Triazole-containing isothiazolidine 1,1-dioxide library synthesis: One-pot, multi-component protocols for small molecular probe discovery

Article abstract of DOI:10.1021/co200093c

The construction of two libraries of triazole-containing isothiazolidine 1,1-dioxides is reported utilizing either a one-pot click/aza-Michael or click/OACC esterification protocol. One core dihydroisothiazole 1,1-dioxide scaffold was prepared rapidly on

Full text of DOI:10.1021/co200093c

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Triazole-Containing Isothiazolidine 1,1-Dioxide Library Synthesis:
One-Pot, Multi-Component Protocols for Small Molecular
Probe Discovery
Alan Rolfe,† Thomas O. Painter,‡ Naeem Asad,† Moon Young Hur,†,‡ Kyu Ok Jeon,†,‡ Marek Brzozowski,†
Sarra V. Klimberg,† Patrick Porubsky,‡ Benjamin Neuenswander,‡ Gerald H. Lushington,†,‡ Conrad Santini,‡
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
S Supporting Information
b
ABSTRACT: The construction of two libraries of triazole-
containing isothiazolidine 1,1-dioxides is reported utilizing
either a one-pot click/aza-Michael or click/OACC esterification
protocol. One core dihydroisothiazole 1,1-dioxide scaffold was
prepared rapidly on multigram scale via ring-closing metathesis
(RCM) and was subjected to a one-pot multicomponent click/
aza-Michael protocol with an array of amines and azides for the
generation of a 180-member triazole-containing isothiazolidine
1,1-dioxide library. Alternatively, three daughter scaffolds were
generated via the aza-Michael of three amino alcohols, followed by a one-pot, multicomponent click/esterification protocol utilizing
a ring-opening metathesis polymerization (ROMP)-derived coupling reagent, oligomeric alkyl carbodiimide (OACC) to generate a
41-member library of triazole-containing isothiazole 1,1-dioxides.
KEYWORDS: triazole-containing isothiazolidine 1, 1-dioxide, sultams, one-pot, aza-Michael, RCM, ROMP
functionality incorporated within the cycle for diversification
utilizing an aza-Michael protocol. Aza-Michael reactions are
efficient pathways that, historically, have been broadly utilized
to access a variety of heterocycles.6 Specifically, the hetero-
Michael reaction has been utilized as an efficient cyclization
protocol to access a variety of sultam motifs leading to the
proposed triazole-containing isothiazolidine 1,1-dioxide library.7
1. INTRODUCTION
The need for discovery of new pharmaceutical leads and small
molecule probes has led to efforts focusing on the advancement
of current high-throughput screening and the corresponding
small molecule screening collections. This effort has been driven
by the development and emergence of methods, protocols, and
technologies to access diverse collections of small molecules in a
rapid fashion.1 Sultams (cyclic sulfonamide analogues) have
surfaced in recent years as important targets in drug discovery
because of their extensive chemical and biological profiles.2 In
this regard, β-amino sultams and their corresponding sulfonate
analogues are a relatively new chemotype that has shown
interesting biological properties. Such reports include the inhibi-
tion of HIV-1 replication and antibacterial activity (Figure 1).3
Building on these aforementioned reports, it was envisioned
that a library of β-amino sultams, specifically triazole-containing
isothiazolidine 1,1-dioxides, could be rapidly generated via a
facile one-pot click/aza-Michael diversification protocol of ring-
closing metathesis (RCM)-derived dihydroisothiazole 1,1-diox-
ide core scaffold 2 with a series of amines, azides and acids
(Figure 2).
2. RESULTS AND DISCUSSION
The construction of isothiazolidine 1,1-dioxides libraries was
envisioned by the diversification of core dihydroisothiazole 1,1-
dioxide core scaffolds via a one-pot, multicomponent protocol
pairing an aza-Michael diversification reaction with other ortho-
gonal reaction pathways. To this effect, the corresponding core
scaffold 2-(prop-2-yn-1-yl)-2,3-dihydroisothiazole 1,1-dioxide 2 was
rapidly generated on multigram scale via a 3-step sulfonylation,
RCM, propargylation protocol (Scheme 1).8,9 Notably, the addition
of metathesis catalyst [(IMesH2)(PCy3)(Cl)2Ru=CHPh; cat-B],9,10
in 5 equal portions of 0.5 mol % (total 2.5 mol %) every 30 min
was key to maintaining the observed high conversion of the
RCM cyclization.
Utilizing RCM,4 simple 5-, 6-, and 7-membered sultam
derivatives from the corresponding allyl and vinyl sulfonamides
were readily accessed.5 In the cases of RCM with vinyl sulfona-
mides, the corresponding sultam retains the R,β-unsaturated
Received: May 21, 2011
Revised:
July 19, 2011
Published: August 25, 2011
r
2011 American Chemical Society
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Figure 1. Biologically active β-amino sultams and sulfonates.
Figure 2. One-pot, multicomponent synthesis of triazole-containing isothiazole 1,1-dioxides via orthogonal reactions.
Scheme 1. Gram Synthesis of Core 2-(Prop-2-yn-1-yl)-2,3-dihydroisothiazole 1,1-Dioxide 2 via RCM
one-pot protocol was investigated. In this regard, the one-pot
click/aza-Michael protocol with azide {G} and pyrrolidine 6 was
investigated (Table 1). Initial efforts combined both reaction
conditions into the same pot (Table 1, entry 1) yielding the
desired product in 62% yield. This yield was improved to 96%
after increasing the CuI catalyst load to 30 mol % (Table 1, entry 2),
while additional optimization led to the use of lower equival-
ents of amine without affecting yield (Table 1, entry 5).
Table 1. Optimization of One-Pot Click/aza-Michael
Reaction Conditions
With these optimized conditions in hand, a validation library
was investigated for the diversification of dihydroisothiazole 1,1-
dioxide 2 with a variety of 2° amine nucleophiles (Table 2).
Reactions were carried out in 1-dram vials using reaction blocks,
whereby crude reaction mixtures were diluted in EtOAc, filtered
through a SiO2 SPE, and subjected to a QC check, followed by
purification via automated mass-directed LCMS.
azide {G}
amine 6
CuI
DBU
entrya
(equiv)
(equiv)
(mol %)
(mol %)
yield (%)
1
2
3
4
5
2
2
1
2
2
2
10 mol %
30 mol %
30 mol %
30 mol %
30 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
62%
96%
78%
95%
96%
2
With the successful synthesis of the 8-member validation
library, two libraries A and B were proposed for the synthesis
of 180-triazole-containing isothiazole 1,1-dioxides derivatives via
the diversification of dihydroisothiazole 1,1-dioxide 2 utilizing
amines (3ꢀ17) and azides {AꢀR} (Figure 3).
1
1.2
1.2
a Reactions carried out utilizing 2 (50 mg, 0.32 mmol, 1 equiv) in 0.5 M
EtOH at 60 °C for 12 h.
Library Design. For all three libraries A, B, and C, a full matrix
library was designed using in silico analysis, literature precedence,
and observed synthetic results.10 A virtual library incorporating
all possible building block combinations of azides, 2° amines and
acids (library C) was constructed for each scaffold (2, 18, 19, and 20)
(Figure 4). Physico-chemical property filters were applied,
guiding the elimination of undesirable building blocks that led to
With the desired core sultam 2 in hand, initial efforts focused
on the diversification of the core via solely an aza-Michael or click
reaction.8 After successful diversification of 2 utilizing either
reactions in high yield, the combination of both reactions in a
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Table 2. Library Prototype Utilizing Dihydroisothiazole 1,1-Dioxide 2
entrya
yield
final purityc
mass
entryb
yield
final purityc
mass
4{G}
6{G}
7{G}
8{G}
52%
45%
42%
47%
99%
99%
92%
99%
89.3 mg
75.4 mg
56.2 mg
63.9 mg
4{O}
14{O}
15{O}
16{O}
43%
41%
40%
43%
100%
98%
97%
98%
22.9 mg
22.3 mg
19.4 mg
22.3 mg
a Reaction conditions: Dihydroisothiazole 1,1-dioxide 2 (50 mg, 1 equiv), azide (2 equiv), amine (1.2 equiv), CuI (30 mol %), DBU (10 mol %), dry
EtOH (0.5 M), 60 °C, 12 h. b Reaction conditions: Dihydroisothiazole 1,1-dioxide 2 (20 mg, 1 equiv), azide (2 equiv), amine (1.2 equiv), CuI (30 mol
%), DBU (10 mol %), dry EtOH (0.5 M), 60 °C, 12 h. c Purified by an automated preparative reverse phase HPLC (detected by mass spectroscopy).
Purity was determined by HPLC with peak area (UV) at 214 nm and % rounded up to nearest 1%.
products with undesirable in-silico properties.11 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 comparing against the
MLSMR screening set (ca. 7/2010; ∼330,000 unique chemical
structures). Guided by this library design analysis, the corre-
sponding amines 3ꢀ17, azides {AꢀR} and acids 21ꢀ25 and
sultams (2, 18ꢀ20) (Figures 3 and 4) were chosen to generate
234 proposed sultams (libraries A, B, and C).
Library A and B. Utilizing the optimized conditions, library A
(132-member) was designed and generated utilizing azides AꢀL
with amines 3ꢀ13 via a one-pot click/aza-Michael transforma-
tion. Library B (48-member) was also generated utilizing azides
AꢀL with piperazines 14ꢀ17 via a sequential 2-step click/aza-
Michael protocol, instead of the previously used one-pot method.
This 2-step sequence was necessary to efficiently remove the Cu
catalyst from the crude material without the need of an aqueous
workup because of increased affinity for the SiO2 SPE of the
corresponding final compounds bearing both a triazole and
piperazine moiety. Overall, all 180 triazole-containing isothia-
zole-1,1-dioxide members of library A and B were successfully
generated, with 167 out of the 180 compounds possessing >90%
final purity after purification by automated mass-directed LCMS
(Scheme 2).12
click/oligomeric alkyl cyclohexylcarbodiimide (OACC)
esterification to generate the desired 90-membered library
(Scheme 4).
Key to the combination of these orthogonal reaction pathways
is the utilization of an immobilized, soluble ring-opening me-
tathesis polymerization (ROMP)-derived coupling reagent
OACC.13 This high load reagent allows for efficient coupling
of a variety of acids with 18, 19, or 20, followed by facile removal
via a simple precipitation/filtration protocol.
Initially, the three daughter isothiazole 1,1-dioxide scaffolds
18, 19, and 20 were generated via aza-Michael of the correspond-
ing amino alcohols with dihydroisothiazole 1,1-dioxide 2 in an
efficient multigram synthesis. With these core isothiazole-1,1-
dioxide (18, 19, and 20) scaffolds prepared, a 90-member library
was designed utilizing a combination of 18, 19, and 20 with
azides MꢀP and acids {21ꢀ25} (Figure 4).
Using the aforementioned method, a one-pot click/OACC
esterification protocol for the synthesis of library C was achieved
utilizing 1.2 equiv of acid {21ꢀ25}, azide (2 equiv), OACC
(1.5 equiv), CuI (30 mol %), DBU (10 mol %), and anhydrous
CH2Cl2 (Table 3). Reactions were carried out at 50 °C for 12 h,
whereby upon completion the crude reactions were diluted,
filtered, and concentrated. Utilizing these conditions an initial
validation set of isothiazolidine-1,1-dioxides was investigated to
evaluate the reaction conditions (Table 3).
Upon completion, the validation set was diluted in EtOAc to
precipitate the spent oligomer, followed by filtration through a
SiO2 SPE and concentration. All samples were purified by
column chromatography, characterized, and then submitted to
purification by reverse-phase automated mass-directed LCMS.14
Despite their stability when isolated after standard chroma-
tography, it was observed that esters generated with acids 21
and 23 underwent complete hydrolysis during automated
mass-directed LCMS. Analysis indicated that after successful
purification, hydrolysis occurred during the final step of
removal of the solvent utilized (CH3CN, H2O, DMSO, and
NH4OH). Because of this observation, library C was rede-
signed removing acids 21 and 23 to propose a 54-member
library (Scheme 5).
Within the 132-member library A is a unique set of 12 bis-
triazole-containing isothiazole 1,1-dioxides 13{AꢀL} which
were generated through a bis-click/aza-Michael because of the
use of N-methyl propargyl amine 13 as the Michael component
in the presence of 2 equiv of the corresponding azide (Scheme 3).
Library C. Building on the synthesis of 180-member triazole-
containing isothiazole 1,1-dioxides, library C, a 90-member
compound set of derivatives was investigated. This involved
the synthesis of three daughter scaffolds (18, 19, and 20,
Figure 4) synthesized from dihydroisothiazole 1,1-dioxide 2,
which underwent diversification via a one-pot procedure
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Figure 3. Amine (3ꢀ17) and Azide {AꢀR} library building blocks.
Under these conditions, 41 out of 54 compounds were
successfully isolated >90% purity after purification by automated
mass-directed LCMS. Crude reaction analysis indicated that all
54 reactions worked; however, it is proposed that the failed
reactions and low yields observed were due to hydrolysis of the
desired product in the final stages of purification.
purity after purification by automated mass-directed LCMS.
Building on this success, a 41-member library C of triazole-
containing isothiazole 1,1-dioxide library was prepared via a one-
pot, click/OACC esterification utilizing the soluble oligomeric
coupling reagent OACC. Taken collectively, a total of 208
sultams were successfully generated (89% success rate) with
purities >90%. This screening set of sultams represent a diverse motif
not currently reported in the literature and has been submitted
for biological evaluation via high-throughput screening.
3. CONCLUSION
In conclusion, three libraries of triazole-containing isothiazo-
lidine 1,1-dioxides were prepared utilizing either a one-pot click/
aza-Michael or click/esterification protocol for utilization in high
throughput screening (HTS) collections. One core dihydroi-
sothiazole 1,1-dioxide scaffold was prepared on multigram scale
via RCM and rapidly diversified via a one-pot multicomponent
click/aza-Michael protocol to generate a 180-triazole-containing
isothiazole 1,1-dioxide library (A and B). All 180 compounds
were successfully generated, with 167 possessing >90% final
4. EXPERIMENTAL PROCEDURES
General Procedure A for the Synthesis of Library I via a
One-Pot Click/aza-Michael Protocol. To a 1-dram vial containing
2-(prop-2-yn-1-yl)-2,3-dihydroisothiazole 1,1-dioxide 2(50 mg, 0.32 mmol,
1 equiv) was added CuI (18.2 mg, 30 mol %), DBU (5 μL, 10 mol %),
dry EtOH (0.64 mL, 0.5 M), amine (0.38 mmol, 1.2 equiv) and azide
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Figure 4. Library C: Core Scaffolds 18, 19, and 20, azide building blocks MꢀR and acid building blocks {21ꢀ25}.
Scheme 2. Library A and B: Representative Library Members
Demonstrating Final Mass, Purity, and Overall Yield
Scheme 3. One-Pot bis-Click/aza-Michael to Produce
Compounds 13{AꢀL}
Table 3. One-Pot, Click/OACC Esterification
entrya
scaffold
azide
acid
yield (%)b
1
2
3
4
5
6
7
18
18
18
18
19
19
19
P
M
M
P
21
22
23
23
22
23
24
48
52
47
60
40
42
43
(0.64 mmol, 2 equiv). The reaction was heated at 60 °C on a reaction
block for for 12 h, after which time the reactions were cooled, filtered
through a SiO2 SPE into preweighed bar-coded vials, washed with eluent
(2 mL, EtOAc:MeOH 95:5) and concentrated under reduced pressure.
The crude reaction was concentrated and QC/purified by an automated
preparative reverse phase HPLC (detected by mass spectroscopy).
Note: All reactions involving the use and heating of azides were carried out
behind a safety shield taking extra precautions because of the explosive nature
of these materials.
M
M
M
a Reaction conditions: Isothiazole 1,1-dioxide (40 mg, 1 equiv),
acid (1.2 equiv), azide (2 equiv), OACC (1.5 equiv), CuI (30 mol %),
DBU (10 mol %), dry CH2Cl2 (0.2 M), 50 °C, 12 h. b Isolated
yields after standard column chromatography (EtOAc, Rf
0.3ꢀ0.6).
=
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Scheme 4. Library C; One-Pot, Click/OACC Esterification of Isothiazole 1,1-Dioxides 18, 19, and 20
Scheme 5. Generation of Library C via an One-Pot Click/OACC Esterification
General Procedure B for Two-Step Click, aza-Michael with
Amines 14ꢀ17 and Azides AꢀL. To a 1-dram vial contain-
ing 2-(prop-2-yn-1-yl)-2,3-dihydroisothiazole 1,1-dioxide 2 (50 mg,
0.32 mmol, 1 equiv) was added CuI (18.2 mg, 30 mol %), DBU
(5 μL, 10 mol %), dry EtOH (0.64 mL, 0.5 M), and azide (0.64 mmol,
2 equiv). The reaction was heated at 60 °C on a reaction block for 4 h, after
which time the reactions were cooled, filtered through SiO2, washed with
eluent (2 mL, EtOAc), and concentrated under reduced pressure. The
crude was transferred to a 1-dram vial, where DBU (5 μL, 10 mol %), dry
EtOH (0.64 mL, 0.5 M), amine (0.38 mmol, 1.2 equiv) were added. The
reaction was subsequently heated at 60 °C on a reaction block for 10 h, after
which time the reactions were cooled, filtered through a SiO2 SPE and
concentrated into preweighed barcoded vials, washed with eluent (2 mL,
EtOAc:MeOH 95:5) and concentrated under reduced pressure. The crude
reaction was concentrated and QC/purified by an automated preparative
reverse phase HPLC (detected by mass spectroscopy).
General Procedure C for the Synthesis of Cores 18, 19, and
20 via aza-Michael. Into a round-bottom flask was added a solution
of 2-(prop-2-yn-1-yl)-2,3-dihydroisothiazole 1,1-dioxide 2 (1 equiv) in
dry MeOH (1 M). To the stirring solution was added DBU (10 mol %)
and the corresponding amino alcohol (1.5 equiv), and the reaction
mixture was heated at 60 °C for 12 h. After such time, the reaction was
diluted in CH2Cl2/MeOH (9:1), filtered through a silica SPE, and
flushed with CH2Cl2/MeOH (9:1). The resulting isothiazolidine 1,1-
dioxide (18, 19, or 20) was concentrated and carried forward without
the need for further purification.
were cooled, diluted in EtOAc (2 mL), and the corresponding suspension
filtered through a SiO2 SPE into preweighed bar-coded vials, washed with
eluent (2 mL, EtOAc) and concentrated under reduced pressure. The crude
reaction was concentrated and QC/purified by an automated preparative
reverse phase HPLC (detected by mass spectroscopy).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, ta-
b
bulated 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.
Funding Sources
This work was supported by the National Institute of General
Medical Science [Center in Chemical Methodologies and Li-
brary Development at the University of Kansas, (KU-CMLD),
NIH P50 GM069663, NIH P41-GM076302, and the NIH-
STTR R41 GM076765]. Undergraduate funding was provided
by a KU Undergraduate Research Award from the KU Honors
Department and the KU Center for Research (S.V.K and M.B).
General Procedure D for Synthesis of Library C via One-
Pot Click/OACC Esterification Protocol. To a 1-dram vial contain-
ing sultam 18, 19, or 20 (40 mg, 1 equiv) was added CuI (30 mol %),
DBU (10 mol %), dry CH2Cl2 (0.2 M), acid (1.2 equiv), and azide
(2 equiv). To the crude mixture was added a solution of OACC
(1.5 equiv) in dry CH2Cl2 (0.2 M), and the resulting reaction mixture was
heated at 50 °C on a reaction block for 12 h. After which time, the reactions
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