Synthesis of amino-benzothiaoxazepine-1,1-dioxides utilizing a microwave-assisted, SNAr protocol

Article abstract of DOI:10.1021/co200076j

The development of a microwave-assisted, intermolecular S_NAr protocol for the synthesis of a 126-member benzothiaoxazepine-1,1-dioxide library is reported. Diversification of 12 benzothiaoxazepine-1,1-dioxides was achieved in rapid fashion util

Full text of DOI:10.1021/co200076j

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Synthesis of Amino-Benzothiaoxazepine-1,1-dioxides Utilizing a
Microwave-Assisted, SNAr Protocol
Alan Rolfe,† Farman Ullah,§ Thiwanka B. Samarakoon,† Ryan D. Kurtz,† Patrick Porubsky,‡
Benjamin Neuenswander,‡ Gerald H. Lushington,†,‡ Conrad Santini,‡ 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
S Supporting Information
b
ABSTRACT: The development of a microwave-assisted, intermolecu-
lar SNAr protocol for the synthesis of a 126-member benzothiaoxaze-
pine-1,1-dioxide library is reported. Diversification of 12 benzothia-
oxazepine-1,1-dioxideswas achievedinrapid fashionutilizinga variety of
2° amines and amino alcohols to generate an 80-member library. A
second 48-member library was subsequently generated via a two-step
alkylation, intermolecular SNAr diversification protocol.
KEYWORDS: benzothiaoxazepine-1,1-dioxides, sultams, MACOS, SNAr
’ INTRODUCTION
’ RESULTS AND DISCUSSION
A key area of modern-day combinatorial science is the
development and advancement of methodologies, protocols,
and reaction platforms to enable the discovery of small-molecule
probes to advance our understanding of chemical biology.1 One
aspect of this effort is the development of efficient methods to
access collections of heterocycles for high-throughput screening
(HTS). In this regard, the synthesis of core scaffolds on multi-
gram scale, followed by efficient parallel diversification is one
approach to generate diverse compound collections for HTS.
Sultams (cyclic sulfonamide analogues) have emerged as
important targets in drug discovery due to their chemical and
biological profiles.2 Though not found in nature, sultams display
activity across a wide variety of biological targets.3,4 In particular,
benzothiaoxazepine-1,1-dioxide-containing sultams, possessing a
rich content of sp3 amine functionality, have shown biological
activity as antipsychotic agents,5 modulators of histamine H3-
recceptor,6 and glucokinase activators (Figure 1).7
Despite these reports, methods to generate collections of
benzofused sultams for HTS screening are limited.8 In this
regard, efforts have focused on the development of a variety of
methodologies and protocols for the generation of diverse sultam
collections.9 These methodologies include the development of a
variety of protocols namely, “Click-Click-Cyclize”,10 comple-
mentary ambiphile pairing (CAP),11 and reagent-based diversity-
oriented synthesis (DOS).12 Building on these methods, we
herein report the design and synthesis of a 126-member library of
amino-benzothiaoxazepine-1,1-dioxides via a microwave-assisted,
intermolecular SNAr Diversification of core benzothiaoxazepine-1,1-
dioxides scaffolds (Scheme 1).13
The facilitated, scale-out synthesis of small molecules via
microwave-assisted, continuous-flow organic synthesis (MACOS)14
was previously reported for the generation of a number of core
sultam scaffolds.15 When this enabling technology is used, the
generation of benzofused sultams via an intramolecular SNAr cycli-
zation was achieved on multigram scale.15a With this protocol in
hand, we achieved the resynthesis of benzothiaoxazepine-1,1-dioxide
scaffolds 1ꢀ12 possessing both functional and stereochemical
diversity.
Initial investigation focused on the development and optimi-
zation of the corresponding intermolecular SNAr reaction for the
diversification of benzothiaoxazepine-1,1-dioxide 5 with amino
alcohol {8}, chosen to probe chemoselectivity when utilizing
amino alcohols (Table 1). We screened a variety of bases using 3
equiv of amino alcohol {8}, along with a control reaction without
base (Table 1, entries, 1ꢀ4).13b It was observed that after heating
under microwave irradiation at 150 °C for 30 min a 56% yield
could be achieved when no base was present. Additional opti-
mization of solvent (DMF, THF, DMSO), equivalents of {8},
temperature, and reaction time (Table 1, entries 6ꢀ9) revealed
that 5 equivalents of amino alcohol {8} heated at 150 °C for
50 min provided the desired sultam 5{8} now in 90% yield. It is of
note that when only 1 equiv of {8} was used under optimized
conditions, only a 40% yield was achieved. Further, it was found
Received: April 26, 2011
Revised:
June 30, 2011
Published: September 08, 2011
r
2011 American Chemical Society
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Figure 1. Biologically active benzothiaoxazepine-1,1-dioxide-containing sultams.
Scheme 1. Proposed Library Generation via Microwave-Assisted SNAr Diversification to Access Benzofused Sultam Library
Table 1. Optimization of Microwave-Assisted, SNAr Reaction
Conditions Utilizing Sultam E
entry {8} (equiv) base (equiv) solv. temp (°C) time (min) yield (%)a
Figure 2. Synthesis of benzothiaoxazepine-1,1-dioxides 1ꢀ12 via
1
3
3
3
3
3
5
5
5
5
1
5
5
Cs2CO3 (3) DMF
NaOtBu (3) DMF
LiHMDS (3) DMF
150
150
150
150
150
150
150
150
180
180
180
180
30
30
30
30
30
30
30
30
50
50
50
50
20
46
42
47
56
68
48
86
90
40
94
95
MACOS scale-out.
2
3
that DBU (10 mol %) not only increased the yield to 95%, but also
resulted in greater reproducibility (Table 1, entry 11).
4
Et3N (3)
DMF
5
DMF
Library Design. A 144-member, full-matrix library was de-
signed using in silico analysis, literature precedence, and ob-
served synthetic results.16 Twelve benzothiaoxazepine-1,1-
dioxide scaffolds 1ꢀ12 were designed, composed of two sets
of enantiomers at R1 thereby maintaining the ability to generate
stereochemical SAR (SSAR) for each building block combina-
tion. Each set of enantiomers were varied at R1 = Me, iBu, or Ph
with fluorine substitution on the benzofused ring at either 4- or
6-position. With the SNAr derived core sultams in hand, a virtual
library incorporating all possible building block combinations of
2° amine was constructed for each scaffold (Figure 3). Physico-
chemical property filters were applied, guiding the elimination of
undesirable building blocks that led to products with undesirable
in-silico properties.17 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
(<5) and polar surface area. Absorption, distribution, metabolism
and excretion (ADME) properties were calculated along with
diversity analysis using standard H-aware 3D BCUT descriptors
6
DMF
7
THF
8
DMSO
DMSO
DMSO
DMSO
9
10
11
12
DBU (1)
DBU (0.1) DMSO
a Yields are reported after flash column chromatography on silica gel.
comparing against the MLSMR screening set (∼7/2010;
∼330 000 unique chemical structures). Guided by this library
design analysis, benzothiaoxazepine-1,1-dioxides (1ꢀ36) and
amines {1ꢀ9} were chosen to generate the aforementioned
144-member library.
Validation and Library Generation. With these optimized
conditions in hand, a 12-member validation library was prepared
(General Procedure A) in 1 dram vials using the Anton Parr
Synthos 3000 platform.18 Upon completion, the crude reaction
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Figure 3. Benzothiaoxazepine-1,1-dioxides (1ꢀ36) and amines {1ꢀ9} library building blocks. (a) Benzothiaoxazepine-1,1-dioxide scaffolds 13ꢀ14
and 24ꢀ36.
Table 2. 12-Member Validation Library Probing Reaction Scope
sultama
purity (%)b
yield (%)b
quantity (mg)
sultama
purity (%)b
yield (%)b
quantity(mg)
5{2}
5{4}
5{5}
5{6}
5{7}
5{8}
83
97
99
97
74
91
45
51
30
44
36
51
69.0
77.6
42.5
66.9
69.0
71.5
6{4}
6{5}
6{6}
6{8}
21{6}
33{6}
93
97
98
93
96
94
32
47
62
37
51
50
49.0
71.9
94.9
54.3
90.3
93.2
a Reaction conditions: Benzothiaoxazepine-1,1-dioxide 1ꢀ12 (1 equiv, 0.434 mmol), dry DMSO (434 μL, 1M), DBU (7 μL, 10 mol %), and amine
(5 equiv.). b Purified by automated preparative reverse phase HPLC (detected by mass spectroscopy); purity was assessed by HPLC.
mixtures were diluted, filtered through silica SPE, and purified by
automated mass-directed LCMS (Table 2). Library validation
was essential to assess both substrate and reaction scope, along
with evaluating the application of automated mass-directed
LCMS as the final analysis and purification method. Key to
successful library production was the synthesis of compounds in
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Chart 1. Library I: Representative Library Members
Demonstrating Final Quantity, Purity, and Overall Yield
Chart 2. Library II: Representative Library Members
Demonstrating Final Mass, Purity, and Overall Yield
a two-step alkylation-SNAr procedure (General procedure B).
Hence, benzothiaoxazepine-1,1-dioxides 1ꢀ12 were methylated
(13ꢀ24) or allylated (25ꢀ36), concentrated, and submitted to
the aforementioned microwave-assisted SNAr diversification with
amines {6 and 9} (Scheme 2). A total of 46 compounds from the
proposed 48-membered library where prepared with 43 of the 48
possible products having a final purity >90% after automated
purification (Chart 2).19
Final assessment of libraries I and II demonstrated that the
primary objectives set out in the library design were achieved;
final masses ranged between 8ꢀ158 mg and the average final
mass was 68 mg (original target being 50 mg).
Scheme 2. Synthesis of Library II Utilizing a Two-Step
Alkylation-SNAr Protocol
’ CONCLUSION
In conclusion, an efficient microwave-assisted intermolecular-
SNAr protocol for the synthesis of a 126-member collection
(libraries I and II) of amino-benzothiaoxazepine-1,1-dioxides has
been developed. Employing a variety of commercially available
amines, a 126-member library was generated via the microwave
assisted-SNAr diversification at the 4-F and 6-F positions. These
compounds have been submitted for evaluation of their biologi-
cal activity in high-throughput screening assays at the NIH
MLPCN and the results will be reported in due course.
>90% purity in 40ꢀ50 mg quantities, which would be sufficient
for HTS screening via the Molecular Library Probe Center
Network (MLPCN) (20 mg), external biological outreach
screening partners (20 mg), and to retain a sample (10 mg) for
follow-up evaluation or to resupply the NIH MLPCN. Evalua-
tion of this validation library demonstrated that all 12 members
where successfully prepared (average purity = 92%, yield = 45%,
quantity = 71 mg) in the desired sultams final masses, with 10/12
possessing a final purity >90%.
With the validation complete, a 96-membered library (library I)
was proposed for the diversification of core benzothiaoxazepine-
1,1-dioxide scaffolds 1ꢀ12 with amines {1ꢀ9}. Implementing the
optimized SNAr reaction conditions, Library I (96-member) was
generated and purified by automated mass-directed LCMS. A total
of 80 compounds were prepared, with amine enantiomers {1} and
{2} excluded due to decomposition under reaction conditions; all
products were isolated in good overall yield and quantity, with 78
compounds possessing a final purity >90% after automated
purification (Chart 1).19
’ EXPERIMENTAL PROCEDURES
General Procedure A: Microwave-Assisted Diversification
of Benzothiaoxazepine-1,1-dioxides 1ꢀ12 Cores. Into a
1-dram vial was added benzothiaoxazepine-1,1-dioxide 1ꢀ12
(1 equiv, 0.43 mmol), dry DMSO (0.43 mL, 1M), DBU (7 μL, 10
mol %), and the corresponding amine (5 equiv). The reaction
vessel was capped, placed in Anton Paar Synthos 3000 micro-
wave and heated at 180 °C for 50 min [power =1200 W, 8 min
ramp then 50 min hold]. After it was cooled to RT, the crude
reaction mixture was diluted with EtOAc, filtered through a SiO2
SPE and concentrated. The crude product was QC/purified by
an automated preparative reverse phase HPLC (detected by
mass spectroscopy).
General Procedure B: 2-Step Alkylation-SNAr Diversification
of Benzothiaoxazepine-1,1-dioxides 13ꢀ24 and 25ꢀ36 Cores.
Into a round-bottom flask, under Ar, was added benzothiaoxaze-
pine-1,1-dioxide 1ꢀ12 (1 equiv.), Cs2CO3 (3 equiv.), dry DMF
(0.5 M) and alkyl bromide (2 equiv.). The reaction was heated at
Upon completion of library I (80-member), a second 48-
member compound set (library II) was investigated implementing
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RESEARCH ARTICLE
50 °C and stirred for 4ꢀ6 h (TLC monitoring), after which time the
reaction was cooled to RT, filtered through a SiO2 SPE, washed with
EtOAc and concentrated to remove solvent and excess alkylating
reagent. To the crude reaction mixture was added dry DMSO
(0.43 mL, 1M), DBU (7 μL, 10 mol %) and the corresponding
amine (5 equiv.). The reaction vessel was capped, placed in Anton
Paar Synthos 3000 microwave and heated at 180 °C for 50 min
[power =1200 W, 8 min ramp then 50 min hold]. After it was cooled
to room temperature the reaction was diluted in EtOAc, filtered
through a SiO2 SPE and concentrated. The crude reaction mixture
was QC/purified by an automated preparative reverse phase HPLC
(detected by mass spectroscopy).
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, tabulated
b
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.K.H) and organ@yorku.ca(M.G.O.).
Funding Sources
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 and NIH P41-GM076302).
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(19) Representative compounds with full numeric data for each
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dx.doi.org/10.1021/co200076j |ACS Comb. Sci. 2011, 13, 653–658