Automated synthesis of a 184-member library of thiadiazepan-1,1-dioxide-4- ones

Article abstract of DOI:10.1021/co100060x

The construction of a 225-member (3 × 5 × 15) library of thiadiazepan-1,1-dioxide-4-ones was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 184/225 sultams. Three sultam core scaffolds were prepared based upon the utilization of an aza-Michael reaction on a multifunctional vinyl sulfonamide linchpin. The library exploits peripheral diversity in the form of a sequential, two-step [3 + 2] Huisgen cycloaddition/Pd-catalyzed Suzuki-Miyaura coupling sequence.

Full text of DOI:10.1021/co100060x

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Automated Synthesis of a 184-Member Library of Thiadiazepan-1,
1-dioxide-4-ones
Erik Fenster,†,§ Toby R. Long,†,‡,§ Qin Zang,‡ David Hill,† Benjamin Neuenswander,† Gerald H. Lushington,†
Aihua Zhou,‡ Conrad Santini,† and Paul R. Hanson*,†,‡
†Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), 2034 Becker Drive,
Delbert M. Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
‡Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
S Supporting Information
b
ABSTRACT: The construction of a 225-member (3 ꢀ 5 ꢀ 15)
library of thiadiazepan-1,1-dioxide-4-ones was performed on a
Chemspeed Accelerator (SLT-100) automated parallel synthesis
platform, culminating in the successful preparation of 184/225
sultams. Three sultam core scaffolds were prepared based upon
the utilization of an aza-Michael reaction on a multifunctional
vinyl sulfonamide linchpin. The library exploits peripheral diver-
sity in the form of a sequential, two-step [3 þ 2] Huisgen cycloaddition/Pd-catalyzed Suzuki-Miyaura coupling sequence.
KEYWORDS: thiadiazepan-1,1-dioxide-4-ones, parallel synthesis platform, aza-Michael reaction, Huisgen cycloaddition, Suzuki-Miyaura
coupling
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Diversity-oriented synthesis (DOS) has emerged as a power-
ful strategy to produce large libraries of biologically relevant
small-molecules for high throughput screening.1,2 Various stra-
tegies in this area hinge on the ability to generate diverse collec-
tions of molecules in the fewest number of steps possible.3
Among these, functional group pairing (FG-pairing) is a key
concept that is at the heart of the “Build/Couple/Pair (BCP)”
strategy pioneered by Schreiber and co-workers4 and continues
to be the impetus for DOS-based library efforts. Previously,
the inherent chemistry of vinyl sulfonamides was employed
in a “Click, Click, Cyclize” strategy for the facile construction
of skeletally diverse sultam scaffolds via synthetic operations on
a single sulfonamide-based linchpin as outlined in Figure 1.5 In
particular, thiadiazepan-1,1-dioxide-4-one scaffolds represent an
under explored chemotype that was easy to access with the
aforementioned strategy. We herein report the production of a
184-member library6 using an automated sequential alkyl azide
cycloaddition/Suzuki-Miyaura coupling sequence on three core
thiadiazepan-1,1-dioxide-4-one scaffolds which were constructed
using an aza-Michael variant of the “Click, Click, Cyclize” method.
Sulfonamides have long been valued for their rich biological
and chemical profiles rendering them a promising class of com-
pounds in drug discovery.7 Cyclic sulfonamides (sultams),
while not found in nature, exhibit a wide-array of potent
biological activities8 that has inspired the present study aimed
at mining underrepresented chemical space of the titled peptido-
mimetic chemotype9 in hopes of identifying new bioactive
probes.
Efforts toward the construction of the key thiadiazepan-1,1-
dioxide-4-one scaffolds are outlined in Scheme 1. We envisioned
utilizing two functional group handles in regions A/B on sultam
scaffolds 5{1-3} for the attachment of diverse appendages. The
Huisgen [3 þ 2] cycloaddition10 and Suzuki-Miyaura coupling
reactions11 were chosen based upon their well-precedented
efficiency12 and use in library development.13 The introduction
of an alkyne group in quadrant A allows for facile diversification
via the well-known Huisgen [3 þ 2] cycloaddition, while installa-
tion of a bromophenyl group into quadrant B provides the
necessary functionality for various Pd-catalyzed cross-couplings,
such as the Suzuki-Miyaura reaction.
Each of the three sultam scaffolds 5{1-3} were efficiently
accessed using a FG-pairing strategy previously reported,3b,5c in
which L-alanine/valine/leucine methyl ester hydrochlorides
underwent sulfonylation to generate vinyl sulfonamides 2{1-3}.
Subsequent alkylation of sulfonamides 2{1-3}, followed by aza-
Michael addition of propargyl amine, yielded the desired tertiary
sulfonamides 4{1-3}. Initially, the direct intermolecular lacta-
mization from sulfonamides 4 was investigated as a one-step
route to 5. However, despite similar intramolecular transforma-
tions in the literature,9,14 little success was achieved. Efforts were
next directed to a two-step hydrolysis/lactamization15 sequence
Received: November 9, 2010
Revised:
January 11, 2011
Published: February 10, 2011
r
2011 American Chemical Society
244
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|

ACS Combinatorial Science
RESEARCH ARTICLE
Figure 1. Use of a versatile vinyl sulfonamide linchpin to access skeletally diverse sultams.
Scheme 1. Synthesis of Substituted Thiadiazepan-1,1-dioxide-4-one Scaffolds 5{1-3}
to produce scaffolds 5{1-3} in good overall yields on multigram
scale.16,17
loadings could be reduced to as low as 10 mol % without risking a
substantial loss in yield, it was envisioned that an immobilized
source of copper would be more amenable to parallel library syn-
With the desired scaffolds 5{1-3} in hand, we next investi-
gated the validation of the proposed library via diversification
of regions A and B. The logical starting point relied on the noted
selectivity and compatibility of the azide/alkyne [3 þ 2] cyclo-
addition for its use in region A. In this regard, conditions em-
ploying Cu(I) catalysis (Table 1, entry 1) were initially explored
and found to be high-yielding but unfortunately afforded an
undesirable mixture of regioisomers. The use of Cu(II) catalysts
in t-BuOH/H2O, however, saw complete regioselectivity but
suffered from poorer yields (Table 1, entry 2) attributed to poor
substrate solubility. Additional optimization was achieved with
the use of CH2Cl2 (Table 1, entry 3) or acetone (Table 1, entry
4) as cosolvents, which resulted in near quantitative yields. Use
of lower catalyst/additive loadings was also explored to simplify
library purification (Table 1, entries 4-6). Though catalyst
thesis. The use of copper immobilized on Amberlyst (A-21 CuI)18
3
at 20 mol % in CH2Cl2, was found to afford the triazole-containing
sultams 7{1,2} in excellent yield (Table 1, entry 7).
We began investigations into the Suzuki-Miyaura coupling
reaction using Pd(dppf)Cl2 and Cs2CO3 in DMF/H2O (Table 2,
entries 1-4). Near quantitative yields could be achieved with a
catalyst loading of 5 mol % using relatively high temperatures and
prolonged reaction times (Table 2, entry 4). However, these
conditions resulted in difficult emulsions during the aqueous
workups, a situation that renders the reaction impractical in
a parallel platform. This problem was attributed to the choice of
base/solvent combination utilized, and a number of alternative
conditions were next explored (Table 2, entries 5-13). Ulti-
mately, the combinations of Cs2CO3 in DME/H2O provided the
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RESEARCH ARTICLE
Table 1. Validation of Huisgen [3 þ 2] Cycloaddition
entry
catalyst
CuI
loading (mol %)
additive
equiv
solvent
yield (%)
1
2
3
4
5
6
7
10
10
20
20
10
5
2,6-lutidine
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
none
1.2
0.1
0.3
0.3
0.2
0.1
CHCl3
88a
45
97
96
95
78
90
CuSO4 6H2O
t-BuOH/H2O 1:2
3
CuSO4 6H2O
t-BuOH/H2O/CH2Cl2 1:1:1
t-BuOH/H2O/acetone 3:4:1
t-BuOH/H2O/acetone 3:4:1
t-BuOH/H2O/acetone 3:4:1
CH2Cl2
3
CuSO4 6H2O
3
CuSO4 6H2O
3
CuSO4 6H2O
3
A-21 CuI
20
3
a Resulted in a mixture of 1,4- and 1,5-regioisomers in 4:1 ratio.
Table 2. Validation of the Suzuki-Miyaura Coupling Reaction
entry
R2
R3
catalyst
loading (mol %)
base
solvent
temp (°C)
time (h)
yield (%)
1
p-Me-Bn
phenyl
phenyl
phenyl
phenyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)4
1
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
DME/H2O
DME/H2O
DME/H2O
70
70
70
8
8
8
46
51
68
98
85
10
92
90
62
94
89
<5
61
2
p-Me-Bn
3
p-Me-Bn
10
5
4
p-Me-Bn
85
70
70
85
90
75
90
85
70
80
24
14
14
16
16
14
16
16
14
14
5
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
p-MeO-Bn
10
10
10
10
10
10
10
10
10
6
7
8
K3PO4
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
10
11
12
13
Pd(PPh3)4
most convenient workup while retaining high yields (Table 2,
entry 11).19
On the basis of the optimal conditions chosen for both
reactions, studies turned toward combining the two reactions
into a single-step sequence for ease of use in parallel synthesis
(Scheme 2). Sultam 5{1} was first reacted for 14 h with excess
boronic acid and Cs2CO3 from the reaction mixture, followed by
liquid-liquid extraction using CH2Cl2. The resulting solution was
filtered via Si-SPE to remove residual Pd(0) and concentrated
under reduced pressure to afford sultam 9{1,3,2} in excellent yield
over the combined two-step sequence. Overall, this sequence
proved relevant in the transfer of chemistries to parallel methods
in which both workup and purification were minimized.
The combined sequence was next attempted as a rehearsal 2 ꢀ
3 ꢀ 3 validation library using a Chemspeed Accelerator SLT-100
synthesizer21 (Table 3). Azides 6{1-3} were chosen as diverse
representative members of the final library. A small substrate
scope for the Suzuki-Miyaura coupling reaction was also ex-
plored with the choice of electron-deficient and electron-rich
p-methoxybenzyl azide 6{3} in the presence of A-21 CuI, followed
3
by filtration of the catalyst and concentration to yield crude, triazole-
containing sultam 7{1,3}.20 Sultam 7{1,3} was carried forward
to the coupling event without further purification, upon which
was sequentially added, DME, solid Pd(dppf)Cl2, Cs2CO3 in H2O,
and excess boronic acid 8{2} before heating at 85 °C for 14 h.
After which time, a basic workup was performed to remove excess
246
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RESEARCH ARTICLE
Scheme 2. Combined Two-Step Diversification Sequence
Table 3. Chemspeed Rehearsal 2 ꢀ 3 ꢀ 3 Library of Thiadiazepan-1,1-dioxide-4-ones
entry
sultam
azide
boronic acid
product
yield (%)a
purity (%)b
1
5{1}
5{1}
5{1}
5{1}
5{1}
5{1}
5{1}
5{1}
5{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{1}
6{2}
6{2}
6{2}
6{3}
6{3}
6{3}
6{1}
6{1}
6{1}
6{2}
6{2}
6{2}
6{3}
6{3}
6{3}
8{2}
9{1,1,2}
9{1,1,16}
9{1,1,17}
9{1,2,2}
9{1,2,16}
9{1,2,17}
9{1,3,2}
9{1,3,16}
9{1,3,17}
9{2,1,2}
9{2,1,16}
9{2,1,17}
9{2,2,2}
9{2,2,16}
9{2,2,17}
9{2,3,2}
9{2,3,16}
9{2,3,17}
40
44
0
100
91
2
8{16}
8{17}
8{2}
3
0
4
35
37
0
98
5
8{16}
8{17}
8{2}
100
0
6
7
38
33
41
45
44
0
100
87
8
8{16}
8{17}
8{2}
9
10
10
11
12
13
14
15
16
17
18
100
100
0
8{16}
8{17}
8{2}
49
43
0
100
100
0
8{16}
8{17}
8{2}
38
23
16
100
100
94
8{16}
8{17}
a Purified by an automated preparative reverse phase HPLC (detected by mass spectroscopy). b Purity was determined by HPLC with peak area (UV) at
214 nm.
phenyl, and alkyl boronic acids 8. Using the two-step sequence
described above in the Chemspeed platform (0.150 mmol scale),
the resulting 18 crude sultams 9 were subjected to preparative
HPLC purification. In general, yields in the range of 16-49%
were obtained with purities >87% (Figure 2). However, boronic
acid 8{3} (cyclopropyl), was significantly less reactive and
resulted in either no yield or low yields as compared to both
phenyl boronic acids in the sequence (Table 3, entries 3, 6, 9, 12,
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RESEARCH ARTICLE
Figure 2. Crude purity, final purity, and yield from HPLC analysis of Chemspeed rehearsal 2 ꢀ 3 ꢀ 3 library of thiadiazepan-1,1-dioxide-4-ones.
Scheme 3. Building Blocks for the 3 ꢀ 5 ꢀ 15 Library of Thiadiazepan-1,1-dioxide-4-ones
15, and 18). Overall, the results of the validation efforts demon-
strated a successful two-step automated sequence.
5{1-3}.22 Further analysis of the data revealed no definitive
trends in yields between substrates and reagents; however it
was evident that thiophene boronic acid (R3 = 5) was the only
reagent that yielded little or no material for the 15 reactions for
which it was utilized.
In conclusion, we successfully completed the automated
production of a 184/225-member library of thiadiazepan-1,1-
dioxide-4-ones using a Chemspeed Accelerator platform in
which a two-step diversification sequence was performed. The
resulting compounds of this library are in the process of being
distributed to a number of biological collaborators within the
NIH Molecular Libraries Probe Center Network (MLPCN) and
future efforts will focus on the production of targeted libraries of
thiadiazepan-1,1-dioxide 4-ones and related chemotypes, as well
as their anticipated biological evaluation.
With these results in hand, planning began for constructing
the 225-member library using the Chemspeed platform with
the conditions set in place during the rehearsal library. A number
of azides and boronic acids were chosen (Scheme 3) based
on differences in their structure and polarity. On the basis of
the rehearsal library, alkyl boronic acids were excluded from the
final library. Using the validated conditions, the Chemspeed was
then programmed to run three consecutive 3 ꢀ 5 ꢀ 5 reactions
(75 compounds each) for a total of 225 compounds.
Upon completion of the three 75-compound runs, a total of
225 reactions were purified via preparative/mass-directed HPLC
in which 184 compounds were obtained with quantities g20 mg
and with purity >90% starting from 0.150 mmol of sultams
248
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RESEARCH ARTICLE
’ ASSOCIATED CONTENT
D.; Rolfe, A.; Volp, K.; Omar, I.; Hanson, P. R. Metathesis Cascade
Strategies (ROM-RCM-CM): A DOS Approach to Skeletally Diverse
Sultams. Tetrahedron 2009, 65, 4992–5000.
(6) 184 out of 225 members were successfully produced in sufficient
quantities and purities (>10 mg and >90% purity).
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Supporting Information. Experimental procedures, tabu-
b
lated results and data for this library, as well as full characteriza-
tion for representative compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(8) For a comprehensive list of bioactive sultams, see ref 5d and
references cited therein.
Corresponding Author
*E-mail: phanson@ku.edu. Phone: (785) 864-3094. Fax: (785)
864-5396.
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Author Contributions
§Equally contributing authors.
Funding Sources
Financial support of this work was provided by the Institute
of General Medical Sciences and is gratefully acknowledged
(P50-GM069663 and P41-GM076302).
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ACS Combinatorial Science
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purity >95% as determined by 1H NMR.
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hydrolysis/lactamization sequence. For example, ee measurements of
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(19) We also briefly explored the use of Pd-bound FibreCat whereby
reaction workup consisted of a simple SPE filtration event, see: Colacot,
T. J.; Carole, W. A.; Neide, B. A.; Harad, N. Tunable Palladium-
FibreCats for Aryl Chloride Suzuki Coupling with Minimal Metal
Leaching. Organometallics 2008, 27, 5605–5611 Unfortunately, the
fibrous nature of this reagent and its delivery and separation via
automation proved difficult.
(20) Note: Excess volatile azide/CH2Cl2 was removed during the
process of concentrating the reaction mixture under reduced pressure.
(21) Chemspeed Technologies Home Page. http://www.chem-
speed.com/ (accessed April, 10, 2010).
(22) The standards for compound purity and quantity are based
upon those requested for the National Institutes of Health’s Mole-
cular Libraries Small Molecule Repository (http://mlsmr.glpg.com/
MLSMR_HomePage/submitcompounds.html). The compound puri-
ties were determined by reverse-phase HPLC with peak area (UV) at
214 nm.
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