Facile (triazolyl)methylation of MACOS-derived benzofused sultams utilizing ROMP-derived OTP reagents

Article abstract of DOI:10.1021/co2001839

A combination of MACOS scale-out and ROMP-derived oligomeric triazole phosphates (OTP_n) have been successfully utilized for the preparation of a 106-member library of triazole containing benzothiaoxazepine-1,1-dioxides. This report demonstrates

Full text of DOI:10.1021/co2001839

Research Article
pubs.acs.org/acscombsci
Facile (Triazolyl)methylation of MACOS-derived Benzofused Sultams
Utilizing ROMP-derived OTP Reagents
Saqib Faisal,†,∥ Farman Ullah,§ Pradip K. Maity,† Alan Rolfe,† Thiwanka B. Samarakoon,†
Patrick Porubsky,‡ Benjamin Neuenswander,‡ Gerald H. Lushington,†,‡ Fatima Z. Basha,∥
Michael G. Organ,*,‡,§ and Paul R. Hanson*,†,‡
†Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, United States
‡The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), 2034 Becker Drive, Del
Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
§Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
∥H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Science, University of Karachi, Karachi,
Pakistan.
S
* Supporting Information
ABSTRACT: A combination of MACOS scale-out and
ROMP-derived oligomeric triazole phosphates (OTPn) have
been successfully utilized for the preparation of a 106-member
library of triazole containing benzothiaoxazepine-1,1-dioxides.
This report demonstrates the utilization of a suite of soluble
OTPn reagents for facile (triazolyl)methylation of 10 MACOS-
derived sultam scaffolds in purification-free process for parallel
synthesis of small molecule collections for HTS.
KEYWORDS: dihydro-2H-benzothiaoxazepine-1,1-dioxide, sultams, OTP, MACOS, ROMP, (triazolyl)methylation
Building on these efforts, we herein report the utilization of a
microwave-assisted, continuous flow organic synthesis
(MACOS) platform in combination with soluble oligomeric
reagents derived from ring-opening metathesis polymerization
for the rapid, purification-free synthesis of a 106-member
library of benzothiaoxazepine-1,1-dioxides (Scheme 1).
INTRODUCTION
■
The growing demand for the identification and development of
new pharmaceutical leads and probes has prompted current
advances in high-throughput screening.1 Key to this approach is
the development of emerging synthetic methods and
technologies that give rapid access to collections of diverse
small molecules addressing classical bottlenecks in this process.
In this regard, the development of enabling technologies that
allow for the assembly of diverse small molecule collections
where synthesis, diversification and purification are integrated
into one parallel process is a critical facet of early stage drug
discovery. Classical synthetic approaches to small molecule
libraries have suffered from multistep processes requiring costly
and time-consuming purification at every stage. In addition,
issues relating low yielding or unreliable reactions for the
preparation of compounds and key intermediates has a negative
effect on early stage drug discovery.2
In recent years, a variety of enabling technologies have been
developed to address these limitations, giving rapid access to
small molecule HTS screening collections.3 One such
technology has been the development and utilization of
continuous flow technology platforms, which can carry out
multistep processes, combined with inline diversification/
purification, utilizing immobilized reagents/scavengers.4 In
addition to inline purification,5 the ability for automation,6
safe in situ generation of reactive intermediates,7 and rapid
reaction optimization and multigram scale-out makes this a
powerful enabling technology in early stage drug discovery.8
RESULTS AND DISCUSSION
■
Sultams (cyclic sulfonamide analogues) have emerged in recent
years as important targets in drug discovery because of their
extensive chemical and biological profiles.9 Recently, a number
of enabling synthetic methodologies have been developed to
give rapid access to diverse sultam libraries for HTS.10 Building
on these reports, it was envisioned that a variety of core sultam
scaffolds prepared via MACOS could be quickly diversified in a
facile, purification-free process utilizing a suite of ROMP-
derived reagents.11,12 Toward this goal, a suite of soluble, high-
load ROMP-derived benzyl- and triazole- phosphates have been
developed for the facile, purification-free diversification of
nucleophilic small molecules.13 ROMP-derived OTP reagents
are bench stable, free-flowing solids that are readily soluble in a
variety of solvents to generate stock solutions, making them
ideally suited for parallel synthesis. With these reagents in hand,
Received: November 4, 2011
Revised: January 23, 2012
Published: March 5, 2012
© 2012 American Chemical Society
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ACS Combinatorial Science
Research Article
Scheme 1. Facile Library Generation Utilizing MACOS Scale-Out Sultam Scaffolds and ROMP-derived OTPn Reagents
Table 1. Prototype Library Demonstrating Utilization of Scaffolds 1−3, 5, 6, 8−10 with OTP20 Oligomers {1, 2, 4, 9, 11, 12}
a
a
entry
scaffold
OTP20 {X}
yield (%)
entry
scaffold
OTP20 {X}
yield (%)
1
2
3
4
5
6
7
8
1
2
3
3
5
6
8
8
{11}
{12}
{11}
{12}
{12}
{11}
{11}
{12}
85
62
97
92
70
98
98
94
9
9
{1}
{2}
{4}
{9}
{1}
{2}
{4}
{9}
63
89
82
79
68
75
72
75
10
11
12
13
14
15
16
9
9
9
10
10
10
10
a
Reaction conditions: OTP20 (1.5 equiv), NaI (0.5 equiv), Cs2CO3 (3 equiv), dry DMF (0.2 M), and sultam 1−10 (1 equiv). Reaction heated at 90
°C for 2−14 h (TLC analysis).
the (triazolyl)methylation of core benzothiaoxazepine-1,1-
dioxide scaffolds 1−10 scaled-out on the MACOS platform14
was investigated with a suite of oligomeric (triazolyl)methyl
phosphate (OTP) reagents {1−14}.8 Initially, a 16-member
prototype library was investigated for the generation of triazole
containing benzothiaoxazepine-1,1-dioxides (Table 1).
undesirable in-silico properties.16 These metric filters included
standard Lipinski Rule of 5 parameters (molecular weight <
500, ClogP < 5.0, number of H-acceptors < 10, and number of
H-donors < 5), in addition to consideration of the number of
rotatable bonds (<10) and polar surface area. Absorption,
distribution, metabolism and excretion (ADME) properties
were calculated along with diversity analysis using standard H-
aware 3D BCUT descriptors compared against the MLSMR
screening set (∼7/2010; ∼330 000 unique chemical struc-
tures). Guided by this library design analysis, a 96-member
library was designed.
Library Generation. The proposed 96-member library was
prepared in 1-dram vials via a mix-and-match approach using
stock solutions of scaffold (1−10) and OTP20 reagents {1−14}.
Crude purity analysis of the 96-member library demonstrated
that 66 compounds had crude purities of 80−99%, 16
compounds at 70−80% and 8 compounds <70%. Final analysis
of this library after purification by automated mass-directed
LCMS resulted in the successful synthesis of 90 compounds
with 84/90 compounds possessing >90% final purity (Graph
1).17
Utilizing reported conditions for the (triazolyl)methylation of
a variety of nucleophilic species,13a the generation of a 16-
member prototype library was successfully achieved in good
1
yield and crude purity (85−100%, H NMR), demonstrating
both substrate and reagent scope. With the synthesis of a 16-
member prototype library, a 96-member library was designed
with benzothiaoxazepine-1,1-dioxide scaffolds 1−10 and OTP20
oligomers {1−14}.
Library Design. A full-matrix library was designed using in
silico analysis, literature precedence, and observed synthetic
results.15 A virtual library incorporating all possible building
block combinations of sultam scaffolds 1−10 with OTP
reagents {1−14} (Figure 1) was evaluated. Physicochemical
property filters were applied, guiding the elimination of
undesirable building blocks that led to products with
269
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ACS Combinatorial Science
Research Article
Figure 1. Scaffolds (1−10) and OTP20 reagents {1−14} library building blocks.
in this manuscript have been submitted to the University of
Kansas Center for Chemical Methodologies and Library
Development (KU-CMLD) for delivery to the NIH Molecular
Library Small Molecule Repository (MLSMR) for distribution
and broad screening for biological activity within the MLPCN
screening network.
CONCLUSION
■
In conclusion, a 90-member library (out of 96) of triazole
containing benzothiaoxazepine-1,1-dioxides was successfully
prepared combining two enabling technologies, namely
MACOS platform and ROMP-derived OTP reagents. Uti-
lization of a suite of soluble OTPn reagents {1−14}, 10
MACOS-derived sultam scaffolds 1−10 were successfully
diversified in a purification-free parallel process amenable for
automation. Taken collectively, with the prototype library (16
member), a total of 106 out of 112 sultams were successfully
generated (95% success rate) with 100/112 (89% rate)
possessing purities >90%. The compound libraries we report
EXPERIMENTAL SECTION
■
General procedure A, for the (triazolyl)methylation of sultams
1−10 with OTP20 reagents {1−14}. To a 1-dram vial with a
Teflon cap was added a stock solution of OTP20 {1−14} (1.5
equiv) in dry DMF (0.2 M), followed by the addition of NaI
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Research Article
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Chart 1. Final Mass, Purity, and Yield Analysis for
Benzothiaoxazepine-1,1-dioxide Library
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(0.5 equiv) and Cs2CO3 (3 equiv). After the mixture was stirred
for 30 s, the corresponding sultam (1 equiv) was added, and the
reaction mixture was heated to 90 °C for 2−14 h (TLC
analysis). Upon completion, the DMF was removed in vacuo,
crude diluted in EtOAc, filtered via SiO2 SPE, rinsed several
times with EtOAc and concentrated in vacuo to yield the
desired product. The crude reaction was concentrated and QC/
purified by an automated preparative reverse phase HPLC
(detected by mass spectroscopy).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, tabulated results for all libraries, and
full characterization data for representative compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: phanson@ku.edu (P.R.H.); organ@yorku.ca
(M.G.O.).
■
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Funding
This work was supported by the National Institute of General
Medical Science (Center in Chemical Methodologies and
Library Development at the University of Kansas, KU-CMLD,
NIH P50 GM069663, NIH P41-GM076302 and the NIH-
STTR R41 GM076765).
Notes
The authors declare no competing financial interest.
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