A novel and highly regioselective approach to 5-methoxy-6-substituted-3- sulfonyl-δ-enlactams from 5-methoxy-3-sulfonyl glutarimide: Synthesis of cis-2-substituted-3-piperidinols

Article abstract of DOI:10.1021/jo048073e

(Chemical Equation Presented) A convenient method for the preparation of 5-methoxy-6-substituted-3-sulfonyl-δ-enlactams via regioselective nucleophilic addition to 5-methoxy-3-sulfonyl glutarimide is described. Formal syntheses of L-733,060, CP-99,994, an

Full text of DOI:10.1021/jo048073e

A Novel and Highly Regioselective Approach to
5-Methoxy-6-substituted-3-sulfonyl-δ-enlactams from
5-Methoxy-3-sulfonyl Glutarimide: Synthesis of
cis-2-Substituted-3-piperidinols
Min-Ruei Tsai, Bo-Fong Chen, Chih-Ching Cheng, and Nein-Chen Chang*
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
ncchang@mail.nsysu.edu.tw
Received October 29, 2004
A convenient method for the preparation of 5-methoxy-6-substituted-3-sulfonyl-δ-enlactams via
regioselective nucleophilic addition to 5-methoxy-3-sulfonyl glutarimide is described. Formal
syntheses of L-733,060, CP-99,994, and cassine are also reported.
The piperidine ring continues to be a common moiety
in pharmaceutical research. A search of the chemical and
patent literature reveals thousands of references to this
simple ring system in clinical and preclinical research.1
Isofebrifugine (4), which show powerful antimalarial
potential,10 are alkaloids first found in the Chinese plant
Dichroafebrifuga and later in the common hydrangea
(Figure 1).
cis-2-Substituted-3-piperidinols such as (+)-L-733,060
(1)2 and (+)-CP-99,994 (2)3 are known to exhibit a variety
of biological activities including neurogenic inflamma-
tion,4 pain transmission, and regulation of the immune
response.5 They have been implicated in a variety of
disorders including migraine,6 rheumatoid arthritis,7 and
pain.8 It has been established that the cis-relationship
between the two substituents on the piperidine ring and
2S,3S configurations are essential for high-affinity bind-
ing to the human NK1 receptor.9 Febrifugine (3) and
Compounds 1-6 are piperidines, which possess differ-
ent substituents at C-2 and C-3 positions. Introduction
of different substituents at C-2 and controlling the
stereochemistry of C-2 and C-3 in piperidine has been
an important topic.11 Nucleophilic addition to N-acylimin-
ium ions with various carbon-based nucleophiles has
been extensively studied12-18 and reviewed.19 The alter-
(9) (a) Giardina, G. A. M.; Raveglia, L. F.; Grugni, M. Drugs Future
1997, 22, 1235. (b) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron
Lett. 1999, 40, 5071.
(10) (a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem
Soc. 1947, 69, 1837. (b) Koepfli, J. B.; Mead, J. F.; Brockman, J. A.,
Jr. J. Am. Chem. Soc. 1949, 71, 1048.
* Address correspondence to this author. Phone: 886-7-525-2000-
3914. Fax: 886-7-525-3913.
(1) A substructure search of the piperidine ring using the electronic
version of the Drug Data Report (MDL Drug Data Report) revealed a
great number of discrete piperidine entities that have been mentioned
in clinical or preclinical studies.
(2) (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C. J.;
Williams, B. J. EP 528,495 A1, 1993. (b) Harrison, T.; Williams, B. J.;
Swain, C. J.; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4, 2545.
(3) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.;
Snider, R. M. J. Med. Chem. 1992, 35, 4911.
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(5) Perianan, A.; Snyderman, R.; Malfroy, B. Biochem. Biophys. Res.
Commun. 1989. 161, 520.
(6) Moskowitz, M. A. Trends Pharmacol. Sci. 1992, 13, 307.
(7) Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1987, 235, 893.
(8) Otsuka, M.; Yanagisawa, M. J. Physiol. (London) 1988, 395, 255
(11) (a) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099.
(b) Stadler, H.; Bos, M. Heterocycles 1999, 51, 1067. (c) Tomooka, K.;
Nakazaki, A.; Nakai, T. J. Am. Chem. Soc. 2000, 122, 408. (d) Lee, J.;
Hoang, T.; Lewis, S.; Weissman, S. A.; Askin, D.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 2001, 42, 6223. (e) Bhaskar, G.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 915. (f) Tsuritani, N.; Yamada, K.;
Yoshikawa, N.; Shibasaki, M. Chem. Lett. 2002, 276. (g) Yamazaki,
N.; Atobe, M.; Kibayashi, C. Tetrahedron Lett. 2002, 43, 7979. (h) Desai,
M. C.; Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron Lett. 1993, 34, 5831.
(12) (a) Kraus, G. A.; Neuenschwander, K. J. Chem. Soc., Chem.
Commun. 1982, 134. (b) Thaning, M.; Wistrand, L.-G. Helv. Chim. Acta
1986, 69, 1711. (c) Thaning, M.; Wistrand, L.-G. J. Org. Chem. 1990,
55, 1406. (d) Renaud, P.; Seebach, D. Helv. Chim. Acta 1986, 69, 1704.
(e) Arai, Y.; Fujii, A.; Ohno, T.; Koizumi, T. Chem. Pharm. Bull. 1992,
40, 1670.
10.1021/jo048073e CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/08/2005
1780
J. Org. Chem. 2005, 70, 1780-1785

Regioselective Approach to 6-substituted-δ-enlactams
SCHEME 1. Regioselective Reduction of
Asymmetric Glutarimides
SCHEME 2. Addition of Grignard Reagent to
Glutarimide 9
FIGURE 1. Examples of pharmacologically active cis-2-
substituted-3-piperidinols and 2,6-disubstituted-3-piperidinols
native approaches to 2-substituted piperidines are based
on addition of organolithium or Grignard reagents to the
symmetric imide followed by reduction of the resulting
tertiary hydroxylactams with sodium cyanoborohydride
via N-acyliminium ions. Although these methods pro-
vided general ways to prepare 2-substituted piperidines,
two major limitations still existed: (i) acid has to be used
as catalyst to generate the N-acyliminium intermediate,
which is not suitable for acid-sensitive compounds, and
(ii) addition of nucleophiles to unsymmetric imides led
to poor regioselectivity and yields ring opening products
as a mixture. Therefore, the development of new ap-
proaches to 2-substitued piperidines is required.
During the course of our study of regioseletive reduc-
tion of 3-sulfonyl glutarimides 7 at C-6 carbonyl by
sequential addition of sodium hydride and LAH to form
hydroxy lactam 8, the high regioselectivity in the reduc-
tion is controlled by the formation of enolate intermedi-
ate20 (Scheme 1). We envisioned that this result can be
applied to the regioselective introduction of substituent
at C-6 in 3-sulfonyl-5-methoxyglutarimide 9 and further
converted to cis-2-substituted-3-piperidinols. Instead of
addition of hydride to C-6 carbonyl in 9, the addition of
organolithium or Grignard reagents should give the same
regioselectivity.
Results and Discussion
The starting material 3-sulfonyl-5-methoxy glutarim-
ide 9 was easily prepared via stepwise [3+3] annulation
of N-benzyl R-sulfonylacetamide with R,â-unsaturated
ester as we previously described.20,21 With glutarimide 9
in hand, we then first studied its reaction with methyl-
magnesium bromide, which although unsuccessful, re-
vealed some interesting chemistry. A mixture of gluta-
rimide 9 and 1.2 equiv of sodium hydride in THF was
allowed to react at 25 °C for 5 min, then 2 equiv of methyl
Grignard reagent was added in one portion and the
solution was further stirred for 30 min. After general
workup, the undesired product methyl ketone amide 11
was isolated exclusively (Scheme 2).22 Since an excess
(13) (a) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J. Org.
Chem. 1988, 53, 3865. (b) Onoue, H.; Narisada, M.; Uyeo, S.; Mat-
sumura, H.; Okada, K.; Yano, T.; Nagata, W. Tetrahedron Lett. 1979,
3867. (c) Kise, N.; Yamazaki, H.; Mabuchi, T.; Shono, T. Tetrahedron
Lett. 1994, 35, 1561.
(14) (a) Yamada, J.; Sato, H.; Yamamoto, Y. Tetrahedron Lett. 1989,
30, 5611. (b) Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1990,
44, 707. (c) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991, 47, 573.
(d) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60, 5011.
(e) Comins, D. L.; Foley, M. A. Tetrahedron Lett. 1988, 29, 6711. (f)
Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V. Tetrahedron 1991,
47, 1311. (g) Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y.
Tetrahedron Lett. 1990, 31, 6385. (h) Hanson, G. J.; Russell, M. A.
Tetrahedron Lett. 1989, 30, 5751.
(15) (a) Lundkvist, J. R. M.; Wistrand, L.-G.; Hacksell, U. Tetrahe-
dron Lett. 1990, 31, 719. (b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc.
1997, 119, 3409.
(16) (a) Thaning, M.; Wistrand, L.-G. Acta Chem. Scand. 1989, 43,
290. (b) Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.;
Terashima, S. Tetrahedron 1994, 50, 6221. (c) Irie, K.; Aoe, K.; Tanaka,
T.; Saito, S. J. Chem. Soc., Chem. Commun. 1985, 633.
(17) (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc.
1981, 103, 1172. (b) Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata,
K.; Makino, A. J. Org. Chem. 1984, 49, 300. (c) Pilli, R. A.; Russowsky,
D. J. Org. Chem. 1996, 61, 3187.
(21) (a) Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C.
Tetrahedron Lett. 2000, 41, 10273. (b)Huang, C. G.; Chang, B. R.;
Chang, N. C. Tetrahedron Lett. 2002, 43, 2721. (c) Chang, M. Y.; Chen,
S. T.; Chang, N. C. Tetrahedron 2002, 58, 3623. (d) Chang, M. Y.; Chen,
S. T.; Chang, N. C. Tetrahedron 2002, 58, 5075. (e) Hsu, R. T.; Cheng,
L. M.; Chang, N. C.; Tai, H. M. J. Org. Chem. 2002, 67, 5044. (f) Chang,
M. Y.; Chen, S. T.; Chang, N. C. Heterocycles 2002, 57, 2321. (g) Lin,
C. H.; Tsai, M. R.; Wang, Y. S.; Chang, N. C. J. Org. Chem. 2003, 68,
5688. (h) Chang, M. Y.; Chen, S. T.; Chang, N. C. Heterocycles 2003,
60, 99. (i) Chang, M. Y.; Chen, S. T.; Chang, N. C. Synth. Commun.
2003, 33, 1375.
(18) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Takata, J. Chem.
Lett. 1981, 1121. (b) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996,
118, 3299
(19) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(20) Chang, B. R.; Chen, C. Y.; Chang, N. C. Tetrahedron Lett. 2002,
43, 3233.
(22) Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem.
2004, 69, 6001.
J. Org. Chem, Vol. 70, No. 5, 2005 1781

Tsai et al.
TABLE 1. Regioselective Nucleophilic Addition
a All reactions were at room temperature. b All yields were based on 3-sulfonyl glutarimide 9.
SCHEME 3. Addition of Grignard Reagent to
Glutarimide 9 Then Trapping by Ac2O
SCHEME 4. Addition of Grignard Reagent to
Glutarimide 9 Then Trapping by Excess Ac2O
compound 16c was elucidated by NOESY studies.24 The
stereochemistry of 16a, 16b and 16e was assigned by
analogy.
It is interesting to note that when excess acetic
anhydride (>2 equiv) was employed in entry 1, the C-3
acylation product 18 was obtained as the only product
(Scheme 4). The structure of 18 was unequivocally
established by single-crystal X-ray analysis.23 Treatment
of 18 with potassium hydroxide produced 16a.
To demonstrate the synthetic utility of this newly
developed one-pot procedure, the synthesis of cis-2-
substituted-3-piperidinols which existed in a number of
bioactive natural products and drugs were investigated.
L-733,060 (1), CP-99,994 (2), and cassine (5) were chosen
as our target molecules.
The synthesis of 1 and 2 was illustrated in Scheme 5.
Treatment of 17a with sodium amalgam furnished de-
sulfonated product 20, which was further hydrolyzed with
boron tribromide to give the corresponding ketolactam
21. Reduction of dicarbonyl compound 21 with LAH
yielded 22 as a single diastereomer.25 The high diaste-
reoselectivity observed in the reduction of 21 has been
rationalized on the basis of Felkin’s torsional strain
amount of methylmagnesium bromide was employed
during the reaction, the lack of formation of tertiary
alcohol 12 indicated that 10 was the intermediate before
quenching with water.
To avoid the formation of ring opening product 11,
acetic anhydride was added to trap the tertiary alkoxide
10 and afforded δ-enlactam 16a in 90% yield. Presum-
ably, after the formation of acetate 13 (R1 ) H), N-
acyliminium intermediate was produced, which further
isomerized to δ-enlactam 16a (Scheme 3). Encouraged
by these results, various Grignard reagents were inves-
tigated. The corresponding δ-enlactams were obtained in
good yield (Table 1). The addition reactions proceeded
exclusively at the C-6 position in 9 without the formation
of ring-opening product.
The formation of exo or endo enlactam depends on the
type of Grignard reagents. Alkyl Grignard reagents
furnished exclusively exo olefins (entries 1 to 5). Aryl
Grinard reagents produced endo olefins (entries 6 and
7) (Table 1). It is evident that in each alkyl Grignard
reagent addition, a single geometric isomer was obtained.
The structure of 16d was unequivocally established by
single-crystal X-ray analysis.23 The configuration of
(24) NOESY studies of 16c: strong NOE correlation between Ha
and Hb and the absence of a coupling constant between Hd and Hb are
indicative of a chairlike conformation and the equatorial disposition
of the sulfonyl group.
(23) CCDC 250214-250215 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK.; fax +44-1223-336033;
e-mail deposit@ccdc.cam.ac.uk).
1782 J. Org. Chem., Vol. 70, No. 5, 2005

Regioselective Approach to 6-substituted-δ-enlactams
SCHEME 5. Formal Synthesis of (+)-L-733,060 (1)
and (+)-CP-99,994 (2)
present methodology to the synthesis of indolizidines,
quinolizidines and polysubstituted piperidines is under-
way in our laboratory.
Experimental Section
1. Preparation of 11. A solution of glutarimide 9 (387 mg,
1 mmol) in dry THF (5 mL) was added to a rapidly stirred
suspension of sodium hydride (60 mg, 1.5 mmol, 60%) in
tetrahydrofuran (20 mL). After the reaction mixture was
stirred at room temperature for 15 min, methylmagnesium
bromide (1.3 mmol) was added in one portion by syringe. The
resulting mixture was stirred at room temperature for 30 min.
After the reaction was accomplished (monitored by TLC), the
reaction mixture was quenched with water (2 mL) and filtered
through Celite. The organic layer was extracted with EtOAc
(3 × 20 mL) and dried with anhydrous MgSO4, filtered, and
concentrated. The crude product was purified by silica gel
chromatography (n-hexane/ethyl acetate ) 4/1 to 2/1) to afford
11.
2. General Procedure for the Preparation of 5-Meth-
oxy-6-substituted-δ-enlactams. The procedure for the prepa-
ration of 11 was applied to the preparation of 16a-e and
17a,b; however, instead of quenching with water, acetic
anhydride (122.4 mg, 1.2 mmol) was added in one portion, and
the reaction mixture was stirred for an additional 30 min. After
the reaction was finished, the reaction mixture was quenched
with a saturated ammonium chloride solution (1 mL) and
filtered through Celite. The organic layer was extracted with
EtOAc (3 × 20 mL) and dried with anhydrous MgSO4, filtered,
and concentrated. The crude product was purified by silica gel
chromatography (n-hexane/ethyl acetate ) 4/1 to 2/1) to afford
16a-e and 17a,b.
SCHEME 6. Formal Synthesis of Cassine (5)
4-Methoxy-5-oxo-2-(toluene-4-sulfonyl)hexanoic acid
benzylamide (11): 88% yield; white solid; 1H NMR (500 MHz,
CDCl3) δ 7.58-7.56 (m, 2H), 7.38-7.25 (m, 7H), 6.82 (t, J )
5.5 Hz, 0.6H), 6.68 (t, J ) 5.5 Hz, 0.4H), 4.51-4.43 (m, 1.2H),
4.47-4.36 (m, 0.8H), 4.05 (dd, J ) 11.0, 2.5 Hz, 0.6H), 3.99
(dd, J ) 8.5, 3.5 Hz, 0.4H), 3.75 (t, J ) 7.0 Hz, 0.4H), 3.65(dd,
J ) 10.0, 4.0 Hz, 0.6H), 3.34 (s, 1.2H), 3.26 (s, 1.8H), 2.43 (s,
3H), 2.37-2.22 (m, 1.6H), 2.16-2.10 (m, 0.4H), 2.15 (s, 1.8H),
2.14 (s, 1.2H); 13C NMR (125 MHz, CDCl3) δ 209.9 (0.4C), 209.0
(0.6C), 163.4 (0.4C), 163.2 (0.6C), 145.7 (0.6C), 145.6 (0.4C),
137.3 (0.6C), 137.2 (0.4C), 133.0 (0.6C), 132.8 (0.4C), 130.0
(1.2C), 129.8 (0.8C), 129.1 (0.8C), 129.0 (1.2C), 128.8 (1.2C),
128.7 (0.8C), 128.1 (2C), 127.8 (0.6C), 127.7 (0.4C), 83.5 (0.4C),
83.2 (0.6C), 67.1 (0.6C), 66.6 (0.4C), 58.4 (0.6C), 58.2 (0.4C),
44.3, 28.6 (0.6C), 28.2 (0.4C), 25.7 (0.6C), 25.6 (0.4C), 21.7; EI-
MS C21H25NO5S, m/z (%) 91 (100), 404 (M+ + 1, 0.27).
1-Benzyl-5-methoxy-6-methylene-3-(toluene-4-sulfonyl)-
model, which disfavors the equatorial attack of hydride.26
The presence of the N-benzyl functionality in the six-
member ring should flatten the molecule and decrease
the 1,3-diaxial steric interactions, further increasing the
selectivity. Debenzylation of 22 with Pd(OH)2 as catalyst
produced cis-2-phenyl-3-pipericinol 23. The spectral data
of 23 were in agreement with those reported in the
literature.27 Compound 23 has been converted to 1 and
2. Thus, the formal synthesis of 1 and 2 was ac-
complished.
For the synthesis of cassine (5), the key intermediate
25 was readily prepared from 16a, by sodium amalgam
desulfonation followed by hydrolysis of the resulting
methyl ether and finally sodium borohydride reduction28
(Scheme 6).
piperidin-2-one (16a): 90% yield; yellow oil; IR (CHCl3, cm-1
)
1
3024, 1641, 1219; H NMR (500 MHz, CDCl3) δ 7.83 (d, J )
8.5 Hz, 2H), 7.34 (d, J ) 8.5 Hz, 2H), 7.27-7.21 (m, 3H), 7.14
(d, J ) 7.0 Hz, 2H), 5.0 (d, J ) 16.0 Hz, 1H), 4.67 (d, J ) 16.0
Hz, 1H), 4.5 (d, J ) 1.5 Hz, 1H), 4.47 (dd, J ) 12.0, 7.0 Hz,
1H), 4.4 (d, J ) 1.50 Hz, 1H), 4.01 (dd, J ) 4.0, 2.5 Hz, 1H),
3.11 (s, 3H), 2.74 (ddd, J ) 14.0, 7.0, 4.0 Hz, 1H), 2.56 (ddd, J
) 14.0, 12.0, 2.5 Hz 1H), 2.44 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 162.1, 144.7, 141.0, 136.3, 136.0, 129.5 (2C), 129.3
(2C), 128.6 (2C), 127.1, 126.0 (2C), 98.3, 75.8, 62.8, 56.0, 47.2,
26.5, 21.8; HRMS m/z (ESI, M+ + 1) calcd for C21H24NO4S
386.1348, found 386.1422.
In conclusion, we have developed a straightforward
one-pot reaction procedure, which converted readily
available 5-methoxy-3-sulfonyl glutarimide 9 to the cor-
responding 5-methoxy-6-substituted-3-sulfonyl-δ-enlac-
tames. Various substituents have been introduced to the
C-6 position in 9 in high yield. This strategy also provided
a rapid access to cis-2-substituted-3-piperidinols, and was
demonstrated by the formal synthesis of L-733,060 (1),
CP-99,994 (2), and cassine (5). Further application of the
1-Benzyl-5-methoxy-6-propylidene-3-(toluene-4-sulfo-
nyl)piperidin-2-one (16b): 85% yield; yellow oil; IR (CHCl3,
cm-1) 2997, 1685; 1H NMR (500 MHz, CDCl3) δ 7.8 (d, J ) 8.5
Hz, 2H), 7.32 (m, 6H) 7.16 (d, J ) 7.0 Hz, 1H), 5.13 (t, J ) 7.5
Hz, 1H), 5.0 (d, J ) 15.5 Hz, 1H), 4.73 (d, J ) 15.5 Hz, 1H),
4.53 (dd, J ) 8.5, 2.0 Hz, 1H), 4.42 (dd, J ) 11.5, 7.5 Hz, 1H),
3.03 (s, 3H), 2.74 (ddd, J ) 14.5, 8.0, 4.5 Hz, 1H), 2.48-2.44
(m, 1H), 2.42 (s, 3H), 2.09 (dq, J ) 7.5, 7.5 Hz, 2H), 0.91 (t, J
) 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.8, 144.6,
136.6, 136.2, 134.2, 129.4 (2C), 129.2 (2C), 128.5 (2C), 126.9,
(25) (a) Bonjoch, J.; Serret, I.; Bosch, J. Tetrahedron 1984, 40, 2505.
(b) Toyooka, N.; Yoshida, Y.; Momose, T. J. Org. Chem. 1996, 61, 4882.
(c) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J. Org. Chem. 1999,
64, 4919. (d) Koulocheri, S. D.; Magiatis, P.; Haroutounian, S. A. J.
Org. Chem. 2001, 66, 7915.
(26) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 2204. (c) Wu,
Y. D.; Trucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5018.
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3715.
J. Org. Chem, Vol. 70, No. 5, 2005 1783

Tsai et al.
126.8 (2C), 117.5, 68.9, 63.1, 55.6, 47.8, 26.6, 21.7, 20.2, 14.7;
HRMS m/z (ESI, M+ + 1) calcd for C23H28NO4S 414.1661, found
414.1736.
139-140 °C; IR (CHCl3, cm-1) 1724, 1648, 1278; 1H NMR (500
MHz, CDCl3) δ 7.75 (d, J ) 8.5 Hz, 2H), 7.33-7.24, (m, 6H),
7.22 (d, J ) 8.0 Hz, 1H), 5.18 (d, J ) 16.0 Hz, 1H), 4.86 (d, J
) 16.0 Hz, 1H), 4.51 (d, J ) 2.0 Hz, 1H), 4.41 (d, J ) 2.0 Hz,
1H), 3.94 (dd, J ) 4.0, 2.0 Hz, 1H), 3.21 (dd, J ) 14.0, 4.5 Hz,
1H), 3.05 (s, 3H), 2.67 (dd, J ) 14.0, 2.0 Hz, 1H), 2.4 (s, 3H),
2.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.6, 163.6, 145.4,
140.7, 135.9, 134.0, 131.7 (2C), 129.0 (2C), 128.6 (2C), 127.3,
126.5 (2C), 97.9, 79.8, 75.6, 56.0, 47.1, 32.3, 29.1, 21.7; HRMS
m/z (ESI, M+ + 1) calcd for C23H25NO5S 428.1453, found
428.1536. Compound 18 was recrystallized from ethyl acetate
as a colorless prism.
6-Allylidene-1-benzyl-5-methoxy-3-(toluene-4-sulfonyl)-
piperidin-2-one (16c): 85% yield; yellow oil; IR (CHCl3, cm-1
)
2975, 1648, 1392; 1H NMR (500 MHz, CDCl3) δ 7.8 (d, J ) 8.0
Hz, 2H), 7.33-7.21 (m, 6H), 7.16 (d, J ) 7.5 Hz, 1H), 6.51 (dt,
J ) 16.5, 11.0 Hz, 1H), 5.8 (d, J ) 11.0 Hz, 1H), 5.14 (d, J )
16.5 Hz, 1H), 5.12 (d, J ) 16.0 Hz, 1H), 5.11 (dd, J ) 10.0, 1.5
Hz, 1H), 4.7 (d, J ) 16.0 Hz, 1H), 4.7-4.69 (m, 1H), 4.45 (dd,
J ) 12.0, 7.5 Hz, 1H), 3.09 (s, 3H), 2.78 (ddd, J ) 14.0, 7.5,
4.0 Hz, 1H), 2.57-2.45 (m, 1H), 2.43 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 162.1, 144.7, 136.1, 136.1, 135.9, 129.9, 129.5
(2C), 129.3 (2C), 128.6 (2C), 127.2, 126.5 (2C), 118.9, 116.0,
68.8, 62.9, 55.9, 47.7, 26.1, 21.7; HRMS m/z (EI, M+) calcd for
C23H25NO4S 411.1504, found 411.1496.
3. Synthesis of 1-Benzyl-5-methoxy-6-phenyl-3,4-dihy-
dro-1H-pyridin-2-one (20). Sodium amalgam (Na/Hg, 3.0 g)
and sodium phosphate (40 mg) were added to a stirred solution
of 17a (800 mg, 1.78 mmol) in MeOH (20 mL), and the solution
was vigorously stirred for 2 h at room temperature. The
residue was filtered and washed with MeOH (2 × 10 mL). The
combined organic layers were concentrated to obtain the crude
product. The crude product was purified by silica gel chroma-
tography (n-hexane/ethyl acetate 4/1 to 2/1) to afford 20 (469
mg, 90%) as a colorless oil: 90% yield; colorless oil; IR (CHCl3,
1-Benzyl-6-benzylidene-5-methoxy-3-(toluene-4-sulfo-
nyl)piperidin-2-one (16d): 70% yield; white solid; mp 179-
180 °C; IR (CHCl3, cm-1) 2941, 1655, 1281; 1H NMR (500 MHz,
CDCl3) δ 7.8 (d, J ) 8.5 Hz, 2H), 7.35-7.17 (m, 10H), 7.05 (d,
J ) 8.0 Hz, 2H), 6.27 (s, 1H), 5.18 (d, J ) 16.0 Hz, 1H), 4.84
(d, J ) 16.0 Hz, 1H), 4.58 (dd, J ) 4.0, 2.0 Hz, 1H), 4.46 (dd,
J ) 12.0, 7.5 Hz, 1H), 3.0 (s, 3H), 2.79 (ddd, J ) 14.0, 7.5, 4.0
Hz, 1H), 2.52 (ddd, J ) 14.0, 12.0, 2.0 Hz, 1H), 2.45 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 162.3, 144.8, 142.5, 137.4, 136.3,
135.1, 129.4 (2C), 129.4 (2C), 129.0 (2C), 128.6 (2C), 128.2,
127.2 (2C), 126.7 (2C), 125.7, 115.3, 69.6, 63.1, 55.5, 47.8, 25.6,
21.6; HRMS m/z (EI, M+) calcd for C27H27NO4S 461.1661, found
461.1658. Anal. Calcd for C27H27NO4S: C, 70.26; H, 5.9; N,
3.03. Found: C, 70.27; H, 6.01; N, 2.88. Compound 16d was
recrystallized from ethyl acetate as a colorless prism.
1
cm-1) 3031, 1648, 1233; H NMR (500 MHz, CDCl3) δ 7.29-
7.16 (m, 6H), 7.06 (dd, J ) 8.0, 3.0 Hz, 2H), 6.88 (dd, J ) 8.0,
3.0 Hz, 2H), 4.57 (s, 2H), 3.38 (s, 3H), 2.75 (t, J ) 7.0 Hz, 2H),
2.54 (t, J ) 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 169.8,
142.0, 137.9, 132.0, 129.8, 129.7 (2C), 128.8, 128.1 (2C), 127.9,
127.8, 127.3 (2C), 126.8, 56.9, 45.9, 31,9, 21.0; HRMS m/z (EI,
M+) calcd for C19H19NO2 293.1416, found 293.1413.
4. Synthesis of 1-Benzyl-6-phenylpiperidine-2,5-dione
(21). To a solution of 20 (440 mg, 1.5 mmol) in dry CH2Cl2 (10
mL) at -78 °C was added dropwise a 1.0 M solution of boron
tribromide in dichloromethane (1.0 M, 2.0 mL). After the
solution was stirred for 4 h, the reaction contents were
quenched with a saturated aqueous NaHCO3 (10 mL) at 0 °C.
The resulting mixture was stirred for 20 min and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with brine, dried, filtered, and evaporated. The crude
product was purified by silica gel chromatography (n-hexane/
ethyl acetate ) 6/1 to 3/1) to afford 21 (369 mg, 90%): 90%
yield; yellow oil; IR (CHCl3, cm-1) 2996, 1738, 1261; 1H NMR
(500 MHz, CDCl3) δ 7.42-7.26 (m, 8H), 7.17 (d, J ) 8.0 Hz,
2H), 5.63 (d, J ) 14.5 Hz, 1H), 4.78 (s, 1H), 3.55 (d, J ) 14.5
Hz, 1H), 2.84 (dt, J ) 17.5, 9.0 Hz, 2H), 2.73 (dd, J ) 9.0, 5.5
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 202.7, 170.0, 135.8,
134.0, 129.2 (2C), 128.9 (2C), 128.6 (2C), 128.0 (2C), 126.4 (2C),
68.5, 47.7, 34.9, 29.1; HRMS m/z (EI, M+) calcd for C18H17-
NO2S 279.1259, found 279.1257.
1-Benzyl-6-(2-[1,3]dioxolan-2-ylethylidene)-5-methoxy-
3-(toluene-4-sulfonyl)piperidin-2-one (16e): 75% yield;
1
yellow oil; IR (CHCl3, cm-1) 2996, 1638; H NMR (500 MHz,
CDCl3) δ 7.81 (d, J ) 8.0 Hz, 2H), 7.32 (d, J ) 8.0 Hz, 2H),
7.29-7.21 (m, 4H), 7.17 (d, J ) 7.0 Hz, 1H), 5.19 (t, J ) 8.0
Hz, 1H), 5.02 (d, J ) 16.0 Hz, 1H), 4.85 (t, J ) 3.5 Hz, 1H),
4.75 (d, J ) 16.0 Hz, 1H), 4.56 (dd, J ) 4.0, 2.0 Hz, 1H), 4.44
(dd, J ) 11.5, 7.5 Hz, 1H), 3.85-3.75 (m, 4H), 3.05 (s, 3H),
2.75 (ddd, J ) 14.0, 7.5, 4.0 Hz, 1H), 2.49 (ddd, J ) 14.0, 12.0,
2.0 Hz, 1H), 2.47-2.43 (m, 2H), 2.43 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 162.0, 144.7, 137.3, 136.5, 136.3, 129.4 (2C),
129.3 (2C), 128.4 (2C), 127.0, 126.8 (2C), 108.4, 103.0, 69.1,
65.3, 65.1, 63.1, 55.8, 47.7, 31.7, 26.3, 21.7; HRMS m/z (ESI,
M+ + 1) calcd for C25H30NO6S 472.1716, found 472.1735.
1-Benzyl-5-methoxy-6-phenyl-3-(toluene-4-sulfonyl)-
3,4-dihydro-1H-pyridin-2-one (17a): 82% yield; yellow oil;
IR (CHCl3, cm-1) 2968, 1714; 1H NMR (500 MHz, CDCl3) δ
7.87 (d, J ) 8.0 Hz, 2H), 7.37 (d, J ) 8.0 Hz, 2H), 7.31-7.29
(m, 3H), 7.17-7.15 (m, 3H), 7.09-7.07 (m, 2H), 6.87-6.86 (m,
2H), 4.85 (d, J ) 15.5 Hz, 1H), 4.22 (d, J ) 15.5 Hz, 1H), 4.15
(q, J ) 3.5 Hz, 1H), 3.46 (s, 3H), 3.31 (dd, J ) 14.0, 3.5 Hz,
1H), 3.08 (dd, J ) 14.0, 3.5 Hz, 1H), 2.46 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 161.5, 145.3, 137.1, 136.0, 131.4, 129.8
(2C), 129.0 (2C), 128.2 (2C), 128.2 (2C), 128.1 (2C), 128.0 (2C),
127.5 (2C), 127.2, 127.1, 65.9, 57.6, 47.0, 22.2, 21.7; HRMS
m/z (ESI, M+ + 1) calcd for C26H26NO4S 448.1504, found
448.1612.
5. Synthesis of 1-Benzyl-2-phenylpiperidin-3-ol (22). To
a solution of 21 (327 mg, 1.17 mmol) in THF (10 mL) was
added lithium aluminum hydride (77 mg, 2.0 mmol) at room
temperature. The resulting mixture was refluxed for 3 h,
quenched with NH4Cl (1 mL) at the same temperature,
filtered, and then concentrated under reduced pressure. The
residue was diluted with water (5 mL) and extracted with ethyl
acetate (3 × 20 mL). The combined organic layers were washed
with brine, dried, filtered, and evaporated. Purification on the
silica gel (hexane/ethyl acetate ) 3/1 to 1/1) produced the
product 22 (255 mg, 87%): 87% yield; yellow oil; IR (CHCl3,
1-Benzyl-5-methoxy-6-(4-methoxyphenyl)-3-(toluene-
1
cm-1) 2994, 1378, 1254; H NMR (500 MHz, CDCl3) δ 7.48-
4-sulfonyl)-3,4-dihydro-1H-pyridin-2-one (17b): 70% yield;
1
yellow oil; IR (CHCl3, cm-1) 3012, 1685; H NMR (500 MHz,
7.22 (m, 10H), 3.88 (d, J ) 14.0 Hz, 1H), 3.76 (d, J ) 2.0 Hz,
1H), 3.36 (d, J ) 1.5 Hz, 1H), 3.01 (d, J ) 10.0 Hz, 1H), 2.91
(d, J ) 14.0 Hz, 1H), 2.0 (dd, J ) 13.5, 2.0 Hz, 2H), 1.98-1.93
(m, 1H), 1.62 (ddt, 16.0, 13.5, 3.0 Hz, 1H), 1.51-1.47 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 140.8, 132.3, 128.7 (2C), 128.6
(2C), 128.3 (2C), 128.2 (2C), 127.4, 126.8, 72.3, 69.9, 59.4, 53.3,
31.6, 19.8; HRMS m/z (EI, M+) calcd for C18H21NO 267.1623,
found 267.1620.
CDCl3) δ 7.86 (d, J ) 8.0 Hz, 2H), 7.37 (d, J ) 8.0 Hz, 2H),
7.26-7.16 (m, 5H), 7.0-6.82 (m, 4H), 4.85 (d, J ) 15.5 Hz,
1H), 4.22 (d, J ) 15.5 Hz, 1H), 4.15 (dd, 7.0, 3.5 Hz, 1H), 3.86
(s, 3H), 3.45 (s, 3H), 3.29 (dd, J ) 17.5, 3.5 Hz, 1H), 3.06 (dd,
J ) 17.5, 7.0 Hz, 1H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 169.7, 159.1, 141.7, 138.0, 136.7, 133.7, 131.1, 130.9 (2C),
130.6, 129.2 (2C), 128.1 (2C), 127.4 (2C), 126.8, 126.3, 124.3,
113.4 (2C), 65.4, 55.5, 45.8, 32.1, 21.7, 21.4; HRMS m/z (ESI,
M+ + 1) calcd for C27H28NO5S 478.1610, found 478.1721.
6. Synthesis of 2-Phenylpiperidin-3-ol (23). Palladium
hydroxide (20%) on activated carbon (30 mg) was added to the
solution of compound 22 (139 mg, 0.52 mmol) in methanol (100
mL). Then hydrogen was bubbled into the mixture for 1 h, and
3-Acetyl-1-benzyl-5-methoxy-6-methylene-3-(toluene-
4-sulfonyl)piperidin-2-one (18): 95% yield; white solid; mp
1784 J. Org. Chem., Vol. 70, No. 5, 2005

Regioselective Approach to 6-substituted-δ-enlactams
the reaction mixture was stirred for 12 h at room temperature.
The catalyst was filtered through a short plug of Celite and
washed with ethyl acetate (2 × 5 mL), filtered, and concen-
trated to produce product 23 as a white solid: 90% yield; IR
(CHCl3, cm-1) 3645, 3112, 1265; 1H NMR (500 MHz, CDCl3) δ
7.35-7.34 (m, 5H), 3.86 (br s, 1H), 3.78 (d, J ) 1.5 Hz, 1H),
3.21 (dt, J ) 11.5, 2.0 Hz, 1H), 2.8 (dt, J ) 12.0, 2.5 Hz, 1H),
2.05-2.02 (dm, J ) 12.0 Hz, 1H), 1.88 (ddt, J ) 12.0, 12.0,
(125 MHz, CDCl3) δ 207.0, 169.4, 136.4, 128.9 (2C), 128.0 (2C),
127.9, 60.6, 47.4, 35.5, 29.1, 17.5; HRMS m/z (EI, M+) calcd
for C13H15NO2 217.1103, found 217.1110.
8. Synthesis of 1-Benzyl-5-hydroxy-6-methylpiperidin-
2-one (25). To a solution of 24 (95 mg, 0.43 mmol) in methanol
(10 mL) was added sodium boron hydride (10.0 mmol) at room
temperature. The resulting mixture was stirred for 3 h,
quenched with NH4Cl (1 mL) at the same temperature, and
then concentrated under reduced pressure. The residue was
diluted with water (5 mL) and extracted with ethyl acetate (3
× 20 mL). The combined organic layers were washed with
brine, dried, filtered, and evaporated. Purification on silica gel
chromatography (acetone/ethyl acetate ) 1/3 to 1/1) produced
the product 25: 90% yield; yellow oil; IR (CHCl3, cm-1) 3627,
4.0 Hz, 1H), 1.72-1.68 (m, 1H), 1.5 (dm, J ) 13.0 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 141.9, 128.5 (2C), 127.3, 126.6 (2C),
68.9, 65.0, 47.4, 31.9, 19.8; HRMS m/z (ESI, M+ + 1) calcd for
C11H16NO 178.1154, found 178.1228.
7. Synthesis of 1-Benzyl-6-methylpiperidine-2,5-dione
(24). Sodium amalgam (Na/Hg, 3.0 g) and sodium phosphate
(40 mg) were added to a stirred solution of 16a (365 mg, 0.94
mmol) in MeOH (20 mL), and the solution was vigorously
stirred for 2 h at room temperature. The residue was filtered
and washed with MeOH (2 × 10 mL). The combined organic
layers were concentrated to obtain the crude product. Without
purification the crude product was dissolved in the CH2Cl2 (5
mL) then the trifluroacetic acid (cat.) was added. After the
resulting mixture was stirred for 1 h, the solution was
concentrated under reduced pressure and the residue was
diluted with water (20 mL) and potassium carbonate. After
extracted with ethyl acetate (3 × 50 mL), the combined organic
layers were washed with brine (2 × 20 mL), dried over
anhydrous magnesium sulfate, filtered, and evaporated. The
crude product was purified by the silica gel chromatography
(n-hexane/ethyl acetate ) 4/1 to 2/1) to afford 24 (183 mg) as
a colorless oil: 90% yield; IR (CHCl3, cm-1) 2989, 1731, 1662;
1H NMR (500 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 5.25 (d, J )
15.0 Hz, 1H), 4.03 (d, J ) 15.0 Hz, 1H), 3.73 (q, J ) 7.5 Hz,
1H), 2.84-2.65 (m, 4H), 1.36 (d, J ) 7.5 Hz, 3H); 13C NMR
1
3012; H NMR (500 MHz, CDCl3) δ 7.33-7.22 (m, 5H), 5.33
(d, J ) 15.0 Hz, 1H), 3.99 (dt, J ) 10.5, 4.5 Hz, 1H), 3.93 (d,
J ) 15.0 Hz, 1H), 3.44 (dq, J ) 6.5, 5.5 Hz, 1H), 2.64 (ddd, J
) 18.5, 7.5, 4.0 Hz, 1H), 2.53 (ddd, J ) 17.0, 9.0, 8.0 Hz, 1H),
2.04-1.96 (m, 1H), 1.9 (ddd, J ) 17.0, 8.0, 4.0, 1.0 Hz, 1H),
1.22 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.2,
137.3, 128.6 (2C), 127.8 (2C), 127.4, 67.6, 54.8, 47.6, 28.9, 24.9,
13.2; HRMS m/z (EI, M+) calcd for C13H17NO2 219.1259, found
219.1321.
Acknowledgment. The authors thank the National
Science Council of the Republic of China for financial
support.
Supporting Information Available: NMR spectra data
of compounds 11 and 16-25. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO048073E
J. Org. Chem, Vol. 70, No. 5, 2005 1785