An RCM strategy to stereodiverse δ-sultam scaffolds

Article abstract of DOI:10.1021/ol800649n

(Chemicall Equation Presented) An asymmetric approach for the synthesis of substituted δ-sultams with multiple synthetic handles is described. This study demonstrates the facile construction of a stereochemically diverse array of substituted δ-sultams, more specifically substituted 3,4,5,6-dihydro 1,2-thiazine 1,1-dioxides. A pivotal Mitsunobu alkylation/RCM sequence is used to assemble key allyl sultam building blocks possessing a C3 stereogenic handle. All subsequent reactions are achieved with high levels of diastereoselectivity to afford enantiopure δ-sultams in good yields.

Full text of DOI:10.1021/ol800649n

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2223-2226
An RCM Strategy to Stereodiverse
δ-Sultam Scaffolds
María Jiménez-Hopkins and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, Lawrence,
Kansas 66045-7582, and Center for Chemical Methodologies and Library
DeVelopment, UniVersity of Kansas, Lawrence, Kansas 66045
phanson@ku.edu
Received March 20, 2008
ABSTRACT
An asymmetric approach for the synthesis of substituted δ-sultams with multiple synthetic handles is described. This study demonstrates the
facile construction of a stereochemically diverse array of substituted δ-sultams, more specifically substituted 3,4,5,6-dihydro 1,2-thiazine
1,1-dioxides. A pivotal Mitsunobu alkylation/RCM sequence is used to assemble key allyl sultam building blocks possessing a C3 stereogenic
handle. All subsequent reactions are achieved with high levels of diastereoselectivity to afford enantiopure δ-sultams in good yields.
Compounds containing the sulfonamide moiety have gained
wide popularity due to their extensive chemical and biologi-
cal profiles, making them promising candidates in drug
discovery.1 Sultams (cyclic sulfonamides), although not
found in nature,2 have also shown potent biological activity,
including several with medicinal value. A brief survey of
the literature reveals that there are more than 60 sultams with
impressive biological activity. The more prominent include
the antiepileptic agent sulthiame (1) (Figure 1),3 brinzolamide
(2)4 for the treatment of glaucoma, the COX-2 inhibitors
ampiroxicam (3)5 and S-2474 (4),6 novel benzodithiazine
dioxides with both antiviral and anticancer activities (5),7a
selective inhibitors of calpain I (6),7b and most recently
pyrrolo[1,2-b][1,2,5]benzothiadiazepines,8 a new class of
(1) (a) Drews, J. Science 2000, 287, 1960–1964. (b) Scozzafava, A.;
Figure 1. Biologically active sultams.
Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003, 10,
925–953.
(2) Hanessian, S.; Sailes, H.; Therrien, E. Tetrahedron 2003, 59, 7047–
7056.
potential agents for treatment against chronic myelogenous
leukemia. In addition, this impressive biological profile is
augmented by a number of chemical properties including
facile coupling pathways for their formation, stability to
(3) Tanimukai, H.; Inui, M.; Harigushi, S.; Kaneko, J. Biochem.
Pharmacol. 1965, 14, 961–970.
(4) Wroblewski, T.; Graul, A.; Castaner, J. Drugs Future 1998, 23, 365–
369.
(5) Rabasseda, X.; Hopkins, S. J. Drugs Today 1994, 30, 557–563.
(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.; Kawai, S.; Kato, M.; Matsumoto, S. J. Med. Chem.
2000, 43, 2040–2048.
(7) (a) Brzozowski, Z.; Saczewski, F.; Neamati, N. Bioorg. Med. Chem.
Lett. 2006, 16, 5298–5302. (b) Wells, G. J.; Tao, M.; Josef, K. A.; Bihovsky,
R. J. Med. Chem. 2001, 44, 3488–3503.
10.1021/ol800649n CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society

hydrolysis, polarity, and their crystalline nature. Taken
collectively, these attributes have allowed sultams to emerge
as privileged structures in drug discovery.
sultam building blocks 13 and 15. All subsequent reactions
leading to more complex building blocks are achieved with
high levels of diastereoselectivity to afford enantiopure
δ-sultams in good yields (Schemes 2–5).
Traditionally, sultam synthesis has relied on classical
cyclization protocols such as Pictet-Spengler,8 Friedel-
Crafts,9 dianion,10 cyclization of aminosulfonyl chlorides,11
[3 + 2] cycloadditions,12 and Diels-Alder reactions.13
Recently, however, a number of transition-metal-catalyzed
approaches to sultams have come to light, including the use
of Pd-,14 Au-,15 Cu-,16 and Rh-catalyzed cyclizations.17
Moreover, RCM has been reported to generate several
interesting sulfur-containing heterocycles with biological
potential.2,18 Our continuous interest in the development of
transition-metal-catalyzed approaches to sulfur and phos-
phorus heterocycles (S- and P-heterocycles)18 has prompt
us to investigate an RCM approach for the synthesis of chiral,
nonracemic sultams. The method is designed to afford
sultams containing multiple handles as attractive scaffolds
for potential library production with the ultimate goal of
Our approach began with the multigram production of
allylsulfonyl chloride (7).19 Subsequent amination with anhy-
drous NH3, following the procedure reported by Belous and
co-workers, afforded sulfonamide 8 in good yields.19 Mono-
protection with Boc2O20 afforded sulfonamide 9 (93%), pos-
sessing an acidic proton (N-H) suitable for Mitsunobu alky-
lation (Scheme 1). Mitsunobu reaction with chiral, nonracemic
alcohol 11, derived from epoxide 10 using the Christie proto-
col,21 afforded the RCM precursor 12 in good yield (78%).
Initial attempts to obtain 13 via RCM using the second-
generation Grubbs catalyst22 in refluxing CH2Cl2 or DCE were
unsuccessful. Subsequent RCM studies revealed that 13 could
be obtained in good yield when toluene was used as the solvent
under refluxing conditions. Alternatively, Boc-removal in diene
12 using TFA, followed by RCM in refluxing CH2Cl2, afforded
the δ-sultam 15 in excellent yield.23
Scheme 1. RCM Strategy to Sultams 13 and 15
Scheme 2. Facile Route to γ-Hydroxy Sultam 18
The diastereoselective route to the desired δ-sultam 18
continued with dihydroxylation of cyclized products 13 and
15 (Scheme 2). When sultam 15 (R ) H) was first subjected
uncovering interesting biological leads. The method we
herein report utilizes a key Mitsunobu alkylation reaction to
install a stereogenic center at C3 (Scheme 1). Ensuing
metathesis is used as the cyclization event to yield key allyl
(14) (a) Merten, S.; Fro¨hlich, R.; Kataeva, O. AdV. Synth. Catal. 2005,
347, 754–758. (b) Vasudevan, A.; Tseng, P-S.; Djuric, S. W. Tetrahedron
Lett. 2006, 47, 8591–8593.
(8) Silvestri, R.; Marfe`, G.; Artico, M.; La Regina, G.; Lavecchia, A.;
Novellino, E.; Morgante, M.; Di Stefano, C.; Catalano, G.; Filomeni, G.;
Abruzzese, E.; Ciriolo, M. R.; Russo, M. A.; Amadori, S.; Cirilli, R.; La
Torre, F.; Salimei, P. S. J. Med. Chem. 2006, 49, 5840–5844.
(9) (a) Bravo, R. D.; Ca´nepa, A. S. Synth. Commun. 2002, 32, 3675–
3680. (b) Orazi, O. O.; Corral, R. A.; Bravo, R. J. Heterocycl. Chem. 1986,
23, 1701–1708. (c) Katritzky, A. R.; Wu, J.; Rachwal, S.; Rachwal, B.;
Macomber, D. W.; Smith, T. P. Org. Prep. Proced. Int. 1992, 24, 463–467.
(10) Lee, J.; Zhong, Y.-L.; Reamer, R. A.; Askin, D. Org. Lett. 2003,
5, 4175–4177.
(15) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707–2710.
(16) (a) Dauban, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327–2329. (b)
Dauban, P.; Sanie`re, L.; Aure´lie, T.; Dodd, R. H. J. Am. Chem. Soc. 2001,
123, 7707–7708. (c) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits,
O. Org. Lett. 2004, 6, 1573–1575. (d) Zeng, W.; Chemler, S. R. J. Am.
Chem. Soc. 2007, 129, 12948–12949.
(17) (a) Liang, J.-L.; Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Org.
Lett. 2002, 4, 4507–4510. (b) Padwa, A.; Flick, A. C.; Leverett, C. A.;
Stengel, T. J. Org. Chem. 2004, 69, 6377–6386.
(18) (a) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem.
ReV. 2004, 104, 2239–2258. (b) Moriggi, J.-M.; Brown, L. J.; Castro, J. L.;
Brown, R. C. D. Org. Biomol. Chem. 2004, 2, 835–844. (c) Freitag, D.;
Schwab, P.; Metz, P. Tetrahedron Lett. 2004, 45, 3589–3592. (d) Karsch,
S.; Freitag, D.; Schwab, P.; Metz, P. Synthesis 2004, 10, 1696–1712.
(19) Belous, M. A.; Postovsky, I. Y. J. Gen. Chem. USSR 1950, 20,
1761–1770.
(11) Enders, D.; Moll, A.; Bats, J. W. Eur. J. Org. Chem. 2006, 1271–
1274.
(12) Chiacchio, U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.; Grassi,
G.; Piperno, A. Tetrahedron 2001, 57, 3425–3433.
(13) (a) Metz, P.; Seng, D.; Fro¨hlich, R. Synlett 1996, 741–742. (b)
Plietker, B.; Seng, D.; Fro¨hlich, R.; Metz, P. Tetrahedron 2000, 56, 873–
879. (c) Rogatchov, V. O.; Bernsmann, H.; Schwab, P.; Fro¨hlich, R.;
Wibbeling, B.; Metz, P. Tetrahedron Lett. 2002, 43, 4753–4756. (d) Greig,
I. R.; Trozer, M. J.; Wright, P. T. Org. Lett. 2001, 3, 369–371. (e) Wanner,
J.; Harned, A. M.; Probst, D. A.; Poon, K. W. C.; Klein, T. A.; Snelgrove,
K. A.; Hanson, P. R. Tetrahedron Lett. 2002, 43, 917–921.
(20) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379–380.
(21) Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R. Tetrahedron
Lett. 2000, 41, 1255–1259.
(22) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
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Org. Lett., Vol. 10, No. 11, 2008

to dihydroxylation, an inseparable mixture of diastereomers
(dr ∼8:1) was obtained. However, dihydroxylation of the
Boc-protected sultam 13 resulted in the formation of cis-
diol 16 as a single diastereomer in excellent yield (96%).
This result further substantiates the aforementioned A1,2
effects,23 which presumably force the CH2OBn group at C3
into an axial orientation, thus accentuating dihydroxylation
from the opposite face. The relative stereochemistry of 16
was confirmed by X-ray crystallography (see the Supporting
Information). Conversion of this diol to the respective
carbonate was achieved using triphosgene,24,25 followed by
base-promoted elimination with Et3N25 under refluxing DCM
to afford the γ-hydroxy vinyl δ-sultam 18 in 91% yield. This
protocol was previously shown in our laboratory to be
applicable to the synthesis of phosphono sugars.25 Attempted
functionalization of the C4 hydroxyl group in sultam 18 using
various inorganic bases such as NaH, Cs2CO3, or K2CO3
resulted in an unexpected intramolecular Boc-migration onto
the γ-hydroxy group, providing δ-sultam 19 in good to
excellent yields (Scheme 2). Schreiber and co-workers have
previously reported an analogous Boc group migration
event.26 Treatment of sultam 18 with TFA in CH2Cl2 resulted
in Boc removal to afford the γ-hydroxy vinyl δ-sultam 20
as a crystalline solid in 91% yield.
in Scheme 3. Mitsunobu reaction with p-nitrophenol afforded
allylic ether 21 in moderate yields. Attempts to perform the
Mitsunobu reaction with phenol or substituted phenols
containing electron-donating groups were unsuccessful. We
next focused on the addition of nucleophiles into 18.
Consequently, 18 was treated with Cl3CCN in the presence
of catalytic amounts of DBU in CH2Cl2 to afford trichloro-
acetimidate 22 in excellent yield (96%) via an intramolecular
Michael addition. Further treatment of 22 with TFA (CH2Cl2
at rt) afforded amino alcohol 23 in 97% yield (Scheme 3).
This concept was expanded to isocyanates in attempts to form
bicyclic sultams. Treatment of 18 with phenyl isocyanate
(PhNCO) and Et3N in CH2Cl2 at reflux afforded sultam 24
in good yield (64%) via conjugate addition (Scheme 3).
When isopropyl isocyanate (iPrNCO) was utilized under
identical conditions, prolonged reaction times were necessary
to obtain the cyclized product 25 in good yield (78%).
Intermolecular nucleophilic additions of thiols were next
explored. Previous work reported by Roush27 revealed that
vinyl sulfonamides are good Michael acceptors of sulfur
nucleophiles. Addition of PhSH to sultam 18 in the presence
of catalytic amounts of Et3N (CH2Cl2 at rt)28 afforded sultam
26 in good yield (84%) as a mixture of inseparable
diastereomers (dr ∼6:1) as determined by 1H NMR. Addition
of PhCH2SH under identical reaction conditions afforded
sultam 27 in quantitative yield as a separable mixture of
diastereomers with improved diastereoselectivity (dr ∼10:
1). Addition of butanethiol resulted in the formation of sultam
28 in 88% yield as a mixture of inseparable diastereomers
(dr ∼4.5:1). The addition of 2-methyl-propane-2-thiol
[(CH3)3CSH] under the same reaction conditions failed to
produce the Michael adduct, presumably due to steric factors.
Scheme 3. Diversification of Sultam 18
Scheme 4. Diastereoselective Phosphate Displacement
With the desired scaffold 18 in hand, we turned our
attention to an array of diversification reactions highlighted
(23) These results indicated that A1,2-strain between the vicinally
substituted Boc-group at N2 and the CH2OBn group at C3 presumably force
the two terminal olefins to orient in opposite directions, thus requiring higher
temperatures for cyclization.
Interest in potential diversification at the R-position of
sultam 18 led us to explore installation of alkyl groups with
the ultimate goal of incorporating different functional groups
throughout the periphery of the ring. In order to accomplish
this, we explored the use of an SN2′ cuprate displacement
of the corresponding phosphate.29 Thus, treatment of 18 with
(MeO)2P(O)Cl in the presence of N-methylimidazole in
(24) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.; Guntupalli,
P.; Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2003, 125, 15443–15454
.
(25) (a) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2001, 3, 3285–3288.
(b) Stoianova, D. S.; Whitehead, A.; Hanson, P. R. J. Org. Chem. 2005,
70, 5880–5889.
(26) (a) Valentekovich, R. J.; Screiber, S. L. J. Am. Chem. Soc. 1995,
117, 9069–9070. For other examples, see: (b) Bew, S. P.; Bull, S. D.; Davies,
S. G. Tetrahedron Lett. 2000, 41, 7577–7581. (c) Branch, L.; Norrby, P.-
O.; Frydenvag, K.; Krogsgaard-Larsen, P.; Madsen, U. Org. Lett. 2001, 3,
433–435.
(27) Reddick, J. J.; Cheng, J.; Roush, W. R Org. Lett. 2003, 5, 1967–
1970.
(28) Isaksson, D.; Sjo¨din, K.; Ho¨gberg, H.-E. Tetrahedron: Asymmetry
2006, 17, 275–280.
Org. Lett., Vol. 10, No. 11, 2008
2225

CH2Cl2 at 0 °C afforded allylic phosphate 29 in excellent
yield (97%) (Scheme 4).30 Subjection of allylic phosphate
29 to conjugate addition via ethyl cuprate formation under
Knochel’s conditions31 was performed by adding an excess
of diethylzinc cuprate to provide sultam 30 in good yield
(74%) and excellent regio- and diastereoselectivity. The 3,6-
disubstituted δ-sultam 30 was tentatively assigned as the
diastereomer arising from anti addition in accordance with
the Corey mechanism.29b,c This product was further dihy-
droxylated under Os-mediated conditions to afford cis-diol
31 as a single diastereomer in good yield (79%).
The RCM strategy utilized for the facile assembly of δ-
sultam scaffolds prompted our efforts into extending this
methodology for the construction of 7-membered vinylic
sultams as outlined in Scheme 6. Thus, treatment of
styrylsulfonyl chloride33 35 with NH4OH, followed by slow
addition of Boc2O,20 afforded Boc-protected styrylsulfona-
mide 36 in high yield (94%). Mitsunobu alkylation with
chiral, nonracemic alcohol 3734 afforded diene 38 in 82%
yield. Removal of the Boc-group utilizing TFA in CH2Cl2
at rt provided sulfonamide 39 in quantitative yield. RCM in
refluxing DCE afforded the seven-membered ring vinylic
sultam 40 in 86% yield.
Scheme 5. Unexpected Internal SN2 Displacement Pathway
Scheme 6. RCM Strategy to Seven-Membered Sultam 40
A diversification/cuprate addition strategy was next ex-
plored. This approach involved deprotection via removal of
the N-Boc group, followed by benzylation at the free N-H
site to generate sultam 33 (Scheme 5). Initial attempts to
remove the Boc group in sultam 29 using TFA in CH2Cl2
resulted in hydrolysis of the phosphate moiety. Milder
reaction conditions were then studied and revealed that
In conclusion, we have demonstrated a new method to
synthesize a stereochemically diverse array of substituted 1,2-
thiazine 1,1-dioxides. These scaffolds represent novel sul-
tams, which can be utilized in the production of versatile
and novel libraries. These studies are underway and will be
reported in due course.
32
treatment of sultam 29 with 1.0-1.5 equiv of FeCl3
(CH2Cl2, rt, 30 min) afforded, after aqueous workup, sultam
32 in 60% yield. Introduction of an alkyl group at the
nitrogen was sought via benzylation under basic conditions
(BnBr, Cs2CO3, THF, 65 °C) to obtain benzyl sultam 33.
However, a product lacking both phosphate and benzyl
moieties was isolated and later confirmed as aziridine 34.
This unexpected product is presumably the result of direct
internal nucleophilic displacement of the C(4)-substituted
phosphate. Additional studies concerning this internal SN2
displacement pathway are underway.
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, Minority Supplement, M.J.-H.). We thank
Dr. Victor Day of the Molecular Structure Group (MSG) at
the University of Kansas for X-ray analysis. We kindly
acknowledge Materia, Inc., for supplying metathesis catalyst
and Daiso Co., Ltd., Fine Chemical Department for donation
of benzyl-protected glycidol (e-mail: akkimura@daiso.co.jp).
(29) (a) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H.
Synlett 1991, 251–253. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett.
1984, 25, 3063–3066. (c) Whitehead, A.; McParland, J. P.; Hanson, P. R
Org. Lett. 2006, 8, 5025–5028, and references cited therein.
(30) (a) Xu, Y.; Quian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich,
G. D. Tetrahedron 2004, 60, 43–49.
Supporting Information Available: Experimental details
and spectroscopic data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800649N
(31) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059–
1061.
(32) (a) Posp´ısil, J.; Marko´, I. E. J. Am. Chem. Soc. 2007, 129, 3516–
3517. (b) Padro´n, J. I.; Va´zquez, J. T. Tetrahdron: Asymmetry 1995, 6,
857–858.
(33) Culbertson, B. M.; Dietz, S. J. Chem. Soc. C 1968, 992–993.
(34) Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.; Schoemaker,
H. E. Synlett 1998, 192–194.
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