Synthesis of a stereochemically diverse library of medium-sized lactams and sultams via SNAr cycloetherification

Article abstract of DOI:10.1021/co2000218

We have implemented an aldol-based "build/couple/pair" (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via S_NAr cycloetherification. Each scaffold contains two handles, an amine and aryl bromide, for solid-phase diversification via N-capping and Pd-mediated cross coupling. A sparse matrix design strategy that achieves the dual objective of controlling physicochemical properties and selecting diverse library members was implemented. The production of two 8000-membered libraries is discussed including a full analysis of library purity and property distribution. Library diversity was evaluated in comparison to the Molecular Library Small Molecule Repository (MLSMR) through the use of a multifusion similarity (MFS) map and principal component analysis (PCA).

Full text of DOI:10.1021/co2000218

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Synthesis of a Stereochemically Diverse Library of Medium-Sized
Lactams and Sultams via SNAr Cycloetherification
Baudouin Gerard, Jeremy R. Duvall, Jason T. Lowe, Tiffanie Murillo, Jingqiang Wei, Lakshmi B. Akella, and
Lisa A. Marcaurelle*,†
Chemical Biology Platform, The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142,
United States
S Supporting Information
b
ABSTRACT: We have implemented an aldol-based “build/couple/pair”
(B/C/P) strategy for the synthesis of stereochemically diverse 8-mem-
bered lactam and sultam scaffolds via SNAr cycloetherification. Each
scaffold contains two handles, an amine and aryl bromide, for solid-phase
diversification via N-capping and Pd-mediated cross coupling. A sparse
matrix design strategy that achieves the dual objective of controlling
physicochemical properties and selecting diverse library members was
implemented. The production of two 8000-membered libraries is
discussed including a full analysis of library purity and property distribu-
tion. Library diversity was evaluated in comparison to the Molecular
Library Small Molecule Repository (MLSMR) through the use of a multifusion similarity (MFS) map and principal component
analysis (PCA).
KEYWORDS: library design, diversity-oriented synthesis, physicochemical properties, diversity-ranking, maximum dissimilarity,
sparse matrix
’ INTRODUCTION
physicochemical properties suitable for high-throughput screening
and downstream discovery.
Diversity-oriented synthesis (DOS) is a commonly employed
strategy for the facile assembly of structurally diverse molecules
rivaling the complexity of natural products.1 A primary goal of DOS
is the generation of compounds with both skeletal and stereo-
chemical diversity. Recently, we described an aldol-based “build/
couple/pair” (B/C/P) strategy for the generation of a stereoche-
mically diverse set of medium- and large-sized rings via a common
linear template.2 Here, we take advantage of this aldol-based
strategy for the synthesis of fused pyridines (1) and fused sultams
(2) (Figure 1). In the build phase, a series of asymmetric syn- and
anti-aldol reactions were applied to produce four stereoisomers of a
Boc protected β-hydroxy-γ-amino acid (3). Both stereoisomers of
PMB-protected alaninol (4) were also obtained to complementthe
aldol-derived acids. In the couple step, all 8 stereoisomeric amides
were synthesized from the chiral acid and amine building blocks.
The amide was subsequently reduced to generate a secondary
amine (5). Finally, in the pair phase, we utilized an intramolecular
SNAr3 as the key cyclization step to access either the SNAr-Pyr
lactam (1)4 or the SNAr-SO2 sultam (2).5 This work is based on
our previous success with the SNAr reaction for the synthesis of
8- and 9-membered lactams (6 and 7).2 Two 8000-membered
libraries were produced using solid-phase synthesis techniques. All
8 stereoisomers were prepared for each scaffold, providing not only
structureꢀactivity relationships (SAR) in primary screens, but also
stereo/structureꢀactivity relationships (SSAR). A sparse matrix
library design strategy6,7 was utilized to aid in the selection of
diverse library members with built-in structural analogs and
Solution-Phase Synthesis of Library Scaffolds. The synthesis
of SNAr-Pyr scaffold 1 began with acylation of linear amine 5 using
5-bromo-2-chloronicotinoyl chloride 8, which afforded amide 9aꢀd
in good yields (Table 1). The subsequent intramolecular SNAr
reaction showed strong stereochemical dependence. Amide 9a was
converted directly to 10a in excellent yield (94%) upon treatment
with TBAF in THF at 65 °C. However, application of these
conditions to 9b provided lactam 10b in modest yield (71%).
Fortunately, a two step protocol involving TBS-removal with CsF
followed by cyclization with NaH in THF proved effective. Using
this protocol, the syn-aldol derived substrates 9a and 9b were
converted to 10a and 10b, respectively, in high yields (96ꢀ98%)
without need for chromatographic purification. Meanwhile, SNAr
reaction of anti-aldol-derived substrates 9c and 9d proved challen-
ging, as the two-step protocol led to formation of significant amount
of oxazolidinone side-product (40ꢀ50%).8 Use of the one-step
deprotection/cyclization using TBAF in THF led to incomplete
reaction even after 5 days and repeated addition of TBAF. Finally,
the choice of solvent and the use of TBAF in DMF led to complete
conversion of the SNAr reaction with minimal oxazolidinone
formation (10ꢀ15%). Under these conditions, the anti-aldol
derived substrates 9c and 9d gave 84% and 80% of 10c and 10d,
respectively. As our plan called for loading onto solid support
Received: February 1, 2011
Revised:
April 12, 2011
Published: April 28, 2011
r
2011 American Chemical Society
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Figure 1. Synthesis of medium-sized ring scaffolds from a common linear intermediate.
(SynPhaseLanterns)9 using an acid-labile silicon linker, the Boc
protecting group was exchanged for Fmoc, and subsequent DDQ-
mediated PMB removal led to the isolation of primary alcohol 1
(Scheme 1). SNAr-Pyr scaffolds 1aꢀd (and the corresponding
enantiomers ent-1aꢀd) were prepared in 15ꢀ20 g quantities using
this 5-step sequence starting from linear amine 5.
Library Design. With the SNAr-Pyr and SNAr-SO2 scaffolds in
hand, a sparse matrix design strategy was implemented to select
library members to be synthesized.6 A virtual library was con-
structed for each scaffold incorporating 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 and alkynes). Physico-
chemical property filters were then applied to eliminate building
block combinations that led to products with undesirable phys-
icochemical properties. Property filters included the following:
MW e625, ALogP ꢀ1 to 5, H-bond acceptors and donors e 10,
rotatable bonds e 10, and TPSA e 140. To increase the
percentage of “Lipinski compliant” products, a “75/25” rule
was also implemented where 75% of all library members had
MW <500. A total of 1000 compounds per scaffold were selected
from the remaining set using chemical similarity principles,
maximizing diversity but retaining near neighbors for built-in
SAR. 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.
Solid-Phase Library Production. The construction of the
SNAr-Pyr and SNAr-SO2 libraries is outlined in Scheme 3.
Scaffolds 1aꢀd and 2aꢀd (and the corresponding enantiomers)
were loaded onto silicon-functionalized PS-SynPhase Lanterns
(L-series) activated with TfOH in the presence of 2,6-lutidine
(average loading level = 18 umol/Lantern).9,10 The first diversity
site, a secondary amine, was then revealed under standard
conditions required for Fmoc removal (20% piperidine in DMF),
and amines 16aꢀd and 17aꢀd were capped with the selected
A similar approach as described above was utilized in the synthesis
of fused bicyclic sultams.5 All stereoisomers of the common linear
intermediate 5 were coupled with 4-bromo-2-fluorobenzene sulfo-
nyl chloride 12 in good yield to give the SNAr precursor 13
(Table 2). Similar to the fused pyridine systems, the success of
the SNAr reaction involving sulfonamides 13 varied depending on
the relative stereochemistry of the adjacent stereocenters. Mean-
while, sulfonamides 13c and 13d, derived from the syn-aldol
reaction, were easily converted in excellent yield to sultams 14a
and 14b, respectively, by treatment with CsF in DMF at 85 °C.
Sulfonamides 13c and 13d, both derived from the anti-aldol, were
converted to sultams 14c and 14d utilizing the two-step approach
that was employed for substrates 9a and 9b. First, treatment with
CsF gave a mixture of uncyclized TBS deprotected material along
with desired 14. Treatment of the mixture with NaH gave complete
conversion to 14c and 14d, respectively, in good yield over the two
steps. It is important to note, independent of the protocol used, the
product could be isolated in sufficient purity without silica gel
purification. This is in contrast to the SNAr-Pyr substrates, where the
use of TBAF required silica gel purification. Completing the
synthetic sequence required the exchange of the Boc group for
Fmoc followed by DDQ-mediated PMB removal to afford the
desired SNAr-SO2 scaffolds 2aꢀd (and the corresponding enantio-
mers ent-2aꢀd) in good yield in 15ꢀ20 g quantities (Scheme 2).
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Table 1. SNAr Cyclization to Form Lactams 10aꢀda
a Method A: (a) CsF (5 equiv), DMF, 85 °C; (b) NaH (5 equiv), THF, 0 °C to rt; Method B: TBAF (5 equiv), DMF, 65 °C.
Scheme 1. Preparation of Final SNAr-Pyr Scaffold 1
electrophiles (sulfonyl chlorides 1ꢀ11, isocyanates 12ꢀ26, car-
boxylic acids 27ꢀ50, and aldehydes 51ꢀ71) or skipped (72) to
yield compounds 18aꢀd{1ꢀ72} and 19aꢀd{1ꢀ72}. Next,
Sonogashira and Suzuki cross-coupling reactions were carried
out to introduce appendage diversity at R2. For the Sonogashira
reaction, the Lantern-bound aryl bromides were heated at 60 °C in
DMF overnight in the presence of DIEA, CuI, Pd(PPh3)2Cl2, and
the selected alkynes {1ꢀ24}. Meanwhile, for the Suzuki reaction,
the Lanterns were heated at 60 °C in EtOH for 5 days in the
presence of Et3N, Pd(PPh3)2Cl2 and boronic acids {25ꢀ44}.
Removal of residual Pd and Cu was achieved by washing the
Lanterns with 0.1 M NaCN. Finally, cleavage with HF-pyridine in
THF afforded library members 20aꢀd{1ꢀ72,1ꢀ45} and 21aꢀ
d{1ꢀ72,1ꢀ45} with an average yield of 90 and 91%, respectively.11
All library products were analyzed by ultraperformance liquid
chromatography, and compound purity was assessed by UV detec-
tion at 210 nm. An overview of compound purity for the SNAr-Pyr
and SNAr-SO2 libraries with respect to building blocks and stereo-
chemistry is provided in Figures 2 and 3. The average purity of the
SNAr-Pyr library was 85%, with 89% of the library being >75% pure,
while the average purity of the SNAr-SO2 library was 85%, with 91%
of the library being >75% pure. (See Figures S5 and S6, Supporting
Information). In general, all building blocks performed well during
the library production with the exception of certain reagent
combinations. For example, compounds containing the dimethyli-
soxazole urea (18aꢀd{25} and 19aꢀd{25}) performed poorly in
the subsequent Suzuki reaction, presumably because of reduction of
the NꢀO bond, as an M þ 2 impurity was observed by LCMS for
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Table 2. SNAr Cyclization to Form Sultams 14aꢀda
a Method A: CsF (5 equiv), DMF, 85 °C; Method B: (a) CsF (5 equiv), DMF, 85 °C; (b) NaH (1 equiv), THF, 0 °C to rt.
Scheme 2. Preparation of Final SNAr-SO2 Scaffold 2
this reagent combination. Meanwhile products of reductive alkyla-
tion with 3-pyridyl benzaldehyde 18aꢀd{68} and 19aꢀd{68}
performed poorly in the subsequent Sonogashira reaction. The
success of the cross-coupling reaction in the presence of a free amine
at R1 to produce library members 20aꢀd{72,1ꢀ44} and 21aꢀ
d{72,1ꢀ44} was highly variable depending on the nature of the
boronic acid and alkyne but in general was problematic. Surprisingly,
the use of acetaldehyde for reductive alkylation at R1 resulted in
compounds (20aꢀd{2,1ꢀ72} and 21aꢀd{2,1ꢀ72}) of low purity
for both libraries.
the pairing stage giving rise to different molecular architectures.
The SNAr-Pyr and SNAr-SO2 scaffolds have differences in their
physicochemical properties such as molecular weight (372/407),
ALogP (1.2/1.5), and TPSA, (75/87) that ultimately influence
product selection (Table 3). As evident in Figures 2 and 3 the
selected building block combinations vary significantly for these
two scaffolds. For example, products are spread evenly in the
SNAr-Pyr library (Figure 2), as compared to the SNAr-SO2 library
(Figure 3) for which small aliphatic building block combinations
are favored (e.g., acids 27ꢀ34 and aldehydes 51ꢀ54). Analysis of
the SNAr-Pyr and SNAr-SO2 libraries reveals that the property
profile for each library was within the intended range for the library
Library Analysis. The SNAr-Pyr and SNAr-SO2 libraries origi-
nate from the same linear intermediate (5, Figure 1) and vary in
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Chart 1. Building Blocks {1ꢀ72} Used for Amine Capping at R1
design (MW e 625, ALogP ꢀ1 to 5, H-bond acceptors and
donors e 10, rotatable bonds e 10, and TPSA e 140). Not sur-
prisingly, SNAr-SO2 library members have higher mean values for MW
and TPSA because of inherent differences between the initial scaffolds.
The structural diversity of library members resulting from
SNAr-Pyr and SNAr-SO2 pathways was analyzed in comparison
to the NIH Molecular Library Small Molecule Repository
(MLSMR) as we intended to submit a subset of these com-
pounds 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 representation and Tanimoto coefficient as the
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Chart 2. Building Blocks {1ꢀ45} Used for Cross-Coupling Reactions at R2
Scheme 3. Solid-Phase Synthesis of SNAr-Pyr and SNAr-SO2 Libraries on SynPhase Lanterns
similarity measure.13 In this method, each molecule in the test set
(SNAr-Pyr and SNAr-SO2 library members) is compared to every
molecule in the reference set (MLSMR) and the largest similarity
score and the mean similarity score to the reference set is obtained.
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Figure 2. Purity analysis (UV 210 nm) for SNAr-Pyr Library. Library members are displayed as blocks of 8 stereoisomers (see legend) and reagents used
for solid-phase diversification are shown on the x- and y-axes. (See Charts 1 and 2 for detailed list of reagents).12
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 4 shows the MFS
map comparing SNAr-Pyr and SNAr-SO2 libraries 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 in the plot.) The maximum
mean similarity of each library is 0.15 indicative of their overall
structural diversity with respect to the MLSMR reference set. There
are no compounds with maximum similarity equal to or greater than
0.45 in the MLSMR, which clearly illustrates the regions of chemical
space unexplored by the MLSMR.
We also carried out a principal components analysis (PCA)14
using 16 structural and physicochemical descriptors (including
MW, ALogP, rotatable bonds, and TPSA) for the MLSMR and
SNAr-Pyr and SNAr-SO2 libraries. The PCA plot is shown in
Figure 5. The DOS libraries property space is embedded in the
MLSMR property space with ∼75% of compounds being
Lipinski compliant. This observation is particularly important
because it dispels the common notion that DOS may not render
compounds with good properties.15 While occupying desirable
property space we have covered new chemical space of structural
diversity.
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Figure 3. Purity analysis (UV 210 nm) for SNAr-SO2 Library. Library members are displayed as blocks of 8 stereoisomers (see legend) and reagents
used for solid-phase diversification are shown on the x- and y-axes. (See Charts 1 and 2 for detailed list of reagents).12
Table 3. Property Analysis for SNAr-Pyr and SNAr-SO2 Libraries
property
SNAr-Pyr scaffolda (n = 1)
SNAr-SO2 scaffolda (n = 1)
SNAr-Pyr libraryb (n = 7045)
SNAr-SO2 libraryb (n = 6690)
MW
372
1.2
75
4
407
1.5
87
4
484
2.7
95
504
2.9
105
7.2
6.0
1.3
ALogP
TPSA
rotatable bonds
HBA
7.3
6.1
1.3
5
5
HBD
2
2
a Property analysis of bare scaffolds, where R1 and R2 = H. b Property analysis (mean value) of all registered library samples passing QC requirements
(purity >75%).
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members illustrates that the sparse matrix design achieved the
intended outcome of structural diversity and favorable physico-
chemical properties. Screening of these compounds is currently
underway in multiple biochemical and cell-based assays.
’ ASSOCIATED CONTENT
S
Supporting Information. Additional material as de-
b
scribed in the text. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lisa_marcaurelle@h3biomedicine.com.
Present Addresses
†H3 Biomedicine Inc., 300 Technology Square, Cambridge,
MA 02139
Figure 4. Multifusion similarity map comparing the SNAr-Pyr (red) and
SNAr-SO2 (blue) libraries to the MLSMR. The reference set (MLSMR)
is not shown on the map (see text for details).
’ ACKNOWLEDGMENT
This work was funded in part by the NIGMS-sponsored
Center of Excellence in Chemical Methodology and Library
Development (Broad Institute CMLD; P50 GM069721), as well
as the NIH Genomics Based Drug Discovery U54 grants Dis-
covery Pipeline RL1CA133834 (administratively linked to NIH
Grants RL1HG004671, RL1GM084437, and UL1RR024924).
We would like to thank Dr. Stephen Johnston for analytical
support and Anita Vrcic for sorting, cleavage and formatting of
library members.
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’ CONCLUSION
In summary, we have implemented an aldol-based “build/
couple/pair” (B/C/P) strategy for synthesis of stereochemically
diverse 8-membered lactam and sultam scaffolds via SNAr cy-
cloetherification. A sparse matrix design strategy was implemented
to select library members for synthesis to achieve a balance betw-
een diversity and built-in structural analogs. Analysis of final library
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