydrogen bonding model for flavin coenzyme. Bioorg. Med.
Chem. Lett. 2002, 12, 151−154.
630
dx.doi.org/10.1021/co300098v | ACS Comb. Sci. 2012, 14, 621−630