Build/couple/pair strategy for the synthesis of stereochemically diverse macrolactams via head-to-tail cyclization

Article abstract of DOI:10.1021/co200161z

A build/couple/pair (B/C/P) strategy was employed to generate a library of 7936 stereochemically diverse 12-membered macrolactams. All 8 stereoisomers of a common linear amine precursor were elaborated to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds were further diversified via capping of two amine functionalities on SynPhase Lanterns. Reagents used for solid-phase diversification were selected using a sparse matrix design strategy with the aim of maximizing coverage of chemical space while adhering to a preset range of physicochemical properties.

Full text of DOI:10.1021/co200161z

Research Article
pubs.acs.org/acscombsci
Build/Couple/Pair Strategy for the Synthesis of Stereochemically
Diverse Macrolactams via Head-to-Tail Cyclization
Mark E. Fitzgerald, Carol A. Mulrooney, Jeremy R. Duvall, Jingqiang Wei, Byung-Chul Suh,
Lakshmi B. Akella, Anita Vrcic, and Lisa A. Marcaurelle*,†
Chemical Biology Platform, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142,
United States
S
* Supporting Information
ABSTRACT: A build/couple/pair (B/C/P) strategy was
employed to generate a library of 7936 stereochemically diverse
12-membered macrolactams. All 8 stereoisomers of a common
linear amine precursor were elaborated to form the correspond-
ing 8 stereoisomers of two regioisomeric macrocyclic scaffolds
via head-to-tail cyclization. Subsequently, these 16 scaffolds were
further diversified via capping of two amine functionalities on
SynPhase Lanterns. Reagents used for solid-phase diversification were selected using a sparse matrix design strategy with the aim
of maximizing coverage of chemical space while adhering to a preset range of physicochemical properties.
KEYWORDS: diversity-oriented synthesis, macrocycle, stereochemistry, solid-phase synthesis
INTRODUCTION
■
We have a long-standing interest in the design and synthesis of
small-molecule libraries that combine the structural complexity
of natural products and the efficiency of high-throughput syn-
thesis.1−4 Recent evidence has shown the importance of struc-
tural complexity as measured by sp3 content and the presence
of stereocenters for the successful transition from discovery
to the clinic.5 As such, macrocycles are an important class of
organic molecules showing a variety of impressive biological
activities.6,7 There are numerous macrocycles currently in
development or approved by the FDA for clinical use, including
natural products (1, Figure 1)8 and their derivatives (2),9 as
well as some designed and synthesized de novo (3).10 The large
occurrence of macrocycles in nature and their impressive
biological activities may be derived from the fact that they often
exhibit both preorganization as well as flexibility, both of which
can aid binding to biological targets.11,12 Based off of these
Figure 1. Select bioactive macrocycles in development or approved for
observations, we have utilized macrocyclic compounds in the
past as a source of diversity and structural complexity within
our screening collection.1−3 In this work, we present a continua-
tion of this effort to build a small-molecule library that contains
macrocyclic compounds but occupies a distinct area of chemical
space.
Utilizing a three phase build/couple/pair (B/C/P) synthetic
strategy,13 we have previously reported a route to medium-sized
rings and macrocycles (Figure 2) starting from 1,2-amino
alcohol 4 and aldol-derived γ-amino acid 5.1,14 A key feature
of the B/C/P strategy is the ability to generate the com-
plete matrix of stereoisomers lending to the study of stereo/
structure−activity relationships (SSAR) upon biological
screening.1,15 Thus all eight stereoisomers of amine 6 were
prepared and utilized in downstream pairing reactions includ-
ing nucleophilic aromatic substitution (SNAr), Huisgen macro-
clinical use.
cyclization and ring-closing metathesis (RCM) to yield
scaffolds 7−11. In the current study, we have expanded this
chemistry to include a pairing reaction, which cyclizes the linear
template from “head-to-tail” (HtoT) leading to macrocycles 12
and 13. This pairing strategy increases the number of stereo-
genic centers contained within the ring as compared to the pre-
viously prepared scaffolds, as well as decreases the number
of rotatable bonds present in the final compounds. As evident
by a molecular shape-based diversity analysis derived from
Received: September 29, 2011
Revised: December 20, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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Figure 2. An aldol-based B/C/P strategy generating macrocycles and medium-sized rings via nucleophilic aromatic substitution (SNAr), ring-closing
metathesis (RCM), Huisgen cycloaddition and head-to-tail (HtoT) cyclization.
Figure 3. Principal moments of inertia (PMI) analysis of the HtoT macrolactam scaffolds as compared to previously prepared aldol-based scaffolds:
RCM, Click (1,5 and 1,4) and SnAr (8 and 9).1 PMI ratios are plotted in the triangular scatter plot. Minimum energy conformers ≤3 kcal/mol from
the global minimum are plotted on the graph for all diastereomers.
normalized principal moments of inertia (PMI) ratios,1,16
macrolactams 12 and 13 occupy a distinct region of 3-dimen-
sional space as compared to scaffolds 7−11 (Figure 3). Surprisingly,
the HtoT scaffolds are much more rod-like than the RCM-
derived macrolactams.
RESULTS AND DISCUSSION
■
At the onset of this project, we envisioned two potential pair-
ing strategies to effect HtoT macrocyclization: (1) an intra-
molecular SNAr reaction or (2) macrolactamization (Figure 4).
Because of the overall success of the intramolecular SNAr
reaction for the formation of the medium sized rings 7
and 8 in our initial study,1 we first set our sights on the
Figure 4. Potential HtoT macrocyclization strategies.
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application of this method to access macrolactam 12. The
synthesis of the SNAr substrate begins with allyl carbamate
formation accomplished by treatment of amine 6 with
allyl chloroformate under Schotten−Baumann conditions
(Scheme 1). This was followed by TBS removal with TBAF
and methylation of the resultant secondary alcohol with
methyl iodide. This synthetic sequence led to orthogonally
protected diamine 16 in 54−80% yield. The choice of
DMF as a solvent and the use of excess MeI was impera-
tive to prevent intramolecular carbamate formation. The
terminal PMB and Boc protecting groups were removed
simultaneously upon treatment with TFA in the presence of
anisole as a cation scavenger. Amidation of the resulting
crude amino alcohol was then accomplished resulting in
SNAr substrate 14 in yields of 56−70% for the two steps.
The key SNAr macrocyclization was first attempted utilizing
conditions developed in our previous studies.1,4 Treatment of
14 with NaH in THF at 0 °C led solely to the formation of
oxazolidinone 18, which could not be avoided even with careful
exclusion of water and the use of KH. Heating alcohol 14 in the
presence of excess CsF was also attempted, which showed no
consumption of starting material by LC/MS at room tem-
perature but ultimately led to decomposition after extended
heating (>1 day). The use of DBU in DMF17 was also unsuccessful
even after extended heating. Finally, desired product 12 could
be obtained using TBAF in THF/DMF (in the presence
of 4 Å molecular sieves)18 however the yields were generally
low (25−45%) and highly variable. In light of the problems
encountered promoting this transformation we decided to
shift our efforts to a macrolactamization approach via inter-
mediate 15 (Figure 4).
The synthesis of 15 (Scheme 2) commenced with PMB
deprotection of intermediate 16 via treatment with DDQ in
buffered CH2Cl2. The primary alcohol was subsequently sub-
jected to an intermolecular SNAr reaction with aryl fluoride
20, in the presence of TBAF and 4 Å molecular sieves in
THF/DMF resulting in ether 21 in good yield (55−75%). Bis-
deprotection of the Boc and t-butyl ester groups provided crude
amino acid 15 which was gratifyingly converted to macrocyle
12 in good yield (83%) upon treatment with BOP-Cl in the
presence of DIEA.
Scheme 1. Synthesis of Scaffold 12 via SNAr Macrocyclization
Scheme 2. Synthesis of Scaffold 12 via Macrolactamization
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Scheme 3. Synthesis of Scaffold 13 via Macrolactamization
In order to access the meta-alkoxynitro macrocycle (13), we
next decided to investigate a modified synthetic route in which
the intermolecular SNAr reaction was replaced with a
Mitsunobu reaction19 to install the nitrobenzoic acid. As
shown in Scheme 3, primary alcohol 19 was treated with
phenol 22 in the presence of DIAD and PPh3 to give phenyl
ether 23 in 75−85% yield. The Boc and t-butyl ester groups
were removed with TFA and the resulting amino acid (24)
cyclized in the presence of BOP-Cl to afford macrocycle 13 in
78% yield over two steps.
With established routes to both the para- and meta-
alkoxynitro scaffolds, all eight isomers of macrocycles 12
and 13 were synthesized in 5-g quantities in preparation for
solid-phase library production. The key macrocyclization
reaction proceeded in high yield for all eight isomers of
the linear amine scaffold (Table 1). The stereochemistry of
efficiency with combined yields for the double deprotection and
lactamization ranging from 75 to 88%.
To load the scaffolds onto solid-phase for library prod-
uction, SynPhase Lanterns20 functionalized with a mono-
methoxy Backbone Amide Linker (BAL)21−23 were selected.
Use of the BAL linker allows for loading via an amine
(in this case an aniline) without sacrificing a diversity site.
Immobilization would be achieved via reductive alkylation,
while subsequent N-capping with sulfonyl chlorides, acid
chlorides and isocyanates would afford the corresponding
sulfonamides, amides and ureas upon cleavage with TFA.
Thus, chemoselective reduction of the nitro functionality was
achieved with SnCl2 to afford anilines 25 and 26 (Scheme 4)
Scheme 4. Reduction of Aryl Nitro Group (Only One
Stereoisomer Shown)
Table 1. Macrolactamization Yields for all Stereo- and
Regioisomers
for loading onto solid-support. Of note, reduction of the meta-
alkoxynitroaryl group proved more sluggish than the para-
regioisomer requiring heating at 60 °C for full conversion.
Nitro reduction proceeded smoothly for all isomers in yields
ranging from 80 to 89%.
With ample quantities of all stereoisomers of anilines 25 and
26 in hand, a sparse matrix design strategy was implemented to
select library members to be synthesized.24 A virtual library was
constructed (for each scaffold) incorporating all possible
building block combinations at R1 (aniline) and R2 (secondary
amine) using a master list of reagents (R1 = sulfonyl chlorides,
isocyanates, and acid chlorides; R2 = sulfonyl chlorides,
a
Isolated yields after silica gel chromatography.
precursors 15 and 24, along with the regiochemistry of the aryl
nitro substitutent, did not appear to influence the cyclization
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Chart 1. Building Blocks for Aniline Capping (R1)
isocyanates, acids, and aldehydes).25 This provided a virtual
library of 7845 compounds per scaffold. Physicochemical
property filters were then applied to eliminate building block
combinations that led to products with undesired physico-
chemical properties.26 The following property filters were
applied to yield a total of 5363 compounds: MW ≤ 625, ALogP
−1 to 5, H-bond acceptors and donors ≤ 10, rotatable bonds ≤
10, and TPSA ≤ 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
496 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 include 22 sulfonyl chlorides, 19
isocyanates and 26 acid chlorides for aniline capping
(Chart 1) along with 2 sulfonyl chlorides, 3 isocyanates, 21
acids, and 22 aldehydes for secondary amine capping (Chart 2).
The same set of reagents was used for each stereo- and
regioisomer, thereby maintaining the ability to generate SSAR
for each building block combination. The property distribution
for the selected products (7936 compounds total) is shown in
Figure 5 and Table 2.
As shown in Scheme 5, scaffolds 25a−h and 26a−h were
loaded onto the BAL functionalized SynPhase L-Series Lanterns
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Chart 2. Building Blocks for Amine Capping (R2)
via treatment with an excess of NaBH3CN in 2% AcOH/DMF
at 40 °C for 3 days. (Lanterns were equipped with radio
frequency transponders to enable tracking and sorting of library
members.) Scaffolds 25 and 26 contain two handles for the
introduction of appendage diversity: the immobilized aniline
and a protected secondary amine, both suitable for reaction
with various electrophiles. The first diversity site, the aniline,
was reacted with a total of 68 building blocks including
isocyanates, sulfonyl chlorides and acid chlorides.27,28 The
second diversity site was then revealed via removal of the Alloc
group upon treatment with Pd(PPh3)4 in the presence of excess
1,3-dimethyl barbituric acid. This secondary amine was capped
with 49 building blocks including isocyanates, sulfonyl
chlorides, acids, and aldehydes. This was followed by cleavage
from the Lantern, which was achieved by treatment with a 1:1
solution of TFA:1,2-dichloroethane, to afford a total of 7936
products with an average yield of 8.5 μmol/Lantern. On
average, yields were slightly higher for the para-aniline derived
compounds than the meta-aniline compounds (9.1 μmol vs
8.0 μmol).29
All library products were analyzed by ultraperformance liquid
chromatography, and compound purity was assessed by UV
detection at 210 nm. An overview of library purity with respect
to building blocks and stereochemistry is provided in Figure 6.
The average purity of the library was 86% with 84% of the
library being >75% pure. In general, all building blocks
performed well during library production other than a few
which are worth discussion. Reagents used for capping diversity
site 1 which resulted in lower purities include ethyl sulfonyl
chloride (R1 = 2) and cyclopentyl isocyanate (R1 = 25), both of
which affected products predominantly for the meta-cores
across most diversity site 2 building blocks. Isoxazole acid
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Figure 5. Molecular weight and ALogP distribution for HtoT library
members.
Table 2. Property Analysis for the HtoT Library
a
property
MW
HT scaffold (n = 1)
HT library (n = 7936)
321
0.7
77
1
489
2.2
97
ALogP
TPSA
rotatable bonds
HBA
4.7
5.8
1.4
Figure 6. Purity analysis (UV 210 nm) for the HtoT Library. Library
members are displayed as blocks of 16 isomers (8 stereoisomers X 2
regioisomers) (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. Products where R2 = H are not shown.
(SC = Sulfonyl chlorides, IS = Isocyanates).
5
HBD
2
a
Property analysis of bare scaffolds, where R1 and R2 = H.
chloride (R1 = 63) led to low purity final compounds for most
of the 16 cores and diversity site 2 building blocks. Overall,
building blocks used to diversify the secondary amine faired
better in terms of final product purity, with only one building
block (oxazole-4-carbaldehyde, R2 = 47) showing reduced
purities across R1 building blocks.
CONCLUSIONS
■
A novel library of 7936 12-membered macrocycles was
successfully prepared via a macrocyclization pairing reaction.
Sixteen cores were synthesized from 8 isomers of linear amine
scaffold 9 to establish “built-in” stereo/structure-activity relationships
Scheme 5. Solid-Phase Library Synthesis on SynPhase Monomethoxy BAL Lanterns
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ASSOCIATED CONTENT
* Supporting Information
General information, library scaffold synthesis, solid-phase
synthesis, QC analysis, and computational methods. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: lisa_marcaurelle@h3biomedicine.com.
■
Present Address
†H3 Biomedicine, 300 Technology Square, Cambridge, MA
02139
ACKNOWLEDGMENTS
■
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).
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product-like macrocycles by a sequence of Ugi-4CR and SNAr-based
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