A convenient new route to piperidines, pyrrolizidines, indolizidines, and quinolizidines by cyclization of acetylenic sulfones with β- and γ-chloroamines. Enantioselective total synthesis of indolizidines (-)-167B, (-)-209D, (-)-209B, and (-)-207A

Article abstract of DOI:10.1021/jo000080p

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyrrole, respectively. The conjugate additions of a series of acyclic and cyclic secondary β- and γ-chloroamines to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were deprotonated with LDA in THF at -78 °C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic γ-chloroalkylbenzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)-pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)-piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syntheses were achieved by employing chiral chloroamines derived from amino acids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-Δ-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R,8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-Δ^5,6-indolizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of (-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfonyl)-Δ-indolizid ine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford (-)-indolizidine 207A.

Full text of DOI:10.1021/jo000080p

J . Org. Chem. 2000, 65, 4543-4552
4543
A Con ven ien t New Rou te to P ip er id in es, P yr r olizid in es,
In d olizid in es, a n d Qu in olizid in es by Cycliza tion of Acetylen ic
Su lfon es w ith â- a n d γ-Ch lor oa m in es. En a n tioselective Tota l
Syn th esis of In d olizid in es (-)-167B, (-)-209D, (-)-209B, a n d
(-)-207A
Thomas G. Back* and Katsumasa Nakajima
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
tgback@ucalgary.ca.
Received J anuary 20, 2000
The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their
free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the
corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-
toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyrrole,
respectively. The conjugate additions of a series of acyclic and cyclic secondary â- and γ-chloroamines
to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were
deprotonated with LDA in THF at -78 °C, and the resulting sulfone-stabilized carbanions
underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic γ-chloroalkyl-
benzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)-
pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)-
piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines,
and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also
prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syn-
theses were achieved by employing chiral chloroamines derived from amino acids or other
enantiopure precursors. Further transformations of several of the products provided concise
syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-
∆
5,6-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive
desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly
produced (-)-indolizidine 209D, while (-)-(8R,8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-∆5,6
-
indolizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of
(-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfonyl)-∆5,6-indolizidine produced the cor-
responding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group
with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford
(-)-indolizidine 207A.
Acetylenic sulfones 1 have many synthetic applica-
tions.1 Because of the electron-withdrawing effect of the
sulfone moiety, unsaturated sulfones such as 1 function
as efficient dienophiles and dipolarophiles in cycloaddi-
tions.2 Acetylenic sulfones can also undergo single or
double conjugate additions at the â-position with a
variety of nucleophiles, while the resulting vinyl or
saturated alkyl sulfones afford sulfone-stabilized R-carb-
anions when deprotonated with strong bases.3 Thus, it
is in principle possible to introduce one or two nucleo-
philes and one or two electrophiles, at the â- and
R-positions, respectively. Moreover, since the sulfone
group can be subsequently removed by a variety of
reductive, oxidative, or alkylative methods,4 the original
acetylenic sulfone functions as the synthetic equivalent
of hypothetical dipole or multipole species (Scheme 1).
Intramolecular acylations or alkylations of sulfone-
stabilized anions have been employed in several previous
ring-closure techniques.5 We recently reported6 that the
conjugate addition of primary â-amino ester 2 to acety-
lenic sulfone 1 (R ) n-Pr), followed by intramolecular
acylation of the corresponding anion, afforded the enami-
none 3, which then served as a key intermediate in the
synthesis of (-)-pumiliotoxin C (4) (Scheme 2). We now
describe variations of this cyclization protocol that sig-
(3) For reviews of sulfone-stabilized carbanions, see: (a) ref 1a,
Chapter 3. (b) Block, E. Reactions of Organosulfur Compounds;
Academic Press: New York, 1978; Chapter 2. (c) Na´jera, C.; Sansano,
J . M. Recent Res. Dev. Org. Chem. 1998, 2, 637. For examples of
sulfone-stabilized vinyl carbanions, see: (d) Eisch, J . J .; Galle, J . E.
J . Org. Chem. 1979, 44, 3279. (e) Kleijn, H.; Vermeer, P. J . Organomet.
Chem. 1986, 302, 1. (f) Na´jera, C.; Yus, M. J . Org. Chem. 1988, 53,
4708. (g) Pelter, A.; Ward, R. S.; Little, G. M. J . Chem. Soc., Perkin
Trans. 1 1990, 2775. (h) Caturla, F.; Na´jera, C. Tetrahedron 1997, 53,
11449.
* 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) For reviews, see: (a) ref 1a, Chapter 6. (b) De Lucchi, O.;
Pasquato, L. Tetrahedron 1988, 44, 6755. For lead references, see: (c)
Back, T. G.; Bethell, R. J .; Parvez, M.; Taylor, J . A.; Wehrli, D. J . Org.
Chem. 1999, 64, 7426. (d) Shen, M.; Schultz, A. G. Tetrahedron Lett.
1981, 22, 3347.
(4) (a) See ref 1a, Chapter 9. (b) Na´jera, C.; Yus, M. Tetrahedron
1999, 55, 10547.
10.1021/jo000080p CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

4544 J . Org. Chem., Vol. 65, No. 15, 2000
Back and Nakajima
Sch em e 1
Sch em e 3
procuring adequate amounts for biological studies. The
application of our sulfone-based cyclization procedure to
the synthesis of several dendrobatid alkaloids of the
indolizidine class was therefore also investigated.
Sch em e 2
Resu lts a n d Discu ssion
During the cyclization leading to 3, and in several other
examples that were subsequently investigated with other
â-amino esters,9a we observed varying degrees of compet-
ing proton transfer from the R-position of the ester to that
of the sulfone.9b This resulted in the recovery of signifi-
cant amounts of the unreacted enamine sulfone and
decreased the efficiency of the desired ring-closure step.
When R-amino esters 5a and 5b were similarly employed
with acetylenic sulfone 1 (R ) n-Bu), cyclization occurred
efficiently but was accompanied by enolization and
aromatization to afford the corresponding pyrroles 7a and
7b via the conjugate addition products 6a and 6b,
respectively (Scheme 3). To circumvent proton transfer
and aromatization, we next investigated the use of â- and
γ-chloroamines in a variation of the original technique,
where ring closure occurs via intramolecular alkylation
instead of acylation (Scheme 4).
The required chloroamines in Scheme 4 were prepared
by chlorination of the corresponding amino alcohols with
thionyl chloride. Products 8a ,10 8c,11 8e,12 and 8f 12 were
prepared as reported in the literature. Thus, enantiopure
chloroamine 8c was obtained from (L)-proline, while 8e
and 8f were employed as racemic mixtures. Arndt-
Eistert homologation13 of (L)-proline14a followed by reduc-
tion afforded the known amino alcohol precursor of
8d .14b,14c Similar homologation of (L)-alanine provided the
known ester 9,15 which was transformed into 8b as shown
in Scheme 5. Ester 11 was obtained from (R)-R-methyl-
benzylamine by literature methods16 and was converted
into 8g as shown in Scheme 5. Both 8b and 8g were thus
nificantly extend the scope of the original method. In
particular, the use of readily available chloroamines in
place of amino esters provides access to a variety of
nitrogen heterocycles,7 including the four dendrobatid
alkaloids of the title.
Dendrobatid alkaloids8 are contained in the toxic skin
secretions of certain neotropical frogs and other species.
These compounds serve as a defense against predation
and have been employed by hunters in the rain forests
of Central and South American as blow-gun dart poisons.
The structures and toxicity of the dendrobatid alkaloids
vary widely. For example, some of the indolizidines in
this class are noncompetitive blockers of nicotinic recep-
tor channels, thus making them of pharmacological and
medicinal interest. Furthermore, the very limited amounts
available from natural sources make the development of
synthetic approaches to these compounds necessary for
(5) For illustrative examples, see: (a) Ghera, E.; Maurya, R.; Ben-
David, Y. J . Org. Chem. 1988, 53, 1912. (b) Grimm, E. L.; Levac, S.;
Coutu, M. L. Tetrahedron Lett. 1994, 35, 5369. (c) Grimm, E. L.; Coutu,
M. L.; Trimble, L. A. Tetrahedron Lett. 1993, 34, 7017. (d) Gamble, M.
P.; Giblin, G. M. P.; Taylor, R. J . K. Synlett 1995, 779. (e) Magnus, P.;
Booth, J .; Magnus, N.; Tarrant, J .; Thom, S.; Ujjainwalla, F. Tetrahe-
dron Lett. 1995, 36, 5331. (f) McCombie, S. W.; Shankar, B. B.;
Ganguly, A. K. Tetrahedron Lett. 1987, 28, 4123. (g) Date, M.;
Watanabe, M.; Furukawa, S. Chem. Pharm. Bull. 1990, 38, 902. (h)
Carretero, J . C.; Arraya´s, R. G. J . Org. Chem. 1995, 60, 6000. (i)
Carretero, J . C.; Arraya´s, R. G. J . Org. Chem. 1998, 63, 2993. (j)
Carretero, J . C.; Arraya´s, R. G.; Storch de Garcia, I. Tetrahedron Lett.
1997, 38, 8537. (k) Carretero, J . C.; Arraya´s, R. G. Synlett 1999, 49.
(l) Crich, D.; Natarajan, S.; Crich, J . Z. Tetrahedron 1997, 53, 7139.
(6) Back, T. G.; Nakajima, K. J . Org. Chem. 1998, 63, 6566.
(7) Preliminary communication: Back, T. G.; Nakajima, K. Org. Lett.
1999, 1, 261.
(8) For general reviews of dendrobatid alkaloids, see: (a) Daly, J .
W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, Chapter 1. (b)
Witkop, B.; Go¨ssinger, E. In The Alkaloids: Chemistry and Pharmacol-
ogy; Brossi, A., Ed.; Academic Science, New York, 1983; Vol. 21,
Chapter 5. (c) Daly, J . W.; Brown, G. B.; Mensah-Dwumah, M.; Myers,
C. W. Toxicon 1978, 16, 163. (d) Mensah-Dwumah, M.; Daly, J . W.
Toxicon 1978, 16, 189. (e) Daly, J . W.; Myers, C. W. Whittaker, N.
Toxicon 1987, 25, 1023.
(9) (a) Nakajima, K. Ph.D. Thesis, University of Calgary, 2000. (b)
The success of intramolecular acylations of sulfone-stabilized carban-
ions can be attributed to the greater kinetic acidity of the sulfone
moiety, despite the generally higher pKa values of sulfones compared
to esters.
(10) Dolfini, J . E.; Dolfini, D. M. Tetrahedron Lett. 1964, 2103.
(11) Piper, J . R.; J ohnston, T. P. J . Org. Chem. 1963, 28, 981.
(12) Norton, T. R.; Seibert, R. A.; Benson, A. A.; Bergstrom, F. W.
J . Am. Chem. Soc. 1946, 68, 1572.
(13) For lead references, see March, J . In Advanced Organic
Chemistry, 4th ed.; Wiley: New York, 1992; pp 1083-1085.
(14) For the Arndt-Eistert homologation of (L)-proline, see: (a)
Cassal, J .-M.; Fu¨rst, A.; Meier, W. Helv. Chim. Acta 1976, 59, 1917.
The preparation of racemic 8d has also been reported; see: (b) Sandoz
Ltd., Neth. Appl. Patent 6,600,184; J uly, 13, 1966 via Chem. Abstr.
1967, 66, 2580r. (c) Mahesh, V. K.; Sharma, R.; Maheshwari, M. Indian
J . Chem, Sect. B 1984, 23, 486.
(15) Drey, C. N. C.; Mtetwa, E. J . Chem. Soc., Perkin Trans. 1 1982,
1587.
(16) Bardou, A.; Ce´le´rier, J .-P.; Lhommet, G. Tetrahedron Lett. 1998,
39, 5189.

Enantioselective Synthesis of Substituted Indolizidines
J . Org. Chem., Vol. 65, No. 15, 2000 4545
Sch em e 4
Sch em e 6
Ta ble 1. Cycliza tion s of Ch lor oa m in es w ith Acetylen ic
Su lfon es
Sch em e 5
obtained as essentially pure enantiomers. All of the
chloroamines shown in Scheme 4 were isolated and
stored as their hydrochloride salts, which are stable for
prolonged periods at -20 °C.
Acetylenic sulfone 1a was prepared by a literature
method17 from bis(trimethylsilyl)acetylene. Compounds
1b-1i were obtained by selenosulfonation of the corre-
sponding acetylenes,18 followed by selenoxide elimination
(Scheme 6). The selenosulfonation step was performed
after O-benzylation of the corresponding acetylenic al-
cohols in the synthesis of 1h and 1i but was more
effectively carried out directly on 3-butyn-1-ol, followed
by silylation and selenoxide elimination in the prepara-
tion of 1g. Enyne 1j was prepared as described earlier.19
a
Solvent, temperature (∆ ) reflux; RT ) room temperature),
and time (h) are given for the conjugate addition step. All
cyclization steps were performed in THF at -78 °C for 5-45 min
in the presence of excess LDA. A small excess (1.1-1.2 equiv) of
the chloroamine hydrochloride was employed; the yield is based
on the acetylenic sulfone. c Equimolar amounts of the chloroamine
hydrochloride and acetylenic sulfone were used.
b
The results of the cyclizations of chloroamines 8 with
acetylenic sulfones 1 are listed in Table 1. In general,
the chloroamines were liberated from their hydrochloride
salts just prior to use by treatment with aqueous potas-
sium hydroxide. The conjugate additions of the corre-
sponding free bases20 proceeded smoothly in solvents such
as benzene, dichloromethane, or THF at room tempera-
(17) Chen, Z.; Trudell, M. L. Synth. Commun. 1994, 24, 3149.
(18) For the preparation of acetylenic sulfones by selenosulfonation,
see: (a) Back, T. G. In Organoselenium Chemistry-A Practical
Approach; Back, T. G., Ed.; Oxford University Press: Oxford, 1999;
Chapter 9. (b) Back, T. G.; Collins, S.; Kerr, R. G. J . Org. Chem. 1983,
48, 3077. (c) Miura, T.; Kobayashi, M. J . Chem. Soc., Chem. Commun.
1982, 438.
(19) Back, T. G.; Lai, E. K. Y.; Muralidharan, K. R. J . Org. Chem.
1990, 55, 4595.

4546 J . Org. Chem., Vol. 65, No. 15, 2000
Back and Nakajima
Sch em e 7
respectively, as the starting chloroamine. Moreover, since
the chloroamines can be prepared from R-amino acids or
other enantiopure precursors (vide supra), enantioselec-
tive syntheses of the product heterocycles are possible,
as illustrated by entries 2-9.
Further stereoselective transformations of the enamine
sulfone moieties of the products are also possible. This
was exemplified in our earlier synthesis of pumiliotoxin
C6 by preferential hydrogenation and hydrogenolysis of
the enol triflate of 3 from the exo side, followed by
reductive desulfonylation. We now report that the enam-
ine sulfone groups in several of the products in Table 1
were reduced with high R-stereoselectivity with sodium
cyanoborohydride in acidic media, via the corresponding
iminium ions.22,23 This process, followed by reductive
desulfonylation, therefore provides a short enantioselec-
tive route to dendrobatid alkaloids of the indolizidine
class that contain substituents in the 5- or 5,8-positions.
Thus, the enamine moieties of cyclized products 15 and
17 were reduced with sodium cyanoborohydride in the
presence of trifluoroacetic acid, followed by desulfonyla-
tion with sodium in liquid ammonia.24 Although no
significant formation of the corresponding 5-epimers was
detected, the crude products contained traces (<5%) of
unsaturated byproducts, tentatively identified by NMR
analysis as the corresponding ∆6,7 analogues 29 and 30,
respectively. The latter compounds were presumably
formed by a competing base-catalyzed elimination of
p-toluenesulfinic acid in the desulfonylation step. The
entire crude mixture was therefore hydrogenated to
reduce the byproducts, thereby affording the desired
alkaloids (-)-indolizidine 167B (31, R ) n-Pr)25 and (-)-
ture or at reflux. The addition in entry 2 proceeded slowly
in these solvents, but the rate was enhanced in ethanol.
The adducts were typically obtained as pure E-isomers
(NMR), as expected from precedents with other additions
of secondary amines to acetylenic sulfones.20a,d,f The
cyclization step was then conducted by evaporation of the
solvent (if other than THF) and treatment of the crude
adduct with LDA in THF at -78 °C for a few minutes.
The products were isolated in the yields indicated in
Table 1. In some cases, it was expedient to employ a small
excess of the chloroamine to compensate for losses during
its liberation from the corresponding hydrochloride. In
such cases the yield in Table 1 is calculated on the basis
of the acetylenic sulfone. Thus, in entry 4, a modest
improvement in the yield of 15 from 84% to 94% was
observed when 1.1 equiv of the chloroamine 8d was
employed. When primary chloroamines were similarly
investigated, the conjugate addition step proceeded in the
normal manner, but attempts at subsequent cyclizations
failed, resulting in the recovery of the enamine sulfone
intermediate. This can be attributed to the lower reactiv-
ity in the intramolecular alkylation of the enamide anion
27, derived from a primary amine, compared to that of
the sulfone-stabilized vinyl carbanion 28, which was
generated from a secondary amine (Scheme 7). Thus,
N-benzylation of the chloroamine was necessary in
entries 1 and 2 to obtain the desired products 12 and
13.
The examples in Table 1 indicate that the method is
applicable to the synthesis of a variety of nitrogen
heterocycles containing the enamine sulfone moiety.
These include 2- or 2,6-disubstituted piperidines (entries
1 and 2), a 3-substituted pyrrolizidine (entry 3), 5-, 5,8-,
or 3-substituted indolizidines (entries 4-6, 7-9 and 10,
respectively), and 4-substituted quinolizidines (entries
11-15).21 It is worth noting that the substituent origi-
nating from the acetylenic sulfone can be incorporated
into either the 5- or 3-position of the corresponding
indolizidine products (i.e., entries 4-9 and 10, respec-
tively). This was achieved by choosing either a pyrrolidine
with a pendant 2-chloroethyl side chain (i.e., 8d or 8g)
or a piperidine with a chloromethyl substituent (i.e., 8e),
indolizidine 209D (32, R ) n-C6H13)
26 in overall yields of
60% and 74%, respectively (Scheme 8). Enamine sulfone
18 was similarly converted into (-)-indolizidine 209B
(21) For lead references, see: 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.
(22) For the stereoselective reduction of other enamines via their
iminium ions with NaBH3CN-TFA, see: Comins, D. L.; Weglarz, M.
A. J . Org. Chem. 1991, 56, 2506.
(23) The generally high stereoselectivity of hydride reductions of
similar bicyclic iminium ions has been rationalized on the basis of
conformational and stereoelectronic effects: Stevens, R. V. Acc. Chem.
Res. 1984, 17, 289.
(24) For a general procedure for reductive desulfonylation with Na-
liquid NH3, see: Marshall, J . A.; Cleary, D. G. J . Org. Chem. 1986,
51, 858.
(25) For previous syntheses of (-)-indolizidine 167B (31), 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.; Ce´le´rier, J . P.; Lhommet, G. Tetrahedron Asymmetry 1992, 3, 695.
(e) Fleurant, A.; Saliou, C.; Ce´le´rier, J . P.; Platzer, N.; Moc, T. V.;
Lhommet, G. J . Heterocycl. Chem. 1995, 32, 255. (f) J efford, C. W.;
Wang, J . B. Tetrahedron Lett. 1993, 34, 3119. (g) J efford, C. W.; Tang,
Q.; Zaslona, A. J . Am. Chem. Soc. 1991, 113, 3513. (h) Polniaszek, R.
P.; Belmont, S. E. J . Org. Chem. 1990, 55, 4688.
(26) For previous syntheses of (-)-indolizidine 209D (32), see: refs
25c, 25f, 25h, and (a) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M.
J . Org. Chem. 1995, 60, 398. (b)Åhman, J .; Somfai, P. Tetrahedron
1995, 51, 9747. (c) J efford, C. W.; Sienkiewicz, K.; Thornton, S. R. Helv.
Chim. Acta 1995, 78, 1511. (d) Takahata, H.; Kubota, M.; Ihara, K.;
Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E.
Tetrahedron: Asymmetry 1998, 9, 3289.
(20) For examples of conjugate additions of amines to acetylenic
sulfones, see: (a) Truce, W. E.; Brady, D. G. J . Org. Chem. 1966, 31,
3543. (b) Truce, W. E.; Markley, L. D. J . Org. Chem. 1970, 35, 3275.
(c) Truce, W. E.; Onken, D. W. J . Org. Chem. 1975, 40, 3200. (d)
Stirling, C. J . M. J . Chem. Soc. 1964, 5863. (e) Pink, R. C.; Spratt, R.;
Stirling, C. J . M. J . Chem. Soc. 1965, 5714. (f) McMullen, C. H.;
Stirling, C. J . M. J . Chem. Soc. B 1966, 1217. (g) McDowell, S. T.;
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G.; Bethell, R. J .; Parvez, M.; Wehrli, D. J . Org. Chem. 1998, 63, 7908.

Enantioselective Synthesis of Substituted Indolizidines
J . Org. Chem., Vol. 65, No. 15, 2000 4547
Sch em e 8
Sch em e 9
(33)27 in 66% overall yield, without the appearance of
unsaturated byproducts, thereby obviating the hydroge-
nation step.
We next attempted to prepare (-)-indolizidine 207A
(40),28 an unsaturated analogue of 33, via substitution
of the corresponding chloride 35 with a vinyl cuprate
reagent. The alcohol 34 was obtained from enamine
sulfone 20 in the usual manner (Scheme 9). However,
conversion of the latter into the free base of the corre-
sponding chloride 35 resulted in spontaneous cyclization
to 36. When the procedure was repeated with the
homologue 19, where similar cyclization was expected to
be less favorable as a result of the formation of a four-
membered ring, the corresponding chloride 38 was easily
obtained from alcohol 37. Treatment of 38 with the
higher order cuprate 3929 then afforded the desired
product 40 (Scheme 9).
loids: (-)-indolizidines 167B, 209D, 209B, and 207A.
Further opportunities exist for modifying the enamine
sulfone functionality in a synthetically useful manner
and these are under continued investigation.
In conclusion, the conjugate additions of acyclic or
cyclic secondary â- or γ-chloroamines to acetylenic sul-
fones proceed smoothly under mild conditions. The crude
products undergo cyclization when treated with LDA, via
intramolecular alkylation of the corresponding sulfone-
stabilized vinyl carbanions. The products thus obtained
include variously substituted piperidines, pyrrolizidines,
indolizidines, and quinolizidines, all containing the enam-
ine sulfone moiety. Since the required chloroamines can
be obtained from R-amino acids or other enantiopure
precursors, the products can be prepared enantioselec-
tively. The cyclic enamine sulfones that are obtained in
this manner can be reduced stereoselectively and desul-
fonylated. The utility of this protocol was illustrated by
the enantioselective synthesis of four dendrobatid alka-
Exp er im en ta l Section
NMR spectra were recorded in deuteriochloroform and are
reported relative to residual chloroform or TMS as the internal
standard. Where 13C NMR signals are assigned as C, CH, CH2,
or CH3, the assignments are based on DEPT experiments.
Chromatography refers to flash chromatography on silica gel
(230-400 mesh), unless otherwise noted.
2-Ben zyl-5-n -b u t yl-3-h yd r oxy-4-(p -t olu en esu lfon yl)-
p yr r ole (7a ). A solution of (L)-phenylalanine methyl ester (5a )
(228 mg, 1.27 mmol) and 1-(p-toluenesulfonyl)-1-hexyne30 (1c)
(255 mg, 1.08 mmol) in 2 mL of benzene was refluxed for 3 h
and concentrated in vacuo. The residual oil was chromato-
graphed over neutral alumina. Elution with 25% ethyl acetate-
hexanes furnished 372 mg (83% based on 1c) of a 1:2 E,Z
mixture (NMR) of the corresponding conjugate addition prod-
uct 6a as a yellow oil, which was used directly in the next step.
A solution of the above enamine sulfone 6a (155 mg, 0.373
mmol) in 1.0 mL of THF was added to LDA (0.37 mmol) in 2.0
mL of THF at -78 °C. It was stirred at -78 °C for 40 min and
then at room temperature for 24 h. The concentrated crude
product was chromatographed without further manipulation.
Elution with 50% ethyl acetate-hexanes afforded 62 mg (43%)
of 7a as a yellow oil, which crystallized from dichloromethane-
hexanes to give white needles: mp 184-186 °C; IR (KBr) 3390,
3188, 1678, 1283, 1137 cm-1; 1H NMR31 (400 MHz) δ 8.81 (br
s, 1 H), 7.71 (d, J ) 8.2 Hz, 2 H), 7.27 (d, J ) 8.1 Hz, 2 H),
7.02 (t, J ) 7.4 Hz, 1 H), 6.97 (d, J ) 7.4 Hz, 2 H), 6.87 (t,
(27) For previous syntheses of (-)-indolizidine 209B (33), see: refs
16, 26b, 26c, and (a) Michael, J . P.; Gravestock, D. Pure Appl. Chem.
1997, 69, 583. (b) Aube´, J .; Rafferty, P. S.; Milligan, G. L. Heterocycles
1993, 35, 1141. (c) Satake, A.; Shimizu, I. Tetrahedron: Asymmetry
1993, 4, 1405. (d) Shishido, Y.; Kibayashi, C. J . Org. Chem. 1992, 57,
2876. (e) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.;
Lidert, Z.; Swithenbank, C. J . Org. Chem. 1991, 56, 1393.
(28) For previous syntheses of (-)-indolizidine 207A (40), see: ref
27d and (a) Comins, D. L.; LaMunyon, D. H.; Chen, X. J . Org. Chem.
1997, 62, 8182. (b) Taber, D. F.; Rahimizadeh, M.; You, K. K. J . Org.
Chem. 1995, 60, 529.
(29) (a) Lipshutz, B. H.; Crow, R.; Dimock, S. H.; Ellsworth, E. L.;
Smith, R. A. J .; Behling, J . R. J . Am. Chem. Soc. 1990, 112, 4063. (b)
Lipshutz, B. H. In Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: Chichester, 1994; p 315.
(30) Back, T. G.; Krishna, M. V. J . Org. Chem. 1987, 52, 4265; the
general method of ref 18 was used in the preparation of 1c.

4548 J . Org. Chem., Vol. 65, No. 15, 2000
Back and Nakajima
J ) 7.6 Hz, 2 H), 6.03 (br s, 1 H), 3.34 (d, J ) 13.2 Hz, 1 H),
3.24 (d, J ) 13.1 Hz, 1 H), 3.02-2.92 (m, 1 H), 2.69-2.59 (m,
1 H), 2.46 (s, 3 H), 1.35-1.10 (m, 4 H), 0.80 (t, J ) 7.0 Hz, 3
H); 13C NMR (100 MHz) δ 193.6 (C), 183.0 (C), 143.1 (C), 140.4
(C), 132.7 (C), 130.0 (CH), 129.3 (CH), 127.9 (CH), 126.7 (CH),
126.4 (CH), 105.9 (C), 88.5 (C), 42.5 (CH2), 29.3 (CH2), 28.9
(CH2), 22.4 (CH2), 21.5 (CH3), 13.6 (CH3); MS(EI) m/z (%) 383
(M+, 5), 381 (37), 91 (100); HRMS calcd for C22H25NO3S
383.1555, found 383.1517.
7.40-7.25 (m, 5 H), 3.95-3.73 (m, 4 H), 3.10-2.92 (m, 1 H),
1.85-1.68 (m, 1 H), 1.67-1.48 (m, 1 H), 1.21 (d, J ) 6.3 Hz, 3
H). The product was dissolved in chloroform (30 mL), and HCl
gas was bubbled through the solution while cooling at 0 °C.
Thionyl chloride (3.0 mL, 41 mmol) was added dropwise over
5 min at 0 °C, and the resulting solution was refluxed for 2 h
and concentrated in vacuo. The residue was triturated with
methanol (30 mL), and a small amount of decolorizing charcoal
was added. The mixture was refluxed for 30 min, filtered
through Celite, and the filtrate was concentrated in vacuo to
give a light yellow solid. Recrystallization from ethanol-ether
provided 3.547 g (73%) of the hydrochloride salt of 8b as white
5-n -Bu t yl-3-h yd r oxy-2-(2-m et h ylt h ioet h yl)-4-(p -t olu -
en esu lfon yl)p yr r ole (7b). Following the preceding proce-
dure, the conjugate addition of methionine methyl ester (5b)
(1.2 equiv) to 1c30 provided 88% (based on 1c) of 6b as an oil,
which was directly subjected to the LDA-mediated cyclization
to afford 36% of 7b as a solid: mp 145-147 °C (from dichlo-
romethane-hexanes); IR (KBr) 3242, 1674, 1282, 1137, 1082
cm-1; 1H NMR31 (400 MHz) δ 8.45 (br s, 1 H), 7.82 (d, J ) 7.6
Hz, 2 H), 7.26 (d, J ) 7.2 Hz, 2 H), 5.40 (br s, 1 H), 3.14-3.00
(m, 1 H), 2.98-2.83 (m, 1 H), 2.45-2.33 (m, 1 H), 2.40 (s, 3
H), 2.33-2.22 (m, 1 H), 2.19-2.09 (m, 1 H), 2.06-1.98 (m, 1
H), 1.94 (s, 3 H), 1.75-1.60 (m, 2 H), 1.50-1.38 (m, 2 H), 0.92
(t, J ) 7.3 Hz, 3 H); 13C NMR (100 MHz) δ 193.3 (C), 182.5
(C), 143.5 (C), 140.4 (C), 129.4 (CH), 126.2 (CH), 105.5 (C),
87.7 (C), 35.4 (CH2), 29.34 (CH2), 29.28 (CH2), 27.1 (CH2), 22.5
(CH2), 21.4 (CH3), 15.2 (CH3), 13.6 (CH3); MS(EI) m/z (%) 367
(M+, 11), 365 (52), 210 (100), 91 (80), 61 (92); HRMS calcd for
crystals: mp 140-141 °C; [R]20 +1.8 (c 1.03, CHCl3). Anal.
D
Calcd for C11H17NCl2: C, 56.42; H, 7.32; N, 5.98. Found: C,
56.38; H, 7.24; N, 5.96. The free base of 8b was obtained as a
yellow oil by treatment with aqueous KOH, extraction with
dichloromethane, drying (MgSO4), and concentration in vac-
uo: 1H NMR (200 MHz) δ 7.45-7.20 (m, 5 H), 3.87 (d, J )
13.0 Hz, 1 H), 3.76 (d, J ) 13.0 Hz, 1 H), 3.70 (dt, J ) 10.7,
7.0 Hz, 1 H), 3.62 (dt, J ) 11.1, 6.8 Hz, 1 H), 2.93 (sextet, J )
6.3 Hz, 1 H), 2.05-1.73 (m, 2 H), 1.15 (d, J ) 6.3 Hz, 3 H).
The free base was used immediately without storage.
(+)-(2S)-2-(2-Ch lor oet h yl)p yr r olid in e Hyd r och lor id e
(8d ). Chlorination of (2S)-2-(2-hydroxyethyl)pyrrolidine14 was
carried out according to the procedure used for the preparation
of 8b. Hydrochloride salt of 8d : mp 99-100 °C; [R]23 +14.7
D
(c 1.10, CHCl3). Anal. Calcd for C6H13NCl2: C, 42.37; H, 7.71;
N, 8.24. Found: C, 42.14; H, 7.48; N, 8.05. The free base of 8d
was obtained by treatment with aqueous KOH as in the case
of 8b and was used immediately: 1H NMR (200 MHz) δ 3.64
(t, J ) 6.7 Hz, 2 H), 3.32-3.12 (m, 1 H), 3.08-2.78 (m, 2 H),
2.07-1.64 (m, 6 H), 1.41-1.20 (m, 1 H).
C
18H25NO3S2 367.1276, found 367.1241.
Meth yl (-)-(3S)-3-(Ben zoyla m in o)bu ta n oa te (10). A
mixture of N-Cbz amino ester 915 (5.095 g, 20.30 mmol) and
p-toluenesulfonic acid monohydrate (4.241 g, 22.32 mmol) in
methanol (50 mL) was hydrogenated over 10% palladium on
charcoal (516 mg) at room temperature and at 1 atm for 16.5
h. It was then filtered through Celite, and the filtrate was
concentrated to give a yellow oil. This was dissolved in
dichloromethane (50 mL) and triethylamine (11.5 mL, 82.6
mmol). Benzoyl chloride (2.36 mL, 20.3 mmol) was slowly
added. The resulting mixture was stirred at room temperature
for 30 min, washed with aqueous KOH, dried (MgSO4), and
concentrated in vacuo. The solid residue was further washed
with hexane to provide 4.455 g (99%) of 10 as a white solid:
mp 106-108 °C (from dichloromethane-hexanes); lit.32 108-
(+)-(2S,2′S)-2-[2′-(1′-Ch lor op r op yl)]p yr r olid in e Hyd r o-
ch lor id e (8g). A solution of ester 1116 (5.059 g, 18.40 mmol)
in 50 mL of ether was added to a suspension of lithium
aluminum hydride (2.864 g, 75.37 mmol) in 200 mL of ether
at 0 °C, and the mixture was stirred at room temperature for
1 h. Excess lithium aluminum hydride was destroyed by the
cautious addition of water, and the white precipitate was
removed by filtration. The filtrate was washed with aqueous
KOH, dried (MgSO4), and concentrated in vacuo to give 4.944
g of the corresponding alcohol as a light yellow oil: 1H NMR
(200 MHz) δ 7.45-7.20 (m, 5 H), 3.65 (q, J ) 6.6 Hz, 1 H),
3.45 (dd, J ) 10.9, 3.5 Hz, 1 H), 3.26 (dd, J ) 10.8, 9.7 Hz, 1
H), 3.10-2.75 (m, 3 H), 1.90-1.65 (m, 3 H), 1.64-1.45 (m, 2
H), 1.40 (d, J ) 6.5 Hz, 3 H), 0.60 (d, J ) 6.8 Hz, 3 H).
The above product was hydrogenated over 1.373 g of 10%
palladium on charcoal in 60 mL of ethanol at 1 atm at room
temperature for 6 days. The catalyst was removed by filtration
through Celite, and the filtrate was concentrated in vacuo. The
residual oil was triturated with chloroform, washed with
aqueous KOH, dried (MgSO4), and concentrated in vacuo to
give 2.52 g of the corresponding secondary amine as a yellow
oil: 1H NMR (200 MHz) δ 4.25 (br m, 2 H), 3.63 (dd, J ) 10.8,
3.6 Hz, 1 H), 3.51 (dd, J ) 10.8, 8.7 Hz, 1 H), 3.07-2.70 (m, 3
H), 2.00-1.67 (m, 2 H), 1.66-1.35 (m, 3 H), 0.80 (d, J ) 6.8
Hz, 3 H).
109 °C; [R]20 -42.1 (c 0.86, CHCl3); lit.32 [R]D -42.0 (c 0.77,
D
CHCl3).
(+)-(3S)-3-Ben zyla m in o-1-ch lor ob u t a n e H yd r och lo-
r id e (8b). A solution of 10 (4.570 g, 20.68 mmol) in 35 mL of
THF was added dropwise over 5 min to a suspension of lithium
aluminum hydride (3.924 g, 103.3 mmol) in 150 mL of ether
at 0 °C. The resulting mixture was stirred at room temperature
for 47 h. Excess lithium aluminum hydride was destroyed by
the cautious addition of water, and the precipitate was
removed by filtration. The aqueous layer was basified with
KOH, and the product was extracted with ether, dried
(MgSO4), and concentrated in vacuo to give the corresponding
amino alcohol33 as a light yellow oil: 1H NMR (200 MHz) δ
The product was dissolved in 40 mL of chloroform, and HCl
gas was bubbled through the mixture at 0 °C. Thionyl chloride
(5.4 mL, 74 mmol) was added dropwise over 5 min at 0 °C,
and the resulting solution was refluxed for 3 h and concen-
trated in vacuo. The residue was triturated with methanol (20
mL), refluxed for 30 min with a small amount of decolorizing
charcoal, and filtered through Celite. The filtrate was concen-
trated in vacuo, and the decolorizing procedure was repeated
to give a light yellow solid, which was recrystallized from
ethanol-ether to give 2.357 g (70%) of the hydrochloride salt
(31) The diastereotopic methylene protons in the substituents at C-2
and C-5 in the 1H NMR spectra of 7a and 7b suggest the predominance
of the keto tautomers in these compounds. However, the presence of
seven quaternary carbon and only five CH signals in the DEPT
spectrum of 7a and of six quaternary carbon and only two CH signals
in that of 7b is consistent with their enol tautomers, as is the absence
of a signal in their 1H NMR spectra attributable to the proton at the
stereocenter (C-2) of the keto tautomer. The diastereotopic nature of
the methylene protons in 7a and 7b is possibly due to asymmetry
caused by intramolecular hydrogen bonding between the sulfone
oxygen atoms and the hydroxyl groups of the enol tautomers, resulting
in torsion of the arylsulfonyl moieties relative to the pyrrole rings. The
averaging of NMR signals of the keto and enol forms would occur if
equilibration of the tautomers was sufficiently rapid on the NMR time
scale. This appears to be unlikely but cannot be completely ruled out.
For a kinetic study of the tautomerization of other 3-hydroxypyrroles,
see: Capon, B.; Kwok, F. J . Am. Chem. Soc. 1989, 111, 5346.
(32) Estermann, H.; Seebach, D. Helv. Chim. Acta 1988, 71, 1824.
(33) The racemic amino alcohol is a known compound: Bartoli, G.;
Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. J . Org. Chem.
1994, 59, 5328.
of 8g as a pale yellow solid: mp 109-110 °C; [R]18 +15.0 (c
D
0.80, CHCl3). Anal. Calcd for C7H15NCl2: C, 45.67; H, 8.21;
N, 7.61. Found: C, 45.42; H, 8.48; N, 7.47. The free base of 8g
was obtained by treatment with aqueous KOH solution as in
the case of 8b and was used immediately: 1H NMR (200 MHz)
δ 3.67 (d, J ) 4.6 Hz, 2 H), 3.07-2.81 (m, 3 H), 2.20 (br s, 1
H), 2.02-1.60 (m, 4 H), 1.47-1.22 (m, 1 H), 1.03 (d, J ) 6.7
Hz, 3 H).

Enantioselective Synthesis of Substituted Indolizidines
J . Org. Chem., Vol. 65, No. 15, 2000 4549
1-(p-Tolu en esu lfon yl)-1-h ep tyn e (1d ) a n d Acetylen ic
Su lfon es 1b, 1e, 1f, a n d 1j. A solution of 1-heptyne (1.02 mL,
7.79 mmol) and Se-phenyl p-tolueneselenosulfonate34 (1.216
g, 3.910 mmol) in 10 mL of chloroform was irradiated in a
Rayonet minireactor equipped with 300 nm lamps for 1 h.
MCPBA (1.350 g, 7.824 mmol) was added, and the mixture
was stirred at room temperature for 10 min. It was washed
with aqueous KOH, dried (MgSO4), and concentrated in vacuo.
The residue was dissolved in 10 mL of chloroform, and the
mixture was refluxed for 1 h and concentrated in vacuo.
Chromatography of the crude product (elution with 5% ethyl
acetate-hexanes) afforded 799 mg (82%) of 1d 35 as a light
yellow oil: 1H NMR (200 MHz) δ 7.88 (d, J ) 8.4 Hz, 2 H),
7.37 (d, J ) 8.0 Hz, 2 H), 2.47 (s, 3 H), 2.35 (t, J ) 7.1 Hz, 2
H), 1.65-1.45 (m, 2 H), 1.42-1.18 (m, 4 H), 0.87 (t, J ) 6.9
Hz, 3 H); 13C NMR (50 MHz) δ 144.8, 138.9, 129.6, 126.8, 97.2,
78.1, 30.5, 26.4, 21.7, 21.4, 18.6, 13.5; MS(EI) m/z (%) 250 (M+,
0.5), 139 (50), 95 (94), 91 (100).
NMR (50 MHz) δ 144.9, 138.6, 137.3, 129.6, 128.1, 127.4, 127.2,
126.9, 94.0, 78.7, 72.6, 66.0, 21.4, 20.2; MS(EI) m/z (%) 314
(M+, 4), 207 (44), 91 (100). Anal. Calcd for C18H18O3S: C, 68.76;
H, 5.77. Found: C, 68.58; H, 5.95.
Compound 1i was prepared in the same manner from
4-pentyn-1-ol in 75% yield as an oil: IR (film) 2209, 1293, 1156
1
cm-1; H NMR (200 MHz) δ 7.87 (d, J ) 8.4 Hz, 2 H), 7.41-
7.27 (m, 7 H), 4.46 (s, 2 H), 3.49 (t, J ) 5.9 Hz, 2 H), 2.51 (t,
J ) 7.1 Hz, 2 H), 2.46 (s, 3 H), 1.85 (quintet, J ) 6.5 Hz, 2 H);
13C NMR (50 MHz) δ 144.9, 138.9, 137.9, 129.7, 128.1, 127.4,
127.3, 127.0, 96.5, 78.4, 72.8, 67.8, 27.1, 21.5, 15.7; MS(EI)
m/z (%) 328 (M+, 4), 173 (76), 171 (98), 91 (100); HRMS calcd
for C19H20O3S 328.1133, found 328.1133.
Cycliza tion of Ch lor oa m in es w ith Acetylen ic Su lfon es
(see Ta ble 1). A sample procedure is provided below for the
preparation of 12 in entry 1, as well as characterization data
for the other products. The other entries in the Table were
carried out in the same manner as entry 1, except for changes
in conditions during the conjugate addition step as listed in
the table.
Compound 1e was prepared similarly from 1-octyne in 87%
yield and had spectroscopic properties in accord with those
reported for a sample prepared by a different method.36
Compounds 1b,6,18a 1f,18b and 1j19 were prepared by seleno-
sulfonation of the corresponding acetylenes as described
previously.
1-Ben zyl-2-n -bu tyl-3-(p-tolu en esu lfon yl)-1,4,5,6-tetr ah y-
d r op yr id in e (12). Chloroamine 8a 10 was liberated from its
hydrochloride (131 mg, 0.595 mmol) by treatment with aque-
ous KOH solution, extraction with dichloromethane, drying
(MgSO4), and concentration by rotatory evaporator without
heating. A solution of the resulting free base and 1-(p-
toluenesulfonyl)-1-hexyne (1c) (126 mg, 0.534 mmol) in 3 mL
of benzene was refluxed for 18.5 h and concentrated in vacuo.
The residue was dissolved in 3 mL of THF and added to 1.07
mmol of LDA in 3 mL of THF at -78 °C. The mixture was
stirred at -78 °C for 15 min and was then quenched by
filtration through neutral alumina. The filtrate was concen-
trated in vacuo, and the residue was chromatographed (elution
with 10% ethyl acetate-hexanes) to afford 211 mg (94%) of
4-(ter t-Bu tyld im eth ylsilyloxy)-1-(p-tolu en esu lfon yl)-1-
bu tyn e (1g). A solution of 3-butyn-1-ol (102 mg, 1.46 mmol)
and Se-phenyl p-tolueneselenosulfonate34 (224 mg, 0.720 mmol)
in 3.0 mL of chloroform was irradiated at 300 nm for 2 h as in
the preparation of 1d . The mixture was concentrated in vacuo,
and chromatography of the residue (elution with 25% ethyl
acetate-hexanes) furnished the selenosulfonation adduct as
a light yellow oil (237 mg). This was dissolved in 3.0 mL of
DMF, imidazole (86 mg, 1.3 mmol) and tert-butyldimethylsilyl
chloride (182 mg, 1.21 mmol) were added, and the mixture was
stirred at room temperature for 2 h. The solution was diluted
with 10% aqueous HCl, extracted with ether, dried (MgSO4),
concentrated, and chromatographed. Elution with 2% ethyl
acetate-hexanes afforded the corresponding silyl ether as a
yellow oil (295 mg). This was treated with MCPBA (210 mg,
1.22 mmol) and subjected to selenoxide elimination as in the
preparation of 1d . Chromatography (elution with 5% ethyl
acetate-hexanes) provided 155 mg (64%) of 1g as a colorless
12 (based on 1c) as an oil: IR (film) 1566, 1276, 1127 cm-1
;
1H NMR (400 MHz) δ 7.76 (d, J ) 8.2 Hz, 2 H), 7.39-7.25 (m,
5 H), 7.13 (d, J ) 7.1 Hz, 2 H), 4.40 (s, 2 H), 3.08 (t, J ) 5.6
Hz, 2 H), 2.84-2.72 (m, 2 H), 2.52 (t, J ) 6.3 Hz, 2 H), 2.42 (s,
3 H), 1.82-1.72 (m, 2 H), 1.50-1.38 (m, 2 H), 1.37-1.22 (m, 2
H), 0.85 (t, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz) 155.6, 142.1,
141.7, 137.3, 129.0, 128.5, 127.1, 126.1, 125.8, 100.1, 53.5, 48.5,
31.3, 28.3, 24.7, 22.6, 21.3, 21.1, 13.4; MS(EI) m/z (%) 383 (M+,
34), 277 (100), 228 (84); HRMS calcd for C23H29NO2S 383.1919,
found 383.1927.
oil: IR (film) 2202, 1253, 1155 cm-1 1H NMR (400 MHz) δ
;
7.88 (d, J ) 8.3 Hz, 2 H), 7.36 (d, J ) 8.1 Hz, 2 H), 3.74 (t,
J ) 6.4 Hz, 2 H), 2.57 (t, J ) 6.5 Hz, 2 H), 2.47 (s, 3 H), 0.85
(s, 9 H), 0.03 (s, 6 H); 13C NMR (50 MHz) δ 145.1, 138.9, 129.8,
127.3, 94.3, 79.1, 59.9, 25.7, 23.4, 21.6, 18.1, -5.5; MS(EI) m/z
(%) 323 (M+ - Me, 12), 281 (100); HRMS calcd for C17H26O3-
SSi - Me 323.1137, found 323.1156.
(+)-(6S)-1-Ben zyl-6-m eth yl-2-n -p r op yl-3-(p-tolu en esu l-
fon yl)-1,4,5,6-tetr a h yd r op yr id in e (13): oil; IR (film) 1557,
1280, 1127 cm-1; 1H NMR (200 MHz) δ 7.76 (d, J ) 8.4 Hz, 2
H), 7.42-7.24 (m, 5 H), 7.13 (d, J ) 8.2 Hz, 2 H), 4.66 (d, J )
16.4 Hz, 1 H), 4.21 (d, J ) 16.9 Hz, 1 H), 3.39-3.22 (m, 1 H),
3.09 (ddd, J ) 14.4, 10.3, 5.1 Hz, 1 H), 2.70-2.29 (m, 3 H),
2.42 (s, 3 H), 1.75-1.32 (m, 4 H), 1.04 (d, J ) 6.7 Hz, 3 H),
0.91 (t, J ) 7.4 Hz, 3 H); 13C NMR (50 MHz) δ 153.9, 142.0,
141.6, 137.7, 128.9, 128.4, 127.0, 125.9, 125.7, 98.9, 51.6, 51.1,
30.5, 26.3, 22.6, 21.1, 20.4, 16.8, 13.8; MS(EI) m/z (%) 383 (M+,
24), 228 (62), 200 (55), 91 (100); HRMS calcd for C23H29NO2S
4-Ben zyloxy-1-(p-tolu en esu lfon yl)-1-bu tyn e (1h ) a n d
5-Ben zyloxy-1-(p-tolu en esu lfon yl)-1-p en tyn e (1i). 3-Bu-
tyn-1-ol (4.026 g, 57.51 mmol) was added to a suspension of
sodium hydride (60 wt. % in mineral oil) (5.577 g, 139.4 mmol)
in 40 mL of DMF, and the mixture was stirred at 0 °C for 45
min. Benzyl bromide (10.3 mL, 86.6 mmol) was added, and
stirring was continued at 0 °C for 40 min. The mixture was
diluted with ether, washed with 10% aqueous HCl, dried
(MgSO4), and concentrated in vacuo to give a yellow oil. This
was dissolved in 50 mL of chloroform, Se-phenyl p-toluenese-
lenosulfonate34 (8.827 g, 28.38 mmol) was added, and the
mixture was subjected to selenosulfonation and selenoxide
elimination as in the preparation of 1d to afford 4.538 g (51%)
of 1h : mp 54-55 °C (from dichloromethane-hexanes); IR
383.1919, found 383.1932; [R]18 +68.5 (c 1.53, CHCl3).
D
(-)-(7a S)-3-n -Bu tyl-2-(p-tolu en esu lfon yl)-∆2,3-p yr r olizi-
d in e (14): mp 78-79 °C (from dichloromethane-hexanes);
1
IR (KBr) 1567, 1282, 1123 cm-1; H NMR (400 MHz) δ 7.69
(d, J ) 8.2 Hz, 2 H), 7.25 (d, J ) 8.1 Hz, 2 H), 3.77-3.66 (m,
1 H), 3.22 (dt, J ) 10.9, 7.6 Hz, 1 H), 3.18-3.04 (m, 2 H), 2.76-
2.62 (m, 2 H), 2.39 (s, 3 H), 2.20-2.10 (m, 1 H), 1.90-1.67 (m,
3 H), 1.62-1.48 (m, 1 H), 1.47-1.29 (m, 4 H), 0.91 (t, J ) 7.1
Hz, 3 H); 13C NMR (100 MHz) 163.1, 142.3, 140.5, 129.3, 126.3,
104.2, 62.6, 46.4, 33.3, 31.0, 30.3, 25.8, 24.9, 22.6, 21.4, 13.8;
MS(EI) m/z (%) 319 (M+, 37), 290 (42), 213 (100), 120 (99), 91
1
(KBr) 2206, 1293, 1161 cm-1; H NMR (200 MHz) δ 7.89 (d,
J ) 8.5 Hz, 2 H), 7.42-7.23 (m, 7 H,), 4.51 (s, 2 H), 3.61 (t,
J ) 6.6 Hz, 2 H), 2.67 (t, J ) 6.7 Hz, 2 H), 2.46 (s, 3 H); 13C
(75); [R]19 -356.7 (c 1.19, CHCl3). Anal. Calcd for C18H25
-
D
NO2S: C, 67.67; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.94;
N, 4.39.
(34) (a) Back, T. G. In Organoselenium Chemistry-A Practical
Approach; Back, T. G., Ed.; Oxford University Press: Oxford, 1999;
Chapter 5, p 105. (b) Back, T. G.; Collins, S.; Krishna, M. V. Can. J .
Chem. 1987, 65, 38.
(35) Compound 1d was reported previously (ref 18c), but no spec-
troscopic data was provided.
(-)-(8a S)-5-n -P r op yl-6-(p-tolu en esu lfon yl)-∆5,6-in d oli-
zid in e (15): mp 95-96 °C (from dichloromethane-hexanes);
1
IR (KBr) 1551, 1282, 1123 cm-1; H 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
(36) Iwata, N.; Morioka, T.; Kobayashi, T.; Asada, T.; Kinoshita, H.;
Inomata, K. Bull. Chem. Soc. J pn. 1992, 65, 1379.

4550 J . Org. Chem., Vol. 65, No. 15, 2000
Back and Nakajima
(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, 27.4, 25.1, 23.6, 22.3, 21.2,
14.2; MS(EI) m/z (%) 319 (M+, 40), 227 (91), 164 (100), 91 (68);
[R]20D -246.7 (c 1.12, CHCl3). Anal. Calcd for C18H25NO2S: C,
67.67; H, 7.89; N, 4.39. Found: C, 67.91; H, 7.80; N, 4.42.
(-)-(8a S)-5-n -Bu tyl-6-(p-tolu en esu lfon yl)-∆5,6-in d olizi-
d in e (16): mp 109-110 °C (from dichloromethane-hexanes);
(m, 7 H), 0.93 (t, J ) 6.9 Hz, 3 H); 13C NMR (100 MHz) 160.7,
141.5, 141.1, 128.9, 125.6, 98.2, 61.3, 44.1, 34.5, 31.1, 29.9, 25.4,
23.7, 23.4, 22.5, 21.0, 13.4; MS(EI) m/z (%) 333 (M+, 19), 227
(100), 178 (46). Anal. Calcd for C19H27NO2S: C, 68.43; H, 8.16;
N, 4.20. Found: C, 68.10; H, 8.29; N, 4.15.
(()-3-(p-Tolu en esu lfon yl)-∆3,4-q u in olizid in e (22): mp
127-129 °C (from dichloromethane-hexanes); IR (KBr) 1617,
1282, 1159 cm-1; 1H NMR (400 MHz) δ 7.70 (d, J ) 8.2 Hz, 2
H), 7.26 (d, J ) 9.4 Hz, 2 H), 7.17 (s, 1 H), 3.33 (br d, J ) 12.7
Hz, 1 H), 3.01 (dt, J ) 12.5, 2.8 Hz, 1 H), 2.92-2.82 (m, 1H),
2.40 (s, 3 H), 2.25-2.12 (m, 2 H), 1.93-1.80 (m, 2 H), 1.74-
1.64 (m, 2 H), 1.63-1.34 (m, 3 H), 1.32-1.28 (m, 1 H); 13C NMR
(100 MHz) 144.6, 142.2, 139.4, 129.3, 126.8, 102.4, 53.9, 52.9,
31.4, 28.6, 25.8, 23.9, 21.3, 19.0; MS(EI) m/z (%) 291 (M+, 59),
136 (100), 91 (32). Anal. Calcd for C16H21NO2S: C, 65.94; H,
7.26; N, 4.81. Found: C, 65.97; H, 7.04; N, 4.71.
1
IR (KBr) 1541, 1281, 1128 cm-1; H NMR (400 MHz) δ 7.69
(d, J ) 8.2 Hz, 2 H), 7.21 (d, J ) 8.1 Hz, 2 H), 3.47 (br t, J )
8.8 Hz, 1 H), 3.33-3.25 (m, 1 H), 3.25-3.15 (m, 1 H), 2.89-
2.78 (m, 1 H), 2.58 (br dd, J ) 16.1, 3.9 Hz, 1 H), 2.51-2.41
(m, 1 H), 2.37 (s, 3 H), 2.37-2.29 (m, 1 H), 2.16-2.02 (m, 2
H), 1.98-1.88 (m, 1 H), 1.87-1.72 (m, 1 H), 1.60-1.30 (m, 5
H), 1.28-1.13 (m, 1 H), 0.88 (t, J ) 7.1 Hz, 3 H); 13C NMR
(100 MHz) 155.0, 142.5, 141.6, 129.1, 126.0, 97.4, 58.1, 47.0,
32.2, 31.0, 30.0, 27.6, 25.2, 23.7, 23.0, 21.3, 13.7; MS(EI) m/z
(%) 333 (M+, 18), 227 (100); [R]20D -245.4 (c 1.31, CHCl3). Anal.
Calcd for C19H27NO2S: C, 68.43; H, 8.16; N, 4.20. Found: C,
68.12; H, 7.89; N, 4.11.
(()-4-n -Bu tyl-3-(p-tolu en esu lfon yl)-∆3,4-qu in olizid in e
(23): mp 102-103 °C (from dichloromethane-hexanes); IR
(KBr) 1548, 1283, 1183, 1124 cm-1; 1H NMR (400 MHz) δ 7.70
(d, J ) 8.2 Hz, 2 H), 7.24 (d, J ) 8.1 Hz, 2 H), 3.76 (br d, J )
13.5 Hz, 1 H), 3.07-2.99 (m, 1 H), 2.81-2.50 (m, 3 H), 2.58-
2.42 (m, 2 H), 2.40 (s, 3 H), 1.90-1.80 (m, 2 H), 1.72-1.22 (m,
10 H), 0.86 (t, J ) 6.8 Hz, 3 H); 13C NMR (100 MHz) 155.3,
142.4, 141.6, 129.0, 125.7, 101.0, 56.6, 47.8, 32.1, 30.7, 28.4,
28.2, 26.4, 24.2, 22.5, 22.0, 21.1, 13.5; MS(EI) m/z (%) 347 (M+,
27), 241 (100), 192 (88), 150 (79), 91 (77). Anal. Calcd for
(-)-(8a S)-5-n -Hexyl-6-(p-tolu en esu lfon yl)-∆5,6-in d olizi-
d in e (17): mp 75-76 °C (from dichloromethane-hexanes);
1
IR (KBr) 1559, 1291, 1149 cm-1; H NMR (400 MHz) δ 7.72
(d, J ) 8.1 Hz, 2 H), 7.24 (d, J ) 8.0 Hz, 2 H), 3.55-3.45 (m,
1 H), 3.38-3.17 (m, 2 H), 2.95-2.79 (m, 1 H), 2.67-2.56 (m, 1
H), 2.52-2.30 (m, 2 H), 2.39 (s, 3 H), 2.18-2.02 (m, 2 H), 2.00-
1.90 (m, 1 H), 1.88-1.73 (m, 1 H), 1.63-1.15 (m, 10 H), 0.89
(d, J ) 6.9 Hz, 3 H); 13C NMR (50 MHz) δ 154.9, 142.4, 141.5,
129.0, 125.9, 97.2, 58.0, 46.9, 32.1, 31.3, 30.2, 29.5, 28.9, 27.5,
25.2, 23.6, 22.4, 21.2, 13.9; MS(EI) m/z (%) 361 (M+, 23), 227
(100), 206 (61), 136 (61), 91 (60); HRMS calcd for C21H31NO2S
C
20H29NO2S: C, 69.12; H, 8.41; N, 4.03. Found: C, 69.48; H,
8.27; N, 3.98.
(()-4-P h en yl-3-(p -t olu en esu lfon yl)-∆3,4-q u in olizid in e
(24): mp 123-126 °C (from dichloromethane-hexanes); IR
(KBr) 1566, 1294, 1148 cm-1; 1H NMR (400 MHz) δ 7.38-7.20
(m, 3 H), 7.34 (d, J ) 8.2 Hz, 2 H), 7.15-7.02 (m, 2 H), 7.12
(d, J ) 8.0 Hz, 2 H), 3.20-3.10 (m, 1 H), 2.97 (br d, J ) 13.3
Hz, 1 H), 2.70 (ddd, J ) 15.9, 6.8, 4.8 Hz, 1 H), 2.59 (ddd, J )
15.8, 8.5, 4.8 Hz, 1 H), 2.48 (dt, J ) 13.0, 2.3 Hz, 1 H), 2.37 (s,
3 H), 2.02-1.90 (m, 1 H), 1.87-1.75 (m, 1 H), 1.74-1.56 (m, 2
H), 1.52-1.33 (m, 3 H), 1.30-1.15 (m, 1 H); 13C NMR (100
MHz) 154.3, 141.6, 141.6, 134.7, 129.8, 128.9, 128.8, 128.2,
127.5, 127.4, 126.4, 103.9, 56.6, 49.4, 32.4, 28.8, 26.2, 24.2, 21.8,
21.3; MS(EI) m/z (%) 367 (M+, 48), 212 (64), 210 (100), 91 (43).
Anal. Calcd for C22H25NO2S: C, 71.90; H, 6.86; N, 3.81.
Found: C, 71.81; H, 6.59; N, 3.79.
361.2076, found 361.2105; [R]19 -224.1 (c 0.83, CHCl3).
D
(-)-(8R,8a S)-8-Meth yl-5-n -p en tyl-6-(p-tolu en esu lfon yl)-
∆
5,6-in d olizid in e (18): oil; IR (film) 1561, 1283, 1127 cm-1
;
1H NMR (200 MHz) δ 7.72 (d, J ) 8.2 Hz, 2 H), 7.24 (d, J )
7.9 Hz, 2 H), 3.60-3.45 (m, 1 H), 3.40-3.22 (m, 1 H), 2.95-
2.75 (m, 2 H), 2.58 (dd, J ) 15.8, 4.7 Hz, 1 H), 2.52-2.45 (m,
1 H), 2.39 (s, 3 H), 2.21-1.75 (m, 3 H), 1.65-1.18 (m, 9 H),
0.98 (d, J ) 6.5 Hz, 3 H), 0.88 (br t, J ) 6.9 Hz, 3 H); 13C NMR
(50 MHz) δ 154.6, 142.4, 141.4, 128.9, 125.8, 97.0, 63.7, 47.2,
33.4, 32.4, 31.9, 31.0, 30.0, 28.5, 23.6, 22.1, 21.2, 17.8, 13.8;
MS(EI) m/z (%) 361 (M+, 1), 240 (100); HRMS calcd for C21H31
-
NO2S 361.2076, found 361.2053; [R]23D -190.0 (c 1.26, CHCl3).
(-)-(8R,8a S)-5-(2-Ben zyloxyet h yl)-8-m et h yl-6-(p-t olu -
en esu lfon yl)-∆5,6-in d olizid in e (19): oil; IR (film) 1547, 1284,
(()-4-(2-ter t-Bu tyld im eth ylsilyloxy)eth yl-3-(p-tolu en e-
su lfon yl)-∆3,4-qu in olizid in e (25): oil; IR (film) 1561, 1283,
1
1
1147 cm-1; H NMR (400 MHz) δ 7.49 (d, J ) 8.1 Hz, 2 H),
1178 cm-1; H NMR (400 MHz) δ 7.70 (d, J ) 8.2 Hz, 2 H),
7.40-7.25 (m, 5 H), 7.23 (d, J ) 8.0 Hz, 2 H), 4.56 (d, J ) 12.0
Hz, 1 H), 4.52 (d, J ) 12.0 Hz, 1 H), 3.86-3.75 (m, 1 H), 3.74-
3.60 (m, 2 H), 3.40-3.25 (m, 2 H), 3.00-2.81 (m, 2 H), 2.54
(dd, J ) 15.9, 4.5 Hz, 1 H), 2.40 (s, 3 H), 2.20-2.10 (m, 1 H),
2.03-1.85 (m, 2 H), 1.82-1.65 (m, 1 H), 1.45-1.18 (m, 2 H),
0.98 (d, J ) 6.5 Hz, 3 H); 13C NMR (100 MHz) δ 151.2, 142.1,
141.9, 138.6, 129.3, 128.3, 127.6, 127.5, 126.2, 98.5, 73.0, 70.0,
64.1, 48.2, 33.5, 32.5, 31.3, 30.9, 23.7, 21.4, 17.9; MS(EI) m/z
(%) 425 (M+, 0.1), 264 (26), 252 (100), 162 (75), 107 (81); HRMS
calcd for C25H31NO3S 425.2025, found 425.2031; [R]21D -161.1
(c 1.00, CHCl3).
7.24 (d, J ) 8.0 Hz, 2 H), 4.01 (br d, J ) 13.4 Hz, 1 H), 3.77-
3.63 (m, 2 H), 3.18-2.90 (m, 3 H), 2.73 (dt, J ) 12.9, 2.1 Hz,
1 H), 2.50-2.42 (m, 2 H), 2.40 (s, 3 H), 1.88-1.77 (m, 2 H),
1.71-1.64 (m, 1 H), 1.63-1.27 (m, 5 H), 0.89 (s, 9 H), 0.05 (s,
6 H); 13C NMR (100 MHz) 152.2, 142.1, 142.0, 129.3, 126.1,
102.5, 62.6, 57.1, 48.6, 32.5, 32.1, 28.7, 26.7, 26.0, 24.5, 22.3,
21.4, 18.3, -5.3; MS(EI) m/z (%) 449 (M+, 1), 252 (97), 160
(100); HRMS calcd for C24H39NO3SiS 449.2420, found 449.2417.
(()-4-(1-Cycloh exen yl)-3-(p-tolu en esu lfon yl)-∆3,4-qu in -
1
olizid in e (26): oil; IR (film) 1554, 1285, 1131 cm-1; H NMR
(400 MHz) separate signals attributed to cisoid and transoid
conformers of 26 were present in a ca. 1:1 ratio, δ 7.63 (d, J )
8.0 Hz, 2 H), 7.62 (d, J ) 8.0 Hz, 2 H), 5.19 (br s, 1 H), 5.14
(br s, 1 H); other signals overlapped; 13C NMR (100 MHz)
signals of the two conformers could not be unequivocally
assigned and are listed together, δ 157.3, 156.6, 143.1, 142.9,
141.3, 133.1, 132.8, 129.1, 128.7, 128.6, 128.2, 126.0, 100.8,
99.8, 56.3, 55.3, 48.4, 48.3, 32.5, 32.3, 29.5, 29.0, 28.9, 27.9,
26.6, 26.3, 24.9, 24.2, 22.0, 21.9, 21.2, 21.1, 21.0; MS(EI) m/z
(-)-(8R,8a S)-5-(3-Ben zyloxyp r op yl)-8-m eth yl-6-(p-tolu -
en esu lfon yl)-∆5,6-in d olizid in e (20): oil; IR (film) 1562, 1283,
1
1127 cm-1; H NMR (200 MHz) δ 7.71 (d, J ) 8.2 Hz, 2 H),
7.42-7.30 (m, 5 H), 7.23 (d, J ) 7.9 Hz, 2 H), 4.53 (s, 2 H),
3.68-3.48 (m, 3 H), 3.40-3.25 (m, 1 H), 3.08-2.78 (m, 2 H),
2.72-2.49 (m, 2 H), 2.40 (s, 3 H), 2.25-1.68 (m, 6 H), 1.50-
1.19 (m, 2 H), 0.98 (d, J ) 6.5 Hz, 3 H); 13C NMR (100 MHz)
δ 154.1, 142.1, 141.4, 138.3, 129.0, 128.0, 127.1, 127.1, 125.7,
97.2, 72.4, 69.7, 63.7, 47.2, 33.3, 32.3, 30.9, 29.0, 27.0, 23.5,
21.1, 17.7; MS(EI) m/z (%) 439 (M+, 0.6), 240 (100); HRMS
calcd for C26H33NO3S 439.2181, found 439.2191; [R]19D -150.5
(c 2.11, CHCl3).
(%) 371 (M+, 4), 216 (44), 83 (100); HRMS calcd for C22H29
NO2S 371.1919, found 371.1903.
-
(-)-In d olizid in e 167B (31). Trifluoroacetic acid (1.0 mL,
13 mmol) was added dropwise to a suspension of 15 (422 mg,
1.32 mmol) and sodium cyanoborohydride (835 mg, 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 solution, dried (MgSO4), and
concentrated in vacuo to provide a yellow oil. This was
dissolved in 3.5 mL of THF and 30 mL of liquid ammonia.
Sodium (912 mg, 39.7 mg-atom) was added, and the mixture
(()-3-n -Bu t yl-2-(p -t olu en esu lfon yl)-∆2,3-in d olizid in e
(21): mp 118-119 °C (from dichloromethane-hexanes); IR
(KBr) 1556, 1286, 1136 cm-1; 1H NMR (400 MHz) δ 7.70 (d, J
) 8.2 Hz, 2 H), 7.25 (d, J ) 8.1 Hz, 2 H), 3.50 (br d, J ) 13.5
Hz, 1 H), 3.41-3.29 (m, 1 H), 2.80 (dd, J ) 13.3, 10.3 Hz, 1
H), 2.80-2.53 (m, 3 H), 2.39 (s, 3 H), 2.27 (dd, J ) 13.3, 9.7
Hz, 1 H), 1.88-1.78 (m, 1 H), 1.77-1.61 (m, 2 H), 1.50-1.32

Enantioselective Synthesis of Substituted Indolizidines
J . Org. Chem., Vol. 65, No. 15, 2000 4551
was stirred at -33 °C for 15 min. Solid ammonium chloride
was added, and the ammonia was allowed to evaporate. The
residue was dissolved in 10% HCl solution and washed with
ether. The aqueous layer was basified with KOH, and the
product was extracted with ether, dried (MgSO4), and concen-
trated in vacuo to provide crude 31, containing ca. 5% of a
byproduct tentatively assigned as the ∆6,7-derivative 29, on
the basis of the observation of its olefinic signals in the 1H
NMR spectrum. The mixture was hydrogenated in 4 mL of
ethanol over 10% palladium on charcoal (32 mg) at room
temperature and at 1 atm for 1 h. The mixture was filtered
through Celite, and the filtrate was concentrated in vacuo. The
residue was treated with 3.0 mL of 1 M HCl-ether, and the
resulting solid was recrystallized from ethanol-ether, basified
with aqueous KOH solution, extracted with dichloromethane,
dried (MgSO4), and concentrated in vacuo to afford 132 mg
(60%) of (-)-indolizidine 167B (31) 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,
methanol (5.0 mL) and refluxed with a small amount of
decolorizing charcoal for 30 min. It was filtered through Celite,
and the filtrate was concentrated in vacuo to give a yellow
solid, which was recrystallized from ethanol-ether to afford
599 mg (84%) of the hydrochloride salt 35 as white crystals:
mp 265-267 °C; [R]23 -27.2 (c 1.04, CHCl3). Anal. Calcd for
D
C
12H23NCl2: C, 57.14; H, 9.19; N, 5.56. Found: C, 56.79; H,
9.07; N, 5.54.
Basification of 35 with aqueous KOH solution, extraction
with chloroform, drying (MgSO4), and concentration in vacuo
provided a quantitative yield of the quaternary salt 36 as a
colorless oil: 1H NMR (400 MHz) δ 4.52-4.39 (m, 1 H), 4.10-
3.97 (m, 1 H), 3.82 (dt, J ) 12.0, 5.6 Hz, 1 H), 3.70 (t, J ) 9.6
Hz, 1 H), 3.53-3.39 (m, 1 H), 3.35-3.20 (m, 1 H), 2.45-2.15
(m, 6 H), 2.00-1.80 (m, 4 H), 1.78-1.48 (m, 3 H), 1.03 (d, J )
6.2 Hz, 3 H); 13C NMR (100 MHz) δ 74.0, 69.7, 61.4, 49.4, 30.9,
28.9, 27.7, 27.4, 25.0, 18.3, 17.9, 17.8.
(-)-(5S,8R,8a S)-5-(2-H yd r oxyet h yl)-8-m et h ylin d olizi-
d in e (37). Following the procedure described for the prepara-
tion of 31, cyclic enamine 19 was reduced to crude 37
containing a trace of the corresponding ∆6,7 unsaturated
derivative. After hydrogenation, the crude product was sub-
jected to Kugelrohr distillation (bp 110-130 °C at 0.05 mmHg)
14.4; MS(EI) m/z (%) 167 (M+, 4), 124 (100); [R]20 -106.9 (c
D
1.10, CH2Cl2); lit.25b [R]25 -116.6 (c 0.0042, CH2Cl2); lit.25c
D
[R]24 -112 (c 1.25, CH2Cl2); lit.25e [R]20 -115 (c 1.16, CH2-
D
D
Cl2); lit.25h [R]D -111.3 (c 1.3, CH2Cl2).
to afford 66% of 37 as a colorless oil: IR (film) 3600-3100 cm-1
;
1H NMR (200 MHz) δ 4.15 (br s, 1 H), 3.97 (dt, J ) 10.5, 4.4
Hz, 1 H), 3.77-3.62 (m, 1 H), 3.47 (dt, J ) 8.5, 2.7 Hz, 1 H),
2.38-2.21 (m, 1 H), 2.18-1.18 (m, 12 H), 1.15-0.95 (m, 1 H),
0.88 (d, J ) 6.3 Hz, 3 H); 13C NMR (50 MHz) δ 71.3, 61.0,
59.5, 51.9, 35.9, 34.8, 33.2, 29.8, 28.7, 19.9, 18.6; MS(EI) m/z
(-)-In d olizid in e 209D (32). Following the preceding pro-
cedure, cyclic enamine 17 was reduced to crude 32 containing
a trace of the corresponding ∆6,7 unsaturated derivative 30.
Hydrogenation and chromatography of the crude product
(elution with 17% ether-hexanes) afforded 74% of (-)-indolizi-
dine 209D (32) as a colorless oil: 1H NMR (200 MHz) δ 3.27
(dt, J ) 8.4, 2.1 Hz, 1 H), 2.05-1.55 (m, 10 H), 1.54-1.05 (m,
13 H), 0.88 (t, J ) 6.3 Hz, 3 H); 13C NMR (50 MHz) δ 65.0,
63.9, 51.5, 34.6, 31.8, 31.0, 30.9, 30.5, 29.7, 25.8, 24.7, 22.6,
20.4, 14.1; MS(EI) m/z (%) 209 (M+, 0.7), 124, 100); [R]19D -84.9
(%) 183 (M+, 0.7), 182 (1), 138 (100); HRMS calcd for C11H21
-
NO 183.1623, found 183.1622; [R]21 -42.4 (c 1.32, CHCl3).
D
(-)-(5S ,8R ,8a S )-5-(2-Ch lor oe t h yl)-8-m e t h ylin d olizi-
d in e Hyd r och lor id e (38). Following the procedure for the
preparation of 35, the hydrochloride salt of 38 was obtained
as a white solid in 74% yield: mp 153-154 °C (from ethanol-
(c 0.98, CH2Cl2); lit.25c [R]26 -80.6 (c 1.15, CH2Cl2); lit.26b [R]D
D
-83.6 (c 0.77, CH2Cl2); lit.25f [R]20D -76.5 (c 0.74, CH2Cl2); lit.25h
ether); [R]21 -70.0 (c 0.40, CHCl3). Anal. Calcd for C11H21
-
D
[R]D -80.4 (c 1, CH2Cl2); lit.26c [R]20D -87.6 (c 1, CH2Cl2); lit.26d
NCl2: C, 55.46; H, 8.89; N, 5.88. Found: C, 55.12; H, 8.78; N,
5.83. The free base of 38 was used immediately in the next
step: 1H NMR (200 MHz) δ 3.72-3.45 (m, 2 H), 3.23 (dt, J )
8.2, 2.6 Hz, 1 H), 2.28-1.18 (m, 13 H), 1.11-0.92 (m, 1 H),
0.87 (d, J ) 6.3 Hz, 3 H).
[R]25 -89.64 (c 1.880, CH2Cl2).
D
(-)-In d olizid in e 209B (33). Following the procedure de-
scribed for the preparation of 31, cyclic enamine 18 was
reduced to crude 33, which did not contain any of the
corresponding ∆6,7 unsaturated derivative. Chromatography
(elution with 2% triethylamine-hexanes) afforded 66% of (-)-
indolizidine 209B (33) as a pale yellow oil: 1H NMR (400 MHz)
δ 3.27 (dt, J ) 8.7, 2.0 Hz, 1 H), 2.01-1.82 (m, 3 H), 1.88-
1.55 (m, 5 H), 1.54-1.15 (m, 11 H), 1.02-0.92 (m, 1 H), 0.89
(t, J ) 7.0 Hz, 3 H), 0.87 (d, J ) 6.5 Hz, 3 H); 13C NMR (100
MHz) δ 71.3, 63.5, 51.8, 36.5, 34.6, 33.7, 32.2, 31.2, 29.0, 25.4,
22.6, 20.3, 18.8, 14.0; MS(EI) m/z (%) 209 (M+, 1.4), 138 (100);
(-)-In d olizid in e 207A (40). Diallyl dilithium cyanocuprate
(39) was prepared according to a literature procedure.29 An
ethereal solution of methyllithium (6.0 mL, 1.4 M, 8.4 mmol)
was added to a suspension of copper(I) cyanide (379 mg, 4.23
mmol) in 4.0 mL of THF at -78 °C, and the resulting clear
solution was stirred at 0 °C for 5 min. Allyltri-n-butylstannane
(2.68 mL, 8.65 mmol) was then added, and the resulting yellow
mixture was stirred at 0 °C for 50 min. The hydrochloride salt
of 38 (101 mg, 0.424 mmol) was dissolved in dichloromethane,
washed with aqueous KOH solution, dried (MgSO4), and
concentrated in vacuo to give a yellow oil. It was dissolved in
THF (3 mL) and added to the solution containing the cuprate
at -78 °C. After 15 min, the mixture was warmed to 0 °C and
stirred for 1 h. It was diluted with 10% HCl and washed with
ether. The aqueous layer was basified with KOH, and the
product was extracted with ether, dried (MgSO4), and concen-
trated in vacuo. Chromatography (elution with 5% triethyl-
amine-hexanes) provided 53 mg (60%) of (-)-indolizidine
207A (40) as a light yellow oil: 1H NMR (400 MHz) δ 5.81
(ddt, J ) 17.0, 10.2, 6.7 Hz, 1 H), 5.01 (br d, J ) 17.1 Hz, 1
H), 4.95 (br d, J ) 10.2 Hz, 1 H), 3.27 (dt, J ) 8.3, 2.4 Hz, 1
H), 2.15-1.82 (m, 5 H), 1.81-1.59 (m, 5 H), 1.55-1.18 (m, 7
H), 1.10-0.91 (m, 1 H), 0.87 (d, J ) 6.5 Hz, 3 H); 13C NMR
(100 MHz) δ 138.8, 114.4, 71.3, 63.3, 51.8, 36.5, 34.1, 33.7, 31.3,
29.1, 25.1, 20.3, 18.8; MS(EI) m/z (%) 207 (M+, 2.4), 138 (100);
[R]21 -83.5 (c 1.36, CHCl3); lit.28a [R]22.5 -103.2 (c 0.47,
[R]21 -87.7 (c 1.26, MeOH); lit.27b [R]D -96.5 (c 0.62, MeOH);
D
lit.26b [R]D -91.0 (c 0.55, MeOH); lit.27c [R]24 -90.1 (c 1.38,
D
MeOH); lit.16 [R]20D -95 (c 0.585, MeOH); lit.27d [R]28D -91.3 (c
0.58, MeOH); lit.27e [R]20 -94.3 (c 1.85, MeOH).
D
(-)-(5S,8R,8a S)-5-(3-Hyd r oxyp r op yl)-8-m eth ylin d olizi-
d in e (34). Following the procedure described for the prepara-
tion of 31, cyclic enamine 20 was reduced to crude 34
containing a trace of the corresponding ∆6,7 unsaturated
derivative. After hydrogenation, the product was subjected to
Kugelrohr distillation (bp 130-140 °C at 0.05 mmHg) to afford
66% of 34 as a colorless oil: IR (film) 3287 cm-1; 1H NMR (200
MHz) δ 3.75-3.45 (m, 2 H), 3.28 (dt, J ) 8.5, 2.2 Hz, 1 H),
2.15-1.18 (m, 16 H), 1.10-0.91 (m, 1 H), 0.86 (d, J ) 6.3 Hz,
3 H); 13C NMR (50 MHz) δ 71.0, 62.5, 61.9, 51.5, 35.8, 33.3,
31.3, 29.6, 28.6, 28.0, 19.9, 18.6; MS(EI) m/z (%) 196 (M+ - 1,
0.2), 138 (100); HRMS calcd for C12H22NO (M+ - 1) 196.1701,
found 196.1697; [R]18 -65.4 (c 1.10, CHCl3).
D
(-)-(5S,8R,8a S)-5-(3-Ch lor op r op yl)-8-m et h ylin d olizi-
d in e Hyd r och lor id e (35) a n d Its Cycliza tion to th e
Qu a ter n a r y Am m on iu m Sa lt 36. HCl gas was bubbled
through a solution of alcohol 34 (560 mg, 2.84 mmol) in 8 mL
of chloroform at 0 °C. Thionyl chloride (0.630 mL, 8.63 mmol)
was then added, and the mixture was refluxed for 4 h and
concentrated in vacuo. The residue was triturated with
D
D
CHCl3); lit.28b [R]D -85.25 (c 0.174, EtOH); lit.27d [R]28 -86.5
D
(c 0.95, CHCl3).
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial support.

4552 J . Org. Chem., Vol. 65, No. 15, 2000
Back and Nakajima
Su p p or tin g In for m a tion Ava ila ble: 1H- and 13C NMR
spectra of new compounds that do not have elemental analyse
and of (-)-indolizidines 167B, 209D, 209B and 207A (38
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O000080P