A flexible approach toward trisubstituted piperidines and indolizidines: Synthesis of 6-epi-indolizidine 223A

Article abstract of DOI:10.1021/jo034324s

2,5,6-Trisubstituted piperidines are readily prepared by a combination of an aza-Achmatowicz oxidation of a furyl-substituted benzenesulfonamide followed by a conjugate addition to the resulting 2H-pyridone and subsequent addition of various nucleophiles

Full text of DOI:10.1021/jo034324s

A F lexible Ap p r oa ch tow a r d Tr isu bstitu ted P ip er id in es a n d
In d olizid in es: Syn th esis of 6-epi-In d olizid in e 223A
J oel M. Harris† and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received March 11, 2003
2,5,6-Trisubstituted piperidines are readily prepared by a combination of an aza-Achmatowicz
oxidation of a furyl-substituted benzenesulfonamide followed by a conjugate addition to the resulting
2H-pyridone and subsequent addition of various nucleophiles to a transient N-sulfonyliminium
ion. The stereochemistry of the conjugate addition product is the result of axial attack from the
face opposite the diaxial substituents at C2 and C6. This can be attributed to steric hindrance between
the pseudoaxially oriented 2,6-substituents and the equatorially approaching nucleophile, thereby
leading to the exclusive formation of the kinetically favored axial 1,4-adduct. Indolizidine alkaloid
223A was isolated from a skin extract of a Panamanian population of the dendrobatid Dendrobates
pumilio Schmidt (Dendrobatidae). Synthesis of the originally proposed structure of this alkaloid
was achieved in 13 steps in 13.1% overall yield by using an aza-Achmatowicz oxidative rearrange-
ment and a diastereoselective 1,4-conjugate addition as the key steps. The structure of the natural
223A alkaloid (5b) differs from that of the epi-isomer 5a synthesized in this study in the
configuration at the 6-position of the indolizidine ring.
Nitrogen-containing saturated heterocyclic systems are
important core structures in organic chemistry because
of their presence in many natural products.1 For this
reason, simple procedures for the formation of substituted
piperidines and pyrrolidines are highly desirable.2 Aza-
fused bicyclic alkaloids having indolizidine or quinolizi-
dine ring systems have also been the targets of many
synthetic efforts due to their interesting and potent
biological activities including antiviral, antitumor, and
glucosidate inhibitions.3 The bicyclic structural motifs of
these alkaloids are found in a variety of terrestrial and
marine sources such as bacteria, fungi, higher plants,
invertebrates, and vertebrates.4 Accordingly, novel strat-
egies for the stereoselective synthesis of six-membered
aza-bicyclic systems continue to receive attention from
the synthetic community.5-13 In the past, addition of
organometallic reagents to N-acyl pyridinium salts,14
hetero-Diels-Alder reactions of imines,15 Lewis acid or
electrophile-induced cyclizations of imines or iminium
ions,16 and reactions of bicyclo cyano piperidines and
lactams17 have been employed for this purpose. Most of
(5) For recent reviews, see: Sardina, F. J .; Rapoport, H. Chem. Rev.
1996, 96, 1825. Lekevits, E. Chem. Heterocycl. Compd. 1995, 31, 639.
(6) Chutian, S.; Alcudia, A.; Yin, J .; Liebeskind, L. S. J . Am. Chem.
Soc. 2001, 123, 12477. Enders, D.; Thiebes, C. Pure Appl. Chem. 2001,
73, 573. Comins, D. L.; J oseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, E. J ., Ed.; J AI Press: Greenwich, CT, 1996; Vol.
2, p 251. Laschat, S.; Dickner, T. Synthesis 2000, 1781. J ohnson, T.
A.; Curtis, M. D.; Beak, P. J . Am. Chem. Soc. 2001, 123, 1004. Amat,
M.; Perez, M.; Nuria, L.; Bosch, J .; Lago, E.; Molins, E. Org. Lett. 2001,
3, 611.
(7) Ojima, I.; Lula, D. M. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, 1999; Vol.
13, pp 371-412.
(8) J efford, C. W. Curr. Org. Chem. 2000, 4, 205.
(9) Broggini, G.; Zecchi, G. Synthesis 1999, 905.
(10) Kibayashi, C.; Aoyagi, S. Synlett 1995, 873.
† NIH Postdoctoral fellow; grant GM 64027-0.
(11) Husson, H.-P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383.
(12) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Bieraugel, H. Eur.
J . Org. Chem. 1999, 959.
(13) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev.
1995, 95, 1677.
(14) Comins, D. L.; Killpack, M. O. J . Am. Chem. Soc. 1992, 114,
10973. Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem. Soc.
1994, 116, 4719.
(15) Grieco, P. A.; Larsen, S. D. J . Am. Chem. Soc. 1985, 107, 1768.
Waldmann, H.; Braun, M. J . Org. Chem. 1992, 57, 4444. Ishihara, K.;
Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J . Am. Chem. Soc.
1994, 116, 10520.
(16) Flann, C.; Malone, T. C.; Overman, L. E. J . Am. Chem. Soc.
1987, 109, 6097. Tietze, L. F.; Bratz, M. Chem. Ber. 1989, 122, 997.
Overman, L. E.; Sarkar, A. K. Tetrahedron Lett. 1992, 33, 4103.
Laschat, S.; Fro¨hlich, R.; Wibbeling, B. J . Org. Chem. 1996, 61, 2829.
(17) Guerrier, L.; Royer, J .; Grierson, D. S.; Husson, H. P. J . Am.
Chem. Soc. 1983, 105, 7754. Amat, M.; Llor, N.; Bosch, J . Tetrahedron
Lett. 1994, 35, 2223. Munchhof, M. J .; Meyers, A. I. J . Am. Chem. Soc.
1995, 117, 5399. Francois, D.; Lallemand, M. C.; Selkti, M.; Tomas,
A.; Kunesch, N.; Husson, H. P. Angew. Chem., Int. Ed. 1998, 37, 104.
(1) Roth, H. J .; Kleeman, A. Pharmaceutical Chemistry; J ohn Wiley
and Sons: New York, 1988. Elbein, A. D.; Molyneux, R. In Alkaloids,
Chemical and Biological Perspectives; Pelletier, W., Ed.; J ohn Wiley
and Sons: New York, 1987; Vol. 57, p 1. Gogfraid, T.; Miller, R.; Wibo,
M. Pharmacol. Rev. 1986, 38, 321.
(2) Dewick, P. M. In Medicinal Natural Products; J . Wiley & Sons:
Chichester, UK, 1997; Chapter 6. Pichon, M.; Figadere, B. Tetrahedron:
Asymmetry 1996, 7, 927 and references therein. Yus, M.; Foubelo, F.
J . Org. Chem. 2001, 66, 6207. Hill, K. R. Chem. Alkaloids 1970, 385.
Laschat, S.; Dickner, T. Synthesis 2000, 13, 1781. Laschat, S. Liebigs
Ann. 1997, 1, 1. Wang, C. J . J .; Wuonola, M. A. Org. Prep. Proced. Int.
1992, 24, 583. Baliah, V.; J eyaraman, R.; Chandrasekaran, L. Chem.
Rev. 1983, 83, 379.
(3) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles 1988, 27, 1465.
Robins, D. J . Nat. Prod. Rep. 1995, 12, 413. Michael, J . P. Nat. Prod.
Rep. 1997, 14, 619.
(4) Bosch, J .; Bonjoch, J . Studies in Natural Product Chemistry;
Rahman, A. U., Ed.; Elseview: New York, 1988; Vol. 1, p 31. O’Hagan,
D. Nat. Prod. Rep. 2000, 17, 435-446. Bailey, P. D.; Millwood, P. A.;
Smith, P. D. Chem. Commun. 1998, 6, 633.
10.1021/jo034324s CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
J . Org. Chem. 2003, 68, 4371-4381
4371

Harris and Padwa
F IGURE 1. Indolizidine (1) and quinolizidine (3) scaffolds.
F IGURE 2. Structures of indolizidine 223A.
the known indolizidine alkaloids are either 3,5- or 5,8-
substituted (Figure 1).18
SCHEME 1
Quite a number of indolizidine alkaloids have been
isolated from the skin secretions of neotropical frogs,19
and some have been shown to function as noncompetitive
blockers for muscle-type and ganglionic nicotinic receptor
channels.20 Of these, indolizidines 167B (1) and 209D (2),
structurally simple bicyclic gephyrotoxin alkaloids pos-
sessing a single substituent at C5 of the indolizidine
skeleton,21 were isolated in minute quantities from
unidentified dendrobatid frogs in a single population and
have been attractive synthetic targets.22,23 In 1997, a new
subclass of amphibian alkaloids (223A) was isolated from
a skin extract of a Panamanian population of the frog
dendrobatid Dendrobates pumilio Schmidt (Dendro-
batidae).24 Three homologues of indolizidine 223A were
also detected with different substituents, but their rela-
tive stereochemical structures have yet to be determined.
Alkaloid 223A possesses the relatively rare 5,6,8-trisub-
stituted indolizidine ring. The structure of 223A was
originally postulated as 5a based upon GC-MS, GC-FTIR,
by a total synthesis, using a series of Michael-type
conjugate additions to enaminoesters as the key steps.26
A critical problem in the total synthesis of various
indolizidine alkaloids involves setting the stereocenters
in the piperidine ring. When we initiated our work in
this area in early 2001, our synthetic goal was to develop
a stereoselective synthesis of 5a since that was the
presumed structure of 223A at that point in time.24 We
envisioned an approach to indolizidines such as 9 (Scheme
1) that is based on an aza-Achmatowicz oxidation reac-
tion, a process defined as the conversion of furylamides
such as 6 into 1,6-dihydro-2H-pyridin-3-ones (i.e., 7).27
This novel oxidative rearrangement has been used for
the synthesis of azasaccharides,28 izidine structures,
â-lactam intermediates, and unusual amino acids and,
we believe, possesses significant potential for the prepa-
ration of a variety of piperidine-based alkaloids.29 In this
paper we describe the successful application of this
approach for the synthesis of 6-epi-indolizidine 223A (5a ).
1
and H NMR spectral studies.24 In a subsequent report
published last year, the original proposed configuration
at the 6-position of 223A was found to be incorrect and
the structure was subsequently revised to 5b.25 The
relative stereochemistry of natural 223A was established
(18) Michael, J . P. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, CA, 2001; Vol. 55, pp 91-258. Micheal, J . P. Nat.
Prod. Rep. 2000, 17, 579. Daly, J . W. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: San Diego, CA, 1998; Vol. 50, pp 141-171. Daly,
J . W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: San Diego, CA, 1993; Vol. 43, pp 185-288.
(19) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly,
J . W. Tetrahedron 1986, 42, 3453.
(20) Aronstam, R. S.; Daly, J . W.; Spande, T. F.; Narayanan, T. K.;
Albuquerque, E. X. Neurochem. Res. 1986, 11, 1227.
(21) Daley, J . W. Fortschr. Chem. Org. Naturst. 1982, 41, 205.
(22) For some syntheses of indolizidine 167B, see: Polniaszek, R.
P.; Belmont, S. E. J . Org. Chem. 1990, 55, 4688. J efford, C. W.; Tang,
Q.; Zaslona, A. J . Am. Chem. Soc. 1991, 113, 3513. J efford, C. W.;
Wang, J . B. Tetrahedron Lett. 1993, 34, 3119. Takahata, H.; Bandoh,
H.; Momose, T. Heterocycles 1995, 41, 1797. Lee, E.; Li, K. S.; Lim, J .
Tetrahedron Lett. 1996, 37, 1445. Weymann, M.; Pfrengle, W.; Scholl-
meyer, D.; Kunz, H. Synthesis 1997, 1151. Angle, S. R.; Henry, R. M.
J . Org. Chem. 1997, 62, 8549. Chalard, P.; Remuson, R.; Gelas-Mialhe,
Y.; Gramain, J . C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661.
Cheˆnevert, R.; Ziarani, G. M.; Dasser, M. Heterocycles 1999, 51, 593.
(23) For some syntheses of indolizidine 209D, see: Ahman, J .;
Somfai, P. Tetrahedron Lett. 1995, 51, 303. Ahman, J .; Somfai, P.
Tetrahedron 1995, 51, 9747. Nukui, S.; Sodeoka, M.; Sasai, H.;
Shibasaki, M. J . Org. Chem. 1995, 60, 398. J efford, C. W.; Sienkiewicz,
K.; Thornton, S. R. Helv. Chim. Acta 1995, 78, 1511. Takahata, H.;
Kubota, M.; Ihara, K.; Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi,
A. T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998, 9, 3289.
Cheˆnevert, R.; Ziarani, G. M.; Morin, M. P.; Dasser, M. Tetrahedron:
Asymmetry 1999, 10, 3117. Yamazaki, N.; Ito, T.; Kibayashi, C. Org.
Lett. 2000, 2, 465. Back, T. G.; Nakajima, K. J . Org. Chem. 2000, 65,
4543.
Resu lts a n d Discu ssion
aza-Achmatowicz products incorporate functionality
that is easily modified and can be utilized to construct
complex nitrogen heterocycles. In his early studies of the
aza-Achmatowicz reaction, Ciufolini reported that car-
bamate protected furfurylamines are somewhat unstable
and readily hydrolyze to 3-hydroxypyridines under typi-
cal oxidation conditions.27 Independent work by Zhou30
and Altenbach,31 however, showed that a sulfonamide
(26) Momose, T.; Toyooka, N. J . Org. Chem. 1994, 59, 943. Toyooka,
N.; Tanaka, K.; Momose, T.; Daly, J . W.; Garraffo, H. M. Tetrahedron
1997, 53, 9553.
(27) For an excellent review of the subject, see: Ciufolini, M. A.;
Hermann, C. Y. W.; Dong, Q.; Shimiizu, T.; Swaminathan, S.; Xi, N.
Synlett. 1998, 105.
(28) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401.
(29) For a preliminary report, see: Harris, J . M.; Padwa, A. Org.
Lett. 2002, 4, 2029.
(24) Garraffo, H. M.; J ain, P.; Spande, T. F.; Daly, J . W. J . Nat.
Prod. 1997, 60, 2.
(25) Toyooka, N.; Fukutome, A.; Nemoto, H.; Daly, J . W.; Spande,
T. F.; Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4, 1715.
4372 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of 6-epi-Indolizidine 223A
SCHEME 2a
SCHEME 3a
a
Reagents and conditions: (a) TsNH2, BF3‚OEt2, heat, 80%; (b)
MeMgI, THF, 0 °C, 95%; (c) m-CPBA, CH2Cl2, 0 °C, 85%; (d)
(MeO)3CH, BF3‚OEt2, CH2Cl2, 0 °C, 85%.
protecting group was nicely compatible with the aza-
Achmatowicz oxidation reaction. Consequently, we chose
to work with an N-tosyl protecting group because of its
robust nature and the ease of purification of the resulting
products. To test our strategy for the eventual synthesis
of indolizidine 223A, we needed to evaluate the stereo-
chemical aspects of the proposed 1,4-conjugate addition
to the dihydro-2H-pyridone intermediate (i.e., 7 f 8)
(Scheme 1).
a
Reagents and conditions: (a) MeLi, CuCN, Et2O, -78 °C; (b)
PhLi, CuCN, THF, -78 °C; (c) vinylMgBr, CuI, THF, -78 °C; (d)
EtMgBr, CuI, THF, -78 °C; (e) PhSH, MeOH, 0 °C; (f) NH2CH2-
CO2Me, Et3N, MeOH, rt.
Treatment of 2H-pyridinone 14 with various cuprate
reagents (Scheme 3, entries 1-4) proved to be remark-
ably stereoselective, providing the Michael adducts 15-
18 in pure diastereomeric form and in high yield.
Thiophenol and glycine methyl ester also furnished 1,4-
addition products 19 and 20 in high yield.36 The stereo-
chemistry of the Michael addition products was unam-
biguously assigned on the basis of NMR spectroscopic
analysis as well as an X-ray crystal structure of com-
pound 15. The stereochemistry of the conjugate addition
product is the result of axial attack from the face opposite
the diaxial substituents at C2 and C6. This may be
attributed to steric hindrance between the pseudoaxially
oriented 2,6-substituents and the equatorially approach-
ing nucleophile, thereby leading to the exclusive forma-
tion of the kinetically favored axial 1,4-adduct.37 It should
be noted that related conjugate additions in the literature
with dihydropyranulosides as substrates generally led to
the formation of a mixture of diastereomers.38 More than
likely, the absence of a tosyl group makes the molecule
more flexible, thereby permitting attack from both sides
of the π-bond.38
Stereoselective functionalization of the pyridinone ring
at the 6-position was accomplished by treating the
heterocyclic system with allyl trimethylsilane under the
influence of BF3‚OEt2 at 0 °C (Scheme 4). For example,
the reaction of compound 14 with CH2dCHCH2SiMe3 and
BF3‚OEt2 afforded 21 in 85% yield. Similarly, treating
15 and 18 with allyl silane under comparable reaction
conditions furnished 22 and 23 in 85% yield, respectively.
Isopropenyl acetate reacted with 15 in the presence of
BF3‚OEt2 to give ketone 24 in 85% isolated yield. In all
Preparation of a model furyl sulfonamide (i.e., 12) was
first carried out to probe the stereochemical issues that
we would need to deal with in our planned approach
toward indolizidine alkaloid 223A. The synthesis of 12
was readily accomplished by condensation of furfural (10)
with p-toluenesulfonamide, using BF3‚OEt2 as the cata-
lyst (80% yield) (Scheme 2). Treatment of the resulting
imine 11 with methylmagnesium iodide produced 12 in
95% yield. Sulfonylamide 12 was oxidatively rearranged
by using m-CPBA in the aza-Achmatowicz reaction to
furnish hemiaminal 13 in 85% yield. Conversion of the
hydroxyl to the corresponding methoxy group was carried
out by using trimethylorthoformate and catalytic BF3‚
OEt2 which afforded 6-methoxy-2-methyl-1-(toluene-4-
sulfonyl)-1,6-dihydro-2H-pyridin-3-one (14) in 85% yield.
The stereochemical assignment of 14 as the cis-isomer
is based on NMR spectroscopic analysis (1D-NOE). The
exclusive formation of 14 can be rationalized by assuming
that A1,3-strain of the tosyl group forces the methoxy and
methyl groups to adopt a pseudoaxial orientation. It
should be noted that this stereochemistry (vide infra)
does not follow from previous literature results with
related systems.32,33 The earlier reports have either
suggested that the trans-dihydropyridinone isomer re-
sults from the oxidative cyclization,32 or else the config-
uration of the product was not unequivocally elucidated.33
1
The H NMR data for dihydropyridinone 14 was consis-
tent with those of similar compounds determined to have
the cis-stereochemistry at C2 and C6.34,35
(30) Yang, C. F.; Xu, Y. M.; Liao, L. X.; Zhou, W. S. Tetrahedron
Lett. 1998, 39, 9227.
(31) Altenbach, H. J .; Wischnat, R. Tetrahedron Lett. 1995, 36, 4983.
(32) Zhou, W. S.; Lu, Z. H.; Xu, Y. M.; Liao, L. X.; Wang, Z. M.
Tetrahedron 1999, 55, 11959. Zhou, W. S.; Xie, W. G.; Lu, Z. H.; Pan,
X. F. J . Chem. Soc., Perkin Trans. 1 1995, 2599.
(33) Lu, Z. H.; Zhou, W. S. J . Chem. Soc., Perkin Trans. 1 1993,
593. Zhou, W. S.; Xie, W. G.; Lu, Z. H.; Pan, X. F. Tetrahedron Lett.
1995, 36, 1291.
(35) Liao, L. X.; Wang, Z. M.; Shang, Z. X.; Zhou, W. S. Tetrahedron:
Asymmetry 1999, 10, 3649.
(36) For some related 1,4-additions, see ref 34.
(37) The 2-axial conformation of N-acylpiperidines is well estab-
lished. See: Brown, J . D.; Foley, M. A.; Comins, D. L. J . Am. Chem.
Soc. 1988, 110, 7445.
(38) Apostolopoulos, C. D.; Couladouros, E. A.; Georgiadis, M. P.
Liebigs Ann. Chem. 1994, 781. Couladouros, E. A.; Apostolopoulos, C.
D.; Georgiadis, M. P. Carbohydr. Res. 1993, 249, 399.
(34) Koulocheri, S. D.; Magiatis, P.; Skaltsounis, A. L.; Haroutou-
nian, S. A. Tetrahedron 2000, 56, 6135.
J . Org. Chem, Vol. 68, No. 11, 2003 4373

Harris and Padwa
SCHEME 4a
SCHEME 5a
a
Reagents and conditions: (a) CH2dCHCH2SiMe3, BF3‚OEt2,
CH2Cl2, 0 °C, 80%; (b) Grubbs catalyst, CH2Cl2, 25 °C, 60%; (c)
CH2dCHCH2SiMe3, TiCl4, CH2Cl2, 0 °C, 90%; (d) Grubbs catalyst,
CH2Cl2, 25 °C, 80%.
a
Reagents and conditions: (a) CH2dCHCH2SiMe3, BF3‚OEt2,
ium ions by reaction with various nucleophiles in the
presence of a Lewis acid. The stereochemistry associated
with the conjugate additions was established by X-ray
analysis and is believed to arise from A1,3-strain between
the tosyl and adjacent substituents. Encouraged by these
results we decided to apply the method toward the
synthesis of the originally proposed indolizidine alkaloid
223A (5a ).
CH2Cl2, 0 °C, 85%; (b) CH2dC(OAc)Me, BF3‚OEt2, CH2Cl2, 0 °C,
70%; (c) CH2dCHCH2SiMe3, BF3‚OEt2, CH2Cl2, 0 °C, 85%.
of the above examples, a single diastereomer was isolated
whose stereochemistry was assigned as the 2,6-cis-
disubstituted isomer. This assignment rests on literature
analogy39 and is also consistent with a NOE enhancement
between the hydrogens on the C2-methyl group and the
methylene hydrogens of the allyl side chain at C6. As
suggested by others,40 the preference for the 2,6-cis-
Syn th esis of 6-epi-In d olizid in e 223A (5a ). The
scarcity of 5,6,8-trisubstituted indolizidines as natural
products and the uncertainty surrounding the originally
proposed structure of indolizidine 223A (5a ) prompted
us to attempt its synthesis. With the model conjugate
addition studies of dihydropyridone 14 in hand, we
turned our attention to the synthesis of the structurally
more complex dihydro-2H-pyridone 32, which bears the
requisite three-carbon side chain at the C2-position of the
ring necessary for the eventual preparation of 5a (see
Scheme 1). Our initial efforts to prepare furyl sulfona-
mide 30 using the Grignard reagent derived from a silyl-
protected 3-bromopropan-1-ol as outlined in Scheme 2
furnished a complex mixture of products. Instead, we
opted to synthesize 30 by first preparing the benzophe-
none-derived imine 29. Treatment of this compound with
n-BuLi followed by reaction of the resulting lithiate with
1-bromo-3-tert-butyldiphenyl-siloxypropane afforded the
expected alkylated imine. A subsequent hydrolysis was
followed by treatment of the resulting amine with tosyl
chloride, which gave sulfonamide 30 in 66% overall yield
from furfurylamine (Scheme 6). Oxidative rearrangement
of 30 by treatment with 1.2 equiv of m-CPBA in CH2Cl2
for 4 h at room temperature yielded the 6-hydroxy-2,6-
dihydropyridinone 31 as a single diastereomer. Com-
pound 31 reacted with allyl silane under the influence
of BF3‚OEt2 to produce the desired dihydropyridinone 32
in 64% yield over two steps.43 The stereochemical assign-
ment of 32 as the cis-isomer is based on NMR spectro-
scopic analysis (1D-NOE). We believe that the steric bulk
of the tosyl group directs the attack of the nucleophile of
the intermediate N-sulfonyliminium ion to the side of the
C2-substituent group, resulting in the formation of the
cis-product.
disubstituted product can be rationalized by the A1,3
-
strain present between the tosyl and methyl groups
thereby causing the tosyl group to shield the opposite face
of the molecule. The steric bulk associated with the tosyl
group directs the attack of the nucleophile on the imi-
nium ion to the side of the C2-methyl group, leading to
the formation of the cis-product.
In the past few years, the use of the ring-closing
metathesis reaction (RCM)41 for creating heterocyclic
systems42 from acyclic diolefins has increased enormously
as a result of the ruthenium alkylidene catalysts that
have been developed by Grubbs and co-workers.41
Prompted by the ease with which pyridinones 25 and 27
can be prepared (Scheme 5), we decided to investigate
their ring-closing olefin metathesis chemistry. The key
cyclization reaction of 25 and 27 was performed with the
Grubbs ruthenium benzylidene catalyst Cl2(PCy3)2-
RudCHPh (3 mol %) in CH2Cl2 under an atmosphere of
nitrogen. Dienes 25 and 27 were completely consumed
within 3 h at room temperature furnishing the hexa-
hydro-1H-pyridine and octahydroquinoline ring systems
26 and 28 in 60 and 80% yield, respectively.
The above model studies show that 2-methyl-6-meth-
oxy-2,6-dihydro-2H-pyridin-3-one (14) readily undergoes
conjugate addition with various nucleophiles to deliver
cis-substituted 2,6-piperidines. The resulting products
can be further utilized as precursors for N-sulfonylimin-
(39) Shono, T.; Matsumara, Y.; Tsubata, K.; Uchida, K. J . Org.
Chem. 1986, 51, 2590.
(40) Hopman, J . C. P.; van de Berg, E.; Ollero, L. O.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315.
(41) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(42) For several examples of the synthesis of piperidines via olefin
metathesis, see: Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992,
114, 7324. Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett. 1996, 65.
Rutjes, F. P. J . T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677.
J o, E.; Na, Y.; Chang, S. Tetrahedron Lett. 1999, 40, 5581.
(43) So as to shorten the overall synthesis, the crude hemiaminal
31 was treated directly with BF3‚OEt2 and allyl silane instead of
converting it to the corresponding methoxy derivative as had been done
with the related hemiaminal 13.
4374 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of 6-epi-Indolizidine 223A
SCHEME 6a
SCHEME 8a
a
Reagents and conditions: (a) n-BuLi, THF, BrCH2CH2CH2OTB-
DPS, 86%; (b) 1 N HCl, acetone, 95%; (c) TsCl, NEt3, CH2Cl2, 90%;
(d) m-CPBA, CH2Cl2; (e) CH2dCHCH2SiMe3, BF3‚OEt2, CH2Cl2,
0 °C, 64% over two steps.
SCHEME 7a
a
Reagents and conditions: (a) PtO2, H2, EtOH, 95%; (b) TBAF,
THF, 90%; (c) Na, C10H8, -78 °C; (d) CBr4, PPh3, Et3N, 50% over
three steps; (e) PtO2, H2, EtOH, 90%.
settled on a sequence that involved converting 33 to the
corresponding vinyl triflate (34). This turned out to be
an extremely facile process and proceeded in excellent
yield. Thus, treatment of pyridinone 33 with N-phenyl-
trifluoromethane sulfonimide44 in THF at -78 °C with
NaHMDS afforded triflate 34 in 95% yield. Installation
of a C2-carbon group was accomplished by using the
standard Stille coupling conditions45 of vinyl tributyltin,
Pd(PPh3)4, and lithium chloride, which afforded triene
35 in 85% yield (Scheme 7).
With ready access to triene 35, we initially opted to
reduce all of the π-bonds present in the molecule. Our
first efforts were directed toward catalytic hydrogenation
using palladium on charcoal as the catalyst. However,
all of our attempts to fully reduce triene 35 with this
catalyst as well as other platinum, rhodium, and iridium
catalysts failed to give any detectable quantities of the
desired tetrasubstituted piperidine. Fortunately, reduc-
tion of triene 35 to 1,2,3,6-tetrahydropyridine 36 with 1
atm of hydrogen and PtO2 over a 36-h period proceeded
smoothly and in 95% yield (Scheme 8). Final cyclization
of the indolizidine core was accomplished by first removal
of the silyl group with TBAF. The next step involved
cleavage of the N-tosyl functionality. Removal of N-tosyl
groups is substrate dependent and often requires harsh
conditions such as HBr/AcOH.46 We found, however, that
cleavage of the sulfonyl group from 37 occurred easily
when sodium naphthalenide (3 equiv) in THF was used.47
a
Reagents and conditions: (a) (Et)2CuMgBr, THF, 0 °C, 90%;
(b) PhNTf2, NaHMDS, -78 °C, 95%; (c) CH2dCHSnBu3, Pd-
(PPh3)4, LiCl, THF, 85%.
The next step involved Michael addition of an ethyl
group onto the â-position of the enone π-system. We were
pleased to find that the reaction of 32 with (Et)2CuMgBr
in THF at -78 °C gave the 1,4-conjugate addition product
33 as a single diastereomer in 90% yield (Scheme 7). The
1
stereochemistry of 33 was determined by the H NMR
coupling constants and NOE enhancements. The high
diastereoselectivity encountered in the formation of 33
can be rationalized by axial attack of the organo-cuprate
reagent from the face opposite the diaxial substituents
at C2 and C6 as was similarly observed in our model
studies with dihydropyridinone 14.
To install the remaining carbon functionality present
in indolizidine 223A, we needed to convert the keto group
into a C3-ethyl substituent and also control the stereo-
chemistry at this carbon site. Our first attempts involved
a Wittig or J ulia olefination reaction at the ketonic
center. However, all of our efforts to carry out this
transformation failed and only recovered starting mate-
rial was obtained. The low reactivity of pyridinone 33 is
probably related to the fact that the substituent groups
at C2, C3, and C6 are all in an axial orientation thereby
creating a sterically crowded environment around the
carbonyl group. After considerable experimentation, we
(44) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(45) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(46) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991; pp 379-381.
(47) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311.
J . Org. Chem, Vol. 68, No. 11, 2003 4375

Harris and Padwa
and 7.2 Hz), 5.37 (d, 1H, J ) 8.4 Hz), 5.97 (dd, 1H, J ) 3.2
and 0.8 Hz), 6.12 (dd, 1H, J ) 3.2 and 1.6 Hz), 7.14 (dd, 1H,
J ) 1.6 and 0.8 Hz), 7.21 (d, 2H, J ) 8.4 Hz), and 7.68 (d, 2H,
J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 20.7, 21.4, 47.2,
106.0, 109.9, 126.9, 129.3, 137.5, 141.7, 143.0, and 154.0.
Rather than isolate and purify the expected secondary
amine 38, we simply converted the hydroxyl group into
the corresponding bromide with carbon tetrabromide and
triphenylphosphine. Addition of an excess of triethy-
lamine resulted in spontaneous cyclization to give 39 in
50% overall yield for the 3-step sequence starting from
36. Reduction of the double bond present in 39 proceeded
without difficulty. Thus, subjection of a sample of 39 to
an atmosphere of hydrogen with PtO2 as the catalyst
proceeded from the least hindered side and furnished
racemic epi-indolizidine 223A (5a ) in 98% yield (Scheme
8). The 1H and 13C NMR and IR spectra of 5a did not
match the literature values originally reported by Daly
and co-workers.24 That our synthesis has delivered the
originally proposed structure24 is beyond doubt, given the
excellent agreement between our data and the spectro-
scopic properties reported by Professor Toyooka for epi-
indolizidine 223A (5a ) in the recent 2002 communication
(see Supporting Information).25,48
In conclusion, we have described a 13-step synthesis
of epi-indolizidine 223A (5a ) in 13.1% overall yield. The
approach involves a flexible combination of an aza-
Achmatowicz oxidative rearrangement followed by a
stereoselective allylsilane addition to a N-sulfonylimin-
ium ion and a subsequent 1,4-conjugate addition. These
synthetic studies have allowed us to define the scope of
the aza-Achmatowicz reaction and to optimize the dias-
tereoselective introduction of substituents at the 5-, 6-,
and 8-positions of the indolizidine skeleton. Further
application of this strategy for related indolizidine alka-
loids is under study and will be reported at a later date.
6-Meth oxy-2-m eth yl-1-(tolu en e-4-su lfon yl)-1,6-dih ydr o-
2H-p yr id in -3-on e (14). A 0.39-g (1.1 mmol) sample of sul-
fonamide 12, 4 mL of CH2Cl2, and 0.39 g (2.3 mmol) of m-CPBA
were placed in a round-bottom flask and the mixture was
stirred for 2 h. The reaction was quenched with a saturated
aqueous NaHCO3 solution (15 mL) and 15 mL of ether was
added. The solution was extracted with ether, the layers were
separated, and the organic layer was dried (MgSO4). Concen-
tration under reduced pressure followed by purification by
silica gel chromatography gave 0.27 g (85%) of 6-hydroxy-2-
methyl-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-one
(13): IR (thin film) 1686, 1597, 1165, and 1066 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.59 (d, 3H, J ) 7.2 Hz), 2.38 (s, 3H),
3.82 (br s, 1H), 4.36 (q, 1H, J ) 7.2 Hz), 5.90 (dd, 1H, J ) 4.8
and 1.2 Hz), 5.96 (dd, 1H, J ) 10.0 and 1.2 Hz), 6.86 (dd, 1H,
J ) 10.4 and 4.8 Hz), 7.25 (d, 2H, J ) 8.4 Hz), and 7.62 (d,
2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5, 22.1, 57.0,
73.3, 126.2, 126.7, 130.0, 136.5, 143.5, 144.3, and 195.3.
The above 6-hydroxy-2H-pyridin-3-one (1.0 g, 3.5 mmol) was
dissolved in 20 mL of CH2Cl2 and trimethyl orthoformate (780
µL, 7.1 mmol) and BF3‚OEt2 (45 µL, 0.36 mmol) were added
to the solution. The solution was stirred for 3 h at 0 °C and
quenched with a saturated aqueous NaHCO3 solution (25 mL)
and 40 mL of ether was added. The solution was extracted
with ether, the layers were separated, and the organic layer
was dried (MgSO4). Concentration under reduced pressure and
purification by silica gel chromatography gave 0.89 g (85%) of
14: mp 113-115 °C; IR (thin film) 1692, 1597, 1340, 1080,
and 1014 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.56 (d, 3H, J )
7.6 Hz), 2.38 (s, 3H), 3.57 (s, 3H), 4.30 (q, 1H, J ) 7.6 Hz),
5.58, (dd, 1H, J ) 4.8 and 0.8 Hz), 5.82 (dd, 1H, J ) 10.4 and
0.8 Hz), 6.82 (dd, 1H, J ) 10.4 and 4.8 Hz), 7.24 (dd, 2H, J )
8.0 and 1.2 Hz), and 7.56 (dd, 2H, J ) 8.0 and 1.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 20.8, 21.5, 56.0, 57.2, 80.7, 126.6,
126.8, 130.0, 136.1, 142.5, 144.1, and 195.5. Anal. Calcd for
Exp er im en ta l Section
N-(1-F u r a n -2-ylet h yl)-4-m et h ylb en zen esu lfon a m id e
(12). A 28.1-g (292 mmol) sample of 2-furfural (10), 300 mL of
toluene, 40.0 g (234 mmol) of p-toluenesulfonamide, and 0.5 g
(3 mmol) of p-toluenesulfonic acid were placed in a round-
bottom flask with a Dean-Stark trap and heated at reflux for
10 h. The reaction turned a deep brown color. After 10 h,
charcoal was added to the hot solution and the mixture was
stirred for 1 h and filtered. The solvent was removed under
reduced pressure to give N-1-furan-2-ylmethylene-4-methyl-
benezenesulfonamide (11) as a tan solid. Recrystallization from
benzene gave 62.0 g (85%) of 11 as pure brown crystal: mp
100-101 °C (lit.49 mp 101-102 °C); IR (thin film) 1605, 1542,
C
14H17NO4S: C, 56.93; H, 5.81; N, 4.75. Found: C, 56.81; H,
5.69; N, 4.70.
6-Met h oxy-2,5-d im et h yl-1-(t olu en e-4-su lfon yl)p ip er i-
d in -3-on e (15). In a 10-mL round-bottom flask under nitrogen
was added CuCN (0.1 g, 1.1 mmol) and 2 mL of THF and the
mixture was cooled to -78 °C. A solution of MeLi (2.2 mL of
1.0 M ether solution) was added dropwise and the solution was
allowed to warm to 0 °C over 20 min. The solution was cooled
to -78 °C, compound 14 (0.25 g, 0.85 mmol) in 2 mL of THF
was added, and the mixture was stirred at -78 °C for 45 min.
The solution was quenched with a saturated aqueous NH4Cl
solution (20 mL) and 20 mL of ether was added. The solution
was extracted with ether, the layers were separated and
washed with a saturated aqueous NaHCO3 solution, and the
organic layer was dried (MgSO4). Concentration under reduced
pressure and purification by silica gel chromatography gave
0.24 g (90%) of 15: mp 108-110 °C; IR (thin film) 1728, 1455,
1349, 1164, and 1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.78
(d, 3H, J ) 7.2 Hz), 1.42 (d, 3H, J ) 7.2 Hz), 1.64 (dd, 1H, J
) 15.2 and 8.4 Hz), 2.22 (m, 1H), 2.35 (s, 3H), 2.51 (dd, 1H, J
) 15.2 and 4.8 Hz), 3.44 (s, 3H), 4.08 (q, 1H, J ) 7.2 Hz), 4.94
(dd, 1H, J ) 4.0 and 0.8 Hz), 7.24 (d, 2H, J ) 8.4 Hz), and
7.64 (d, 2H, J ) 8.4 Hz);13C NMR (100 MHz, CDCl3) δ 18.2,
19.7, 21.4, 34.7, 40.0, 55.5, 59.1, 89.4, 127.0, 129.8, 137.0, 143.9,
and 207.9. Anal. Calcd for C15H21NO4S: C, 57.86; H, 6.80; N,
4.50. Found: C, 57.72; H, 6.61; N, 4.43.
1
1467, 1319, 1289, 1089, and 1023 cm-1; H NMR (400 MHz,
CDCl3) δ 2.41 (s, 3H), 6.63 (dd, 1H, J ) 2.8 and 1.6 Hz), 7.33
(m, 3H), 7.73 (d, 1H, J ) 1.6 Hz), 7.86 (dd, 2H, J ) 6.8 and
2.8 Hz) and 8.80 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5,
113.7, 124.7, 128.0, 128.2, 129.7, 135.1, 144.5, 149.7, 155.6.
The above compound (1.0 g, 4.0 mmol) was dissolved in 15
mL of THF and cooled to 0 °C and then methylmagnesium
bromide (2.7 mL of a 3.0 M solution (8.0 mmol)) was added to
the solution. The reaction was quenched with a saturated
aqueous NaHCO3 solution (30 mL) and 30 mL of ether was
added. The solution was extracted with ether, the layers were
separated, and the organic layer was dried (MgSO4). Concen-
tration under reduced pressure and purification by silica gel
chromatography gave 1.0 g (95%) of benzenesulfonamide 12:
mp 72-73 °C (lit.50 mp 72-73 °C); IR (thin film) 1599, 1427,
1333, 1152, and 1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.41
(d, 3H, J ) 7.2 Hz), 2.37 (s, 3H), 4.52 (dq, 1H, J ) 14.8, 7.2
6-Meth oxy-2-m eth yl-5-p h en yl-1-(tolu en e-4-su lfon yl)p i-
p er id in -3-on e (16). In a 10-mL round-bottom flask under
nitrogen was added CuCN (0.08 g, 0.83 mmol) and 2 mL of
THF and the mixture was cooled to -78 °C. A solution of PhLi
(2.2 mL of 0.75 M ether solution) was added dropwise and the
solution was allowed to warm to 0 °C over 20 min. The solution
(48) We wish to thank Professor Naoki Toyooka for providing us
with photocopies of the proton and carbon NMR spectra of synthetic
epi (5a ) and revised (5b) indolizidine alkaloids 223A.
(49) Trost, B. M.; Marrs, C. J . Org. Chem. 1991, 56, 6468.
(50) Zhou, W. S.; Lu, Z. H.; Wang, Z. M. Tetrahedron 1993, 49, 2641.
4376 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of 6-epi-Indolizidine 223A
was cooled to -78 °C, compound 14 (0.19 g, 0.64 mmol) in 2
mL of THF was added, and the mixture was stirred at -78 °C
for 45 min. The solution was quenched with a saturated
aqueous NH4Cl solution (20 mL) and 20 mL of ether was
added. The solution was extracted with ether, the layers were
separated and washed with a saturated aqueous NaHCO3
solution, and the organic layer was dried (MgSO4). Concentra-
tion under reduced pressure and purification by silica gel
chromatography gave 0.22 g (90%) of 16: mp 109-111 °C; IR
under nitrogen was added compound 14 (0.1 g, 0.34 mmol), 5
mL of MeOH, and thiophenol (105 µL, 1.0 mmol). The mixture
was stirred for 6 h at room temperature. The reaction mixture
was concentrated under reduced pressure and purified by silica
gel chromatography to give 0.12 g (85%) of 19: IR (thin film)
1
1730, 1597, 1439, 1347, 1164, 1094, and 1068 cm-1; H NMR
(400 MHz, CDCl3) δ 1.52 (d, 3H, J ) 7.2 Hz), 2.39 (s, 3H),
2.79 (dd, 1H, J ) 15.2 and 4.4 Hz), 2.97 (dd, 1H, J ) 15.6 and
8.8 Hz), 3.52 (s, 3H), 3.53 (ddd, 1H, J ) 8.8, 4.4, and 2.0 Hz),
4.06 (q, 1H, J ) 7.2 Hz), 5.41 (dd, 1H, J ) 4.4 and 2.0 Hz),
7.23 (d, 2H, J ) 8.0 Hz), 7.40-7.34 (m, 5H), and 7.61 (d, 2H,
J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 19.6, 21.5, 39.4,
47.5, 55.7, 59.0, 87.4, 127.5, 128.4, 129.3, 129.7, 133.5, 136.2,
144.0, and 205.5; FAB HRMS calcd for [(C20H23NO4S2) + Li]+
412.1229, found 412.1221.
1
(thin film) 1732, 1597, 1353, 1165, and 1094 cm-1; H NMR
(400 MHz, CDCl3) δ 1.59 (d, 3H, J ) 7.2 Hz), 2.22 (dd, 1H, J
) 15.6 and 10.4 Hz), 2.38 (s, 3H), 2.59 (dd, 1H, J ) 15.6 and
4.8 Hz), 3.37 (ddd, 1H, J ) 10.4, 5.2, and 4.8 Hz), 3.46 (s, 3H),
4.16 (q, 1H, J ) 7.2 Hz), 5.36 (dd, 1H, J ) 5.2 and 1.2 Hz),
7.05-7.03 (m, 2H), 7.38 (dd, 2H, J ) 7.6 and 2.0 Hz), 7.17 (d,
2H, J ) 7.6 Hz), and 7.27-7.25 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 19.6, 21.4, 31.9, 45.2, 55.7, 58.9, 90.2, 127.0, 127.2,
127.3, 128.9, 129.9, 136.4, 139.7, 143.8, and 208.6. Anal. Calcd
for C20H23NO4S: C, 64.32; H, 6.21; N, 3.75. Found: C, 64.29;
H, 6.02; N, 3.81.
6-Meth oxy-2-m eth yl-1-(tolu en e-4-su lfon yl)-5-vin ylp ip -
er id in -3-on e (17). In a 10-mL round-bottom flask under
nitrogen was added CuI (0.2 g, 1.0 mmol) and 3 mL of THF
and the mixture was cooled to -78 °C. Vinylmagnesium
bromide (2.7 mL of a 0.8 M THF solution (2.1 mmol)) was
added dropwise and the solution was allowed to warm to -20
°C over 20 min. The solution was cooled to -78 °C, compound
14 (0.21 g, 0.7 mmol) in 3 mL of THF was added, and the
mixture was stirred at -78 °C for 1 h. The reaction was
quenched with a saturated aqueous NH4Cl solution (20 mL)
and 20 mL of ether was added. The solution was extracted
with ether, the layers were separated and washed with
saturated aqueous NaHCO3 solution, and the organic layer
was dried (MgSO4). Concentration under reduced pressure and
purification by silica gel chromatography gave 0.2 g (87%) of
[2-Meth oxy-6-m eth yl-5-oxo-1-(tolu en e-4-su lfon yl)p ip -
er id in -3-yla m in o]a cetic Acid Meth yl Ester (20). In a 10-
mL round-bottom flask under nitrogen was placed compound
14 (0.1 g, 0.34 mmol), 5 mL of MeOH, glycine methyl ester
hydrochloride (0.17 g, 1.4 mmol), and triethylamine (284 µL,
2.0 mmol). The mixture was stirred for 10 h at room temper-
ature. The reaction was quenched with a saturated aqueous
NH4Cl solution (15 mL) and 15 mL of ether was added. The
solution was extracted with ether, the layers were separated
and washed with a saturated aqueous NaHCO3 solution, and
the organic layer was dried (MgSO4). Concentration under
reduced pressure and purification by silica gel chromatography
gave 0.08 g (60%) of [2-methoxy-6-methyl-5-oxo-1-(toluene-4-
sulfonyl)piperidin-3-ylamino]acetic acid methyl ester 20: IR
(thin film) 1740, 1597, 1438, 1331, 1210, 1163, and 1095 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.47 (d, 3H, J ) 7.2 Hz), 2.06
(dd, 1H, J ) 15.2 and 7.0 Hz), 2.38 (s, 3H), 2.87 (dd, 1H, J )
15.2 and 4.4 Hz), 3.24 (dd, 1H, J ) 7.0 and 4.4 Hz), 3.27 (d,
2H, J ) 2.6 Hz), 3.50 (s, 3H), 3.70 (s, 3H), 4.05 (q, 1H, J ) 7.2
Hz), 5.15 (d, 1H, J ) 2.6 Hz), 7.25 (d, 2H, J ) 8.0 Hz), and
7.75 (d, 2H, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 19.9,
21.5, 38.7, 48.0, 52.0, 55.4, 57.4, 59.4, 86.3, 127.5, 129.7, 136.8,
143.8, 172.2, and 206.0; FAB HRMS calcd for [(C17H24N2O6S)
+ Li]+ 391.1515, found 391.1515.
17: IR (thin film) 1731, 1452, 1354, 1330, 1164, and 1093 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.48 (d, 3H, J ) 7.2 Hz), 1.90
(dd, 1H, J ) 15.6 and 4.8 Hz), 2.38 (s, 3H), 2.58 (dd, 1H, J )
15.6 and 4.8 Hz), 2.82 (m, 1H), 3.48 (s, 3H), 4.10 (q, 1H, J )
7.2 Hz), 4.91 (d, 1H, J ) 10.4 Hz), 4.94 (d, 1H, J ) 17.2 Hz),
5.10 (d, 1H, J ) 4.4 Hz), 5.44 (ddd, 1H, J ) 17.2, 10.4, and 6.8
6-Allyl-2-m eth yl-1-(tolu en e-4-su lfon yl)-1,6-d ih yd r o-2H-
p yr id in -3-on e (21). In a 10 mL round-bottom flask under
nitrogen was placed compound 14 (0.58 g, 2.0 mmol), 7 mL of
CH2Cl2, allyl trimethylsilane (625 µL, 3.93 mmol), and BF3‚
OEt2 (250 µL, 1.96 mmol). The mixture was stirred for 2 h at
0 °C. The reaction mixture was quenched with a saturated
aqueous NH4Cl solution (15 mL) and 30 mL of ether was
added. The solution was extracted with ether, the layers were
separated and washed with a saturated aqueous NaHCO3
solution, and the organic layer was dried (MgSO4). Concentra-
tion under reduced pressure and purification by silica gel
chromatography gave 0.51 g (85%) of 21: mp 78-80 °C; IR
(thin film) 1686, 1597, 1398, 1357, 1333, 1167, 1120, 1095, and
Hz), 7.25 (d, 2H, J ) 8.4 Hz), and 7.64 (d, 2H, J ) 8.4 Hz); 13
C
NMR (100 MHz, CDCl3) δ 19.9, 21.5, 37.3, 43.5, 55.5, 59.2,
87.8, 117.2, 127.2, 129.7, 136.0, 136.9, 144.0, and 207.5; FAB
HRMS calcd for [(C16H21NO4S) + Li]+ 330.1351, found 330.1361.
5-E t h yl-6-m et h oxy-2-m et h yl-1-(t olu en e-4-su lfon yl)p i-
p er id in -3-on e (18). In a 25-mL round-bottom flask under
nitrogen was added CuI (0.39 g, 2.0 mmol) and 5 mL of THF
and the mixture was cooled to -78 °C. Ethylmagnesium
bromide (3.9 mL of a 1.0 M ether solution (3.9 mmol)) was
added dropwise and the solution was allowed to warm to -20
°C over 20 min. The solution was cooled to -78 °C, compound
14 (0.5 g, 1.7 mmol) in 5 mL of THF was added, and the
mixture was stirred at -78 °C for 1 h. The reaction was
quenched with a saturated aqueous NH4Cl solution (20 mL)
and 20 mL of ether was added. The solution was extracted
with ether, the layers were separated and washed with
saturated aqueous NaHCO3 solution, and the organic layer
was dried (MgSO4). Concentration under reduced pressure and
purification by silica gel chromatography gave 0.47 g (85%) of
1
1044 cm-1; H NMR (400 MHz, CDCl3) δ 1.49 (d, 3H, J ) 7.2
Hz), 2.36 (s, 3H), 2.52 (m, 1H), 2.71 (m, 1H), 4.47 (q, 1H, J )
7.2 Hz), 4.58 (m, 1H), 5.18 (ddd, 1H, J ) 17.2, 3.2, and 1.6
Hz), 5.19 (d, 1H, J ) 10.4 Hz), 5.79 (dd, 1H, J ) 10.4 and 2.0
Hz), 5.91 (m, 1H), 6.82 (dd, 1H, J ) 10.4 and 4.4 Hz), 7.22 (d,
2H, J ) 8.4 Hz), and 7.58 (d, 2H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 21.5, 21.6, 41.7, 53.5, 56.9, 119.0, 124.8, 126.7,
129.9, 133.2, 136.2, 143.8, 147.8, and 194.8. Anal. Calcd for
18: IR (thin film) 1731, 1597, 1459, 1352, 1163, and 1093 cm-1
;
C16H19NO3S: C, 62.93; H, 6.28; N, 4.59. Found: C, 62.77; H,
1H NMR (400 MHz, CDCl3) δ 0.82 (t, 3H, J ) 7.2 Hz), 1.09
(m, 1H), 1.29 (m, 1H), 1.42 (d, 3H, J ) 7.6 Hz), 1.59 (dd, 1H,
J ) 15.2 and 10.0 Hz), 1.95 (m, 1H), 2.36 (s, 3H), 2.40 (dd,
1H, J ) 15.2 and 5.2 Hz), 3.43 (s, 3H), 4.09(q, 1H, J ) 7.2
Hz), 5.00 (dd, 1H, J ) 4.4 and 0.8 Hz), 7.25 (d, 2H, J ) 8.0
Hz), and 7.64 (d, 2H, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3)
δ 11.1, 19.2, 21.4, 25.9, 38.4, 41.5, 55.3, 59.0, 88.5, 126.9, 129.8,
136.9, 143.9, and 208.3; FAB HRMS calcd for [(C16H23NO4S)
+ Li]+ 332.1508, found 332.1513.
6.12; N, 4.49.
6-Allyl-2,5-d im eth yl-1-(tolu en e-4-su lfon yl)p ip er id in -3-
on e (22). In a 5-mL round-bottom flask under nitrogen was
placed compound 15 (0.024 g, 0.08 mmol), 1 mL of CH2Cl2,
allyl trimethylsilane (25 µL, 0.15 mmol), and BF3‚OEt2 (20 µL,
0.15 mmol). The mixture was stirred for 2 h at 0 °C. The
reaction mixture was quenched with a saturated aqueous NH4-
Cl solution (15 mL) and 30 mL of ether was added. The
solution was extracted with ether, the layers were separated
and washed with a saturated aqueous NaHCO3 solution, and
the organic layer was dried (MgSO4). Concentration under
6-Meth oxy-2-m eth yl-5-p h en ylsu lfa n yl-1-(tolu en e-4-su l-
fon yl)p ip er id in -3-on e (19). In a 10-mL round-bottom flask
J . Org. Chem, Vol. 68, No. 11, 2003 4377

Harris and Padwa
reduced pressure and purification by silica gel chromatography
gave 0.0.2 g (85%) of 22: IR (thin film) 1728, 1455, 1336, 1162,
and 1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.93 (d, 3H, J )
6.4 Hz), 1.42 (d, 3H, J ) 7.2 Hz), 1.48 (dd, 1H, J ) 15.6 and
11.2 Hz), 1.94 (m, 1H), 2.17 (dd, 1H, J ) 15.6 and 3.6 Hz),
2.42 (s, 3H), 2.56 (m, 2H), 3.70 (q, 1H, J ) 6.8 Hz), 4.31 (q, J
) 7.2 Hz), 5.11 (m, 2H), 5.91 (dddd, 1H, J ) 16.8, 10.4, 7.2,
and 7.2 Hz), 7.30 (d, 2H, J ) 8.0 Hz), and 7.69 (d, 2H, J ) 8.0
Hz); 13C NMR (100 MHz, CDCl3) δ 20.6, 21.5, 32.2, 43.1, 58.9,
59.7, 117.9, 127.1 (2C), 129.9 (2C), 134.7, 136.7, 143.8, and
209.3; FAB HRMS calcd for [(C17H23NO3S) + Li]+ 328.1559,
found 328.1551.
1H, J ) 15.6 and 3.6 Hz), 2.41 (s, 3H), 2.49 (m, 2H), 2.61 (m,
1H), 3.86 (dd, 1H, J ) 12.4 and 6.4 Hz), 4.31 (q, 1H, J ) 7.6
Hz), 5.00 (m, 2H), 5.12 (m, 2H), 5.49 (ddd, 1H, J ) 16.8, 10.0,
and 7.2 Hz), 5.90 (dddd, 1H, J ) 17.2, 10.0, 7.2, and 7.2 Hz),
7.29 (d, 2H, J ) 8.0 Hz), and 7.68 (d, 2H, J ) 8.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 20.6, 21.5, 40.7, 41.2, 41.6, 57.7,
58.9, 117.2, 118.1, 127.2, 129.9, 134.5, 136.4, 138.0, 143.9, and
208.7; FAB HRMS calcd for [(C18H23NO3S) + Li]+ 340.1559,
found 340.1560.
2-Meth yl-1-(tolu en e-4-su lfon yl)-1,2,4,4a,7,7a-h exah ydr o-
[1]p yr id in -3-on e (26). In a 10-mL round-bottom flask under
nitrogen was placed compound 25 (0.05 g, 0.15 mmol), 2 mL
of CH2Cl2, and Grubb’s catalyst (6.2 mg, 0.008 mmol). The
reaction mixture was stirred for 6 h at 25 °C. The reaction
mixture was filtered through a plug of silica gel, concentrated
under reduced pressure, and purified by silica gel chromatog-
raphy to give 0.03 g (60%) of 26: IR (thin film) 1724, 1598,
1448, 1351, 1167, and 1060 cm-1; 1H NMR (600 MHz, CDCl3)
δ 1.60 (d, 3H, J ) 7.2 Hz), 2.13 (dd, 1H, J ) 18.6 and 13.8
Hz), 2.41 (s, 3H), 2.69 (m, 2H), 2.79 (dd, 1H, J ) 18.6 and 5.4
Hz), 2.90 (ddd, 1H, J ) 15.6, 5.4, and 3.0 Hz), 3.26 (m, 1H),
4.16 (q, 1H, J ) 7.2 Hz), 5.66 (d, 1H, J ) 6.0 Hz), 5.87 (ddd,
1H, J ) 6.0, 4.0, and 3.0 Hz), 7.31 (d, 2H, J ) 8.4 Hz), and
7.65 (d, 2H, J ) 8.4 Hz); 13C NMR (150 MHz, CDCl3) δ 21.5,
23.6, 39.1, 41.1, 43.5, 63.4, 63.9, 127.5, 130.1, 130.2, 131.9,
133.3, 144.1, and 207.8; FAB HRMS calcd for [(C16H19NO3S)
+ Li]+ 312.1246, found 312.1258.
5,6-Dia llyl-2-m eth yl-1-(tolu en e-4-su lfon yl)p ip er id in -3-
on e (27). In a 25-mL round-bottom flask under nitrogen was
placed compound 21 (0.13 g, 0.40 mmol), 4.0 mL of CH2Cl2,
allyl trimethylsilane (100 µL, 0.614 mmol), and TiCl4 (50 µL,
0.45 mmol). The mixture was stirred for 2 h at 0 °C. The
reaction mixture was quenched with a saturated aqueous NH4-
Cl solution (15 mL) and 30 mL of ether was added. The
solution was extracted with ether, the layers were separated
and washed with a saturated aqueous NaHCO3 solution, and
the organic layer was dried (MgSO4). Concentration under
reduced pressure and purification by silica gel chromatography
gave 0.13 g (90%) of 27: IR (thin film) 1728, 1641, 1598, 1444,
1337, 1164, and 1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.40
(d, 3H, J ) 7.6 Hz), 1.59 (dd, 1H, J ) 15.2 and 10.8 Hz), 1.89
(m, 2H), 2.23 (dd, 1H, J ) 15.2, and 4.0 Hz), 2.41 (s, 3H), 2.48
(m, 2H), 3.84 (dd, 1H, J ) 6.8 Hz), 4.33 (q, 1H, J ) 7.6 Hz),
5.12-4.95 (m, 4H), 5.53 (dddd, 1H, J ) 17.2, 10.4, 7.6, and
7.6 Hz), 5.85 (dddd, 1H, J ) 16.4, 10.6, 7.2, and 7.2 Hz), 7.29
(d, 2H, J ) 8.0 Hz), and 7.68 (d, 2H, J ) 8.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 20.0, 21.5, 37.5, 38.3, 40.4, 41.5, 56.9, 59.1,
118.0, 118.3, 127.1, 129.8, 133.9, 134.6, 136.9, 143.8, and 209.2;
FAB HRMS calcd for [(C19H25NO3S) + Li]+ 354.1715, found
354.1711.
2-Meth yl-1-(tolu en e-4-su lfon yl)-1,4,4a,5,8,8a-h exah ydr o-
2H-qu in olin -3-on e (28). In a 10-mL round-bottom flask
under nitrogen was placed compound 27 (0.045 g, 0.13 mmol),
2 mL of CH2Cl2, and Grubb’s catalyst (5.5 mg, 0.007 mmol).
The reaction mixture was stirred for 6 h at 25 °C, filtered
through a plug of silica gel, concentrated under reduced
pressure, and purified by silica gel chromatography to give 0.03
g (80%) of 28: IR (thin film) 1728, 1597, 1437, 1359, 1338,
1311, 1166, and 1099 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.15
(dd, 1H, J ) 16.4 and 14.4 Hz), 1.48 (d, 3H, J ) 7.6 Hz), 1.80
(m, 1H), 2.03 (m, 1H), 2.13 (dd, 1H, J ) 16.4 and 2.4 Hz), 2.19
(m, 1H), 2.28 (m, 1H), 2.41 (s, 3H), 2.88 (ddd, 1H, J ) 16.4,
5.6, and 5.6 Hz), 3.50 (ddd, 1H, J ) 10.8, 10.8, and 4.8 Hz),
4.39 (q, 1H, J ) 7.6 Hz), 5.62 (m, 1H), 5.69 (m, 1H), 7.29 (d,
2H, J ) 8.4 Hz), and 7.64 (d, 2H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 21.5, 22.1, 32.7, 33.1, 36.4, 42.6, 57.2, 59.4,
125.3, 126.5, 126.9, 130.0, 135.8, 143.8, and 208.9; FAB HRMS
calcd for [(C17H21NO3S) + Li]+ 326.1402, found 326.1411.
6-Allyl-5-eth yl-2-m eth yl-1-(tolu en e-4-su lfon yl)piper idin -
3-on e (23). In a 5-mL round-bottom flask under nitrogen was
placed compound 18 (0.05 g, 0.15 mmol), 1.5 mL of CH2Cl2,
allyl trimethylsilane (50 µL, 0.31 mmol), and BF3‚OEt2 (20 µL,
0.15 mmol). The mixture was stirred for 2 h at 0 °C. The
reaction mixture was quenched with a saturated aqueous NH4-
Cl solution (15 mL) and 30 mL of ether was added. The
solution was extracted with ether, the layers were separated
and washed with a saturated aqueous NaHCO3 solution, and
the organic layer was dried (MgSO4). Concentration under
reduced pressure and purification by silica gel chromatography
gave 0.043 g (85%) of 23: IR (thin film) 1728, 1598, 1458, 1338,
1163, and 1093 cm-1 1H NMR (400 MHz, CDCl3) δ 0.78 (t,
;
3H, J ) 7.2 Hz), 1.18 (m, 2H), 1.42 (d, 3H, J ) 7.6 Hz), 1.57
(dd, 1H, J ) 14.8, and 11.2 Hz), 1.72 (m, 1H), 2.28 (dd, 1H, J
) 14.8 and 4.0 Hz), 2.42 (s, 3H), 2.47 (m, 1H), 2.48 (dd, 1H, J
) 14.4 and 7.2 Hz), 3.82 (m, 1H), 4.32 (q, 1H, J ) 7.6 Hz),
5.10 (m, 2H), 5.88 (dddd, 1H, J ) 17.6, 10.4, 7.2, and 7.2 Hz),
7.30 (d, 2H, J ) 8.4 Hz), and 7.69 (d, 2H, J ) 8.4 Hz); 13C
NMR (100 MHz, CDCl3) δ 10.8, 20.1, 21.5, 27.1, 39.5, 40.2,
41.5, 57.3, 59.1, 117.9, 127.1, 129.8, 134.7, 137.0, 143.7, and
209.5; FAB HRMS calcd for [(C18H25NO3S) + Li]+ 342.1715,
found 342.1711.
2,5-Dim eth yl-6-(2-oxo-p r op yl)-1-(tolu en e-4-su lfon yl)p i-
p er id in -3-on e (24). In a 25-mL round-bottom flask under
nitrogen was placed compound 15 (0.18 g, 0.56 mmol), 5 mL
of CH2Cl2, isopropenyl acetate (125 µL, 1.12 mmol), and BF3‚
OEt2 (70 µL, 0.56 mmol). The mixture was stirred for 2 h at 0
°C. The reaction mixture was quenched with a saturated
aqueous NH4Cl solution (15 mL) and 30 mL of ether was
added. The solution was extracted with ether, the layers were
separated and washed with a saturated aqueous NaHCO3
solution, and the organic layer was dried (MgSO4). Concentra-
tion under reduced pressure and purification by silica gel
chromatography gave 0.13 g (70%) of 24: IR (thin film) 1720,
1
1597, 1553, 1455, 1357, 1336, 1164, and 1122 cm-1; H NMR
(600 MHz, CDCl3) δ 0.83 (d, 3H, J ) 7.2 Hz), 1.43 (dd, 1H, J
) 15.6 and 3.6 Hz), 1.47 (d, 3H, J ) 7.2 Hz), 1.89 (m, 1H),
2.17 (dd, 1H, J ) 15.6 and 3.6 Hz), 2.25 (s, 3H), 2.41 (s, 3H),
2.77 (dd, 1H, J ) 16.8 and 7.2 Hz), 3.09 (dd, 1H, J ) 17.4 and
3.6 Hz), 4.00 (ddd, 1H, J ) 7.2, 7.2, and 3.6 Hz), 4.40 (q, 1H,
J ) 7.2 Hz), 7.30 (d, 2H, J ) 8.0 Hz), and 7.66 (d, 2H, J ) 8.0
Hz); 13C NMR (150 MHz, CDCl3) δ 19.5, 21.2, 21.5, 29.7, 33.7,
42.9, 51.8, 54.7, 59.0, 127.0, 130.0, 136.2, 143.9, 205.5, and
208.6; FAB HRMS calcd for [(C17H23NO4S) + Li]+ 344.1508,
found 344.1501.
6-Allyl-2-m eth yl-1-(tolu en e-4-su lfon yl)-5-vin yl-p ip er i-
d in -3-on e (25). In a 25-mL round-bottom flask under nitrogen
was placed compound 17 (0.29 g, 0.90 mmol), 8.0 mL of CH2-
Cl2, allyl trimethylsilane (285 µL, 1.80 mmol), and BF3‚OEt2
(170 µL, 1.35 mmol). The mixture was stirred for 2 h at 0 °C.
The reaction mixture was quenched with a saturated aqueous
NH4Cl solution (15 mL) and 30 mL of ether was added. The
solution was extracted with ether, the layers were separated
and washed with a saturated aqueous NaHCO3 solution, and
the organic layer was dried (MgSO4). Concentration under
reduced pressure and purification by silica gel chromatography
gave 0.24 g (80%) of 25: IR (thin film) 1728, 1683, 1641, 1452,
Ben zh yd r ylid en e-fu r a n -2-ylm eth yla m in e (29). A 50-g
(515 mmol) sample of furfurylamine, 1 L of toluene, benzophe-
none (78 g (430 mmol)), and BF3‚OEt2 (5.5 mL (43 mmol)) were
placed in a 2-L round-bottom flask with a Dean-Stark trap
1
1337, and 1093 cm-1; H NMR (400 MHz, CDCl3) δ 1.44 (dd,
3H, J ) 7.6 Hz), 1.64 (dd, 1H, J ) 15.6 and 12.4 Hz), 2.15 (dd,
4378 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of 6-epi-Indolizidine 223A
and heated at reflux for 12 h. The solvent was removed under
reduced pressure to give imine 29 as a yellow solid. Recrys-
tallization from MeOH gave 101 g (90%) of pure white
crystals: mp 51-53 °C (lit.51 mp 52-53 °C); IR (thin film) 1623,
1576, 1446, 1290, and 1006 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.57 (s, 2H), 6.24 (dd, 1H, J ) 3.2 and 0.8 Hz), 6.34 (dd, 1H,
J ) 3.2 and 2.0 Hz), 7.25 (m, 2H), 7.35 (m, 4H), 7.48 (m, 3H),
7.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 51.1, 106.3, 110.2,
127.7, 128.0, 128.6, 130.1, 136.3, 139.5, 141.6, 153.7, and 169.9.
Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found:
C, 82.85; H, 5.85; N, 5.43.
Ben zh yd r ylid en e-[4-(ter t-bu tyld ip h en ylsila n yloxy)-1-
fu r a n -2-ylbu tyl]a m in e. In a 250-mL round-bottom flask
under nitrogen was added the above compound (5.0 g, 23
mmol) to 75 mL of THF and the mixture was cooled to -78
°C. A solution of n-BuLi (10.2 mL of a 2.5 M hexane solution)
was added dropwise and the solution was stirred for 30 min.
A sample of 1-bromo-3-tert-butyldiphenylsilanyloxypropane
(9.6 g, 25 mmol) was added and the solution was stirred at 0
°C for 4 h. The reaction was quenched with a saturated
aqueous NaHCO3 solution (50 mL) and 50 mL of ether was
added. The solution was extracted with ether, the layers were
separated, and the organic layer was dried (MgSO4). Concen-
tration under reduced pressure and purification by silica gel
chromatography gave 11 g (86%) of the titled compound: IR
(thin film) 1661, 1622, 1446, 1428, 1316, 1278, 1111, and 1001
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 1.45 (m, 2H),
1.58 (m, 2H), 2.05 (m, 2H), 3.62 (t, 1H, J ) 6.8 Hz), 4.49 (dd,
1H, J ) 7.2 and 5.6 Hz), 6.15 (d, 1H, J ) 3.2 Hz), 6.32 (dd,
1H, J ) 3.2 and 2.0 Hz), 7.20 (m, 1H), 7.38 (m, 10H), 7.65 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 14.1, 19.2, 22.6, 26.8, 29.2,
31.5, 60.1, 63.7, 105.3, 109.9, 127.5, 127.9, 128.3, 128.4, 128.7,
129.5, 130.0, 130.1, 132.4, 134.0, 135.5, 136.7, 139.8, 141.4,
156.7, and 168.4; FAB HRMS calcd for [(C37H39NO2Si) + Li]+
564.2910, found 564.2902.
4-(t er t -Bu t yld ip h e n ylsila n yloxy)-1-fu r a n -2-ylb u t yl-
a m in e. A 3.2-g (5.8 mmol) sample of the above compound, 30
mL of acetone, and 30 mL of 1 N HCl were placed in a round-
bottom flask and the mixture was stirred for 2 h. The reaction
was quenched with solid K2CO3 until a pH of 7-8 and then
100 mL of ether was added. The solution was extracted with
ether, the layers were separated, and the organic layer was
dried (MgSO4). Concentration under reduced pressure gave 2.2
g (95%) of the titled compound: IR (thin film) 1663, 1428, 1111,
and 1008 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.06 (s, 9H), 1.56
(m, 2H), 2.00 (m, 2H), 3.68 (t, 1H, J ) 6.4 Hz), 4.49 (dd, 1H,
J ) 7.6 and 6.0 Hz), 6.11 (d, 1H, J ) 3.6 Hz), 6.29 (dd, 1H, J
) 3.6 and 2.0 Hz), 7.32 (dd, 1H, J ) 2.0 and 0.8), 7.39 (m,
5H), 7.67 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 19.2, 26.8,
31.4, 57.9, 63.7, 105.1, 109.9, 127.6, 129.5, 133.9, 135.5 (2C),
141.3, and 156.4; FAB HRMS calcd for [(C24H31NO2Si) + Li]+
400.2284, found 400.2300.
(100 MHz, CDCl3) δ 19.1, 21.4, 26.8, 28.5, 31.4, 51.6, 63.1,
106.7, 109.9, 126.9, 127.6, 129.3, 129.6, 133.7, 135.5, 141.8,
142.9, and 152.9. Anal. Calcd for C31H37NO4SSi: C, 67.97; H,
6.81; N, 2.56. Found: C, 67.76; H, 6.80; N, 2.57.
6-Allyl-2-[3-(ter t-b u t yld ip h en ylsila n yloxy)-p r op yl]-1-
(tolu en e-4-su lfon yl)-1,6-d ih yd r o-2H-p yr id in -3-on e (32). A
0.5-g (0.9 mmol) sample of compound 30, 5 mL of CH2Cl2, and
m-CPBA (0.19 g, 1.1 mmol) were placed in a round-bottom
flask and the mixture was stirred for 4 h. The reaction mixture
was quenched with a saturated aqueous NaHCO3 solution (15
mL) and 15 mL of ether was added. The solution was extracted
with ether, the layers were separated, and the organic layer
was dried (MgSO4). Concentration under reduced pressure
gave 0.4 g (80%) of 2-[3-(tert-butyldiphenylsilanyloxy)propyl]-
6-hydroxy-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-
one (31). This compound was immediately used in the next
step without purification.
The above 6-hydroxy-2H-pyridin-3-one 31 (0.4 g, 0.7 mmol)
was dissolved in 5 mL of CH2Cl2 and allyl trimethylsilane (232
µL, 1.46 mmol) and BF3‚OEt2 (150 µL, 1.46 mmol) were added
to the solution. The solution was stirred for 3 h at 0 °C and
quenched with a saturated aqueous NaHCO3 solution (25 mL)
and 40 mL of ether was added. The solution was extracted
with ether, the layers were separated, and the organic layer
was dried (MgSO4). Concentration under reduced pressure and
purification by silica gel chromatography gave 0.34 g (80%) of
32: IR (thin film) 1686, 1428, 1359, 1335, 1165, and 1111 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 1.87 (m, 4H), 2.37
(s, 3H), 2.50 (m, 1H), 2.77 (m, 1H), 3.72 (m, 2H), 4.41 (dd, 1H,
J ) 10.0 and 5.6 Hz), 4.54, (dddd, 1H, J ) 6.4, 4.4, 4.4, and
2.0 Hz), 5.17 (m, 2H), 5.77 (dd, 1H, J ) 10.4 and 2.0 Hz), 5.94
(dddd, 1H, J ) 16.8, 10.4, 7.2, and 7.2 Hz), 6.74 (dd, 1H, J )
10.8 and 4.8 Hz), 7.23 (d, 2H, J ) 8.0 Hz), 7.41 (m, 6H), 7.58
(d, 2H, J ) 8.0 Hz), and 7.67 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 19.1, 21.5, 26.8, 28.7, 31.3, 41.1, 53.7, 61.5, 62.9,
119.0, 124.9, 126.7, 127.6, 129.5, 129.9, 133.4, 133.6, 135.5,
136.2, 143.8, 146.8, and 194.3; FAB HRMS calcd for [(C34H41
-
NO4SSi) + Li]+ 594.2686, found 594.2698.
6-Allyl-2-[3-(ter t-b u t yld ip h en ylsila n yloxy)p r op yl]-5-
eth yl-1-(tolu en e-4-su lfon yl)p ip er id in -3-on e (33). In a 50-
mL round-bottom flask under nitrogen was added CuI (0.4 g,
2.2 mmol) and 20 mL of THF, and the mixture was cooled to
-78 °C. Ethylmagnesium bromide (3.7 mL of a 1.0 M ether
solution (3.7 mmol)) was added dropwise and the solution was
allowed to warm to 0 °C over 20 min. The solution was cooled
to -78 °C, compound 32 (1.1 g, 1.9 mmol) in 5 mL of THF was
added, and the mixture was stirred at -78 °C for 1 h. The
reaction was quenched with a saturated aqueous NH4Cl
solution (30 mL) and 30 mL of ether was added. The solution
was extracted with ether, the layers were separated and
washed with saturated aqueous NaHCO3 solution, and the
organic layer was dried (MgSO4). Concentration under reduced
pressure and purification by silica gel chromatography gave
1.0 g (90%) of 33: IR (thin film) 1725, 1428, 1341, 1163, and
N-[4-(ter t-Bu tyld ip h en ylsila n yloxy)-1-fu r a n -2-ylbu tyl]-
4-m eth ylben zen esu lfon a m id e (30). The above compound
(2.2 g, 5.5 mmol) was dissolved in 25 mL of CH2Cl2 and
triethylamine (1.6 mL, 11.7 mmol) and p-toluenesulfonyl
chloride (2.2 g, 11.7 mmol) were added to the solution at room
temperature. The solution was stirred for 12 h and quenched
with a saturated aqueous NaHCO3 solution (30 mL) and 75
mL of ether was added. The solution was extracted with ether,
the layers were separated, and the organic layer was dried
(MgSO4). Concentration under reduced pressure and purifica-
tion by silica gel chromatography gave 2.7 g (90%) of 30 as a
yellow solid: mp 89-90 °C; IR (thin film) 3268, 1472, 1428,
1
1111 cm-1; H NMR (600 MHz, CDCl3) δ 0.77 (t, 3H, J ) 7.8
Hz), 1.04 (s, 9H), 1.69 (m, 4H), 1.91 (m, 2H), 2.17 (dd, 1H, J )
15.6 and 3.0 Hz), 2.40 (s, 3H), 2.54 (m, 4H), 3.66 (m, 2H), 3.74
(dd, 1H, J ) 15.0 and 6.6 Hz), 4.18 (dd, 1H, J ) 9.6 and 5.4
Hz), 5.10 (m, 2H), 5.98 (dddd, 1H, J ) 17.4, 9.6, 7.2, and 7.2
Hz), 7.27 (d, 2H, J ) 7.8 Hz), 7.39 (m, 6H), 7.65 (m, 6H); 13C
NMR (150 MHz, CDCl3) δ 19.2, 21.5, 26.6, 26.8, 29.1, 30.3,
30.6, 38.5, 40.4, 41.6, 57.7, 62.9, 63.6, 117.5, 127.2, 127.6, 129.6,
129.9, 133.7, 135.2, 135.6, 136.6, 143.8, and 209.5; FAB HRMS
calcd for [(C36H47NO4SSi) + Li]+ 624.3155, found 624.3125.
1
1332, 1161, 1111, 1094, and 1010 cm-1; H NMR (400 MHz,
Tr iflu or om eth a n esu lfon ic Acid 6-Allyl-2-[3-(ter t-bu t-
yld ip h en ylsila n yloxy)p r op yl]-5-et h yl-1-(t olu en e-4-su l-
fon yl)-1,2,5,6-tetr a h yd r op yr id in -3-yl Ester (34). In a 10-
mL round-bottom flask under nitrogen was added compound
33 (0.23 g, 0.36 mmol), N-phenyltrifluoromethanesulfonimide
(0.26 g, 0.73 mmol), and 4 mL of THF, and the solution was
cooled to -78 °C. A solution of NaHMDS (0.5 mL of 1.0 M
THF solution (0.47 mmol)) was added dropwise and the
CDCl3) δ 1.03 (s, 9H), 1.48 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H),
3.59 (t, 2H, J ) 6.4 Hz), 4.42 (dd, 1H, J ) 15.6 and 7.2 Hz),
4.92 (d, 1H, J ) 8.4 Hz), 5.89 (d, 1H, J ) 3.2 Hz), 6.11 (dd,
1H, J ) 3.2 and 1.6 Hz), 7.13 (dd, 1H, J ) 2.0 and 0.8 Hz),
7.17 (d, 2H, J ) 8.0 Hz), 7.39 (m, 6H), 7.62 (m, 6H); 13C NMR
(51) Popandova-Yambolieva, K. Synth. Commun. 1990, 20, 1857.
J . Org. Chem, Vol. 68, No. 11, 2003 4379

Harris and Padwa
mixture was stirred at -78 °C for 3 h and at room temperature
for 9 h. The reaction was quenched with a saturated aqueous
solution of NaHCO3 (20 mL) and 20 mL of ether was added.
The solution was extracted with ether, the layers were
separated, and the organic layer was dried (MgSO4). Concen-
tration under reduced pressure and purification by silica gel
chromatography gave 0.26 g (95%) of 34: IR (thin film) 1422,
1343, 1213, 1142, and 1111 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.70 (t, 3H, J ) 6.8 Hz), 0.92 (m, 2H), 1.05 (s, 9H), 1.83 (m,
2H), 2.00 (m, 1H), 2.10 (dd, 1H, J ) 6.8 and 6.4 Hz), 2.28 (m,
1H), 2.38 (s, 3H), 2.46 (m, 1H), 3.66 (m, 2H), 3.82 (dd, 1H, J )
10.4 and 4.4 Hz), 4.59 (dd, 1H, J ) 6.4 and 5.6 Hz), 5.05 (d,
1H, J ) 16.8 Hz), 5.09 (d, 1H, J ) 10.0 Hz), 5.70 (d, 1H, J )
5.2 Hz), 5.74 (dddd, 1H, J ) 17.2, 10.4, 8.4, and 5.6 Hz), 7.24
(d, 2H, J ) 8.0 Hz), 7.40 (m, 6H), 7.67 (m, 4H), 7.71 (d, 2H, J
) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 11.7, 19.1, 21.4, 26.6,
26.8, 30.4, 32.8, 39.7, 41.1, 53.3, 54.1, 63.4, 118.3, 118.4 (q,
1C, J ) 318.7 Hz), 118.5, 127.2, 127.6, 129.5, 133.8, 134.8,
135.5 (2C), 138.1, 143.6, and 146.7; FAB HRMS calcd for
[(C37H46NF3O6S2Si) + Li]+ 756.2648, found 756.2651.
THF solution (0.16 mmol)). The mixture was stirred for 2 h at
room temperature. The reaction was quenched with a satu-
rated aqueous solution of NaHCO3 (10 mL) and 20 mL of ether
was added. The solution was extracted with ether, the layers
were separated, and the organic layer was dried (MgSO4).
Concentration under reduced pressure and purification by
silica gel chromatography gave 0.04 g (90%) of 37: IR (thin
film) 3510, 1458, 1331, and 1158 cm-1 1H NMR (600 MHz,
;
CDCl3) δ 0.71 (t, 3H, J ) 6.6 Hz), 0.90 (t, 3H, J ) 7.8 Hz),
0.92 (t, 3H, J ) 7.8 Hz), 1.90-1.40 (m, 12H), 1.98 (m, 1H),
2.36 (s, 3H), 3.65 (m, 4H), 4.16 (dd, 1H, J ) 6.6 and 6.0 Hz),
5.15 (d, 1H, J ) 3.6 Hz), 7.20 (d, 2H, J ) 7.8 Hz), and 7.62 (d,
2H, J ) 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 11.8, 12.0, 14.0,
20.5, 21.4, 27.3, 27.8, 30.7, 32.6, 39.8, 40.2, 54.8, 55.3, 62.7,
120.8, 127.2, 129.2, 138.7, 138.9, and 142.8; FAB HRMS calcd
for [(C22H35NO3S) + Li]+ 400.2498, found 400.2488.
6,8-Die t h yl-5-p r op yl-1,2,3,5,6,8a -h e xa h yd r oin d oliz-
in e (39). In a 25-mL round-bottom flask under nitrogen was
added sodium metal (0.028 g, 1.2 mmol) and 5 mL of THF,
then naphthalene (0.16 g, 1.2 mmol) was added to the mixture.
The solution was stirred for 1 h during which time a dark
green color appeared. The solution was cooled to -78 °C and
compound 37 (0.16 g, 0.41 mmol) was added to the solution.
The reaction mixture was stirred at -78 °C for 1 h, the reaction
was quenched with water (10 mL), and 10 mL of ether was
added. The solution was extracted with ether, the layers were
separated, and the organic layer was dried (MgSO4). Concen-
tration under reduced pressure gave 3-(3,5-diethyl-6-propyl-
1,2,5,6-tetrahydropyridin-2-yl)propan-1-ol (38) that was im-
mediately used in the next step without purification.
2-Allyl-6-[3-(ter t-b u t yld ip h en ylsila n yloxy)p r op yl]-3-
et h yl-1-(t olu en e-4-su lfon yl)-5-vin yl-1,2,3,6-t et r a h yd r o-
p yr id in e (35). A 0.23-g (0.3 mmol) sample of compound 34,
lithium chloride (0.05 g, 1.2 mmol), palladium tetrakistriph-
enylphosphine (0.04 g, 0.03 mmol), 5 mL of THF, and vinyl
tributyltin (350 µL, 1.2 mmol) were placed in a 10-mL round-
bottom flask and heated to reflux for 12 h. The reaction was
quenched with saturated aqueous NaHCO3 (15 mL) and 25
mL of ether was added. The solution was extracted with ether,
the layers were separated, and the organic layer was dried
(MgSO4). Concentration under reduced pressure and purifica-
tion by column chromatography gave 0.16 g (85%) of 35: IR
A sample of the above compound (0.4 mmol), 5 mL of CH2-
Cl2, carbon tetrabromide (0.18 g, 0.53 mmol), and triphen-
ylphosphine (0.14 g, 0.53 mmol) were placed in a 10-mL round-
bottom flask and stirred for 6 h. The reaction mixture was
quenched with triethylamine (570 µL, 4.07 mmol) and the
solution was stirred for 30 min. The solution was washed with
aqueous saturated NaHCO3 and extracted with ether, the
layers were separated, and the organic layer was dried
(MgSO4). Concentration under reduced pressure and purifica-
tion by column chromatography gave 0.045 g (50%) of 39: IR
1
(thin film) 1428, 1338, 1159, 1111, and 1036 cm-1; H NMR
(600 MHz, CDCl3) δ 0.72 (t, 3H, J ) 7.2 Hz), 0.96 (m, 2H),
1.06 (s, 9H), 1.64 (m,1H), 1.82 (m, 2H), 1.98 (m, 2H), 2.37 (s,
3H), 2.46 (m, 1H), 2.63 (m, 1H), 3.61 (ddd, 1H, J ) 9.0, 4.8,
and 4.8 Hz), 3.70 (ddd, 1H, J ) 10.8, 5.4 and 5.4 Hz), 3.76
(ddd, 1H, J ) 10.2, 7.2 and 4.8 Hz), 4.74 (dd, 1H, J ) 10.8
and 3.6 Hz), 5.05 (m, 3H), 5.17 (d, 1H, J ) 17.4 Hz), 5.43 (d,
1H, J ) 3.6 Hz), 5.89 (dddd, 1H, J ) 15.6, 11.4, 8.4, and 6.6
Hz), 6.13 (dd, 1H, J ) 18.0 and 11.4 Hz), 7.18 (d, 2H, J ) 8.4
Hz), 7.39 (m, 6H), 7.60 (d, 2H, J ) 8.4 Hz), 7.68 (m, 4H); 13C
NMR (150 MHz, CDCl3) δ 11.2, 19.2, 21.4, 26.8, 27.4, 29.9,
31.4, 39.2, 43.2, 52.8, 55.5, 63.6, 111.9, 117.5, 127.4, 127.6,
129.0, 129.2, 133.9, 135.3, 135.5, 136.5, 137.8, 138.1, and 142.8;
FAB HRMS calcd for [(C38H49NO3SSi) + Li]+ 624.3362, found
634.3372.
1
(thin film) 2961, 1459, 1377, 1251, 1171, and 1143 cm-1; H
NMR (400 MHz, CDCl3) δ 0.90 (t, 3H, J ) 7.6 Hz), 0.91 (t, 3H,
J ) 7.2 Hz), 1.01 (t, 3H, J ) 7.6 Hz), 1.27-1.17 (m, 2H), 1.58-
1.46 (m, 4H), 1.80-1.68 (m, 2H), 2.02-1.91 (m, 4H), 2.10-
2.05 (m, 1H), 2.19-2.14 (m, 1H), 2.31 (q-like, 1H, J ) 8.4 Hz),
2.91 (m, 1H), 2.94 (ddd, 1H, J ) 8.4, 8.4, and 4.0 Hz), and
5.29 (dd, 1H, J ) 2.0 and 1.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 10.6, 12.4, 14.7, 18.9, 21.6, 25.0, 26.1, 27.6, 34.0, 39.4, 48.1,
61.5, 63.8, 122.1, and 140.2; FAB HRMS calcd for [(C15H27N)
+ Li]+ 222.2222, found 222.2223.
6-[3-(ter t-Bu tyld ip h en ylsila n yloxy)p r op yl]-3,5-d ieth yl-
2-p r op yl-1-(t olu en e-4-su lfon yl)-1,2,3,6-t et r a h yd r op yr i-
d in e (36). A 0.21-g (0.33 mmol) sample of compound 35,
platinum oxide (0.01 g, 0.017 mmol), and 5 mL of EtOH were
placed in a 10-mL round-bottom flask. The flask was evacuated
and filled with hydrogen via a balloon and stirred under an
atmosphere of hydrogen for 24 h. The solution was filtered
through a pad of Celite and concentration under reduced
pressure and purification by column chromatography gave 0.2
g (95%) of 36: IR (thin film) 1458, 1331, 1158, 1111, and 1036
6-epi-In d olizid in e 223A (5a ). A 0.03-g (0.14 mmol) sample
of compound 39, platinum oxide (2 mg), and 2 mL of EtOH
were placed in a 10-mL round-bottom flask. The flask was
evacuated and filled with hydrogen via a balloon and was
stirred under an atmosphere of hydrogen for 24 h. The solution
was filtered through a pad of Celite and concentration under
reduced pressure and purification by column chromatography
gave 0.03 g (98%) of 6-epi-indolizidine 223A (5a ): IR (thin film)
1
cm-1; H NMR (600 MHz, CDCl3) δ 0.77 (t, 3H, J ) 7.2 Hz),
0.91 (t, 3H, J ) 7.8 Hz), 0.97 (t, 3H, J ) 7.2 Hz), 1.05 (s, 9H),
1.40 (m, 2H), 1.52 (m, 2H), 1.62 (m, 2H), 1.75 (m, 3H), 1.91
(m, 2H), 2.00 (m, 1H), 2.37 (s, 3H), 3.64 (m, 2H), 3.69 (m, 2H),
4.16 (dd, 1H, J ) 7.2 and 4.8 Hz), 5.19 (d, 1H, J ) 3.6 Hz),
7.19 (d, 2H, J ) 7.8 Hz), 7.39 (m, 6H), and 7.67 (m, 6H); 13C
NMR (150 MHz, CDCl3) δ 11.8, 12.0, 13.9, 19.2, 20.4, 21.4,
26.8, 27.2, 27.7, 30.8, 32.3, 39.6, 40.2, 54.7, 55.6, 63.6, 120.7,
127.2, 127.5, 129.1, 129.4, 133.9, 135.5, 138.8, 139.1, and 142.5;
FAB HRMS calcd for [(C38H53NO3SSi) + Li]+ 638.3675, found
638.3650.
1459, 1378, 1325, 1171, 1047, and 933 cm-1 1H NMR (600
;
MHz, CDCl3) δ 0.60 (q, 1H, J ) 12.0 Hz), 0.88 (t, 9H, J ) 7.2
Hz), 1.06 (m, 2H), 1.75-1.17 (br m, 13H), 1.92 (dt, 3H, J )
13.2, and 3.6 Hz), 3.15 (t, 1H, J ) 8.4 Hz); 1H NMR (400 MHz,
D2O/DCl) δ 0.90-0.83 (m, 9H), 1.00 (q, 1H, J ) 12.4 Hz), 1.20
(m, 2H), 1.35 (m, 1H), 1.55 (m, 3H), 1.65 (m, 2H), 1.73 (m,
2H), 2.00 (m, 3H), 2.31 (m, 1H), 2.98-2.88 (m, 2H), 3.04 (q,
1H, J ) 10.0 Hz), 3.65 (ddd, 1H, J ) 10.0, 10.0, and 3.6 Hz);
13C NMR (100 MHz, CDCl3) δ 11.1 (2C), 14.8, 17.9, 20.8, 24.7,
26.1, 28.9, 33.1, 35.3, 40.0, 42.4, 52.1, 67.4, and 70.0; 13C NMR
(100 MHz, D2O/DCl) δ 9.7, 9.9, 13.8, 16.6, 19.3, 23.4, 24.8, 26.9,
29.9, 32.9, 38.2, 39.6, 51.4, 67.8, and 71.8; FAB HRMS calcd
for [(C15H29N) + H]+ 224.2378, found 224.2378.
3-[3,5-Diet h yl-6-p r op yl-1-(t olu en e-4-su lfon yl)-1,2,5,6-
tetr ah ydr opyr idin -2-yl]pr opan -1-ol (37). In a 10-mL round-
bottom flask under nitrogen was placed compound 36 (0.05 g,
0.08 mmol), 1.0 mL of THF, and TBAF (0.16 mL of a 1.0 M
4380 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of 6-epi-Indolizidine 223A
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (grant CHE-0132651).
We thank our colleague, Dr. Kenneth Hardcastle, for
his assistance with the X-ray crystallographic studies
together with grants NSF CHE-9974864 and NIH S10-
RR13673.
J O034324S
J . Org. Chem, Vol. 68, No. 11, 2003 4381