Synthesis of sultam scaffolds via intramolecular oxa-michael and diastereoselective baylis-hillman reactions

Article abstract of DOI:10.1021/ol8009072

(Chemical Equation Presented) A divergent synthetic approach to new sultams utilizing intramolecular oxa-Michael and Baylis-Hillman reactions of readily prepared vinyl sulfonamides and suitably protected amino alcohols, is reported. A variety of seven- an

Full text of DOI:10.1021/ol8009072

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2951-2954
Synthesis of Sultam Scaffolds via
Intramolecular Oxa-Michael and
Diastereoselective Baylis-Hillman
Reactions
Aihua Zhou and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, Lawrence,
Kansas 66045-7582, and the Center for Chemical Methodologies and Library
DeVelopment (CMLD) at the UniVersity of Kansas
phanson@ku.edu
Received April 19, 2008
ABSTRACT
A divergent synthetic approach to new sultams utilizing intramolecular oxa-Michael and Baylis-Hillman reactions of readily prepared vinyl
sulfonamides and suitably protected amino alcohols, is reported. A variety of seven- and eight-membered ring sultam scaffolds were synthesized
using oxa-Michael pathways, whereas both five- and six-membered rings were synthesized using Baylis-Hillman methods. Baylis-Hillman
reactions proceed with good to excellent levels of diastereoselectivity, and oxa-Michael reactions leading to eight-membered ring sultams
provide empirical evidence validating 8-endo-trig cyclization pathways.
Sulfonamides and their analogs have a rich chemical and
biological history and have emerged as a promising class of
compounds in drug discovery.1 Sultams (cyclic sulfona-
mides), although not found in nature, have also shown potent
biological activity, including several displaying a wide
spectrum of activities.2 The more prominent include the
antiepileptic agent Sulthiame3 (Figure 1), Brinzolamide4 for
the treatment of glaucoma, the COX-2 inhibitors Ampiroxi-
cam5 and S-2474,6 and selective inhibitors of cysteine
proteases involved in the progression of malaria.7 In addition,
a number of benzodithiazine dioxides and benzoxathiazepine
1,1-dioxides displaying anti-HIV-1 activity8 and the ability
to activate glucokinase9 (type II diabetes), respectively, have
been uncovered.
Traditionally, sultam syntheses have relied on classical
cyclization protocols and a number of transition-metal-
(2) (a) Silvestri, R.; Marfe`, G.; Artico, M.; La Regina, G.; Lavecchia,
A.; Novellino, E.; Morgante, M.; Di Stefano, C.; Catalano, G.; Filomeni,
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La Torre, F.; Salimei, P. S. J. Med. Chem. 2006, 49, 5840–5844. (b)
Lebegue, N.; Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard, P.;
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7363–7373.
(3) Tanimukai, H.; Inui, M.; Hariguchi, S.; Kaneko, Z. Biochem.
Pharmacol. 1965, 14, 961–970.
(1) (a) Drews, J. Science 2000, 287, 1960–1964. (b) Scozzafava, A.;
Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003, 10,
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10.1021/ol8009072 CCC: $40.75
Published on Web 06/14/2008
2008 American Chemical Society

reaction have only recently gained favor,13 where elegant
work in this area has elevated the status of the intramolecular
variant.15 Although the Michael accepting ability of vinyl
sulfones is well-documented,16 their vinyl sulfonamide
counterparts have assumed a far less prominent role as viable
Michael acceptors.10,17 We herein report the first examples
of intramolecular oxa-Michael and Baylis-Hillman reactions
of vinyl sulfonamides to afford an array of novel five-, six-,
seven-, and eight-membered ring sultam scaffolds in good
to excellent yields. The Baylis-Hillman reactions proceed
with good to excellent levels of diastereoselectivity, ulti-
mately yielding interesting sultam scaffolds. Overall, this
divergent route can be used to produce skeletally diverse
scaffolds from a single percursor in excellent yields.
Scheme 1. Synthesis of Seven- and Eight-Membered Ring
Sultams via Intramolecular Oxa-Michael Reactions
Figure 1. Biologically active sultams.
catalyzed processes that have recently been reported.10
Interest in the generation of new sultams for biological
screening has provided impetus for exploring the Michael-
accepting ability of vinyl sulfonamides. In particular, we
aimed to study the titled intramolecular oxa-Michael and
Baylis-Hillman approaches for the synthesis of chiral,
nonracemic sultams.
The oxa-Michael11 and Baylis-Hillman12,13 reactions have
emerged as simple yet powerful methods for C-O and C-C
bond formation. Both processes necessitate the presence of
a competent electron-deficient Michael accepting moiety. The
intermolecular oxa-Michael reaction has a long history dating
back to its original discovery in 1878, roughly 5 years before
the well-known Michael reaction was revealed.11 The in-
tramolecular version of the oxa-Michael reaction has seen a
renaissance and has been extensively utilized in natural
product synthesis for over 2 decades.14
The titled route began with the assembly of TBS-protected
amino alcohols, which represent cheap and versatile building
blocks for sultam scaffold synthesis. These TBS-protected
alcohols were reacted with 2-chloroethanesulfonyl chloride
to produce vinyl sulfonamides 2 in good yields (Scheme 1).
Subsequent benzylation/allylation reactions of vinyl sulfona-
(14) (a) See ref 11c and references therein. (b) Nicolaou, K. C.; Hwang,
C.-K.; Duggan, M. E. J. Am. Chem. Soc. 1989, 111, 6682–6690. (c) Evans,
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(f) Chandrasekhar, S.; Rambabu, C.; Shyamsunder, T. Tetrahedron Lett.
2007, 48, 4683–4685.
In contrast, the Baylis-Hillman reaction was discovered
in 1972.12 Intramolecular versions of the Baylis-Hillman
(6) Inagaki, M.; Tsuri, T.; Jyoyama, H.; Ono, T.; Yamada, K.;
Kobayashi, M.; Hori, Y.; Arimura, A.; Yasui, K.; Ohno, K.; Kakudo, S.;
Koizumi, K.; Suzuki, R.; Kato, M.; Kawai, S.; Matsumoto, S. J. Med. Chem.
2000, 43, 2040–2048.
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1048. (b) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 2402–2403. (c) Frank, S. A.; Mergott,
D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404–2405. (d) Keck,
G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687–3690. (e) Huddleston, R. R.;
Krische, M. J. Synlett. 2003, 12–21. (f) Reddy, L. R.; Saravanan, P.; Corey,
E. J. J. Am. Chem. Soc. 2004, 126, 6230–6231. (g) Yeo, J. E.; Yang, X.;
Kim, H. J.; Koo, S. Chem. Commun. 2004, 236–237. (h) Aroyan, C. E.;
Vasbinder, M. M.; Miller, S. J. Org. Lett. 2005, 7, 3849–3851. (i) Shi, M.;
Chen, L. H.; Li, C. Q. J. Am. Chem. Soc. 2005, 127, 3790–3800. (j) Krafft,
M. E.; Haxell, T. F. N.; Seibert, K. A.; Abboud, K. A. J. Am. Chem. Soc.
2006, 128, 4174–4175. (k) Teng, W.-D.; Huang, R.; Kwong, C. K.-W.;
Shi, M.; Toy, P. H. J. Org. Chem. 2006, 71, 368–371. (l) Nakano, A.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357–5360.
(16) (a) Truce, W. E.; Wellisch, E. J. Am. Chem. Soc. 1952, 74, 2881–
2884. (b) Luis, A.-L.; Krische, M. J. Synthesis 2004, 2579–2585. (c)
Meadows, D. C.; Gervay-Hague, J. Med. Res. ReV. 2006, 26, 793–814. (d)
Oh, K. Org. Lett. 2007, 9, 2973–2975. (e) Esteves, A. P.; Silva, M. E.;
Rodrigues, L. M.; Oliveira-Campos, A. M. F.; Hrdina, R. Tetrahedron Lett.
2007, 48, 9040–9043. (f) Das, I.; Pal, T. K.; Pathak, T. J. Org. Chem. 2007,
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(7) Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gut, J.; Rosental,
P. J. Biorg. Med. Chem. Lett. 2006, 16, 4115–4119.
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(10) For an extensive list of both classical and transition-metal-catalyzed
cyclization reactions, see: Jime´nez-Hopkins, M.; Hanson, P. R. Org. Lett.
2008, 10, 2223–2226.
(11) (a) Loydl, F. Justus Liebigs Ann. C 1878, 192, 80–89. (b) Berkessel,
A. Methods of Organic Chemistry (Hueben-Weyl), 4th ed.; G. Thieme:
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Org. Lett., Vol. 10, No. 14, 2008

mides 2 yielded vinyl sulfonamides 3 in good yields over
three steps. The intramolecular oxa-Michael reaction was
initiated by TBS-deprotection with TBAF in THF to afford
the unique seven- and eight-membered ring sultams, respec-
tively, in excellent yield under mild condition.
Table 2. Intramolecular Baylis-Hillman Reactions
Several examples of this straighforward procedure were
examined as outlined in Table 1. In all cases the cyclization
entry product
R1
i-Pr
i-Bu
i-Bu
R2
yielda (%) dr (5/6)
Table 1. Synthesis of Seven- and Eight-Membered Ring
Sultams via Intramolecular Oxa-Michael Reactions
1
2
3
4
5
6
5a/6a
5b/6b
5c/6c
5d/6d
5e/6e
5f/6f
CH2CHdCH2
CH2Ph(o-Br)
CH2CHdCH2
69
71
67
69
72
71
63:37
62:38
76:24
77:23
88:12
90:10
CH2Ph CH2CCH
CH2Ph CH2Ph(o-Br)
CH2Ph CH2Ph
a Yield of three steps.
entry product
n
R1
i-Pr
R2
total yielda (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
1
1
2
1
2
1
1
CH2CHdCH2
61
60
54
production of the bicyclic sultam 8 in excellent yields via
an oxa-Michael pathway (Scheme 2). In contrast, treatment
CH2Ph CH2Ph(o-Br)
CH2CHdCH2
CH2Ph CH2Ph(o-Me)
H
59b
53b
58b
61b
H
i-Bu
i-Bu
CH2Ph(o-F)
CH2Ph(m-Cl)
CH2Ph
Scheme 2. Synthesis of Bicyclic Sultam Scaffold
4g
a Total yield of all four steps. b Sultams 4d-g were synthesized through
chromatography-free linear synthesis; see Supporting Information for
reaction procedure.
proceeded without incident. In several cases, the entire linear
sequence could be run without the need for chromatography,
ultimately resulting in the production of oxathiazepine- and
oxathiazocine-dioxides, seven- and eight-membered ring
systems, in excellent yields, respectively. To the best of our
knowledge, this work represents the first report of using
intramolecular oxa-Michael reactions to generate an eight-
membered ring and enriches Baldwin’s rules for ring
closure.18
An orthogonal pathway leading to an intramolecular
Baylis-Hillman reaction was next investigated. We observed
that the intramolecular oxa-Michael reaction pathway was
not operative under acidic conditions, and thus, a 10 mol %
aqueous solution of HCl was implemented for TBS-depro-
tection of vinylsulfonamide 3. Subsequent Dess-Martin
oxidation yielded the aldehyde vinyl sulfonamide, which
underwent smooth Baylis-Hillman reaction upon the addi-
tion of DABCO (10 mol %). Overall, the intramolecular
Baylis-Hillman reaction was completed within 2-4 h,
affording the vinyl sultam 5 in excellent yields and with
moderate to good levels of diastereoselectivity (Table 2).
Several other organocatalysts such as DMAP, DBU, quinine,
quinidine, and brucine were also screened in this process.
Overall, DABCO proved to be the most efficient for both
yield and competitive diastereoselectivity.19,20
of 7 with the aforementioned orthogonal conditions involving
acidic deprotection, oxidation, and addition of DABCO
yielded the bicyclic sultam 10 with good yield and excellent
diastereoselective ratio.
The method was extended to the readily prepared second-
ary alcohol, TBS-protected trans-2-amino-cyclohexanol
(Scheme 3). Vinylsulfonylation and benzylation yielded the
vinyl sulfonamide 12 in excellent yields. Treatment with
TBAF yielded the bicyclic sultam 13 in excellent yield via
an oxa-Michael pathway, and treatment with the orthogonal
Baylis-Hillman conditions yielded the unique bicyclic vinyl
sultam 15 in modest yield and extended reaction time (53%,
72 h) yet with excellent diastereoselectivity (dr > 95:5).
We next investigated the feasibility of extending the
method to the generation of δ-sultams (Scheme 4). To
address this question, chiral, nonracemic amino TBS-
protected alcohol 16 was synthesized starting from (S)-
glycidyl trityl ether.21 Subsequent TBS-protection and vi-
nylsulfonylation with 2-chloroethanesulfonyl chloride af-
The TBS-protected prolinol-derived vinyl sulfonamide 7
was next studied where treatment with TBAF resulted in the
(19) The stereochemistry of major product 5 was determined by 1D-
NOE and NOESY experiments; see Supporting Information.
(18) Although Baldwin defined 7-endo-trig as favorable, 8-endo-trig
pathways were not defined; see: Baldwin, J. E. J. Chem. Soc., Chem.
Commun. 1976, 73, 4–736.
(20) To the best of our knowledge, this work represents the first report
of using an intramolecular Baylis-Hillman reaction to generate a sultam.
Org. Lett., Vol. 10, No. 14, 2008
2953

Scheme 3
.
Baylis-Hillman Reaction via Keto Vinyl
Scheme 4. Highly Diastereoselective Intramolecular
Baylis-Hillman Reaction to Generate δ-Sultam
Sulfonamide
pleted within short order and occur with excellent yields. In
addition, good to excellent levels of diastereoselectivity were
achieved throughout the Baylis-Hillman study. Overall,
these two reactions can be conveniently combined into one
synthetic route to produce skeletally diverse scaffolds from
a single percursor in excellent yields. In addition, the method
is highly amenable to library generation and current efforts
are currently engaged in this endeavor.
forded vinyl sulfonamide 18. TBS-deprotection with TBAF
afforded the δ-sultam 19 in excellent yield via an intramo-
lecular oxa-Michael pathway. The Baylis-Hillman pathway
was initiated by use of a selective, orthogonal deprotection
of the trityl ether in 18 at -10 °C using Me2AlCl (CH2Cl2
solution) to yield vinylsulfonamide 20 in good yield. The
resulting alcohol was oxidized to aldehyde 21 using the
Dess-Martin agent as previously described. Treatment with
DABCO afforded the δ-sultam scaffold 22 in excellent yield
and diastereoselectivity (dr > 95:5).22 The intramolecular
oxa-Michael reaction of 20 was also pursued to afford the
eight-membered-ring sultam by using NaH in THF. This
reaction proceeded quickly and gave a high yield of the eight-
membered-ring sultam 23.
In summary, the first examples of intramolecular oxa-
Michael and Baylis-Hillman reactions to synthesize five-,
six-, seven-, and eight-membered ring sultams have been
attained. Moreover, empirical evidence validating 8-endo-
trig cyclization pathways in oxa-Michael reactions has been
presented that enriches Baldwin’s rules for ring closure. The
titled oxa-Michael and Baylis-Hillman reactions are com-
Acknowledgment. This investigation was generously
supported by funds provided by the National Institutes of
General Medical Sciences Center for Chemical Methodolo-
gies and Library Development at the University of Kansas
(P50 GM069663) and NIGMS Pilot-Scale Libraries Program
(NIH P41 GM076302). The authors thank Dr. David
VanderVelde (Director of the NMR Laboratory at The
University of Kansas) for helpful discussions regarding NMR
structure assignments. The authors also thank Daiso Co., Ltd.,
Fine Chemical Department for donation of trityl-protected
glycidol. (email: akkimura@daiso.co.jp).
Supporting Information Available: Experimental details
and spectral characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) Regioselective ring-opening of glycidyl trityl ether with isobuty-
lamine gave the amino alcohol 16 in excellent yield.
(22) Confirmed by 1H measurements in different NMR solvents; see
Supporting Information.
OL8009072
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Org. Lett., Vol. 10, No. 14, 2008