The first examples of bridgehead bicyclic sultams [12]

Full text of DOI:10.1021/ja992161c

8126
J. Am. Chem. Soc. 1999, 121, 8126-8127
The First Examples of Bridgehead Bicyclic Sultams
Leo A. Paquette* and Silvana M. Leit
EVans Chemical Laboratories
The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed June 24, 1999
feature closely parallels the staggered conformation adopted by
The sulfonamide antibiotics hold the prestigious position of
being the first synthetic compounds to have had utility in human
therapy. These exciting developments spawned considerable
R-sulfonyl carbanions (see 5), where the lone pair orbital is
likewise gauche to the two oxygens that are engaged in contact
1
12-14
ion-pairing to the metal ion.
It is not clear, at this point, if
interest in their use in veterinary practice and in the preparation
of many hundreds of cyclic variants (i.e., sultams). In recent
changes in the orientation of the nitrogen lone pair relative to
the O-S-O internuclear angle will translate into altered reactiv-
ity. This intriguing structural question could be addressed by the
synthesis of small bridgehead sultams. Our expectations are that
such molecules will be very weak bases, comparable to aliphatic
congeners,15 and may exhibit a chemical robustness appreciably
greater than that of their carbonyl analogues. A direct synthetic
entry to title compounds offering the structural features given by
2
years, reagents containing the important sultam functionality as
a key structural feature have emerged. Representative examples
3
include Davis’s stereoselective oxidizing agent 1, the N-acyl and
N-enoyl derivatives of 10,2-camphorsultam (2) developed by
4
Oppolzer, and Differding’s saccharin-based electrophilic fluori-
nating agent 3.5
6-10 is recorded herein.
Despite the extent of attention accorded this class of com-
pounds, the literature holds no report of any small bridgehead
bicyclic sultam. The few carbonyl analogues (lactams) that are
The operational strategy was based on the expectation that the
6
7
known are highly prone to hydrolysis. The angle strain and
enforced torsional distortion, which combine to orient the
nonboned nitrogen lone pair orthogonal to the CdO π-bond and
inhibit resonance interaction, contribute to this uncharacteristic
reactivity. With amide resonance energy amounting to 16-22
five- and six-membered heterocyclic subunits would prove
amenable to generation by free radical cyclization (Scheme 1).
While 5-exo regioselectivity as in 11 is adopted with widespread
16
facility in many hexenyl systems, other observations suggested
17
that 12 should respond in parallel 6-exo fashion. Furthermore,
8
kcal/mol depending on structure and N-CdO overlap being
although displacement reactions on R-halosulfonyl compounds
9
subject to a cos θ relationship, it is obvious that energy costs
18
are generally not feasible for steric and stereoelectronic reasons,
rise steeply as resonance interaction is progressively curtailed in
lactams.
such compounds are amenable to efficient conversion into reactive
19
electrophilic radicals. Since R-sulfonyl radicals are not stabilized,
The corresponding situation in N,N-disubstituted sulfonamides
is much less clear. Their stabilization is derived quite differently.
A search of the Cambridge Crystallographic Data Base for this
compound class furnished more than 200 examples for which
20
they should be prone to rapid intramolecular cyclization.
Scheme 1
coordinates are available.10 Although the -SO
2 2
NR types ranged
from cyclic to cycloaromatic and from amide to amidine, with
resultant notable differences in the geometry at N,11 a decided
preference for orienting the nitrogen lone pair in the bisector of
the O-S-O internuclear angle as in 4 is seen. This structural
(
1) Bowman, W. C.; Rand, M. J. Textbook of Pharmacology, 2nd ed.;
Blackwell: London, 1979; Chapter 34.
2) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. ComprehensiVe
(
Heterocyclic Chemistry II; Elsevier: Oxford, 1996; Vols. 3 and 4.
(12) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277 and relevant
references therein.
(
(
(
3) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919.
4) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241; 1988, 60, 39.
5) (a) Differding, E.; Lang, R. W. HelV. Chim. Acta 1989, 72, 1248. (b)
(13) Raabe, G.; Gais, H.-J.; Fleischhauer, J. J. Am. Chem. Soc. 1996, 118,
4622 and earlier reports by the Gais group.
Differding, E.; R u¨ egg, G. M.; Lang, R. W. Tetrahedron 1991, 32, 1779.
(14) Terrier, F.; Kizilian, E.; Goumont, R.; Faucher, N.; Wakselman, C. J.
Am. Chem. Soc. 1998, 120, 9496.
(
6) (a) Yakhontov, L. N.; Rubtsov, M. V. J. Gen. Chem. USSR (Engl.
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Acta 1987, 70, 1981.
(15) (a) Laughlin, R. G. J. Am. Chem. Soc. 1967, 89, 4268. (b) Olavi, P.;
Virtanen, I.; Maikkula, M. Tetrahedron Lett. 1968, 4855.
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therein.
(17) (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (b) Giese, B.
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon: New York, 1986. (c) Ramaiah, M. Tetrahedron 1987, 43, 3541.
(d) Curran, D. P. Synthesis 1988, 417, 489. (e) Giese, B.; Kopping, B.; G o¨ bel,
T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48,
301. (f) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1996.
(
7) (a) Blackburn, G. M.; Skaife, C. J.; Kay, I. T. J. Chem. Res., Miniprint
980, 3650. (b) Somayaji, V.; Brown, R. S. J. Org. Chem. 1986, 51, 2676.
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1
(
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(
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(
9) Streitwieser, A. Molecular Orbital Theory for Organic Chemists;
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(10) For a comparable search conducted some time ago, consult: Beddoes,
R. L.; Dalton, L.; Joule, J. A.; Mills, O. S.; Street, J. D.; Watt, C. I. F. J.
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(18) (a) Paquette, L. A. Org. React. 1977, 25, 1. (b) Shorter, J. In The
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1
0.1021/ja992161c CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 35, 1999 8127
Table 1. Products of Free Radical Cyclization of
Scheme 2
a,b
Halomethylsulfonamides
A salient feature of the present plan is the ready availability
2
1
22
of ClCH
trithiane under aqueous conditions. Admixture of these reagents
with diallylamine in CH Cl containing H u¨ nig’s base and DMAP
generated 13a and 13b, respectively (Scheme 2). Subjection of
2 2 2 2
SO Cl and BrCH SO Br by halogenation of s-
2
2
a
3 6 6
Reaction conditions: Bu SnH, AIBN, C H , 60 °C, syringe pump.
b
4 to Mitsunobu alkylation23 involving terminal alkenols led in
All compounds exhibited spectra fully compatible with the indicated
1
24
assignment.
high yield to 15a-c. Comparable treatment of the known 16
with 3-buten-1-ol provided 17. Ring-closing metathesis25 of all
the doubly unsaturated sulfonamides proceeded smoothly and
efficiently in the presence of the Grubbs catalyst26 to give 18
and 19.
of affairs is manifested with 18 and 19d, which undergo ring
closure to give 10 and 7, respectively, in preparatively attractive
yields. The drop-off in ring-forming efficiency observed for 8
was not entirely expected. The prominent workability of the 6-exo
pathway involving 12 could represent a useful feasibility calibra-
tion point.
The crystal structure of the smallest bicyclic sultam available
to us has been determined by single-crystal diffraction analysis.
Several features of this molecule are of interest. The cyclohexane
substructure is not impeded by the sulfonyl group from adopting
a chairlike conformation. Also, the exo and endo orientations of
the two oxygens are well defined. More significantly, although
the N lone pair electrons on the bridgehead nitrogen cannot be
located exactly, proper approximations indicate them to be
projected in a plane that bisects the O-S-O angle into very
uneven sectors. The values are -90° and 40°. Thus, the geometry
inherent to 6 results in a significant distortion away from the
equilibrium state represented by 4.
While the heating of 19a with tri-n-butyltin hydride (1.2 equiv)
and AIBN (0.07 equiv) in benzene under syringe pump conditions
resulted simply in reductive dehalogenation (Table 1), more
fruitful results emerged from the comparable handling of the
higher homologues 18 and 19c-e. The elevated strain energy
resident in bridgehead sultam 21 was expected to deter the ring
closure step leading to its formation. Indeed, none of this product
was seen. In the case of 19c, cyclization begins to exhibit the
capacity to compete at a reasonable level with reduction.
Interestingly, both the [3.2.1] and [2.2.2] bicyclic sultams are
generated, the latter product stemming from 6-endo C-C bond
formation. Their relative ratio is 2.2:1. The most favorable state
(
19) Block, E. Reactions of Organosulfur Compounds; Academic Press:
New York, 1978.
20) (a) Oku, M.; Philips, J. C. J. Am. Chem. Soc. 1973, 95, 6495. (b)
(
Nevertheless, all five members of the homologous set are white,
hydrolytically stable crystalline solids, readily amenable to
chromatographic purification27 and long-term storage in the
atmosphere. Clearly, structural enforcement of less than ideal
electronic interactions in these sultams is not being reflected in
hyperreactivity.
Ueno, Y.; Khare, R. K.; Okawara, M. J. Chem. Soc., Perkin Trans. 1 1983,
2
637. (c) Clive, D. L. J.; Boivin, T. L. B.; Angoh, A. G. J. Org. Chem. 1987,
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5
Chanon, M. Tetrahedron 1988, 44, 2925. (e) Clive, D. L. J.; Boivin, T. L. B.
J. Org. Chem. 1989, 54, 1997. (f) Reutrakul, V.; Poolsanong, C.; Pohmakotr,
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Chem., Int. Ed. Engl. 1990, 29, 433. (h) Singleton, D. A.; Church, K. M. J.
Org. Chem. 1990, 55, 4780. (i) Renaud, P. Tetrahedron Lett. 1990, 31, 4601.
(
j) Tsai, Y.-M.; Ke, B.-W.; Lin, C.-H. Tetrahedron Lett. 1990, 31, 6047. (k)
Tsai, Y.-M.; Ke, B.-W.; Yang, C.-T.; Lin, C.-H. Tetrahedron Lett. 1992, 33,
895. (l) Mahadevan, A.; Fuchs, P. L. J. Am. Chem. Soc. 1995, 117, 3272.
Acknowledgment. Financial support was provided by Hoechst Marion
Roussel and the Paquette Research Fund. S.M.L. thanks the Universidad
de Buenos Aires, Argentina, for the award of a Ren e´ Thalmann
postdoctoral fellowship. We also acknowledge Dr. Judith Gallucci for
carrying out the X-ray crystallographic analysis.
7
(
m) Ke, B.-W.; Lin, C.-H.; Tsai, Y.-M. Tetrahedron 1997, 53, 7805. (n)
Imboden, C.; Bourquard, T.; Corminboeuf, O.; Renaud, P.; Schenk, K.;
Zahouily, M. Tetrahedron Lett. 1999, 40, 495.
(
21) Paquette, L. A.; Wittenbrook, L. S. Org. Synth. 1969, 49, 18.
22) Block, E.; Aslam, M. Organic Syntheses; Wiley: New York, 1993;
(
Supporting Information Available: Crystallographic experimental
details for 6, including tables of bond lengths, bond angles, atomic
coordinates, and isotropic/anisotropic displacement parameters (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Collect. Vol. VIII, p 212.
(
23) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React.
1
992, 42, 335.
(
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(
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A. Tetrahedron 1998, 54, 14869. (b) Hanson, P. R.; Probst, D. A.; Robinson,
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JA992161C
(
26) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
(27) The separation of 9 from 6 is challenging because of its relative
percentage in the mixture and the closely similar R values.
f
4
46. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.