production of an array of scaffolds with minimum steps. Both
concepts are at the heart of the “Build/Couple/Pair (BCP)”
strategy pioneered by Schreiber and co-workers.6 This
strategy involves a “Build phase” to assemble chiral building
blocks containing orthogonal sets of functionality suitable
for the subsequent “Coupling and FG pairing” phases en
route to an array of diverse scaffolds. In this regard, interest
in the generation of skeletally diverse sultams for biological
screening has provided impetus for the titled FG pairing
cyclization strategy termed “Click, Click, Cyclize” enroute
to five-, six-, seven-, eight-, and nine-membered ring
sultams.7
array of potent biological activities.9,10 Traditionally, sultam
syntheses have relied on classical cyclization protocols and
a number of transition-metal-catalyzed processes that have
Scheme 1. DOS via “Click, Click, Cyclize” Reaction Manifolds
Figure 1. “Click, Click, Cyclize” or “Click, Click, Click, Cyclize”
recently been reported.10 In this regard, vinyl sulfonamides
represent an emerging chemotype with a wide spectrum of
reaction potential to generate sultams. Literature precedence
has shown their reactivity in Diels-Alder,11 Heck,12 indium-
initiated radical addition,13 and [3 + 2] cycloadditions.14 This
chemical profile is augmented by recent work using ring-
closing metathesis (RCM),10a,15 intramolecular oxa-Michael,
approach to skeletally diverse sultams.
Sulfonamides have long been valued for their rich biologi-
cal and chemical profiles and have emerged as a promising
class of compounds in drug discovery.8 Sultams (cyclic
sulfonamides), although not found in nature, display a wide
(7) “Click” chemistry is a chemical philosophy introduced by K. Barry
Sharpless in 2001 that describes chemistry tailored to generate substances
quickly and reliably by joining small units together; see: Kolb, H.; Finn,
M. G.; Sharpless, K. B Angew. Chem., Int. Ed. 2001, 40, 2004–2021.
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Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003, 10,
925–953.
(11) (a) Brosius, A. D.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
700–709. (b) Greig, I. R.; Tozer, M. J.; Wright, P. T. Org. Lett. 2001, 3,
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Tetrahedron: Asymetry 2001, 12, 1811–1815. (d) Wanner, J.; Harned, A. M.;
Probst, D. A.; Poon, K. W. C.; Klein, T. A.; Snelgrove, K. A.; Hanson,
P. H. Tetrahedron Lett. 2002, 43, 917–721. (e) Rogatchov, V. O.;
Bernsmann, H.; Schwab, P.; Fro¨hlich, R.; Wibbeling, B.; Metz, P.
Tetrahedron Lett. 2002, 43, 4753–4756.
(9) (a) Tanimukai, H.; Inui, M.; Harigushi, S.; Kaneko, J. Biochem.
Pharmacol. 1965, 14, 961–970. (b) Wroblewski, T.; Graul, A.; Castaner,
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2000, 43, 2040–2048. (f) Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.;
Gut, J.; Rosental, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 4115–4119.
(10) For an extensive list of biologically active sultams as well as
classical and transition metal catalyzed cyclization strategies to sultams,
see: (a) Jime´nez-Hopkins, M; Hanson, P. R Org. Lett. 2008, 10, 2223–
2226. (b) Rolfe, A.; Young, K.; Hanson, P. R. Eur. J. Org. Chem. 2008,
5254–5262.
(12) Merten, S.; Fro¨hlich, R.; Kataeva, O.; Metz, P. AdV. Synth. Catal.
2005, 347, 754–758.
(13) Ueda, M.; Miyabe, H.; Nishimura, A.; Miyata, O.; Takemoto, Y.;
Naito, T. Org. Lett. 2003, 5, 3835–3838.
(14) Chiacchio, U.; Corsaro, A.; Gumina, G.; Pistara`, V.; Rescifina, A.;
Alessi, M.; Piperno, A.; Roeo, G.; Romeo, R. Tetrahedron 1997, 53, 13855–
13866.
(15) (a) Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M.
Tetrahedron Lett. 1999, 40, 4761–4764. (b) Hanessian, S.; Sailes, H.;
Therrien, E. Tetrahedron 2003, 59, 7047–7056.
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