A modular reaction pairing approach to the diversity-oriented synthesis of fused- and bridged-polycyclic sultams

Article abstract of DOI:10.1021/ol201962n

A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, S_NAr addition and Mitsunobu alkylation) generating skeletally diverse, tricyclic and bicyclic benzofused sultams is reported. Pairing sulfonylation and S

Full text of DOI:10.1021/ol201962n

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5148–5151
A Modular Reaction Pairing Approach
to the Diversity-Oriented Synthesis
of Fused- and Bridged-Polycyclic Sultams
Thiwanka B. Samarakoon,† Joanna K. Loh,† Alan Rolfe,† Lisa S. Le,†
Sun Young Yoon,† Gerald H. Lushington,‡ and Paul. R. Hanson*,†
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence,
Kansas 66045, United States, and The University of Kansas Center for Chemical
Methodologies and Library Development (KU-CMLD), 2034 Becker Drive, Delbert M.
Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
phanson@ku.edu
Received July 27, 2011
ABSTRACT
A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, SNAr addition and Mitsunobu alkylation) generating skeletally
diverse, tricyclic and bicyclic benzofused sultams is reported. Pairing sulfonylation and SNAr reactions yields bridged, tricyclic and bicyclic benzofused
sultams. Application of the Mitsunobu reaction in a sulfonylationꢀMitsunobuꢀSNAr pairing allows access to benzthiazocine-1,1-dioxides, while a
simple change in the order of pairing to sulfonylationꢀSNArꢀMitsunobu affords structurally different, bridged tricyclic benzofused sultams.
The development of new approaches to access diverse
heterocycle collections for high throughput screening
(HTS) is an important aspect in modern drug discovery.
Diversity-oriented synthesis (DOS) has emerged in recent
years as an enabling strategy for the production of di-
verse collections of heterocycles.1 Key examples of DOS
strategies include functional group pairing and build-couple-
pair (BCP).2 We herein report a reaction pairing strategy
utilizing the ability of ο-fluorobenzene sulfonamides to
undergo nucleophilic aromatic substitution (SNAr) for the
facile generation of benzofused sultam scaffolds.
Sultams (cyclic sulfonamides) represent a class of non-
natural chemotypes that have gained prominence in recent
years due to their activity against a wide spectrum of
biological targets.3,4 Longꢀstanding interest in the facile
generation of sultam scaffolds has prompted the explora-
tion of a reaction pairing strategy described herein. o-
Halobenzene-sulfonyl chlorides and their corresponding
sulfonamides have emerged ashighlyversatile synthons for
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J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.; Rowley, A.; Ryba,
T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross, N. T.;
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Gerard, B.; Duvall, J. R.; Lowe, J. T.; Murillo, T.; Wei, J.; Akella, L. B.;
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† Department of Chemistry, University of Kansas.
‡ The University of Kansas Center for Chemical Methodologies and
Library Development.
(1) (a) Schreiber, S. L. Science 2000, 287, 1964–1969. (b) Burke,
M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613–618. (c)
Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867–3870. (d) Tan, D. S. Nat.
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r
10.1021/ol201962n
Published on Web 09/07/2011
2011 American Chemical Society

Scheme 1. Reaction Pairing Utilizing SulfonylationꢀSNAr with
Amino Alcoholsa
Figure 1. Reaction pairingstrategiestodiversebenzofusedsultams.
a Sulfonylation: NaHCO3, CH2Cl2, H2O, rt. SNAr: Cs2CO3, DMF,
140 °C, mW. Mitsunobu: PPh3, DIAD, THF, rt.
the generation of sultam scaffolds.5 While sulfonylation
and Mitsunobu alkyaltion are well precedented for
sulfonamides,6 the ability of these synthons to undergo
facile nucleophilic aromatic substitution (SNAr) is lesser
known.2f,5 Collectively, it was therefore envisioned that
pairing of the reaction triad (sulfonylation, SNAr addition
and Mitsunobu alkylation) in varying order alongside the
central o-fluorobenzenesulfonyl chloride building blocks
could afford rapid access to both bridged- and fused-
tricyclic sultams. This simple approach obviates the need
for construction of elaborate multifunctional scaffolds and
would merely require o-fluorobenzenesulfonyl chlorides,
amines and alcohols as building blocks. Simple changes in
the reaction pair sequence (e.g., sulfonylationꢀSNAr vs
sulfonylationꢀMitsunobuꢀSNAr) or changes in building
blocks (1,2-amino alcohol vs 1,3-amino alcohol) allows
access to skeletal and stereochemical diversity (Figure 1).
Investigations commenced with the exploration of
pairing (S)-prolinol with 4-bromo-2-fluorobenzenesulfonyl
chloride via a combination of sulfonylation, SNAr and
Mitsunobu methodologies (Scheme 1). Thus, (S)-prolinol
was sulfonylated with 4-bromo-2-fluorobenzenesulfonyl
chloride in CH2Cl2/H2O, in the presence of NaHCO3 to
provide the β-hydroxy o-fluorobenzene sulfonamide 1 in
97% yield. Subjection of the sulfonamide to microwave
(mW) irradiation at 150 °C for 30 min in DMF in the
presence of Cs2CO3 gratifyingly produced the benzofused
tricyclic sultam 2in 88% yield. In contrast, SNAr addition of
(S)-prolinol to n-butyl-derived o-fluorobenzene sulfona-
mide 3 under mW irradiation in DMSO at 140 °C for
30 min afforded the desired SNAr adduct 4 in 97% yield.
Addition of PPh3 to a stirring solution of the prolinol-
derived SNAr adduct in THF (0.05 M), followed by slow
addition of DIAD, was found to proceed quickly (10 min)
to furnish the desired tricyclic benzothiadiazepine-1,1-di-
oxide 5in 91% yield. Overall, this approach rapidly furnishes
different sultam skeletons implementing a single sulfonyl
chloride in conjunction with an amino alcohol by merely
changing the order of reaction pairing.
With these results in hand, the utilization of this reaction
pairing strategy for the generation of benzofused sultams
was explored. Thus, the use of (S)-prolinol alongside
propargylamine derived o-fluorobenzene sulfonamides in
the established SNArꢀMitsunobu pairing afforded the
desired tricycylic sultam 6 in good yield (Scheme 2). A
simple switch in the amino alcohol component to (R)-(þ)-
3-hydroxypyrrolidine gratifyingly afforded the corre-
sponding bridged, tricyclic benzofused sultams 7 and 8 in
good to moderate yield. Of notable importance is the facile
production of the unique bridged tricyclic sultam 7 containing
a bridgehead nitrogen connected to an SO2 moiety. It is pro-
posed that this “bridged sultam”, like corresponding twisted
amides, causes a deviation in the geometry of the sulfonamide
group leading to proposed hybridization and geometry
changes at nitrogen, ultimately affecting physical properties.7,8
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Org. Lett., Vol. 13, No. 19, 2011
5149

Scheme 2. Reaction Pairing Strategy to Access Skeletally Diverse Sultams with an Array of Amino Alcoholsa
a Sulfonylation: R1NH2 [Compounds 6 and 8, (R1 = Propargyl) 10 and 12 (R1 = nBu)], NaHCO3, CH2Cl2, H2O, rt. SNAr: Cs2CO3, DMF, 140 °C,
mW. Mitsunobu: PPh3, DIAD, THF, rt.
It has been reported that twisted amides (anti-Bredt amides)
possess a distorted amide bond, which dramatically affect
stability and reactivity in comparison to their standard
planar amides while increasing the basicity of the N atom
(or bridgehead N).9
Scheme 3. MitsunobuꢀIntramolecular SNAr Strategy to Benzo-
thiazocine-1,6-Dioxidesa
Building on these results, utilization of 2-piperidinemetha-
nol in the established reaction pairing protocol generated the
corresponding benzofused tricyclic sultams 9 and 10 in good
yield (Scheme 2). In contrast, use of 3-hydroxypiperidine
allowed for the synthesis of the bridged benzofused sultams
11 and 12 in satisfactory yields (Figure 1), with 11 (see X-ray,
Supporting Information) possessing similar bridged sultam
structural characteristics as 7. Overall, this reaction pairing
sequence allowed for the rapid generation of a skeletally and
stereochemically diverse collection of benzofused sultams by
simple variation of the amine component.
Alternatively, it was envisioned that utilization of mono-
protected diols, alongside o-fluorobenzene sulfonamides in a
Mitsuonobu alkylation-intramolecular SNAr O-arylation
a i. Sulfonylation: NaHCO3, CH2Cl2, H2O. ii. Mitsunobu: PPh3, DIAD,
THF, rt. iii. Deprotection-SNAr cyclization: TBAF, THF, 150 °C, mW.
would allow access to oxygen-containing benzofused sultams
14aꢀc (Scheme 3). Accordingly, 3-silyloxy-1-propanol was
subjected to Mitsunobu alkylation with n-butyl-derived o-
fluorobenzene sulfonamide to furnish the 3° sulfonamide 3 in
97% yield. It was envisioned that deprotection of the TBS
group under basic conditions would allow for an intramole-
cular SNAr cyclization to take place. Accordingly, a THF
solution of 13a was stirred in the presence of TBAF for 30 min
under mW irradiation at 150 °C to gratifyingly afford
the desired sultam 14a in 88% yield. Application of the
enantiomers (R)- and (S)-3-((tert-butyldimethylsilyl)oxy)
butan-1-ol in the above MitsunobuꢀSNAr pairing sequence
was again found to cleanly furnish the corresponding ben-
zothiazocine-1,1-dioxides 14b and 14c in good yields
(Scheme 3). Overall, change in the order of the pairing of
the SNAr reaction with Mitsunobu alkylation to sulfonyla-
tionꢀMitsunobuꢀSNAr allows for facile access to skele-
tally, as well stereochemically, diverse benzofused sultams.
Utilization of a [3 þ 2] Huisgen cycloaddition reaction
for the production of triazole-containing sultams was next
explored. Hemming and co-workers have reported the
ꢀ
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5150
Org. Lett., Vol. 13, No. 19, 2011

Scheme 4. MitsunobuꢀSNArꢀ[3 þ 2] Cycloaddition RP Ap-
proach to Benzothiadiazepine-6,6-Dioxidesa
a i. Mitsunobu: PPh3, DIAD, THF, rt. ii Azido-SNAr [3 þ 2]
Cyclization: NaN3, 18-c-6, DMF, 90 °C, 6ꢀ10 h.
elegent use of a one pot, tandem alkynylation-[3 þ 2]
cycloaddition approach to triazolosultams,10 while a re-
cent report by Yao and co-workers outline the utilization
of a Cu-catalyzed tandem [3 þ 2] dipolar cycloadditionꢀN-
arylation approach to these motifs utilizing o-bromo and o-
iodobenzenesulfonamides.11,12 However, there are no re-
ports of the use of nonmetal catalyzed, SNArꢀ[3 þ 2]
Huisgen cycloaddition for the generation of benzofused
sultams. Thus, a sulfonylationꢀMitsunobu protocol using
propargyl alcohol and o-fluorobenzene sulfonamide as the
Mitsunobu partners produced the desired propargylated o-
fluorobenzene sulfonamides 16aꢀd in excellent overall yield
(Scheme 4). Azidation of sulfonamides 16aꢀd was carried
out using NaN3 in DMF at 90 °C in the presence of 18-
crown-6 (1 equiv.) for 12 h to afford the tricyclic triazole-
containing sultams 17aꢀd, which had participated in an
intramolecular [3 þ 2] Huisgen cycloaddition ring closure
following intermolecular SNAr azidation. To the best of our
knowledge, this represents the first report of a one-pot
tandem SNAr-intramolecular [3 þ 2] Huisgen cycloaddition
for the synthesis of benzofused sultams.13,14 Overall, the
sulfonylationꢀMitsunobuꢀSNAr protocol is augmented by
pairing with an intramolecular [3 þ 2] cycloaddition proto-
col for the synthesis of triazol-containing benzofused sul-
tams in 3 steps.
Figure 2. Diversity distribution of sultams 2ꢀ12, 14aꢀc and
17aꢀd, (red spheres) relative to analogous MLPCN compounds
(blue) within a chemical space defined by BCUT polarizability
metrics (x-axis reports values of an AM1 polarizability metric scaled
by molecular bond-order profile; y-axis reports an AM1 polariz-
ability metric scaled by an inverse topological distance profile).
conducted against all 1198 compounds (blue) currently pre-
sent in the NIH Molecular Libraries Probe Production Center
Network (MLPCN) that contained the maximum common
substructure (4-bromo-N-propylbenzenesulfonamide) evident
within our own (Figure 2).
In conclusion, we have developed a reaction pairing
strategy employing a reaction triadꢀsulfonylation, Mitsu-
nobu, SNArfor therapid synthesisof a diversecollectionof
benzofused sultams. Simple changes to the order of the
pairing sequence and/or building blocks, allows for access
to skeletal and stereochemical diversity. Overall, this strat-
egy affords a diverse set of heterocycles in 2ꢀ3 steps from
commercially available building blocks. These results are
highly amenable for library production to generate collec-
tions of skeletally diverse sultams for HTS screening.
From chemical informatics analysis, utilizing a multifusion
similarity (MFS) analysis,15 it is apparent that sultams 2ꢀ12,
14aꢀc and 17aꢀd (red) are fairly unique relative to the mani-
fold of currently available analogs, and that there is a reasona-
ble amount of structural diversity present.16 Analysis was
Acknowledgment. This investigation was generously
supported by funds provided by the NIH Center for
Chemical Methodologies and Library Development at
the University of Kansas (P50 GM069663) and NIGMS
Pilot-Scale Libraries Program (NIH P41 GM076302).
The authors kindly acknowledge Dr. Victor Day of the
Molecular Structure Group (MSG) at the University of
Kansas for X-ray analysis. The authors also thank the KU
Honors Program (SY, Undergraduate Research Award),
the KU Office of the Provost, the KU Office of Research
and Graduate Studies, and the KU College of Liberal Arts
and Sciences for support of our program.
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Adv. Synth. Catal. 2011, 353, 41–48.
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(15) See Supporting Information for detailed description of analysis.
(16) (a) Pearlman, R. S.; Smith, K. M. J. Chem. Inf. Comput. Sci.
1999, 39, 28–35 and references therein. (b) DiverseSolutions 8.1; Tripos
Inc.: St. Louis, MO, 2009.
Supporting Information Available.Experimental details
and spectral charactization for all compounds, detailed
in-silico analysis and crystal structure CIF files provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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