Synthesis of substituted piperidines, indolizidines, quinolizidines, and pyrrolizidines via a cycloaddition strategy using acetylenic sulfones as alkene dipole equivalents

Article abstract of DOI:10.1021/ol990592u

(equation presented) The conjugate additions of β- and γ-chloroamines to acetylenic sulfones afford enamine sulfones, which then undergo intramolecular alkylation to produce the corresponding cyclic enamines. This provides a convenient route to substitute

Full text of DOI:10.1021/ol990592u

ORGANIC
LETTERS
1999
Vol. 1, No. 2
261-263
Synthesis of Substituted Piperidines,
Indolizidines, Quinolizidines, and
Pyrrolizidines via a Cycloaddition
Strategy Using Acetylenic Sulfones as
Alkene Dipole Equivalents
,†
Thomas G. Back* and Katsumasa Nakajima
Department of Chemistry, UniVersity of Calgary, Calgary, Alberta, Canada T2N 1N4
tgback@ucalgary.ca
Received April 14, 1999
ABSTRACT
The conjugate additions of â- and γ-chloroamines to acetylenic sulfones afford enamine sulfones, which then undergo intramolecular alkylation
to produce the corresponding cyclic enamines. This provides a convenient route to substituted piperidines, indolizidines, quinolizidines, and
pyrrolizidines. The enantioselective total synthesis of the alkaloid (−)-indolizidine 167B (also named gephyrotoxin 167B) was thus achieved by
the cycloaddition of (S)-2-(2-chloroethyl)pyrrolidine to 1-(p-toluenesulfonyl)-1-pentyne, followed by stereoselective reduction of the enamine
moiety and reductive desulfonylation.
Acetylenic sulfones 1 are readily available compounds with
numerous synthetic applications.1 For example, the electron-
withdrawing sulfone group activates the acetylene moiety
toward conjugate additions to afford â-substituted vinyl
sulfones. Furthermore, vinyl sulfones can be deprotonated
in the R-position,2 thus permitting the introduction of
electrophiles via the corresponding sulfone-stabilized anions.
Finally, the sulfone moiety can be removed at the end of a
synthetic sequence by various reductive desulfonylation
techniques.3 The possibility of employing these three opera-
tions sequentially suggested the use of acetylenic sulfones
as the synthetic equivalents of hypothetical alkene dipole
species 2, where the sulfone functionality acts as a disposable
activating group (Scheme 1). An intramolecular version of
Scheme 1
† Tel.: (403) 220-6256. Fax: (403) 289-9488.
(1) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. (b) Tanaka, K.; Kaji, A. In The Chemistry of Sulphones
and Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; Wiley:
Chichester, 1988; Chapter 15.
(2) (a) Eisch, J. J.; Galle, J. E. J. Org. Chem. 1979, 44, 3279. (b) Kleijn,
H.; Vermeer, P. J. Organomet. Chem. 1986, 302, 1. (c) Na´jera, C.; Yus,
M. J. Org. Chem. 1988, 53, 4708. (d) McCombie, S. W.; Shankar, B. B.;
Ganguly, A. K. Tetrahedron Lett. 1987, 28, 4123. (e) Pelter, A.; Ward, R.
S.; Little, G. M. J. Chem. Soc., Perkin Trans. 1 1990, 2775. (f) Caturla, F.;
Na´jera, C. Tetrahedron 1997, 53, 11449.
Scheme 1 was envisaged as the basis of a novel cyclization
strategy. We now report that acetylenic sulfones undergo
conjugate additions with â- and γ-chloro-substituted second-
10.1021/ol990592u CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

ary amines4 to produce enamine sulfones, which undergo
intramolecular alkylation when deprotonated with LDA to
afford cyclized products 3 and 4, as shown in Scheme 2.5 A
biological and medicinal properties provide added incentive
for the development of versatile new synthetic strategies for
their preparation.
The cyclizations of chloroamines 5, 7, 9, 11, 14, and 16
with acetylenic sulfones 1a-1f to afford products 6, 8, 10,
12, 13, 15, and 17-21 are shown in Table 1. The required
Scheme 2
Table 1. Cyclizations of â- and γ-Chloroamines with
Acetylenic Sulfones
concise and convenient approach to substituted piperidines,
quinolizidines, indolizidines, and pyrrolizidines is thus made
possible. These general types of structures are found
widespread in nature in the corresponding classes of alka-
loids,6 as well as in numerous synthetic analogues. Their
(3) See ref 1a, Chapter 9, and Grossert, J. S. In The Chemistry of
Sulphones and Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.;
Wiley: Chichester, 1988; Chapter 20.
(4) For other examples of conjugate additions of nitrogen nucleophiles
to acetylenic sulfones, see: (a) Back, T. G.; Bethell, R. J.; Parvez, M.;
Wehrli, D. J. Org. Chem. 1998, 63, 7908. (b) Truce, W. E.; Brady, D. G.
J. Org. Chem. 1966, 31, 3543. (c) Truce, W. E.; Markley, L. D. J. Org.
Chem. 1970, 35, 3275. (d) Truce, W. E.; Onken, D. W. J. Org. Chem.
1975, 40, 3200. (e) Stirling, C. J. M. J. Chem. Soc. 1964, 5863. (f)
McMullen, C. H.; Stirling, C. J. M. J. Chem. Soc. B 1966, 1217. (g)
McDowell, S. T.; Stirling, C. J. M. J. Chem. Soc. B 1967, 351. (h) Cossu,
S.; De Lucchi, O.; Durr, R. Synth. Commun. 1996, 26, 4597. (i) Cinquini,
M.; Cozzi, F.; Pelosi, M. J. Chem. Soc., Perkin Trans. 1 1979, 1430.
(5) An intramolecular acylation reaction of an enamine sulfone derived
from a primary amine was recently exploited in the synthesis of pumiliotoxin
C: Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566. To our
knowledge, no cyclizations of enamine sulfones derived from cyclic amines
have been reported, as are required for the introduction of nitrogen at a
ring-fusion site in products 4.
(6) For lead references, see the following. Piperidine alkaloids: (a) Strunz,
G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, 1985; Vol. 26, pp 89-183. (b) Fodor, G. B.; Colasanti, B. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Wiley: New York, 1985; Vol. 3, pp 1-90. Indolizidine and quinolizidine
alkaloids: (c) Howard, A. S.; Michael, J. P. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: Orlando, 1986; Vol. 28, pp 183-308. (d) Herbert,
R. B. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S.
W., Ed.; Wiley: New York, 1985; Vol. 3, pp 241-274. Pyrrolizidine
alkaloids: (e) Wro´bel, J. T. In The Alkaloids; Brossi, A., Ed.; Academic
Press: Orlando, 1985; Vol. 26, pp 327-384. For a list of other reviews of
these classes of alkaloids, see: (f) Dewick, P. M. Medicinal Natural
Products; Wiley: Chichester, 1997; pp 371-374.
(7) The chloroamines were prepared by the following procedures. (a) 5:
Dolfini, J. E.; Dolfini, D. M. Tetrahedron Lett. 1964, 2103. (b) 9: Piper,
J. R.; Johnston, T. P. J. Org. Chem. 1963, 28, 981. (c) For a similar
procedure leading to racemic 11 from the corresponding racemic amino
alcohol, see: Neth. Appl. Patent 6,600,184; July, 13, 1966; Chem. Abstr.
1967, 66, 2580r. (d) 14 and 16: Norton, T. R.; Seibert, R. A.; Benson, A.
A.; Bergstrom, F. W. J. Am. Chem. Soc. 1946, 68, 1572. (e) Chloroamine
7 was prepared from methyl (S)-3-(N-benzoylamino)butanoate by reduction
with lithium aluminum hydride and chlorination with thionyl chloride.
chloroamines7 were easily obtained by chlorination of the
corresponding amino alcohols with thionyl chloride. The
amino alcohols were in turn obtained either commercially
or by the reduction of esters of the corresponding amino
acids. The γ-chloro analogues 7 and 11 required Arndt-
Eistert homologation8 of the corresponding R-amino acids
prior to reduction. The chloroamines were isolated and stored
as their hydrochloride salts, which are stable and easily
handled. The acetylenic sulfones 1a-1f were obtained by
selenosulfonation methodology.9
Typically, the conjugate addition reactions were performed
by stirring the freshly liberated free chloroamine with the
(8) For lead references, see: March, J. In AdVanced Organic Chemistry,
4th ed.; Wiley: New York, 1992; pp 1083-1085.
262
Org. Lett., Vol. 1, No. 2, 1999

acetylenic sulfone in THF or dichloromethane at room
temperature or under reflux. The resulting enamine sulfone
in THF was then added to excess LDA in THF at -78 °C
to effect cyclization. The yields in Table 1 refer to isolated
enamine function with sodium cyanoborohydride,15 followed
by reductive desulfonylation with sodium in liquid am-
monia.16 Catalytic hydrogenation of the crude product then
reduced a small amount (ca. 5%) of the unsaturated byprod-
uct 23 that was formed by competing elimination of the
sulfone group during the desulfonylation step (Scheme 3).
1
products, which were fully characterized (IR, H and 13C
NMR, MS, and either HRMS or elemental analyses).10,11
Table 1 shows that this cyclization technique provides
straightforward access to 2- or 2,6-disubstituted piperidines
(entries 1 and 2), 3-substituted pyrrolizidines (entry 3), 5-
or 3-substituted indolizidines (entries 4-5 and 6, respec-
tively), and 4-substituted quinolizidines (entries 7-11) that
are additionally functionalized as enamine sulfones. Since
the starting chloroamines can be obtained as pure enanti-
omers from the corresponding amino acids, the method can
be employed in the enantioselective preparation of the
corresponding cycloadducts (entries 2-5). Moreover, the
enamine sulfone moiety in the products is amenable to further
synthetic transformations, which are under current investiga-
tion. For example, product 12 from entry 4 was converted
enantioselectively into the naturally occurring alkaloid (-)-
indolizidine 167B (also named gephyrotoxin 167B) (22)12-14
in 60% overall yield by stereoselective reduction of the
Scheme 3
(9) The following acetylenic sulfones were prepared by literature
methods. For 1a, see: (a) Chen, Z.; Trudell, M. L. Synth. Commun. 1994,
24, 3149. (b) Back, T. G.; Collins, S.; Kerr, R. G. J. Org. Chem. 1983, 48,
3077. For 1b: see ref 5. For 1c, see ref 9b and (c) Back, T. G.; Krishna,
M. V. J. Org. Chem. 1987, 52, 4265. For 1d, see ref 9b. For 1f, see: (d)
Back, T. G.; Lai, E. K. Y.; Muralidharan, K. R. J. Org. Chem. 1990, 55,
4595. Compound 1e was prepared via the general method of ref 9b, from
the selenosulfonation of 3-butyn-1-ol, followed by protection as the tert-
butyldimethylsilyl ether and selenoxide elimination.
These preliminary results demonstrate that acetylenic
sulfones act as alkene dipole equivalents and provide the
basis of a useful and versatile cyclization protocol with
secondary â- or γ-chloroamines, thus affording access to a
wide range of nitrogen heterocycles.
(10) In a typical example, chloroamine 11 was liberated from its
hydrochloride (4.75 mmol) with aqueous KOH just prior to use. The free
base and acetylene 1b (3.98 mmol) were stirred in dichloromethane for 5
h at room temperature. The solvent was evaporated in vacuo, the residue
was dissolved in THF and added to excess LDA (8 mmol) in THF at -78
°C, and the mixture was stirred for 2 min. The reaction was quenched by
filtration of the solution through basic alumina. The product was isolated
by chromatography on silica gel (elution with 20% ethyl acetate-hexanes)
to afford 94% (based on 1b) of 12 as white crystals: mp 95-96 °C (from
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
financial support.
OL990592U
(14) Procedure for the Preparation of 22. Trifluoroacetic acid (1.0 mL,
13 mmol) was added dropwise to a suspension of 12 (1.32 mmol) and
NaBH3CN (13.3 mmol) in 15 mL of dichloromethane, and the mixture was
stirred at room temperature for 30 min and refluxed for 30 min. It was
washed with aqueous KOH, dried (MgSO4), and concentrated in vacuo to
provide a yellow oil. This was dissolved in 30 mL of liquid ammonia,
sodium (40 mmol) was added, and the mixture was stirred at -33 °C for
15 min. Solid NH4Cl was added, and the ammonia was allowed to evaporate.
The residue was dissolved in 10% HCl and washed with ether. The aqueous
layer was basified with KOH, and the product was extracted with ether,
dried (MgSO4), and concentrated in vacuo to provide the crude product,
containing ca. 5% of 23 (tentative assignment based on its NMR spectrum).
The mixture was hydrogenated at 1 atm in 4 mL of ethanol with 10% Pd-C
at room temperature and for 1 h. The mixture was filtered through Celite,
and the filtrate was concentrated in vacuo. The residue was treated with 1
M HCl-ether (3.0 mL, 3.0 mmol), and the resulting solid was recrystallized
from ethanol-ether, basified with aqueous KOH, extracted with dichlo-
romethane, dried (MgSO4), and concentration in vacuo to afford 132 mg
(60%) of (-)-indolizidine 167B (22) as a yellow oil: 1H NMR (200 MHz)
δ 3.26 (dt, J ) 8.3, 2.2 Hz, 1 H), 2.05-1.55 (m, 10 H), 1.54-1.02 (m, 7
H), 0.90 (t, J ) 7.1 Hz, 3 H); 13C NMR (50 MHz) δ 64.9, 63.6, 51.5, 36.8,
30.9, 30.8, 30.5, 24.6, 20.3, 19.0, 14.4; mass spectrum, m/z (relative intensity,
%) 167 (M+, 4), 124 (100), 96 (22). [R]20D -106.9 (c 1.10, CH2Cl2), lit.13b
dichloromethane-hexanes): IR (KBr) 1551, 1318, 1282, 1123, 1081 cm-1
;
1H NMR (200 MHz) δ 7.72 (d, J ) 8.2 Hz, 2 H), 7.24 (d, J ) 8.4 Hz, 2
H), 3.58-3.42 (m, 1 H), 3.40-3.15 (m, 2 H), 2.98-2.78 (m, 1 H), 2.68-
2.22 (m, 3 H), 2.39 (s, 3 H), 2.21-2.00 (m, 2 H), 1.99-1.09 (m, 6 H),
0.97 (t, J ) 7.4 Hz, 3 H); 13C NMR (50 MHz) δ 154.6, 142.2, 141.4, 128.9,
125.8, 97.0, 57.9, 46.9, 32.0 (2 signals), 27.4, 25.1, 23.6, 22.3, 21.2, 14.2;
mass spectrum, m/z (relative intensity, %) 319 (M+, 40), 227 (91), 164
(100), 91 (68), 41 (67). Anal. Calcd for C18H25NO2S: C, 67.67; H, 7.89;
N, 4.38. Found: C, 67.91; H, 7.80; N, 4.42. [R]20D -246.7 (c 1.12, CHCl3).
(11) In general, a small excess (10-20%) of the chloroamine hydro-
chloride was employed to compensate for possible losses during the
liberation of the corresponding free base, which was generally used
immediately and without purification. The yields in Table 1 were thus
calculated on the basis of the acetylenic sulfone. When the preparation of
12 was repeated with equimolar amounts of the hydrochloride of 11 and
1b, the yield of 12 was 84%.
(12) Product 22 is a dendrobatid alkaloid found in the toxic skin
secretions of certain species of neotropical frogs. For a general review of
these compounds, see: Daly, J. F.; Spande, T. F. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1986;
Vol. 4, pp 1-274.
(13) For previous syntheses of (-)-indolizidine 167B, see: (a) Weymann,
M.; Pfrengle, W.; Schollmeyer, D.; Kunz, H. Synthesis 1997, 1151. (b)
Angle, S. R.; Henry, R. M. J. Org. Chem. 1997, 62, 8549. (c) Lee, E.; Li,
K. S.; Lim, J. Tetrahedron Lett. 1996, 37, 1445. (d) Fleurant, A.; Saliou,
C.; Ce´le´rier, J. P.; Platzer, N.; Moc, T. V.; Lhommet, G. J. Heterocycl.
Chem. 1995, 32, 255. (e) Jefford, C. W.; Wang, J. B. Tetrahedron Lett.
1993, 34, 3119. (f) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem.
Soc. 1991, 113, 3513. (g) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem.
1990, 55, 4688.
[R]25 -116.6 (c 0.0042, CH2Cl2), lit.13c [R]24 -112 (c 1.25 CH2Cl2),
D
lit.13d [R]20 -115 (c 1.16, CH2Cl2), lit.13g [R]DD-111.3 (c 1.3, CH2Cl2).
D
(15) For a general procedure for reducing other enamines with NaBH3-
CN-TFA, see: Comins, D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56,
2506.
(16) For a general procedure for reductive desulfonylation with Na-
liquid NH3, see: Marshall, J. A.; Cleary, D. G. J. Org. Chem. 1986, 51,
858.
Org. Lett., Vol. 1, No. 2, 1999
263