Alkylation of phenylglycinol-derived oxazolopiperidone lactams. Enantioselective synthesis of β-substituted piperidines

Article abstract of DOI:10.1021/jo060157v

The stereochemical outcome of the alkylation of a variety of phenylglycinol-derived oxazolopiperidone lactams is studied. The influence of the configuration of the C-8a stereocenter and the effect of the substituents at the C-8 and C-8a positions on the s

Full text of DOI:10.1021/jo060157v

Alkylation of Phenylglycinol-Derived Oxazolopiperidone Lactams.
Enantioselective Synthesis of â-Substituted Piperidines
Mercedes Amat,*,† Carmen Escolano,† Oscar Lozano,† Arantxa Go´mez-Esque´,†
Rosa Griera,† Elies Molins,‡ and Joan Bosch†
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona, 08028-Barcelona, Spain,
and Institut de Cie`ncia de Materials (CSIC), Campus UAB, 08193-Cerdanyola, Spain
amat@ub.edu
ReceiVed January 24, 2006
The stereochemical outcome of the alkylation of a variety of phenylglycinol-derived oxazolopiperidone
lactams is studied. The influence of the configuration of the C-8a stereocenter and the effect of the
substituents at the C-8 and C-8a positions on the stereoselectivity of the reaction are discussed. The
synthetic utility of these alkylation reactions is illustrated with the synthesis of cis and trans
3,5-disubstituted, 2,5-disubstituted, and 2,3,5-trisubstituted enantiopure piperidines, and the indole alkaloids
20R- and 20S-dihydrocleavamine.
Introduction
with methyl 5-oxopentanoate. We have also prepared substituted
lactams by stereoselective cyclocondensation reactions of chiral
amino alcohols with racemic or prochiral δ-oxoesters in
processes involving a dynamic kinetic resolution of the racemic
substrate or the desymmetrization of diastereotopic or enan-
tiotopic ester chains.3 These lactams can be subsequently
elaborated by the introduction of further substituents on the
piperidine ring, taking advantage of the functionalization present
in the bicyclic system. Thus, they can undergo stereocontrolled
amidoalkylation reactions4 involving the cleavage of the C-O
Natural and synthetic piperidine derivatives display a broad
range of important biological activities.1 As a consequence, the
development of general methods for their enantioselective
synthesis continues to be the focus of considerable attention.2
Over the last few years we have explored the synthetic utility
of chiral bicyclic δ-lactams derived from (R)- or (S)-phenylg-
lycinol for the enantioselective synthesis of natural products and
pharmaceuticals bearing a piperidine unit as a central structural
feature. With this purpose, we have prepared simple oxazol-
opiperidone lactams by cyclocondensation of phenylglycinol
(2) (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine. Structure,
Preparation, ReactiVity, and Synthetic Applications of Piperidine and its
DeriVatiVes; Elsevier: Amsterdam, The Netherlands, 1991. (b) Kibayashi,
C. In Studies in Natural Products Chemistry. StereoselectiVe Synthesis (Part
G); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Netherlands,1992; Vol.
11, pp 229-275. (c) Cossy, J.; Vogel, P. In Studies in Natural Products
Chemistry. StereoselectiVe Synthesis (Part H); Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1993; Vol. 12, pp 275-363. (d) Angle, S. R.;
Breitenbucher, J. G. In Studies in Natural Products Chemistry (Part J);
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Netherlands, 1995; Vol.
16, pp 453-502. (e) Leclerq, S.; Daloze, D.; Braekman, J.-C. Org. Prep.
Proced. Int. 1996, 28, 501-543. (f) Bailey, P. D.; Millwood, P. A.; Smith,
P. D. Chem. Commun. 1998, 633-640. (g) Husson, H.-P.; Royer, J. Chem.
Soc. ReV. 1999, 28, 383-394. (h) Comins, D. L. J. Heterocycl. Chem. 1999,
36, 1491-1500. (i) Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813.
(j) Guilloteau-Bertin, B.; Compe`re, D.; Gil, L.; Marazano, C.; Das, B. C.
Eur. J. Org. Chem. 2000, 1391-1399. (k) Weintraub, P. M.; Sabol, J. S.;
Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989. (l)
Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729.
† University of Barcelona.
‡ Institut de Cie`ncia de Materials.
(1) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: London, 1985; Vol. 26, pp 89-183. (b) Takahata, H.;
Momose, T. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, CA, 1993; Vol. 44, pp 189-256. (c) Ohmiya, S.; Saito, K.;
Murakoshi, I. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, 1995; Vol. 47, pp 1-114. (d) Schneider, M. J. In Alkaloids:
Chemical and Biological PerpectiVes; Pelletier, S. W., Ed; Pergamon:
Oxford, U.K., 1996; Vol. 10, pp 155-299. (e) Andersen, R. J.; Van Soest,
R. W. M.; Kong, F. In Alkaloids: Chemical and Biological PerpectiVes;
Pelletier, S. W., Ed; Pergamon: Oxford, U.K., 1996; Vol. 10, pp 301-
355. (f) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon Press: New
York, 1999; Vol. 13, pp 1-161. (g) Watson, P. S.; Jiang, B.; Scott, B.
Org. Lett. 2000, 2, 3679. (h) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603-
626 and previous reviews in this series.
10.1021/jo060157v CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/12/2006
3804
J. Org. Chem. 2006, 71, 3804-3815

EnantioselectiVe Synthesis of â-Substituted Piperidines
bond of the oxazolidine ring, nucleophilic alkylation of the
lactam carbonyl group,4b as well as stereoselective conjugate
addition,5 Diels-Alder,6 and dihydroxylation7 reactions on their
unsaturated derivatives. A subsequent reductive removal of the
chiral auxiliary provides easy access to diversely substituted
enantiopure piperidine derivatives.
FIGURE 1. [4.3.0] Bicyclic lactams.
In this paper we report the enolate alkylation of a variety of
phenylglycinol-derived oxazolopiperidone lactams (1-9) and
examine the influence of the configuration of the C-8a stereo-
genic center and the effect of the substituents at the C-8 and
C-8a positions on the stereoselectivity of the reaction. Moreover,
we illustrate the synthetic utility of these alkylation reactions
with the synthesis of cis and trans 3,5-disubstituted, 2,5-
disubstituted, and 2,3,5-trisubstituted enantiopure piperidines and
the alkaloids 20R- and 20S-dihydrocleavamine.
directing effect of the nitrogen lone pair, and the torsional strain
in the transition state have been invoked to account for the
observed stereoselectivities.
The alkylation of enolates derived from [4.3.0] bicyclic
lactams (oxazolopiperidone lactams) has received less attention
than that of their pyrrolidone homologues. Thus, the dialkylation
of C-8a substituted lactams A (R1 ) Me, Et; Figure 1), derived
from (S)-valinol (R2 ) i-Pr; R3 ) H) or (1S,2S)-2-amino-1-
phenyl-1,3-propanediol (R2 ) CH2OH; R3 ) C6H5), was
reported by Meyers et al.12 to give the corresponding endo
products in the second alkylation step in good to excellent
stereoselectivities (endo/exo ratio, 3-50:1). On the other hand,
Moloney et al.13 described that the monoalkylation of the enolate
of the C-3 isomeric [4.3.0] lactams B (R ) H or Me) and C,
derived from 6-oxopipecolic acid, predominantly affords the exo
products with moderate stereoselectivity (exo/endo ratio, 2-10:
1), although the efficiency of the process depends on the
substitution at the hemiaminal system.
The stereoselective double alkylation of chiral bicyclic
lactams has been extensively studied by Meyers, who has
demonstrated that this methodology constitutes a powerful tool
to generate quaternary stereocenters with excellent control over
the absolute stereochemistry.8 The dialkylated lactams provide
access to cyclopentenone, cyclohexenone, and hexahydroinde-
none systems, as well as to carboxylic acids bearing a quaternary
stereocenter, which have been used for the synthesis of
numerous natural and unnatural products in high enantiomeric
purity. The dialkylation of enolates generated from a wide
variety of chiral [3.3.0] bicyclic lactams (oxazolopyrrolidone
lactams) affords products resulting from the endo facial attack
of the electrophile in the second alkylation step with excellent
stereoselectivity (endo/exo ratio, 10-50:1).8 However, slight
structural modifications in the oxazolidine ring (oxygen atom
at the 3-position instead of the 2-position,9 replacement of the
oxygen by a methylene, or introduction of gem-dialkyl substit-
uents at the 2-position8c) have been show to have a dramatic
effect on the endo/exo selectivity. These intriguing results have
stimulated Meyers et al.10 and other authors11 to find a rationale
that explains the origin of the facial stereoselectivity of lactam
enolate alkylations. Thus, steric considerations related to the
concave-convex faces of the enolate, the anti-stereoelectronic
Results and Discussion
Lactams 1-3, 5-7, and 9 (Figure 2) were prepared as
previously described, by a cyclocondensation reaction of (R)-
phenylglycinol with the appropriate δ-oxoacid derivative (see
Experimental Section). Treatment of lactam 2 under acidic
conditions caused the isomerization of the C-8 and C-8a
stereocenters, affording 4. Lactam 8 was obtained from the
known O-benzyl analogue14 by hydrogenolysis, followed by
silylation of the resulting alcohol.
The formation of the enolates of lactams 1-9 and subsequent
alkylations were carried out under the same reaction conditions
in all cases to allow a better comparison of the stereochemical
(3) (a) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez, M.; Bosch, J.
Angew. Chem., Int. Ed. 2002, 41, 335. (b) Amat, M.; Canto´, M.; Llor, N.;
Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67,
5343. (c) Amat, M.; Basas, O.; Perica`s, M. A.; Pasto´, M.; Bosch, J. Chem.
Commun. 2005, 1327. (d) Bassas, O.; Llor, N.; Santos, M. M. M.; Griera,
R.; Molins, E.; Amat, M.; Bosch, J. Org. Lett. 2005, 7, 2817.
(4) (a) Amat, M.; Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53,
719. (b) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org.
Chem. 2003, 68, 1919. (c) Amat, M.; Escolano, C.; Llor, N.; Huguet, M.;
Pe´rez, M.; Bosch, J. Tetrahedron: Asymmetry 2003, 14, 1679.
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N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000,
65, 3074. (b) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins,
E. Org. Lett. 2001, 3, 611. (c) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.
Org. Lett. 2002, 4, 2787. (d) Amat, M.; Pe´rez, M.; Llor, N.; Escolano, C.;
Luque, F. J.; Molins, E.; Bosch, J. J. Org. Chem. 2004, 69, 8681. (e) Amat,
M.; Pe´rez, M.; Minaglia, A. T.; Casamitjana, N.; Bosch, J. Org. Lett. 2005,
7, 3653.
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Ferna´ndez, M. M.; Lo´pez, V.; Molins, E.; Miravitlles, C.; Bosch, J.
Tetrahedron: Asymmetry 2003, 14, 2033.
(7) Amat, M.; Huguet, M.; Llor, N.; Bassas, O.; Go´mez, A. M.; Bosch,
J.; Badia, J.; Baldoma, L. Aguilar, J. Tetrahedron Lett. 2004, 45, 5355.
(8) For reviews, see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503. (b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1. (c)
Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843.
(10) (a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A. J. Org. Chem.
1996, 61, 5712. (b) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J.
F. J. Am. Chem. Soc. 1997, 119, 4565. (c) Meyers, A. I.; Seefeld, M. A.;
Lefker, B. A.; Blake, J. F.; Williard, P. G. J. Am. Chem. Soc. 1998, 120,
7429.
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D.; Maetzke, T.; Petter, W.; Klo¨tzer, B.; Plattner, D. A. J. Am. Chem. Soc.
1991, 113, 1781. (g) Micouin, L.; Jullian, V.; Quirion, J.-C.; Husson, H.-P.
Tetrahedron: Asymmetry 1996, 7, 2839. (h) Ando, K. J. Am. Chem. Soc.
2005, 127, 3964.
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1985, 107, 7776. (b) Meyers, A. I.; Lefker, B. A.; Wanner, K. T.; Aitken,
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Tetrahedron 1987, 43, 5663. (d) Meyers, A. I.; Berney, D. J. Org. Chem.
1989, 54, 4673. (e) Resek, J. E.; Meyers, A. I. Synlett 1995, 145. (e) Reeder,
M. R.; Meyers, A. I. Tetrahedron Lett. 1999, 40, 3115. For some examples
of alkylations of enolate lactams derived from (S)-phenylglycinol and (1R,
2S)-nor-ephedrine, see: (f) Hughes, R. C.; Dvorak, C. A.; Meyers, A. I. J.
Org. Chem. 2001, 66, 5545.
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Kissik, T. P. J. Org. Chem. 1986, 51, 3140. (b) Armstrong, R. W.; DeMattei,
J. A. Tetrahedron Lett. 1991, 32, 5749. (c) Bailey, J. H.; Byfield, A. T. J.;
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C. K. J. Chem. Soc., Perkin Trans. 1 2000, 1977.
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(14) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084.
J. Org. Chem, Vol. 71, No. 10, 2006 3805

Amat et al.
TABLE 2. Alkylation of trans H-3/H-8a Oxazolopiperidone
Lactams
entry
lactam
R3
product
endo/exo
yield (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
4
4
4
4
Me
Et
20
21
22
23
24
25
26
27
28
15:85
0:100
32:68
10:90
23:77
5:95
23:77
17:83
31:69
89
83
FIGURE 2. Phenylglycinol-derived oxazolopiperidone lactams.
CH2CO2t-Bu
CH2CHdCH2
CH2C6H5
45
65a
65a
85
TABLE 1. Alkylation of cis H-3/H-8a Oxazolopiperidone Lactams
Me
CH2CO2t-Bu
CH2CHdCH2
CH2C6H5
77
78a
72a
a Variable amounts of the dialkylated product were isolated (see
Experimental Section).
entry
lactam
R3
product
endo/exo
yield (%)
TABLE 3. Alkylation of 8a-Phenyl-Substituted Oxazolopiperidone
Lactams
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
2
Me
Et
10
11
12
13
14
15
16
17
18
19
76:24
68:32
88:12
48:52
45:55
8:92
71:29
83:17
48:52
10:90
68
76
CH2CO2t-Bu
CH2CHdCH2
CH2CHdCMe2
CH2C6H5
75
80a
49
71
94
Me
CH2CO2t-Bu
CH2CHdCH2
CH2C6H5
85
82a
93
10
entry
lactam
R3
product
endo/exo
yield (%)
a Variable amounts of the dialkylated product were isolated (see
Experimental Section).
1
2
3
4
5
6
7
8
5
5
5
5
6
6
6
6
Et
29
30
31
32
33
34
35
36
59:41
80:20
86:14
82:18
75:25
64:36
100:0
100:0
69a
69
CH2CO2t-Bu
CH2CHdCH2
CH2C6H5
53a
53a
73
results. The enolates were generated by the treatment of lactams
1-9 with LiHMDS15 (1.5 equiv) at -78 °C for 1 h, and then
an excess (2.5 equiv) of the alkylating reagent was added to
ensure a high yield of the alkylation product.16 As can be
observed in Table 1, the alkylation of lactams 1 and 2, both
with an H-3/H-8a cis relationship, with methyl iodide, ethyl
iodide, or tert-butyl bromoacetate (entries 1-3 and 7-8)
afforded the corresponding C-6-substituted lactams 10-12, 16,
and 17 in good chemical yields as mixtures of diastereomers,
with preferential formation of the endo products. However, the
enolates of lactams 1 and 2 when treated with allyl bromide or
prenyl bromide (entries 4, 5, and 9) afforded nearly equimo-
lecular mixtures of the endo and exo isomers, 13, 14, and 18,
respectively, whereas with benzyl bromide (entries 6 and 10)
the corresponding exo isomers 15b and 19b were formed in
good stereoselectivity. Thus, diastereoselection in the alkylation
of lactams 1 and 2 was found to be dependent on the nature of
the alkylating reagent.17
Et
CH2CO2t-Bu
CH2CHdCH2
CH2C6H5
71
48a
55a
a Variable amounts of the dialkylated product were isolated (see
Experimental Section).
20-28 (Table 2). In some cases (entries 2, 4, and 6), excellent
stereoselectivities were observed, especially with ethyl iodide,
which led to a single isomer, 21b,18 in good chemical yield.19
To gain further insight into the factors that influence the
stereochemical course of the reaction, we carried out similar
alkylation reactions from the lithium enolates of 8a-phenyl-
substituted lactams 5 and 6 and 8a-alkyl-substituted lactams 7,
8, and 9. As can be observed in Table 3, the alkylation of
(16) Although epimerization at the C-6 stereocenter may occur to some
extent as a result of the excess of base (1.5 equiv), these reaction conditions
ensure an optimum balance between high chemical yield and stereoselection.
Thus, when only one equivalent of base was used, substantial amounts of
starting material were recovered.
(17) Differences in the stereoselectivity of enolate alkylation reactions
with benzyl halides as compared with other alkylating reagents have been
observed. In some cases, steric reasons have been invoked to explain these
differences: Schwarz, J. B.; Meyers, A. I. J. Org. Chem. 1998, 63, 1619.
See also refs 9b and 9c.
The alkylation of the lithium enolates of lactam 3 and the
8-ethyl-substituted lactam 4, both with an H-3/H-8a trans
relationship, with methyl iodide, ethyl iodide, tert-butyl bro-
moacetate, allyl bromide, and benzyl bromide, in all cases
preferentially afforded the corresponding exo isomers of lactams
(15) The alkylation of lactam 2 using LDA as the base gave poor or
negligible chemical yields: (a) Micouin, L.; Varea, T.; Riche, C.; Chiaroni,
A.; Quirion, J. C.; Husson, H. P. Tetrahedron Lett. 1994, 35, 2529. (b)
Amat, M.; Llor, N.; Hidalgo, J.; Herna´ndez, A.; Bosch, J. Tetrahedron:
Asymmetry 1996, 7, 977. (c) For some preliminary results of the alkylations
leading to 11, 20b, and 24b, see: Amat, M.; Escolano, C.; Llor, N.; Lozano,
O.; Go´mez-Esque´, A.; Griera, R.; Bosch, J. ArkiVoc 2005, 9, 115.
(18) For a preliminary report of this alkylation and the conversion of
21b to (-)-S-decarbomethoxytetrahydrosecodine, see: Amat, M.; Pshen-
ichnyi, G.; Bosch, J.; Molins, E.; Miravitlles, C. Tetrahedron: Asymmetry
1996, 7, 3091.
(19) Lactams 3 and 4 showed a higher tendency to undergo dialkylation
than their respective isomers 1 and 2, in particular, with the more reactive
allyl and benzyl bromide alkylating reagents.
3806 J. Org. Chem., Vol. 71, No. 10, 2006

EnantioselectiVe Synthesis of â-Substituted Piperidines
SCHEME 1. Alkylation of Lactam 8-epi-6
TABLE 4. Alkylation of 8a-Alkyl-Substituted Oxazolopiperidone
Lactams
FIGURE 3. Spatial disposition of oxazolopiperone lactams 1-9.
These results could be accounted for by assuming that in the
enolates derived from lactams 2, 4, 6, and 9 the ethyl substituent
is in a pseudoequatorial position, far away from the nucleophilic
carbon, while the 8a-substituent is pseudoaxially oriented (Figure
3). Consequently, steric factors associated with the size of this
substituent may bias the facial approach of the electrophile.
When R1 is a methyl substituent, the alkylation takes place with
the same level of exo selectivity as in C-8a unsubstituted lactams
(R1dH), except when using the sterically more demanding
benzyl bromide (Table 4, entries 2 and 7). However, when a
bulkier substituent, such as phenyl, occupies the 8a-position,
the exo face is more shielded and the approach of the
electrophile takes place preferentially by the endo face, espe-
cially with bulky alkylating reagents (Table 3). These results
are also in agreement with the exo stereoselectivity observed
in the alkylation of lactam 8-epi-6. In this case, both the 8-ethyl
and 8a-phenyl substituents are pseudoaxially oriented in the
corresponding enolate, thus shielding both the endo face and
the exo face (see the X-ray of compound 39). However, the
closer spatial proximity of the ethyl group to the nucleophilic
carbon of the enolate (in a 1,3-relative position) determines the
facial exo selectivity.
entry
lactam
R3
product
endo/exo
yield (%)
1
2
3
4
5
6
7
7
7
8
9
9
9
9
Et
40
41
42
43
44
45
46
5:95
42:58
5:95
77
69a
81
CH2C6H5
Et
Et
5:95
66a
66
CH2CO2t-Bu
CH2CHdCH2
CH2C6H5
17:83
15:85
67:33
56a
57a
a Variable amounts of the dialkylated product were isolated (see
Experimental Section).
lactams 5 and 6 afforded the corresponding endo isomers 29a-
36a as the major products, in constrast with the preferential
exo facial selectivity observed in the related alkylations from
the 8a-unsubstituted lactams 3 and 4. Excellent stereoselectivities
were observed in the alkylation with allyl and benzyl bromide
(entries 3, 4, 7, and 8).
Interestingly, the lithium enolate of the 8-epimer of lactam 6
(8-epi-6) underwent alkylation with tert-butyl bromoacetate, allyl
bromide, and benzyl bromide to give only the corresponding
exo isomers 37-39 (Scheme 1), although in low yield (<40%).
Thus, a change in the spatial disposition of the 8-ethyl
substituent induces an opposite facial selectivity in the alkylation
reaction, particularly in the reactions with allyl and benzyl
bromide.
Finally, alkylation of the enolates derived from the 8a-alkyl-
substituted lactams 7-9 take place with good to excellent
stereoselectivy when using ethyl iodide, tert-butyl bromoacetate,
and allyl bromide to give the corresponding exo products 40b
and 42b-45b (Table 4), but with benzyl bromide (entries 2
and 7) the stereoselectivity was poor.
For compounds 15b, 20b, 21b,18 32a, 39, and 40b, the
configuration of the stereogenic center generated in the alky-
lation reaction was unequivocally established by single-crystal
X-ray crystallographic analysis (see Supporting Information).
On the other hand, the stereochemical identity of lactams 17
and 26 was confirmed by their conversion into compounds of
known configuration, as will be discussed later. The stereo-
chemistry of the other alkylation products was indirectly
assigned by the correlation of the spectroscopic data, especially
from the 13C NMR chemical shift of carbons C-6 and C-8. Thus,
in the alkylated lactams 10-36 and 40-46, the signals
corresponding to C-6 and C-8 are more shielded (1.5-3.5 ppm)
in the endo than the exo isomers (see Tables 5-8 in the
Supporting Information).
From the above results, it can be concluded that the 8-ethyl
substituent in lactams 2, 4, 6, and 9 does not have a significant
influence on the stereoselectivity of the reaction, because the
endo/exo ratios were similar to those obtained in the alkylation
of the respective 8-deethyl lactams 1, 3, 5, and 7. In contrast,
the presence of a phenyl substituent at the angular 8a-position
in lactams 5 and 6 exerts a dramatic influence on the stereo-
selectivity of the alkylation, reversing the facial selectivity
observed in the alkylation of the 8a-unsubstituted lactams 3 and
4. This effect is not observed when the 8a-substituent is alkyl
(lactams 7, 8, and 9), except in the alkylations using the bulkier
benzyl bromide.
The opposite endo/exo facial selectivity observed in the
alkylation of the diasteromeric lactams 2 and 4 with alkyl halides
and tert-butyl bromoacetate allows the preparation of either cis
or trans enantiopure 3,5-disubstituted piperidines. Thus, borane
reduction of lactams 16a and 17a brought about both the
reduction of the carbonyl lactam and the reductive opening of
the oxazolidine ring to give the corresponding piperidines 47
and 48 (Scheme 2). Hydrogenolysis of the benzylic substituent
in HCl-MeOH solution gave rise to the trans-3,5-disubstituted
piperidines 49 and 50, which were isolated as hydrochlorides.
Similarly, lactams 25b and 26b were reduced with borane to
the corresponding cis-3,5-disubstituted piperidines 51 and 52
J. Org. Chem, Vol. 71, No. 10, 2006 3807

Amat et al.
SCHEME 2. Synthesis of Enantiopure trans
3,5-Disubstituted Piperidines
SCHEME 5. Synthesis of 20S- and 20R-Dihydrocleavamine
SCHEME 3. Synthesis of Enantiopure cis 3,5-Disubstituted
and All-cis 2,3,5-Trisubstituted Piperidines
of 33a took place with retention of the configuration to give
58, which was transformed as above into the enantiopure 2,3,5-
trisubstituted piperidine 60.
In summary, starting from racemic δ-ketoacid derivatives,
in four synthetic steps involving cyclocondensation with (R)-
phenylglycinol, alkylation of the resulting bicyclic lactam,
hydride reduction, and catalytic hydrogenation, a variety of
diversely cis and trans 3,5-disubstituted, 2,5-disubstituted, and
2,3,5-trisubstituted enantiopure piperidines can be obtained. As
both enantiomers of phenylglycinol are commercially available,
the above methodology provides easy access to enantiopure
polysubstituted piperidines in both enantiomeric series.
Finally, to illustrate the usefulness of the methodology for
the enantioselective synthesis of natural products, we have
synthesized the tetracyclic indole alkaloids 20R- and 20S-
dihydrocleavamine,22 which embody a 3,5-disubstituted piperi-
dine moiety but differ in the configuration of the piperidine
carbon bearing the ethyl substituent.23 The assembling of the
skeletal framework of dihydrocleavamines from cis- and trans-
5-ethyl-3-piperidineacetate derivatives required the introduction
of the 2-(3-indolyl)ethyl chain on the piperidine nitrogen and
the closure of the nine-membered ring by electrophilic cycliza-
tion of the carboxylate moiety on the indole 2-position.
Subsequent adjustment of the oxidation level of the resulting
tetracyclic keto lactams would render the target alkaloids.
Removal of the phenylethanol moiety present in the trans-
and cis-5-ethyl-3-piperidineacetates 48 and 52 by hydrogenolysis
using Pd(OH)2 as the catalyst, in the presence of the mixed
anhydride of indole-3-acetic acid and pivalic acid,24 afforded
1-(3-indolylacetyl)piperidines 61a and 61b, respectively, which
were converted in good chemical yields to the corresponding
carboxylic acids 62a and 62b by treatment with TFA (Scheme
5).
SCHEME 4. Synthesis of Enantiopure trans
2,5-Disubstituted and 2,3,5-Trisubstituted Piperidines
(Scheme 3). Debenzylation of the latter either directly under
acidic conditions or via the N-Boc derivative 55 gave the
N-unsubstituted piperidine 54.
Following a similar reaction sequence, compounds resulting
from the alkylation of 8a-substituted lactams 5, 6, and 9 were
converted into enantiopure 2,5- and 2,3,5-substituted piperidines.
In these series, the reductive opening of the oxazolidine ring
involves the stereogenic center at the 2-position of the piperidine
ring. As expected, borane reduction of the 8a-methyl substituted
lactam 43b (Scheme 3) took place with retention of the
configuration20 to give the all-cis 2-methyl-3,5-diethylpiperidine
53, which was then debenzylated to the N-unsubstituted pip-
eridine 56. On the other hand, in accordance with previous
observations on the reduction 8a-phenyl-substituted lactams,21
borane reduction of 32a (Scheme 4) took place with low
stereoselectivity, affording a 67:33 mixture of 57a and its
2-epimer 57b. However, when LiAlH4 or Red-Al were used in
the reduction of 32a, the trans-5-benzyl-2-phenylpiperidine 57a
was obtained in high stereoselectivity (the 57a:57b ratio was
93:7 with LiAlH4 and 95:5 with Red-Al). The major isomer
57a was converted into the corresponding N-Boc derivative 59
following a conventional method. Similarly, LiAlH4 reduction
Closure of the nine-membered ring from the trans isomer 62a
was carried out by heating with polyphosphoric acid (PPA) for
30 min at 90 °C to give the desired tetracyclic keto lactam 63a
in fairly good yield (64%).25 Reduction of keto lactam 63a with
LiAlH4 afforded the alkaloid (-)-20S-dihydrocleavamine, thus
(20) (a) Fre´ville, S.; Ce´le´rier, J. P.; Thuy, V. M.; Lhommet, G.
Tetrahedron: Asymmetry 1995, 6, 2651. (b) Meyers, A. I.; Andres, C. J.;
Resek, J. E.; Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D. A.
Tetrahedron 1999, 55, 8931. (c) Agami, C.; Dechoux, L.; Hebbe, S.;
Me´nard, C. Tetrahedron 2004, 60, 5433.
(21) Amat, M.; Canto´, M.; Llor, N.; Bosch, J. Chem. Commun. 2002,
526.
(22) For a preliminary account of this part of the work, see: Amat, M.;
Escolano, C.; Lozano, O.; Llor, N.; Bosch, J. Org. Lett. 2003, 5, 3139.
(23) (a) Quirin, F.; Debray, M.-M.; Sigaut, C.; Thepenier, P.; Le Men-
Olivier, L.; Le Men, J. Phytochemistry 1975, 14, 812. (b) van Beek, T. A.;
Verpoorte, R.; Svendsen, A. B. Tetrahedron 1984, 40, 737.
(24) Sza´ntay, C.; Bo¨lcskei, H.; Ga´cs-Baitz, E.; Keve, T. Tetrahedron
1990, 46, 1687.
3808 J. Org. Chem., Vol. 71, No. 10, 2006

EnantioselectiVe Synthesis of â-Substituted Piperidines
Hz, 1H, H-2), 4.91 (dap, J ) 6.8 Hz, 1H, H-3), 4.93 (dd, J ) 8.8,
3.2 Hz, 1H, H-8a), 7.21-7.32 (m, 5H, ArH); 13C NMR (100.6
MHz) δ 24.3 (C-7), 28.3 [(CH3)3], 28.6 (C-8),36.8 (CH2COO), 38.5
(C-6), 59.2 (C-3), 74.2 (C-2), 80.9 [C(CH3)3], 89.0 (C-8a), 126.7
(2CH), 127.7 (CH), 128.7 (2CH), 141.8 (C i), 168.6 (NCO), 171.5
(COO). Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23.
Found: C, 68.49; H, 7.71; N, 4.12.
completing the first enantioselective synthesis of this natural
product. Indoloindolizidine 65 was isolated as a byproduct.26
Taking into account that cis-5-ethyl-3-piperidineacetate 62b has
been previously converted into (+)-20R-dihydrocleavamine,27
the above synthesis of this enantiopure piperidine constitutes
an enantioselective formal total synthesis of this alkaloid.28
In conclusion, the enolate alkylation of the phenylglycinol-
derived oxazolopiperidone lactams allows the stereoselective
introduction of a variety of alkyl, benzyl, and functionalized
(allyl, tert-butoxycarbonylmethyl) substituents at the â-position
of the piperidine ring to ultimately lead to diversely substituted
enantiopure piperidines. For C-8a unsubstituted lactams, the
stereochemical outcome of the alkylation depends on the relative
configuration of the C-8a methine carbon. The presence of an
8a-methyl group has a negligible stereochemical effect, but a
bulky 8a-phenyl substituent exerts a dramatic influence on the
stereoselectivity. Finally, the stereoselectivity is not affected by
the presence or absence of an alkyl group at C-8.
[3R,6R(and 6S),8aR]-6-Benzyl-5-oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyridine (15a and 15b). Following
the general procedure, lactam 15a (400 mg, 1.84 mmol) in THF (4
mL), LiHMDS (2.76 mL, 2.76 mmol) in THF (18 mL), and benzyl
bromide (0.54 mL, 4.53 mmol) afforded an 8:92 (calculated by 1H
NMR) mixture of epimers 15a and 15b (402 mg, 71%), which were
separated by flash chromatography (1:1 EtOAc-hexane). 15a: IR
(film) 1655 cm-1; 1H NMR (300 MHz) δ 1.69-1.86 (m, 3H, 1H-
7, H-8), 2.16-2.23 (m, 1H, H-8), 2.48-2.53 (m, 1H, H-6), 2.60
(dd, J ) 12.5, 10.0 Hz, 1H, CH2Ph), 3.12 (dd, J ) 12.5, 3.0 Hz,
1H, CH2Ph), 4.04 (dd, J ) 9.0, 1.0 Hz, 1H, H-2), 4.17 (dd, J )
9.0, 6.6 Hz, 1H, H-2), 4.86 (dd, J ) 9.0, 4.0 Hz, 1H, H-8a), 4.93
(dd, J ) 6.6, 1.0 Hz, 1H, H-3), 7.10-7.37 (m, 10H, ArH); 13C
NMR (75.4 MHz) δ 21.3 (C-7), 25.3 (C-8), 37.4 (CH2Ph), 41.8
(C-6), 58.7 (C-3), 74.1 (C-2), 88.4 (C-8a), 126.2 (CH), 126.4 (2CH),
127.5 (CH), 128.4 (2CH), 128.5 (2CH), 129.0 (2CH), 139.5 (C i
Experimental Section
Bn), 141.4 (C i Ph), 169.6 (NCO); [R]22 -65.0 (c 0.5, MeOH).
D
General Procedure for the Alkylation of Lactams 1-9. A
solution of the lactam (1 mmol) in THF was added to a cooled
(-78 °C) solution of LiHMDS (1 M in THF, 1.5 mmol) in THF.
After stirring the solution at -78 °C for 1 h, the alkylating reagent
(2.5-2.7 mmol) was added, and stirring was continued for an
additional 2 h. The reaction was quenched by the addition of
saturated aqueous NaCl, and the resulting mixture was extracted
with EtOAc and CH2Cl2. The combined organic extracts were
dried and concentrated, and the resulting residue was chromato-
graphed.
Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found:
1
C, 78.30; H, 6.92; N, 4.56. 15b: IR (film) 1654 cm-1; H NMR
(400 MHz) δ 1.47 (dddd, J ) 14.0, 14.0, 11.5, 3.0 Hz, 1H, H-7ax),
1.73 (dddd, J ) 13.1, 13.1, 10.0, 3.0 Hz, 1H, H-8ax), 1.83-1.92
(m, 1H, H-7eq), 2.32 (ddd, J ) 12.0, 6.8, 3.5 Hz, 1H, H-8eq),
2.47 (m, 1H, H-6), 2.64 (dd, J ) 13.6, 10.0 Hz, 1H, CH2Ph), 3.35
(dd, J ) 13.6, 4.0 Hz, 1H, CH2Ph), 4.01 (dd, J ) 9.0, 0.8 Hz, 1H,
H-2), 4.14 (dd, J ) 9.0, 6.5 Hz, 1H, H-2), 4.75 (dd, J ) 10.0, 3.5
Hz, 1H, H-8a), 4.90 (d, J ) 6.5 Hz, 1H, H-3), 7.15-7.32 (m, 10H,
ArH); 13C NMR (75.4 MHz) δ 23.6 (C-7), 28.1 (C-8), 37.7 (CH2
Ph), 43.3 (C-6), 59.1 (C-3), 73.9 (C-2), 88.7 (C-8a), 126.1 (CH),
126.3 (2CH), 127.4 (CH), 128.3 (2CH), 128.4 (2CH), 129.1 (2CH),
139.5 (C i Bn), 141.5 (C i Ph), 168.6 (NCO). Anal. Calcd for
C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 78.31; H, 7.06;
N, 4.56.
tert-Butyl [3R,6R(and 6S),8aR]-5-Oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyridine-6-acetate (12a and 12b).
Following the general procedure, lactam 15a (400 mg, 1.84 mmol)
in THF (4 mL), LiHMDS (2.76 mL, 2.76 mmol) in THF (18 mL),
and tert-butyl bromoacetate (0.67 mL, 4.53 mmol) afforded an 88:
12 (calculated by 1H NMR) mixture of epimers 12a and 12b (430
mg, 75%), which were separated by flash chromatography (1:1
[3R,6S(and 6R),8S,8aR)]-8-Ethyl-6-methyl-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (16a and 16b).
Following the general procedure, lactam 229 (210 mg, 0.85 mmol)
in THF (2 mL), LiHMDS (1.30 mL, 1.30 mmol) in THF (9 mL),
and methyl iodide (132 µL, 2.12 mmol) afforded a 71:29 (calculated
by 1H NMR) mixture of epimers 16a and 16b (210 mg, 94%), which
were separated by flash chromatography (1:4 EtOAc-hexane).
16a: IR (film) 1666 cm-1; 1H NMR (300 MHz) δ 1.04 (t, J ) 7.5
Hz, 3H, CH3CH2), 1.15 (d, J ) 7.2 Hz, 3H, CH3), 1.37 (m, 1H,
CH3CH2), 1.64 (ddd, J ) 14.0, 10.0, 6.5 Hz, 1H, H-7), 1.70-1.86
(m, 2H, H-7, CH3CH2), 1.88-1.98 (m, 1H, H-8), 2.44 (qd, J )
7.2, 4.5 Hz, 1H, H-6), 4.00 (dd, J ) 9.0, 1.0 Hz, 1H, H-2), 4.14
(dd, J ) 9.0, 7.0 Hz, 1H, H-2), 4.54 (d, J ) 8.7 Hz, 1H, H-8a),
1
EtOAc-hexane to EtOAc). 12a: IR (film) 1666, 1720 cm-1; H
NMR (300 MHz) δ 1.42 [s, 9H, (CH3)3], 1.73 (m, 1H, H-7), 1.87-
2.07 (m, 2H, H-7, H-8), 2.20 (dd, J ) 17.7, 10.0 Hz, 1H, CH2-
COO), 2.35 (m, 1H, H-8), 2.69-2.76 (m, 2H, H-6, CH2COO), 4.04
(dd, J ) 9.0, 0.9 Hz, 1H, H-2), 4.19 (dd, J ) 9.0, 6.6 Hz, 1H,
H-2), 4.84 (dap, J ) 7.0 Hz, 1H, H-3), 4.96 (dd, J ) 8.7, 4.5 Hz,
1H, H-8a), 7.21-7.33 (m, 5H, ArH); 13C NMR (75.4 MHz) δ 22.6
(C-7), 25.9 (C-8), 28.0 [(CH3)3], 36.6 (CH2COO), 36.7 (C-6), 58.4
(C-3), 74.2 (C-2), 80.5 [C(CH3)3], 87.5 (C-8a), 126.1 (2CH), 127.3
(CH), 128.4 (2CH), 141.1 (C i), 168.8 (NCO), 171.3 (COO); mp
69-70 °C (EtOAc); [R]22 -8.0 (c 0.1, MeOH). Anal. Calcd for
D
C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.63; H, 7.75;
4.90 (dd, J ) 7.0, 1.0 Hz, 1H, H-3), 7.20-7.35 (m, 5H, ArH); 13
C
1
N, 4.15. 12b: IR (film) 1659, 1727; H NMR (400 MHz) δ 1.40
NMR (75.4 MHz) δ 11.0 (CH3CH2), 18.2 (CH3), 24.6 (CH3CH2),
31.7 (C-7), 34.9 (C-6), 37.6 (C-8), 58.4 (C-3), 73.9 (C-2), 92.3
(C-8a), 125.9 (C-o), 127.1 (C-p), 128.3 (C-m), 141.5 (C i), 170.6
[s, 9H, (CH3)3], 1.69 (m, 1H, H-7), 1.85 (dddd, J ) 14.0, 13.0,
10.0, 3.2 Hz, 1H, H-8a), 2.11 (m, 1H, H-7), 2.41 (ddd, J ) 12.0,
6.5, 3.2 Hz, 1H, H-8eq), 2.46-2.53 (m, 1H, H-6), 2.61 (dd, J )
17.0, 7.0 Hz, 1H, CH2COO), 2.67 (dd, J ) 17.0, 4.0 Hz, CH2-
COO), 4.03 (dd, J ) 9.2, 0.8 Hz, 1H, H-2), 4.19 (dd, J ) 9.2, 6.8
(NCO); [R]22 -28.1 (c 0.5, MeOH); MS-EI m/z 259 (M+, 76),
D
104 (76), 148 (100); HMRS calcd for C16H21NO2, 259.1572; found,
259.1573. 16b: IR (film) 1662 cm-1; 1H NMR (300 MHz) δ 1.05
(t, J ) 7.5 Hz, 3H, CH3CH2), 1.18 (d, J ) 7.2 Hz, 3H, CH3), 1.20
(m, 1H, H-7), 1.36 (m, 1H, CH3CH2), 1.76-1.92 (m, 2H, CH3CH2,
H-8), 2.11 (ddd, J ) 13.8, 6.6, 3.0 Hz, 1H, H-7), 2.32 (m, 1H,
H-6), 4.01 (dd, J ) 9.3, 1.2 Hz, 1H, H-2), 4.13 (dd, J ) 9.3, 6.9
Hz, 1H, H-2), 4.52 (d, J ) 8.7 Hz, 1H, H-8a), 4.86 (dd, J ) 6.9,
1.2 Hz, 1H, H-3), 7.23-7.30 (m, 5H, ArH); 13C NMR (75.4 MHz)
δ 10.9 (CH3CH2), 17.0 (CH3), 24.0 (CH3CH2), 32.9 (C-7), 36.8
(25) For a discussion of the mechanism and yield of related cyclizations,
see: (a) Ziegler, F. E.; Kloek, J. A.; Zoretic, P. A. J. Am. Chem. Soc. 1969,
91, 2342. (b) See also: Imanishi, T.; Nakai, A.; Yagi, N.; Hanaoka, M.
Chem. Pharm. Bull. 1981, 29, 901.
(26) For the mechanism and formation of similar allylindoloindolizidines
in the LiAlH4 reduction of related tetracyclic nine-membered 16-oxolactams,
see ref 22.
(27) Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A. Tetrahedron Lett.
2000, 41, 3489.
(28) For another enantioselective synthesis, see: Kanada, R. M.;
Ogasawara, K. Tetrahedron Lett. 2001, 42, 7311.
(29) Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. Tetrahedron: Asymmetry
1997, 8, 2237.
J. Org. Chem, Vol. 71, No. 10, 2006 3809

Amat et al.
(C-6), 40.8 (C-8), 59.0 (C-3), 73.8 (C-2), 92.6 (C-8a), 126.3 (C-
7.32 (m, 10H, ArH); 13C NMR (75.4 MHz) δ 10.8 (CH3CH2), 24.0
(CH3CH2), 29.4 (C-7), 37.3 (CH2 Ph), 40.5 (C-8), 43.4 (C-6), 59.1
(C-3), 73.6 (C-2), 92.2 (C-8a), 126.0 (CH), 126.1 (2CH), 127.2
(CH), 128.0 (2CH), 128.2 (2CH), 129.9 (2CH), 139.3 (C i Bn),
141.4 (C i Ph), 168.4 (NCO); [R]22D -49.0 (c 1.0, MeOH); MS-EI
m/z 335 (M+, 35), 104 (100), 148 (76); HMRS calcd for C22H25-
NO2, 335.1885; found, 335.1884. Anal. Calcd for C22H25NO2‚2/
3H2O: C, 76.04; H, 7.64; N, 4.03. Found: C, 76.08; H, 7.30; N,
4.11.
o), 127.2 (C-p), 128.3 (C-m), 141.6 (C i), 169.9 (NCO); [R]22
D
-21.7 (c 0.5, MeOH); MS-EI m/z 259 (M+, 65), 104 (81), 148
(100); HMRS calcd for C16H21NO2, 259.1572; found, 259.1560.
tert-Butyl [3R,6R(and 6S),8S,8aR]-8-Ethyl-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine-6-acetate (17a
and 17b). Following the general procedure, lactam 229 (200 mg,
0.82 mmol) in THF (2 mL), LiHMDS (1.23 mL, 1.23 mmol) in
THF (9 mL), and tert-butyl bromoacetate (0.29 mL, 2.09 mmol)
afforded an 83:17 (calculated by 1H NMR) mixture of epimers 17a
and 17b (248 mg, 85%), which were separated by flash chroma-
tography (1:4 to 3:2 EtOAc-hexane). 17a: IR (film) 1666, 1728
[3R,6S(and 6R),8aS]-6-Allyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (23a and 23b) and (3R,8aS)-6,6-
Diallyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-
a]pyridine (23c). Following the general procedure, lactam 35a (680
mg, 3.13 mmol) in THF (8 mL), LiHMDS (4.69 mL, 4.69 mmol)
in THF (26 mL), and allyl bromide (0.70 mL, 8.08 mmol) afforded
1
cm-1; H NMR (600 MHz) δ 1.02 (t, J ) 7.2 Hz, 3H, CH3CH2),
1.40 (m, 1H, CH3CH2), 1.41 [s, 9H, (CH3)3], 1.64 (ddd, J ) 14.0,
8.4, 6.8 Hz, 1H, H-7), 1.78 (m, 1H, CH3CH2), 1.82 (ddd, J ) 14.0,
7.0, 7.0 Hz, 1H, H-7), 1.94 (m, 1H, H-8), 2.18 (dd, J ) 16.2, 9.0
Hz, 1H, CH2COO), 2.70 (dd, J ) 16.2, 5.0 Hz, 1H, CH2COO),
2.77 (m, 1H, H-6), 4.02 (dd, J ) 9.0, 1.0 Hz, 1H, H-2), 4.15 (dd,
J ) 9.0, 6.7 Hz, 1H, H-2), 4.60 (d, J ) 8.4 Hz, 1H, H-8a), 4.91 (d,
J ) 6.7 Hz, 1H, H-3), 7.25-7.35 (m, 5H, ArH); 13C NMR (75.4
MHz) δ 11.1 (CH3CH2), 25.0 (CH3CH2), 28.0 [(CH3)3], 29.3 (C-
7), 36.6 (C-6), 37.0 (CH2COO), 38.7 (C-8), 58.5 (C-3), 74.1 (C-
2), 80.5 [C(CH3)3], 91.8 (C-8a), 126.0 (2CH), 127.2 (C-p), 128.3
1
a 1:9 (calculated by H NMR) mixture of epimers 23a and 23b
(520 mg, 65%) and the diallyl derivative 23c (150 mg, 16%), which
were separated by flash chromatography (3:7 EtOAc-hexane). 23a:
IR (film) 1647 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.70 (m, 1H,
H-8), 1.80-1.86 (m, 2H, H-7), 2.15-2.25 (m, 2H, H-8, CH2-
CHd), 2.45 (m, 1H, H-6), 2.69 (m, 1H, CH2CHd), 3.77 (dd, J )
9.0, 7.8 Hz, 1H, H-2), 4.47 (dd, J ) 9.0, 7.8 Hz, 1H, H-2), 5.01
(dd, J ) 7.8, 4.5 Hz, 1H, H-8a), 5.04-5.14 (m, 2H, CH2d), 5.25
(t, J ) 7.8 Hz, 1H, H-3), 5.79 (dddd, J ) 16.8, 10.8, 8.4, 6.0 Hz,
1H, CH2dCH), 7.20-7.36 (m, 5H, ArH); 13C NMR (CDCl3, 100.6
MHz) δ 20.6 (C-7), 25.3 (C-8), 35.6 (CH2CHd), 39.4 (C-6), 58.2
(C-3), 72.3 (C-2), 88.3 (C-8a), 117.0 (CH2d), 126.1 (2CH), 127.4
(CH), 128.6 (2CH), 136.4 (CH2dCH), 139.5 (C i), 171.0 (NCO);
[R]22D -138.8 (c 0.5, MeOH), MS-EI m/z 257 (M+, 100), 104 (88),
216 (61); HMRS calcd for C16H19NO2, 257.1416; found, 257.1414.
(2CH), 141.2 (C i), 168.7 (NCO), 171.2 (COO); [R]22 -7.7 (c
D
0.5, MeOH); MS-EI m/z 303 [(M+ - [C(CH3)3]), 12], 104 (84),
148 (100); HMRS calcd for C21H29NO4, 359.2097; found, 359.2092.
Anal. Calcd for C21H29NO4‚1/4H2O: C, 69.30; H, 8.17; N, 3.85.
Found: C, 69.59; H, 8.31; N, 3.85. 17b: IR (film) 1651, 1731 cm-1
;
1H NMR (400 MHz) δ 1.05 (t, J ) 7.6 Hz, 3H, CH3CH2), 1.37-
1.43 [m, 11H, H-7, CH3CH2, (CH3)3], 1.81-1.90 (m, 2H, H-8,
CH3CH2), 2.11 (ddd, J ) 13.6, 6.0, 2.8 Hz, 1H, H-7ax), 2.53 (m,
1H, H-6), 2.60 (dd, J ) 16.4, 7.2 Hz, 1H, CH2COO), 2.68 (dd, J
) 16.4, 3.6 Hz, 1H, CH2COO), 4.02 (dd, J ) 9.0, 1.2 Hz, 1H,
H-2), 4.16 (dd, J ) 9.0, 7.0 Hz, 1H, H-2), 4.50 (d, J ) 8.8 Hz, 1H,
H-8a), 4.90 (d, J ) 6.5 Hz, 1H, H-3), 7.10-7.30 (m, 5H, ArH);
13C NMR (75.4 MHz) δ 11.1 (CH3CH2), 24.3 (CH3CH2), 28.3
[(CH3)3], 30.1 (C-7), 36.9 (CH2COO), 38.9 (C-6), 41.1 (C-8), 59.4
(C-3), 74.1 (C-2), 80.9 [C(CH3)3], 92.6 (C-8a), 126.7 (2CH), 127.6
1
23b: IR (film) 1650 cm-1; H NMR (CDCl3, 300 MHz) δ 1.46-
1.64 (m, 2H, H-7, H-8), 1.97 (m, 1H, H-7), 2.31-2.47 (m, 3H,
H-6, H-8, CH2CHd), 2.60 (m, 1H, CH2CHd), 3.70 (dd, J ) 9.0,
8.1 Hz, 1H, H-2), 4.49 (dd, J ) 9.0, 8.1 Hz, 1H, H-2), 4.98 (dd, J
) 8.8, 4.5 Hz, 1H, H-8a), 5.03-5.12 (m, 2H, CH2d), 5.25 (t, J )
8.1 Hz, 1H, H-3), 5.72 (m, 1H, CH2dCH), 7.21-7.30 (m, 5H,
ArH); 13C NMR (CDCl3, 75.4 MHz) δ 22.4 (C-7), 28.0 (C-8), 36.7
(CH2CHd), 41.3 (C-6), 58.2 (C-3), 72.7 (C-2), 88.8 (C-8a), 117.4
(CH2d), 125.7 (2CH), 127.3 (CH), 128.6 (2CH), 135.0 (CH2d
CH), 139.4 (C i), 170.8 (NCO); [R]22D -55.3 (c 0.5, MeOH); MS-
EI m/z 257 (M+, 98), 104 (100), 216 (71); HMRS calcd for
(C-p), 128.7 (2CH), 141.9 (C i), 168.6 (NCO), 171.5 (COO); [R]22
D
-14.2 (c 0.5, CH2Cl2); MS-EI m/z 303 [(M+ - [C(CH3)3]), 62],
104 (99), 148 (100); HMRS calcd for C21H29NO4, 359.2097; found,
359.2084.
C16H19NO2, 257.1416; found, 257.1428. 23c: IR (film) 1643 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.58-1.78 (m, 2H, H-7, H-8), 1.83
(td, J ) 14.0, 2.7 Hz, 1H, H-7), 2.03 (dd, J ) 13.5, 8.5 Hz, 1H,
CH2CHd), 2.18 (dddd, J ) 12.6, 4.5, 4.5, 3.0 Hz, 1H, H-8), 2.32
(dd, J ) 13.8, 7.5 Hz, 1H, CH2CHd), 2.47 (dm, J ) 13.5 Hz, 1H,
CH2CHd), 2.52 (dm, J ) 13.8 Hz, 1H, CH2CHd), 3.71 (dd, J )
9.0, 8.4 Hz, 1H, H-2), 4.47 (dd, J ) 9.0, 7.8 Hz, 1H, H-2), 4.87
(dd, J ) 9.0, 4.2 Hz, 1H, H-8a), 5.04-5.13 (m, 4H, 2CH2d), 5.19
(tap, J ) 8.1 Hz, 1H, H-3), 5.58 (dddd, J ) 17.0, 10.2, 9.0, 6.0 Hz,
1H, CH2dCH), 5.80 (dddd, J ) 17.0, 9.0, 8.0, 8.0 Hz, 1H, CH2d
CH), 7.24-7.32 (m, 5H, ArH); 13C NMR (CDCl3, 75.4 MHz) δ
24.9 (C-7), 25.8 (C-8), 42.7 (CH2CHd), 43.6 (CH2CHd), 44.8
(C-6), 58.7 (C-3), 73.0 (C-2), 89.0 (C-8a), 118.2 (CH2d), 118.7
(CH2d), 126.1 (CH), 127.4 (C H), 128.6 (2CH), 133.7 (CH2dCH),
134.0 (CH2dCH), 139.6 (C i), 172.5 (NCO); mp 88-90 °C (Et2O);
[3R,6R(and 6S),8S,8aR)]-6-Benzyl-8-ethyl-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (19a and 19b).
Following the general procedure, lactam 229 (200 mg, 0.82 mmol)
in THF (2 mL), LiHMDS (1.23 mL, 1.23 mmol) in THF (9 mL),
and benzyl bromide (250 µL, 2.10 mmol) afforded a 1:9 (calculated
by HPLC) mixture of epimers 19a and 19b (254 mg, 93%), which
were separated by flash chromatography (1:4 EtOAc-hexane).
19a: IR (film) 1651 cm-1; 1H NMR (300 MHz) δ 0.95 (t, J ) 7.5
Hz, 3H, CH3CH2), 1.23 (m, 1H, CH3CH2), 1.40 (m, 1H, H-7), 1.64-
1.80 (m, 2H, CH3CH2, H-8), 1.82 (m, 1H, H-7), 2.54-2.68 (m,
2H, CH2Ph, H-6), 3.05 (dd, J ) 12.0, 3.0 Hz, 1H, CH2Ph), 4.02
(dd, J ) 9.0, 1.5 Hz, 1H, H-2), 4.13 (dd, J ) 9.0, 6.9 Hz, 1H,
H-2), 4.50 (d, J ) 8.4 Hz, 1H, H-8a), 4.92 (dd, J ) 6.9, 1.5 Hz,
1H, H-3), 7.10-7.32 (m, 10H, ArH); 13C NMR (75.4 MHz) δ 11.0
(CH3CH2), 24.2 (CH3CH2), 27.4 (C-7), 37.7 (C-8), 38.0 (CH2Ph),
42.0 (C-6), 58.9 (C-3), 74.0 (C-2), 92.5 (C-8a), 126.2 (CH), 126.4
(2CH), 217.4 (CH), 128.3 (2CH), 128.4 (2CH), 129.3 (2CH), 138.4
(C i Bn), 141.5 (C i Ph), 169.6 (NCO); [R]22D +58.9 (c 1.0, MeOH);
MS-EI m/z 325 (M+, 36), 104 (88), 148 (100); HMRS calcd for
[R]22 -14.5 (c 0.5, MeOH); MS-EI m/z 297 (M+, 15), 91 (56),
D
104 (100); HMRS calcd for C19H23NO2, 297.1729; found, 297.1729.
Anal. Calcd for C19H23NO2: C, 76.74; H, 7.79; N, 4.71. Found:
C, 76.62; H, 8.08; N, 4.54.
[3R,6R(and 6S),8R,8aS]-8-Ethyl-6-methyl-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (25b). Fol-
lowing the general procedure, lactam 4 (200 mg, 0.82 mmol) in
THF (2 mL), LiHMDS (1.23 mL, 1.23 mmol) in THF (9 mL), and
methyl iodide (131 µL, 2.10 mmol) afforded a 5:95 (calculated by
1H NMR) mixture of epimers 25a and 25b (179 mg, 85%). The
major isomer 25b was separated by flash chromatography (3:7
EtOAc-hexane). 25b: IR (film) 1651; 1H NMR (300 MHz) δ 1.02
(t, J ) 7.5 Hz, 3H, CH3CH2), 1.25 (d, J ) 7.2 Hz, 3H, CH3), 1.20-
C22H25NO2, 335.1885; found, 335.1894. 19b: IR (film) 1651 cm-1
;
1H NMR (300 MHz) δ 0.94 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.16
(ddd, J ) 13.8, 12.3, 12.3 Hz, 1H, H-7ax), 1.26 (m, 1H, CH3CH2),
1.69-1.79 (m, 2H, H-8, CH3CH2), 1.84 (ddd, J ) 13.8, 6.0, 2.7
Hz, 1H, H-7eq), 2.51 (m, 1H, H-6), 2.66 (dd, J ) 13.5, 9.6 Hz,
1H, CH2Ph), 3.32 (dd, J ) 13.5, 3.6 Hz, 1H, CH2 Ph), 3.95 (dd, J
) 9.0, 1.2 Hz, 1H, H-2), 4.06 (dd, J ) 9.0, 7.0 Hz, 1H, H-2), 4.39
(d, J ) 8.7 Hz, 1H, H-8a), 4.86 (d, J ) 7.0 Hz, 1H, H-3), 7.14-
3810 J. Org. Chem., Vol. 71, No. 10, 2006

EnantioselectiVe Synthesis of â-Substituted Piperidines
1.25 (m, 1H, H-7), 1.34 (m, 1H, CH3CH2), 1.55 (m, 1H, H-8), 1.76
(m, 1H, CH3CH2), 2.01 (ddd, J ) 13.5, 5.7, 2.7 Hz, 1H, H-7),
2.41 (m, 1H, H-6), 3.72 (dd, J ) 9.0, 8.1 Hz, 1H, H-2), 4.47 (dd,
J ) 9.0, 8.1 Hz, 1H, H-2), 4.67 (d, J ) 8.4 Hz, 1H, H-8a), 5.23
(tap, J ) 7.8 Hz, 1H, H-3), 7.20-7.40 (m, 5H, ArH); 13C NMR
(CDCl3, 75.4 MHz) δ 11.1 (CH3CH2), 18.4 (CH3), 24.7 (CH3CH2),
31.9 (C-7), 37.2 (C-6), 41.0 (C-8), 58.3 (C-3), 72.7 (C-2), 92.9
(C-8a), 125.8 (2CH), 127.3 (CH), 128.6 (2CH), 139.6 (C i), 172.2
Found: C, 81.52; H, 6.62; N, 3.65. 32b: IR (film) 1654 cm-1; 1H
NMR (300 MHz, representative peaks) δ 1.56-1.64 (m, 2H, H-7),
1.95 (ddd, J ) 13.2, 13.2, 4.2 Hz, 1H, H-8), 2.14 (m, 1H, H-8),
2.79 (m, 1H, H-6), 3.00 (dd, J ) 13.2, 3.8 Hz, 1H, CH2Ph), 3.30
(dd, J ) 13.6, 7.4 Hz, 1H, CH2Ph), 3.50 (t, J ) 9.4 Hz, 1H, H-2),
4.37 (dd, J ) 9.2, 8.0 Hz, 1H, H-2), 5.32 (ddt, J ) 9.4, 8.2 Hz,
1H, H-3), 6.83-7.40 (m, 15H, ArH); 13C NMR (75.4 MHz) δ 20.4
(C-7), 36.6 (C-8), 38.1 (CH2Ph), 44.0 (C-6), 60.7 (C-3), 69.5 (C-
2), 97.3 (C-8a), 126.4 (CH), 126.9 (2CH), 127.2 (CH), 127.5 (CH),
128.0 (CH), 128.3 (CH), 130.2 (CH), 137.9 (C i), 138.4 (C i), 141.4
(C i), 172.7 (NCO); MS-EI m/z 383 (M+, 58), 306 (31), 263 (30),
224 (60), 120 (52); HMRS calcd for C26H25NO2, 383.1885; found,
383.1874. 32c: IR (film) 2929, 1652 cm-1; 1H NMR (300 MHz) δ
1.50 (ddd, J ) 14.4, 3.5, 3.5 Hz, 1H, H-7), 1.68 (ddd, J ) 12.4,
12.4, 5.2 Hz, 1H, H-7), 1.80 (ddd, J ) 12.4, 12.4, 2.8 Hz, 1H,
H-8), 1.90 (m, 1H, H-8), 2.40, 3.45 (2d, J ) 12.8 Hz, 2H, CH2Ph),
3.04, 3.42 (2d, J ) 12.4 Hz, 2H, CH2Ph), 3.44 (t, J ) 9.2 Hz, 1H,
H-2), 4.27 (t, J ) 9.2, 8.0 Hz, 1H, H-2), 5.32 (dd, J ) 9.6, 8.4 Hz,
1H, H-3), 6.38 (d, J ) 6.8 Hz, 1H, ArH), 6.93-7.33 (m, 19H,
ArH); 13C NMR (75.4 MHz) δ 21.2 (C-7), 33.6 (C-8), 44.4 (CH2-
Ph), 44.8 (CH2Ph), 48.5 (C-6), 60.9 (C-3), 69.1 (C-2), 97.2 (C-
8a), 126.6 (CH), 126.8 (CH), 126.9 (CH), 127.3 (CH), 127.7 (CH),
127.8 (2CH), 128.0 (2CH), 128.1 (2CH), 128.3 (2CH), 128.4 (2CH),
131.0 (2CH), 131.5 (3CH), 137.2 (C i), 137.5 (C i), 137.7 (C i),
(NCO); [R]22 -128.7 (c 0.5, MeOH); MS-EI m/z 259 (M+, 54),
D
104 (86), 148 (100); HMRS calcd for C16H21NO2, 259.1572; found,
259.1562.
tert-Butyl [3R,6S(and 6R),8R,8aS]-8-Ethyl-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine-6-acetate (26a
and 26b). Following the general procedure, lactam 4 (200 mg, 0.82
mmol) in THF (2 mL), LiHMDS (1.23 mL, 1.23 mmol) in THF (9
mL), and tert-butyl bromoacetate (0.31 mL, 2.10 mmol) afforded
a 23:77 (calculated by 1H NMR) mixture of epimers 26a and 26b
(226 mg, 77%), which were separated by flash chromatography
(1:4 to 3:2 EtOAc-hexane). 26a: IR (film) 1659, 1727; 1H NMR
(400 MHz) δ 1.01 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.38 (m, 1H,
CH3CH2), 1.45 [s, 9H, (CH3)3], 1.60 (m, 1H, H-8), 1.71 (td, J )
14.0, 6.8 Hz, 1H, H-7), 1.76-1.83 (m, 2H, CH3CH2, H-7), 2.34
(dd, J ) 16.0, 11.0 Hz, 1H, CH2COO), 2.86 (dd, J ) 16.0, 3.6 Hz,
1H, CH2COO), 2.95 (m, 1H, H-6), 3.76 (dd, J ) 8.8, 8.0 Hz, 1H,
H-2), 4.45 (dd, J ) 8.8, 8.0 Hz, 1H, H-2), 4.69 (d, J ) 8.0 Hz, 1H,
H-8a), 5.20 (t, J ) 8.0 Hz, 1H, H-3), 7.25-7.33 (m, 5H, ArH);
13C NMR (CDCl3, 100.6 MHz) δ 11.3 (CH3CH2), 24.7 (CH3CH2),
27.9 (C-7), 28.3 ([(CH3)3]), 36.9 (C-6), 38.0 (CH2COO), 38.3 (C-
8), 58.8 (C-3), 72.7 (C-2), 81.0 [C(CH3)3], 92.9 (C-8a), 126.5 (2CH),
127.8 (CH), 129.0 (2CH), 139.6 (C i), 170.5 (NCO), 171.7 (COO);
[R]22D -116.9 (c 0.5, MeOH); MS-EI m/z 303 [(M+ - [C(CH3)3]),
25], 104 (63), 148 (100); HMRS calcd for C21H29NO4, 359.2097;
141.3 (C i), 175.2 (NCO); mp 119-122 °C (Et2O); [R]22 +54.3
D
(c 1.33, CH2Cl2). Anal. Calcd for C33H21NO2‚1/4H2O: C, 82.90;
H, 6.64; N, 2.93. Found: C, 82.93; H, 6.60; N, 2.90.
[3R,6R(and 6S),8R,8aR]-6,8-Diethyl-5-oxo-3,8a-diphenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (33a and 33b)
and (3R,8R,8aR)-6,6,8-Triethyl-5-oxo-3,8a-diphenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3,2-a]pyridine (33c). Following the
general procedure, lactam 621 (1.95 g, 6.07 mmol) in THF (18 mL),
LiHMDS (9.1 mL, 9.1 mmol) in THF (80 mL), and ethyl iodide
(1.27 mL, 15.8 mmol) afforded a 75:25 (calculated by GC/MS)
mixture of epimers 33a and 33b (1.54 g, 73%), traces of 33c, and
recovered lactam 6 (461 mg), which were separated by flash
chromatography (1:9 EtOAc-hexane to EtOAc). 33a: IR (film)
1
found, 359.2106. 26b: IR (film) 1650, 1727 cm-1; H NMR (300
MHz) δ 1.04 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.40 (m, 1H, CH3CH2),
1.45 [s, 9H, (CH3)3], 1.52-1.62 (m, 2H, H-8, H-7), 1.79 (m, 1H,
CH3CH2), 2.03 (dd, J ) 10.5, 5.5 Hz, 1H, H-7), 2.60 (dd, J )
15.0, 7.0 Hz, 1H, CH2COO), 2.65 (m, 1H, H-6), 2.75 (dd, J )
15.0, 2.4 Hz, 1H, CH2COO), 3.71 (dd, J ) 9.0, 7.8 Hz, 1H, H-2),
4.49 (dd, J ) 9.0, 8.0 Hz, 1H, H-2), 4.71 (d, J ) 7.8 Hz, 1H,
H-8a), 5.23 (t, J ) 7.8 Hz, 1H, H-3), 7.25-7.32 (m, 5H, ArH);
13C NMR (CDCl3, 75.4 MHz) δ 11.0 (CH3CH2), 24.5 (CH3CH2),
28.0 [(CH3)3], 28.8 (C-7), 37.4 (CH2COO), 38.8 (C-6), 40.9 (C-8),
58.4 (C-3), 72.7 (C-2), 80.5 [C(CH3)3], 92.4 (C-8a), 125.7 (2CH),
127.2 (CH), 128.5 (2CH), 139.3 (C i), 169.9 (NCO), 171.0 (COO);
[R]22D -125.9 (c 0.5, MeOH); MS-EI m/z 303 [(M+ - [C(CH3)3]),
33], 104 (94), 148 (100); HMRS calcd for C21H29NO4, 359.2097;
found, 360.2162.
[3R,6S(and 6R),8aR]-6-Benzyl-5-oxo-3,8a-diphenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3,2-a]pyridine (32a and 32b) and
(3R,8aR)-6,6-Dibenzyl-5-oxo-3,8a-diphenyl-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (32c). Following the general pro-
cedure, lactam 521 (2.01 g, 6.86 mmol) in THF (20 mL), LiHMDS
(10.30 mL, 10.30 mmol) in THF (80 mL), and benzyl bromide
(2.12 mL, 17.84 mmol) afforded an 82:18 (calculated by GC/MS)
mixture of epimers 32a and 32b (1.40 g, 53%) and the dibenzyl
derivative 32c (257 mg, 8%), which were separated by flash
chromatography (1:9 EtOAc-hexane to EtOAc). 32a: IR (film)
1651 cm-1; 1H NMR (300 MHz) δ 1.55-1.62 (m, 2H, H-7), 1.92
(m, 1H, H-8), 2.06 (ddd, J ) 12.9, 4.2, 4.2 Hz, 1H, H-8), 2.72 (dd,
J ) 12.9, 10.5 Hz, 1H, CH2Ph), 2.81 (m, 1H, H-6), 3.44 (dd, J )
13.2, 3.0 Hz, 1H, CH2Ph), 3.68 (t, J ) 9.3 Hz, 1H, H-2), 4.39 (dd,
J ) 9.3, 8.0 Hz, 1H, H-2), 5.31 (t, J ) 8.4 Hz, 1H, H-3), 7.13-
7.47 (m, 15H, ArH); 13C NMR (75.4 MHz) δ 19.6 (C-7), 34.7 (C-
8), 37.5 (CH2Ph), 41.2 (C-6), 61.0 (C-3), 69.5 (C-2), 97.4 (C-8a),
126.2 (CH), 126.7 (2CH), 127.5 (CH), 128.0 (2CH), 128.2 (2CH),
128.3 (2CH), 128.4 (3CH), 129.2 (2CH), 137.9 (C i), 139.8 (C i),
141.4 (C i), 173.4 (NCO); mp 98-100 °C (Et2O); [R]22D -38.9 (c
0.37, MeOH); MS-EI m/z 383 (M+, 100), 306 (55), 263 (51), 224
(93). Anal. Calcd for C26H25NO2: C, 81.43; H, 6.57; N, 3.65.
1
1651 cm-1; H NMR (300 MHz) δ 0.62 (m, 1H, CH3CH2), 0.94
(t, J ) 7.5 Hz, 3H, CH3CH2), 1.00 (t, J ) 7.6 Hz, 1H, CH3CH2),
1.53 (dap, J ) 13.5, 13.5, 8.5 Hz, 1H, H-7), 1.64-1.85 (m, 4H,
H-7, H-8, 2CH3CH2), 1.98 (m, 1H, CH3CH2), 2.59 (ddd, J ) 8.7,
8.7, 3.9 Hz, 1H, H-6), 3.65 (t, J ) 9.3 Hz, 1H, H-2), 4.40 (dd, J )
9.3, 8.1 Hz, 1H, H-2), 5.23 (t, J ) 8.7 Hz, 1H, H-3), 6.94-6.99
(m, 2H, ArH), 7.10-7.15 (m, 3H, ArH), 7.36-7.44 (m, 5H, ArH);
13C NMR (75.4 MHz) δ 11.6 (2CH3CH2), 23.0 (CH3CH2), 25.4,
25.7 (CH3CH2, C-7), 40.7 (C-6), 45.6 (C-8), 61.3 (C-3), 70.3 (C-
2), 99.2 (C-8a), 127.3 (CH), 127.7 (2CH), 127.8 (2CH), 128.0
(2CH), 128.1 (2CH), 128.4 (CH), 138.0 (C i), 138.2 (C i), 173.2
(NCO); mp 72-74 °C (EtOAc-hexane); MS-EI m/z 349 (M+, 10),
293 (30), 224 (100). Anal. Calcd for C23H27NO2: C, 79.05; H, 7.79;
N, 4.01. Found: C, 79.01; H, 7.78; N, 3.79. 33b: IR (film) 1652
1
cm-1; H NMR (400 MHz) δ 0.60 (m, 1H, H-7), 0.93 (t, J ) 7.6
Hz, 3H, CH3CH2), 1.03 (t, J ) 7.6 Hz, 1H, CH3CH2), 1.20 (m,
1H, CH3CH2), 1.64 (m, 1H, CH3CH2), 1.75 (m, 1H, H-7), 1.83
(m, 1H, H-8), 1.91 (m, 1H, CH3CH2), 2.15 (m, 1H, CH3CH2), 2.41
(m, 1H, H-6), 3.65 (t, J ) 9.2 Hz, 1H, H-2), 4.42 (dd, J ) 9.2, 8.4
Hz, 1H, H-2), 5.29 (dd, J ) 9.2, 8.8 Hz, 1H, H-3), 6.90-6.93 (m,
2H, ArH), 7.11-7.13 (m, 3H, ArH), 7.34-7.43 (m, 5H, ArH); 13
C
NMR (100.6 MHz) δ 11.5 (CH3CH2), 11.8 (CH3CH2), 23.1 (C-7),
26.3 (CH3CH2), 26.5 (CH3CH2), 44.1 (C-6), 46.6 (C-8), 61.0 (C-
3), 70.2 (C-2), 99.1 (C-8a), 127.2 (CH), 127.5 (2CH), 127.7 (2CH),
128.1 (2CH), 128.4 (CH), 128.5 (2CH), 138.0 (C i), 138.5 (C i),
173.5 (NCO); [R]22D +44.6 (c 0.13, MeOH); MS-EI m/z 349 (M+,
7.5), 293 (23), 224 (73), 105 (100). Anal. Calcd for C23H27NO2‚
2/3H2O: C, 76.41; H, 7.90; N, 3.87. Found: C, 76.29; H, 7.84; N,
1
3.56. 33c: H NMR (200 MHz) δ 0.54 (m, 1H), 0.93 (t, J ) 7.5
Hz, 3H, CH3CH2), 0.95 (t, J ) 7.5 Hz, 1H, CH3CH2), 0.98 (t, J )
7.5 Hz, 1H, CH3CH2), 1.45-1.85 (m, 7H), 2.01 (dddd, J ) 10.0,
10.0, 3.4, 3.4 Hz, 1H), 3.66 (t, J ) 9.2 Hz, 1H, H-2), 4.41 (dd, J
J. Org. Chem, Vol. 71, No. 10, 2006 3811

Amat et al.
) 8.8, 8.2 Hz, 1H, H-2), 5.30 (t, J ) 9.2 Hz, 1H, H-3), 6.91-6.96
(m, 2H, ArH), 7.09-7.13 (m, 3H, ArH), 7.33-7.38 (m, 3H, ArH),
7.46-7.51 (m, 2H, ArH); 13C NMR (50.4 MHz) δ 9.2 (CH3), 9.3
(CH3), 11.6 (CH3), 23.3 (CH2), 29.4 (CH2), 30.6 (CH2), 31.7 (CH2),
44.0 (CH), 45.7 (C), 61.0 (CH), 70.0 (CH2), 99.3 (C), 127.0 (CH),
127.6 (CH), 128.0 (CH), 128.2 (CH), 128.5 (CH), 138.0 (C), 138.6
(C), 176.4 (C); MS-EI m/z 377 (M+, 13), 349 (13), 292 (13), 224
(100); HMRS calcd for C25H31NO2, 377.2354; found, 377.2350.
[3R,6R(and 6S),8aS]-6-Ethyl-8a-methyl-5-oxo-3-phenyl-2,3,6,-
7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (40a and 40b). Fol-
lowing the general procedure, lactam 730 (300 mg, 1.30 mmol) in
THF (5 mL), LiHMDS (1.95 mL, 1.95 mmol) in THF (10 mL),
and ethyl iodide (0.27 mL, 3.38 mmol) afforded a 5:95 (calculated
by 1H NMR) mixture of epimers 40a and 40b (259 mg, 77%), which
were separated by flash chromatography (1:1 EtOAc-hexane). 40a:
1H NMR (300 MHz, representative peaks) δ 0.99 (t, J ) 7.5 Hz,
3H), 3.96 (dd, J ) 9.0, 7.5 Hz, 1H), 4.44 (t, J ) 8.4 Hz, 1H), 5.33
(t, J ) 6.9 Hz, 1H), 7.15-7.34 (m, 5H, ArH); 13C NMR (75.4
MHz) δ 11.9 (CH3), 21.7 (CH2), 24.0 (CH3), 24.3 (CH3), 33.5
(CH2), 40.4 (CH), 59.0 (CH), 69.9 (CH2), 93.9 (C), 125.6 (CH),
127.1 (CH), 128.5 (2CH), 140.0 (C i), 172.3 (NCO). 40b: IR (film)
(s, 6H), 0.85 (s, 9H), 0.92 (t, J ) 7.2 Hz, 3H), 0.96 (t, J ) 7.2 Hz,
3H), 1.45-1.91 (m, 11H), 2.27 (ddd, J ) 12.6, 3.3, 3.3 Hz, 1H),
3.59 (m, 2H), 3.83 (t, J ) 8.7 Hz, 1H), 4.49 (t, J ) 9.0 Hz, 1H),
5.36 (t, J ) 8.7, 1H), 7.18-7.34 (m, 5H, ArH); 13C NMR (75.4
MHz) δ 9.17 and 9.09 (CH3), 18.1 (C), 25.1 (CH2), 25.8 (CH3),
27.3 (CH2), 29.0 (CH2), 30.7 (CH2), 31.4 (CH2), 32.0 (CH2), 45.7
(C), 59.1 (CH), 62.3 (CH2), 69.7 (CH2), 95.7 (C), 125.3 (2CH),
126.9 (CH), 128.5 (2CH), 140.2 (C), 174.8 (C); MS-EI m/z 417
[(M+- - C2H4), 1], 388 (3), 310 (2), 272 (100), 252 (6).
[3R,6R(and 6S),8R,8aS]-6,8-Diethyl-8a-methyl-5-oxo-3-phen-
yl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (43b) and
(3R,8R,8aS)-6,6,8-Triethyl-8a-methyl-5-oxo-3-phenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3,2-a]pyridine (43c). Following the
general procedure, lactam 93a (270 mg, 1.04 mmol) in THF (3 mL),
LiHMDS (1.56 mL, 1.56 mmol) in THF (10 mL), and ethyl iodide
(0.17 mL, 2.12 mmol) afforded a 5:95 (calculated by GC/MS)
mixture of epimers 43a and 43b (197 mg, 66%) and the dialkylated
product 43c (19 mg, 6%), which were separated by flash chroma-
tography (3:7 EtOAc-hexane to EtOAc). 43a: IR (film) 1654 cm-1
;
1H NMR (400 MHz) δ 0.98 (t, J ) 7.2 Hz, 3H, CH3CH2), 1.01 (t,
J ) 7.2 Hz, 3H, CH3CH2), 1.15-1.33 (m, 4H, CH3CH2, CH3),
1.45-1.70 (m, 3H, H-7, H-8, CH3CH2), 1.73-1.84 (m, 2H, H-7,
CH3CH2), 1.96 (m, 1H, CH3CH2), 2.39 (m, 1H, H-6), 3.96 (dd, J
) 8.4, 7.2 Hz, 1H, H-2), 4.38 (d, J ) 8.4 Hz, 1H, H-2), 5.29 (t, J
) 7.6 Hz, 1H, H-3), 7.20-7.40 (m, 5H, ArH); 13C NMR (100.6
MHz) δ 11.7 (CH3CH2), 12.0 (CH3CH2), 18.7 (CH3), 23.6
(CH3CH2), 24.8 (CH3CH2), 27.6 (C-7), 40.1 (C-6), 45.0 (C-8), 59.4
(C-3), 70.0 (C-2), 96.3 (C-8a), 125.9 (2CH), 127.4 (CH), 128.6
1
2960, 2876, 1646 cm-1; H NMR (300 MHz) δ 0.99 (t, J ) 7.5
Hz, 3H), 1.45 (s, 3H), 1.65-1.79 (m, 3H), 1.96 (m, 1H), 2.07 (m,
1H), 2.21 (m, 1H), 2.38 (m, 1H), 3.93 (t, J ) 8.7 Hz, 1H), 4.52 (t,
J ) 8.7 Hz, 1H), 5.39 (t, J ) 8.7 Hz, 1H), 7.14-7.36 (m, 5H,
ArH); 13C NMR (75.4 MHz) δ 10.7 (CH3), 22.7 (CH2), 23.5 (CH3),
25.9 (CH2), 34.8 (CH2), 42.7 (CH), 58.4 (CH), 69.6 (CH2), 93.7
(C), 125.0 (CH), 126.9 (CH), 128.4 (2CH), 140.0 (C i), 172.1
(NCO); [R]22 -117.5 (c 0.69, MeOH).
(2CH), 140.0 (C i), 172.1 (NCO); [R]22 -79.5 (c 0.43, MeOH);
D
D
MS-EI m/z 287 (M+, 6), 272 (9), 231 (27), 162 (100); HMRS calcd
for C18H25NO2, 287.1885; found, 287.1887. 43b: IR (film) 1651
[3R,6R(and 6S),8aR]-8a-[3-(tert-Butyldimethylsilyl)propyl]-
6-ethyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-
a]pyridine (42a and 42b) and (3R,8aR)-8a-[3-(tert-Butyldimeth-
ylsilyl)propyl]-6,6-diethyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahy-
dro-5H-oxazolo[3,2-a]pyridine (42c). Following the general pro-
cedure, lactam 8 (200 mg, 0.52 mmol) in THF (3 mL), LiHMDS
(0.78 mL, 0.78 mmol) in THF (8 mL), and ethyl iodide (0.11 mL,
1.35 mmol) afforded a 5:95 (calculated by GC/MS) mixture of
epimers 42a and 42b (175 mg, 81%) and recovered lactam 8 (26
mg), which were separated by flash chromatography (1:4 EtOAc-
hexane). 42a: 1H NMR (300 MHz) δ -0.03 (s, 3H, SiCH3), -0.01
(s, 3H, SiCH3), 0.82 [s, 9H, SiC(CH2)3], 0.98 (t, J ) 7.5 Hz, 3H,
CH2CH3), 1.44-2.02 (m, 9H, CCH2, CH2CH2CH2OSi, H-7, H-8,
CH2CH3), 2.22 (m, 1H, CCH2), 2.31 (m, 1H, H-6), 3.54 (t, J ) 6.3
Hz, 2H, CH2OSi), 3.88 (dd, J ) 9.0, 7.8 Hz, 1H, H-2), 4.42 (t, J
) 8.4, 1H, H-2), 5.32 (t, J ) 8.1 Hz, 1H, H-3), 7.18-7.33 (m, 5H,
ArH); 13C NMR (75.4 MHz) δ -5.3 (SiCH3), 11.8 (CH3CH2), 18.2
[C(CH3)3], 21.6 (CH3CH2), 24.2 (C-7), 25.8 [C(CH3)3], 27.4 (CH2-
CH2OSi), 31.7 (C-8), 30.0 (CCH2), 40.6 (C-6), 59.0 (C-3), 62.4
(CH2OSi), 69.4 (C-2), 95.8 (C-8a), 125.6 (2CH), 127.0 (CH), 128.4
(2CH), 140.0 (C), 172.6 (NCO). 42b: IR (film) 2954, 2858, 1651
1
cm-1; H NMR (300 MHz) δ 0.99 (t, J ) 7.5 Hz, 3H, CH3CH2),
1.02 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.19-1.28 (m, 1H, CH3CH2),
1.34 (dd, J ) 13.5, 10.5 Hz, 1H, H-7), 1.30 (s, 3H, CCH3), 1.58
(ddd, J ) 9.3, 3.5, 3.5 Hz, 1H, H-8), 1.79 (m, 2H, CH3CH2), 1.92
(m, 1H, CH3CH2), 2.04 (ddd, J ) 14.0, 7.8, 3.3 Hz, 1H, H-7),
2.42 (m, 1H, H-6), 3.89 (dd, J ) 9.0, 8.1 Hz, 1H, H-2), 4.49 (t, J
) 9.0 Hz, 1H, H-2), 5.37 (t, J ) 8.4 Hz, 1H, H-3), 7.15-7.35 (m,
5H, ArH); 13C NMR (75.4 MHz) δ 10.9 (CH3CH2), 12.1 (CH3-
CH2), 18.8 (CH3), 23.2 (CH3CH2), 26.3 (CH3CH2), 27.9 (C-7), 43.2
(C-6), 46.2 (C-8), 58.9 (C-3), 69.7 (C-2), 96.1 (C-8a), 125.1 (2CH),
126.9 (CH), 128.5 (2CH), 140.0 (C i), 172.1 (NCO); mp 76-79
°C (EtOAc-hexane); [R]22D -133.3 (c 0.52, MeOH). Anal. Calcd
for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.24; H,
1
8.74; N, 4.73. 43c: IR (film) 1650 cm-1; H NMR (300 MHz) δ
0.89 (t, J ) 7.5 Hz, 3H, CH2CH3), 0.92 (t, J ) 7.5 Hz, 3H,
CH2CH3), 1.03 (t, J ) 7.5 Hz, 3H, CH2CH3), 1.36 (s, 3H, CH3),
1.43-1.85 (m, 9H), 3.88 (t, J ) 9.0 Hz, 1H, H-2), 4.45 (t, J ) 9.0
Hz, 1H, H-2), 5.33 (t, J ) 8.5 Hz, 1H, H-3), 7.19-7.34 (m, 5H,
ArH); 13C NMR (50.3 MHz) δ 9.2 (CH3CH2), 9.4 (CH3CH2), 12.1
(CH3CH2), 18.8 (CH3), 23.4 (CH3CH2), 31.0, 32.0, 32.6 (2CH3CH2,
C-7), 44.7 (C-8), 46.2 (C-6), 59.6 (C-3), 70.0 (C-2), 96.2 (C-8a),
125.3 (2CH), 127.0 (CH), 128.5 (2CH), 140.1 (C i), 174.6 (NCO);
MS-EI m/z 315 (M+, 8), 300 (17), 287 (14), 162 (100); HMRS
calcd for C20H29NO2, 315.2198; found, 315.2192.
1
cm-1; H NMR (300 MHz) δ -0.04 (s, 6H, SiCH3), 0.80 [s, 9H,
C(CH3)3], 0.99 (t, J ) 7.5 Hz, 3H, CH2CH3), 1.47-1.61 (m, 4H,
CH2CH2OSi, CCH2, H-7), 1.71 (m, 1H, CH2CH3), 1.76-1.82 (m,
2H, H-8), 1.91 (m, 1H, CH2CH3), 1.97 (m, 1H, H-7), 2.34 (m, 2H,
CH2CH2CH2OSi, H-6), 3.54 (ddd, J ) 5.7, 5.7, 3.5 Hz, 2H, CH2-
OSi), 3.82 (t, J ) 8.5 Hz, 1H, H-2), 4.50 (t, J ) 8.5, 1H, H-2),
5.37 (t, J ) 8.4 Hz, 1H, H-3), 7.12 (d, J ) 7.5 Hz, 2H, ArH), 7.22
(d, J ) 7.2 Hz, 1H, ArH), 7.26-7.33 (m, 2H, ArH); 13C NMR
(75.4 MHz) δ -5.45 and -5.43 (SiCH3), 10.8 (CH3CH2), 18.0
[C(CH3)3], 22.3 (CH3CH2), 25.7 [C(CH3)3], 26.1 (C-7), 27.1 (CH2-
CH2OSi), 30.4 (C-8), 30.7 (CCH2), 42.9 (C-6), 58.5 (C-3), 62.2
(CH2OSi), 69.6 (C-2), 95.6 (C-8a), 125.1 (2CH), 126.9 (CH), 128.4
(2CH), 140.0 (C), 172.3 (NCO); [R]22D -70 (c 0.84, MeOH); MS-
EI m/z 360 [(M+- - C4H9), 2], 282 (2), 244 (100), 224 (19). In
some experiments, traces of the dialkylated product 42c were
isolated: IR (film) 2956, 1649 cm-1; 1H NMR (300 MHz) δ -0.0
General Procedure for BH3-THF Reduction. BH3-THF (1
M solution in THF, 3-6 mmol) was added to a cooled (-78 °C)
solution of the bicyclic lactam (1 mmol) in THF. The mixture was
stirred, basified with 2 N aqueous NaOH, and extracted with EtOAc
and CH2Cl2. The combined organic extracts were dried and
concentrated, and the resulting residue was chromatographed.
(3S,5S)-3-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-5-methylpi-
peridine (47). Following the general procedure, a mixture of BH3-
THF (3.3 mL, 3.3 mmol) and lactam 16a (287 mg, 1.10 mmol) in
THF (5 mL) was stirred at -78 °C for 2 h and at 0 °C for 4 h to
give piperidine 47 (179 mg, 65%) after flash chromatography (1:4
1
EtOAc-hexane): IR (film) 3444 cm-1; H NMR (300 MHz) δ
0.89 (t, J ) 7.5 Hz, 3H, CH3CH2), 0.93 (d, J ) 7.0 Hz, 3H, CH3),
1.23 (m, 2H, H-4), 1.34 (m, 2H, CH3CH2), 1.62 (m, 1H, H-5), 1.90
(30) Fre´ville, S.; Bonin, M.; Ce´le´rier, J. P.; Husson, H.-P.; Lhommet,
G.; Quirion, J.-C.; Thuy, V. M. Tetrahedron 1997, 53, 8447.
3812 J. Org. Chem., Vol. 71, No. 10, 2006

EnantioselectiVe Synthesis of â-Substituted Piperidines
(m, 1H, H-3), 2.15-2.23 (m, 2H, H-2, H-6), 2.30-2.34 (m, 2H,
H-2, H-6), 3.16 (br s, 1H, OH), 3.59 (dd, J ) 10.5, 5.0 Hz, 1H,
H-2′), 3.69 (dd, J ) 10.2, 5.0 Hz, 1H, H-1′), 3.97 (t, J ) 10.2 Hz,
(2S,5S)-5-Benzyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-phenylpi-
peridine (57a). LiAlH4 (1.39 g, 36.5 mmol) was added to a solution
of lactam 32a (1.40 g, 3.65 mmol) in THF (64 mL), and the mixture
was stirred at room temperature for 15 h. The reaction was quenched
by the addition of cool saturated aqueous NaCl, and the resulting
mixture was extracted with EtOAc. The combined extracts were
dried and concentrated, and the residue was chromatographed
(EtOAc) to afford a 93:7 (calculated by GC/MS) mixture of epimers
57a and 57b (903 mg, 67%). Flash chromatography (1:9 EtOAc-
hexane) gave the major isomer 57a: IR (film) 3460 cm-1; 1H NMR
(300 MHz) δ 0.88 (m, 1H, H-4), 1.51-1.78 (m, 4H, H-3, H-6,
H-4), 1.93 (m, 1H, H-5), 2.38 (dd, J ) 13.5, 8.0 Hz, 1H, CH2Ph),
2.60 (dd, J ) 13.5, 6.0 Hz, 1H, CH2Ph), 3.10 (dm, J ) 11.0 Hz,
1H, H-6), 3.23 (dd, J ) 11.0, 3.0 Hz, 1H, H-2), 3.35 (t, J ) 2.5
Hz, 1H, H-2′), 3.97 (tap, J ) 2.5 Hz, 2H, H-2′, H-1′), 6.98-7.42
(m, 15H, ArH); 13C NMR (75.4 MHz) δ 30.9 (C-4), 37.2 (C-3),
38.5 (C-5), 41.1 (CH2Ph), 51.6 (C-6), 59.3 (C-2′), 61.8 (C-1′), 65.1
(C-2), 125.9 (CH), 127.2 (CH), 127.7 (CH), 127.8 (2CH), 127.9
(2CH), 128.2 (2CH), 128.7 (2CH), 128.9 (2CH), 129.3 (2CH), 134.2
(C i), 139.9 (C i), 143.7 (C i); [R]22D -55.6 (c 0.41, MeOH); MS-
EI m/z 372 [(M + 1), 1], 340 (100), 120 (30), 91 (70); HMRS
calcd for C26H29NO, 371.2249; found, 371.2257.
1H, H-2′), 7.14-7.17 (m, 2H, ArH), 7.25-7.37 (m, 3H, ArH); 13
C
NMR (75.4 MHz) δ 12.0 (CH3), 19.1 (CH3CH2), 25.9 (CH3CH2),
27.5 (C-3), 34.9 (C-5), 37.0 (C-4), 54.4 (C-2), 57.5 (C-6), 60.3
(C-2′), 70.3 (C-1′), 127.6 (CH), 128.0 (2CH), 128.8 (2CH), 136.0
(C i); [R]22D -41.1 (c 1.0, MeOH); MS-EI m/z 246 [(M+ - 1), 1],
91 (20), 216 (100); HMRS calcd for C16H25NO, 247.1936; found,
247.1584.
tert-Butyl (3R,5S)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-
piperidine-3-acetate (48). Following the general procedure, a
mixture of BH3-THF (42.0 mL, 42.0 mmol) and lactam 17a (5.0
g, 14.0 mol) in THF (82 mL) was stirred at -78 °C for 15 min
and at 0 °C for 5 h to give piperidine 48 (3.68 g, 76%) after flash
1
chromatography (1:1 EtOAc-hexane): IR (film) 1726 cm-1; H
NMR (400 MHz) δ 0.88 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.19-1.44
(m, 4H, CH3CH2, H-4), 1.46 (s, 9H, [(CH3)3]), 1.64 (m, 1H, H-5),
2.14-2.27 (m, 3H, H-2, H-3, H-6), 2.22 (dd, J ) 16.5, 6.4 Hz,
1H, CH2COO), 2.41 (dd, J ) 16.5, 10.0 Hz, 1H, CH2COO), 2.44-
2.52 (m, 2H, H-2, H-6), 2.80 (br s, 1H, OH), 3.59 (dd, J ) 10.8,
4.8 Hz, 1H, H-2′), 3.68 (dd, J ) 10.4, 5.0 Hz, 1H, H-1′), 3.97 (t,
J ) 10.4 Hz, 1H, H-2′), 7.13-7.15 (m, 2H, ArH), 7.29-7.34 (m,
3H, ArH); 13C NMR (100.6 MHz) δ 12.0 (CH3CH2), 26.5
(CH3CH2), 28.3 [(CH3)3], 30.7 (C-3), 34.5 (C-5), 35.1 (C-4), 39.2
(CH2COO), 53.2 (C-6), 56.6 (C-2), 60.4 (C-2′), 70.5 (C-1′), 80.5
[C(CH3)3], 128.0 (CH), 128.3 (2CH), 129.1 (2CH), 135.6 (C i),
(2S,3R,5R)-3,5-Diethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-
phenylpiperidine (58). LiAlH4 (910 mg, 24 mmol) was added to
a solution of lactam 33a (835 mg, 2.40 mmol) in THF (42 mL),
and the mixture was stirred at room temperature for 15 h. The
reaction was quenched by the addition of cool saturated aqueous
NaCl, and the resulting mixture was extracted with EtOAc. The
combined extracts were dried and concentrated, and the residue
was chromatographed (5:95 EtOAc-hexane to EtOAc) to afford
172.8 (COO); [R]22 -18.5 (c 0.5, MeOH); MS-EI m/z 348 [(M+
D
+ 1), 1], 260 (100), 316 (45); HMRS calcd for C21H33NO3,
347.2460; found, 347.2462.
1
58 (539 mg, 67%): IR (film) 3451 cm-1; H NMR (400 MHz) δ
tert-Butyl (3R,5R)-5-Ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-
piperidine-3-acetate (52). Following the general procedure, a
mixture of BH3-THF (27.3 mL, 27.3 mmol) and lactam 26b (1.63
g, 4.55 mol) in THF (27 mL) was stirred at -78 °C for 15 min
and at room temperature for 7 h to give piperidine 52 (894 mg,
57%) after flash chromatography (4:1 EtOAc-hexane): IR (film)
0.64 (t, J ) 7.2 Hz, 3H, CH3CH2), 0.91 (t, J ) 7.6 Hz, 3H, CH3-
CH2), 0.93 (m, 1H, H-4), 1.10 (m, 1H, CH3CH2), 1.23 (m, 1H,
CH3CH2), 1.30 (m, 1H, CH3CH2), 1.51 (t, J ) 11.2, 1H, H-6ax),
1.49-1.56 (m, 3H, H-3, H-6, CH3CH2), 1.63 (m, 1H, H-6), 1.91
(ddm, J ) 12.8, 1.6 Hz, 1H, H-4), 3.05 (d, J ) 9.6 Hz, 1H, H-6eq),
3.49 (dd, J ) 10.4 and 5.6 Hz, 1H, H-2′), 3.53 (d, J ) 2.4 Hz, 1H,
H-2), 3.70 (br s, 1H, OH), 4.14 (t, J ) 10.8 Hz, 1H, H-2′), 4.34
(dd, J ) 11.2, 5.6 Hz, 1H, H-2′), 6.86-6.88 (m, 2H, ArH), 7.25-
7.42 (m, 8H, ArH); 13C NMR (100.6 MHz) δ 11.4 (CH3CH2), 12.0
(CH3CH2), 19.0 (CH3CH2), 27.4 (CH3CH2), 32.0 (C-5), 33.3 (C-
4), 42.3 (C-3), 51.9 (C-6), 59.5 (C-2′), 61.0 (C-1′), 69.2 (C-2), 126.7
(CH), 127.7 (CH), 127.9 (2CH), 128.1 (2CH), 129.4 (2CH), 129.6
1
1724 cm-1; H NMR (300 MHz) δ 0.43 (qap, J ) 12.0 Hz, 1H,
H-4ax), 0.85 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.12 (m, 2H, CH3CH2),
1.23 (t, J ) 11.0 Hz, 1H, H-6), 1.42-1.47 (m, 10H, H-5, [(CH3)3]),
1.80 (br d, J ) 12.0 Hz, 1H, H-4), 1.90 (t, J ) 10.5 Hz, 1H, H-2),
2.04-2.08 (m, 3H, H-3, CH2COO), 2.84-2.91 (m, 2H, H-2, H-6),
3.02 (br s, 1H, OH), 3.61 (dd, J ) 10.5, 5.1 Hz, 1H, H-2′), 3.73
(dd, J ) 10.5, 5.1 Hz, 1H, H-1′), 4.01 (t, J ) 10.5 Hz, 1H, H-2′),
7.15-7.18 (m, 2H, ArH), 7.30-7.34 (m, 3H, ArH); 13C NMR (75.4
MHz) δ 11.4 (CH3CH2), 27.1 (CH3CH2), 28.1 [(CH3)3], 34.1 (C-
3), 37.3 (C-4), 38.0 (C-5), 40.6 (CH2COO), 51.5 (C-6), 58.8 (C-
2), 59.8 (C-2′), 69.8 (C-1′), 80.2 [C(CH3)3], 127.7 (CH), 128.0
(2CH), 128.8 (2CH), 135.1 (C i), 171.7 (COO); mp 59-61 °C
(2CH), 134.3 (C i), 141.0 (C i); [R]22 -85.0 (c 0.10, MeOH);
D
MS-EI m/z 338 [(M+ + 1), 1], 306 (100), and 91 (62); HMRS
calcd for C23H31NO, 337.2406; found, 337.2401.
General Procedure for Debenzylation Reactions. A solution
of the N-substituted piperidine in MeOH-HCl was concentrated,
and the residue was dissolved in MeOH. A mixture of the resulting
solution and 10% Pd(OH)2/C was hydrogenated at room temperature
and atmospheric pressure for 24 h. The catalyst was removed by
filtration, the solvent was evaporated, and the resulting residue was
washed with ether to afford the N-unsubstituted piperidine as the
hydrochloride.
(EtOAc-hexane); [R]22 -25.0 (c 0.5, MeOH). Anal. Calcd for
D
C21H33NO3: C, 72.58; H, 9.57; N, 4.03. Found: C, 72.24; H, 9.62;
N, 3.96.
(2R,3R,5S)-3,5-Diethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-
methylpiperidine (53). Following the general procedure, a mixture
of BH3-THF (8.4 mL, 8.4 mmol) and lactam 43b (400 mg, 1.39
mol) in THF (8 mL) was stirred at -78 °C for 15 min and at 0 °C
for 6 h to give piperidine 53 (244 mg, 64%) and recovered lactam
43b (28 mg), which were separated by flash chromatography (1:4
(3S,5S)-3-Ethyl-5-methylpiperidine (49). Following the general
procedure, piperidine 47 (91 mg, 0.37 mmol) in MeOH (5 mL)
and 10% Pd(OH)2-C (25 mg) afforded 49 hydrochloride (40 mg,
1
66%): IR (film) 3388 cm-1; H NMR (500 MHz) δ 0.92 (t, J )
1
EtOAc-hexane): IR (film) 3444 cm-1; H NMR (400 MHz) δ
7.5 Hz, 3H, CH3CH2), 1.07 (d, J ) 7.0 Hz, 3H, CH3), 1.44 and
1.51 (2m, 4H, H-4, CH3CH2), 1.88 (m, 1H, H-5), 2.14 (m, 1H,
H-3), 2.72 (dd, J ) 12.5, 7.5 Hz, 1H, H-2), 2.83 (dd, J ) 12.0, 7.0
Hz, 1H, H-6), 3.10 (dd, J ) 12.5, 4.0 Hz, 1H, H-2), 3.13 (dd, J )
12.0, 4.0 Hz, 1H, H-6), 9.40 (br s, 2H, NH2); 13C NMR (100.6
MHz) δ 11.4 (CH3CH2), 18.4 (CH3), 24.6 (C-3), 25.0 (CH3CH2),
31.4 (C-5), 34.6 (C-4), 47.6 (C-6), 49.4 (C-2); [R]22D - 0.7 (c 4.0,
CH2Cl2).
0.61 (d, J ) 6.8 Hz, 3H, CH3), 0.77 (t, J ) 7.2 Hz, 3H, CH3CH2),
0.77 (m, 1H, H-4), 0.89 (t, J ) 7.6 Hz, 3H, CH3CH2), 1.04 (m,
2H, CH3CH2), 1.22 (m, 2H, CH3CH2), 1.48-1.61 (m, 3H, H-3,
H-4, H-5), 2.25 (t, J ) 11.6 Hz, 1H, H-6), 2.82-2.89 (m, 2H, H-2,
H-6), 3.64 (m, 1H, H-1′), 3.70 (m, 1H, H-2′), 3.90 (dd, J ) 10.8,
5.2 Hz, 1H, H-2′), 7.26-7.36 (m, 5H, ArH); 13C NMR (100.6 MHz)
δ 5.3 (CH3C), 11.4 (CH3CH2), 11.6 (CH3CH2), 26.3 (CH3CH2),
27.4 (CH3CH2), 31.2 (C-4), 38.2 (C-5), 41.8 (C-3), 48.9 (C-6), 51.9
(C-2), 63.0 (C-2′), 67.1 (C-1′), 127.5 (CH), 128.3 (2CH), 128.4
(2R,3R,5S)-3,5-Diethyl-2-methylpiperidine (56). Following the
general procedure, piperidine 53 (40 mg, 0.14 mmol) in MeOH (5
mL) and 10% Pd(OH)2-C (16 mg) afforded 56 hydrochloride (16
(2CH), 140.5 (C i); [R]22 -1.2 (c 0.17, MeOH), MS-EI m/z 276
D
[(M+ + 1), 1], 244 (100), 140 (4), 91 (12).
J. Org. Chem, Vol. 71, No. 10, 2006 3813

Amat et al.
mg, 58%): IR (film) 1728 cm-1; 1H NMR (300 MHz) δ 0.94 (t, J
) 7.2 Hz, 3H, CH3CH2), 0.95 (t, J ) 7.2 Hz, 3H, CH3CH2), 1.03
(m, 1H), 1.21 (d, J ) 7.2 Hz, 3H, CH3), 1.25-1.43 (m, 4H), 1.56-
1.84 (m, 3H), 2.72 (t, J ) 13.0 Hz, 1H), 3.10 (ddd, J ) 13.0, 4.2,
1.8 Hz, 1H), 3.65 (m, 1H); 13C NMR (75.4 MHz) δ 9.4 (CH3),
11.2 (CH3CH2), 11.5 (CH3CH2), 26.2 (CH2), 27.4 (CH2), 30.3
(CH2), 36.8 (C-6), 40.0 (C-5), 43.6 (C-3), 52.3 (C-2); [R]22D +117.5
(c 0.04, MeOH); MS-EI m/z 155 (M+, 10), 140 (100), 126 (41),
84 (31); HMRS calcd for C10H21N, 155.1674; found, 155.1676.
General Procedure for Debenzylation with Introduction of
a Boc Protecting Group. A solution of the N-substituted piperidine
(1 mmol) and di-tert-butyl dicarbonate (1.8 mmol) in EtOAc
containing 10% Pd(OH)2-C was hydrogenated at room temperature
and atmospheric pressure for 48-72 h. The catalyst was removed
by filtration, the solvent was evaporated, and the resulting residue
was chromatographed.
(C-5), 34.4 (CH2CNO), 37.6 (CH2COO), 46.5 (C-6), 50.4 (C-2),
80.3 ([C(CH3)3]), 108.5 (C-2a), 111.2 (CH), 118.4 (CH), 119.1
(CH), 121.6 (CH), 122.6 (CH), 126.7 (C-2b), 136.1 (C-6a), 170.7
(CNO), 171.7 (COO); 13C NMR (75.4 MHz, Rotamer B) δ 11.5
(CH3CH2), 25.4 (CH3CH2), 28.0 [(CH3)3], 30.1 (C-3), 31.3 (C-4),
34.0 (C-5), 35.2 (CH2CNO), 38.0 (CH2COO), 46.7 (C-6), 51.3 (C-
2), 80.5 [C(CH3)3], 108.5 (C-2a), 111.2 (CH), 118.5 (CH), 119.1
(CH), 121.7 (CH), 122.7 (CH), 127.0 (C-2b), 136.1 (C-6a), 170.7
(NCO), 171.7 (COO); [R]22 -27.4 (c 0.5, MeOH); MS-EI m/z
D
384 (M+, 98), 130 (100), 328 (43); HMRS calcd for C18H33NO2,
384.2412; found, 384.2423.
(3R,5S)-5-Ethyl-1-(3-indolylacetyl)piperidine-3-acetic Acid (62a).
TFA (8 mL, 106.6 mmol) was added to a solution of 61a (630 mg,
1.64 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 15 min
and evaporated to afford 62a (511 mg, 95%), which was used in
the next step without ulterior purification: IR (film) 3259, 1712,
1615 cm-1; 1H NMR (300 MHz) δ 0.61 (t, J ) 7.5 Hz, 1.5H, CH3-
CH2), 0.86 (t, J ) 7.5 Hz, 1.5H, CH3CH2), 1.00-1.55 (m, 5H),
1.95-2.40 (m, 3H), 2.81 (m, 0.5H), 3.14 (br d, 0.5H), 3.19-3.28
(m, 1H), 3.50 (m, 0.5H), 3.70 (m, 1H), 3.71-3.95 (m, 2H), 4.06
(m, 0.5H), 6.92-7.33 (m, 5H, ArH, NH), 7.57 (d, J ) 7.8 Hz,
1H), 8.41 (s, 0.5H, COOH), 8.66 (s, 0.5H, COOH); 13C NMR (75.4
MHz) δ 11.0 (CH3), 11.5 (CH3), 25.0 and 25.5 (CH2), 29.6 and
29.9 (CH), 30.9 and 31.3 (CH2), 33.9 and 34.0 (CH), 35.0 and 35.3
(CH2), 36.6 (2CH2), 46.5 and 46.8 (CH2), 50.5 and 51.9 (CH2),
107.8 and 108.0 (C), 111.3 and 111.4 (CH), 118.0 and 118.5 (CH),
119.2 and 119.4 (CH), 121.7 and 122.0 (CH), 122.8 and 123.2 (CH),
126.5 and 126.7 (C), 136.0 and 136.1 (C), 172.3 (NCO), 176.7
(COO); MS-EI m/z 328 (M+, 12), 130 (100), 151 (13); HMRS calcd
for C19H22N2O2, 328.1787; found, 328.1786.
20S-5,16-Dioxodihydrocleavamine (63a). A suspension of 62a
(780 mg, 3.18 mmol) in PPA (48 g) was heated at 90 °C for 30
min. The mixture was poured into ice and basified with saturated
NH4OH solution and extracted with CH2Cl2. The dried combined
organic extracts were concentrated, and the resulting residue was
chromatographed (3:7 EtOAc-hexane to EtOAc) to afford 63a (471
mg, 64%): IR (film) 1634 cm-1; 1H NMR (500 MHz) δ 0.91 (t, J
) 8.0 Hz, 3H, CH3CH2), 1.78 (m, 1H, CH3CH2), 1.29 (m, 1H,
CH3CH2), 1.41 (ddd, J ) 13.0, 13.0, 4.0 Hz, 1H, H-11ax), 1.75
(m, 1H, H-10), 1.89 (dm, J ) 13.0 Hz, 1H, H-11eq), 2.23 (t, J )
12.0 Hz, 1H, H-9), 2.33 (dm, J ) 12.5 Hz, 1H, H-12), 2.38 (dm,
J ) 12.5 Hz, 1H, H-13), 3.20 (dm, J ) 14.0 Hz, 1H, H-15), 3.26
(t, J ) 12.0 Hz, 1H, H-13), 4.02 (dm, J ) 14.0 Hz, 1H, H-15),
4.02 and 4.32 (2d, J ) 17.0 Hz, 2H, H-6), 4.63 (dm, J ) 13.0 Hz,
1H, H-9), 7.13 (m, 1H, ArH), 7.33 (m, 2H, ArH), 7.64 (dd, J )
8.0, 0.5 Hz, 1H, ArH), 9.11 (br s, 1H, NH); 13C NMR (75.4 MHz)
δ 11.1 (CH3CH2), 27.1 (CH3CH2), 30.8 (C-10), 35.0 (C-6), 35.7
(C-12), 37.6 (C-11), 42.4 (C-13), 49.8 and 50.0 (C-9 and C-15),
111.8 (CH), 115.6 (CH), 120.6 (CH), 121.0 (C-5b), 126.9 (CH),
128.7 (CH), 133.0 (CH), 135.4 (CH), 170.4 (NCO), 194.3 (COO);
[R]22D -287.3 (c 0.5, MeOH); MS-EI m/z 310 (M+, 100), 143 (83),
198 (67); HMRS calcd for C19H22N2O2, 310.1681; found, 310.1681.
Anal. Calcd for C19H22N2O2‚1/2H2O: C, 71.45; H, 7.26; N, 8.77.
Found: C, 71.16; H, 7.03, N, 8.66.
(2S,5S)-5-Benzyl-1-(tert-butoxycarbonyl)piperidine (59). Fol-
lowing the general procedure, piperidine 57a (650 mg, 1.74 mmol),
di-tert-butyl dicarbonate (685 mg, 3.14 mmol) in EtOAc (110 mL),
and 10% Pd(OH)2-C (284 mg) gave the N-Boc derivative 59 (460
mg, 75%) after flash chromatography (1:4 EtOAc-hexane): IR
1
(film) 3026, 1801, 1685 cm-1; H NMR (400 MHz) δ 1.39 (m,
1H, H-3), 1.47 [s, 9H, (CH3)3], 1.65 (m, 1H, H-4), 1.90 (m, 1H,
H-5), 2.06 (ddd, J ) 12.4, 8.4, 4.0 Hz, 1H, H-3), 2.17 (m, 1H,
H-4), 2.66 (dd, J ) 13.6, 7.6 Hz, 1H, CH2Ph), 2.81 (dd, J ) 13.6,
8.0 Hz, 1H, CH2Ph), 2.97 (dd, J ) 13.6, 4.0 Hz, 1H, H-6), 3.90 (d,
J ) 13.6 Hz, 1H, H-6), 5.40 (t, J ) 4.4 Hz, 1H, H-2), 7.17-7.35
(m, 10H, ArH);13C NMR (100.6 MHz) δ 23.7-23.8 (C-3, C-4),
28.4 [(CH3)3], 35.5 (C-5), 37.5 (CH2Ph), 42.9 (C-6), 53.5 (C-2),
79.7 [C(CH3)3], 125.9 (CH), 126.3 (2CH), 126.4 (CH), 128.2 (2CH),
128.5 (2CH), 129.1 (2CH), 140.6 (C i), 140.9 (C i), 156.1 (NCO).
(2S,3R,5R)-1-(tert-Butoxycarbonyl)-3,5-diethyl-2-phenylpi-
peridine (60). Following the general procedure, piperidine 58 (375
mg, 1.11 mmol), di-tert-butyl dicarbonate (434 mg, 2.0 mmol) in
EtOAc (70 mL), and 10% Pd(OH)2-C (180 mg) gave the N-Boc
derivative 60 (257 mg, 73%) after flash chromatography (1:4
1
EtOAc-hexane): IR (film) 1689 cm-1; H NMR (400 MHz) δ
0.86 (t, J ) 7.6 Hz, 3H, CH3CH2), 0.96 (t, J ) 7.6 Hz, 3H, CH3-
CH2), 1.01 (m, 1H, CH3CH2), 1.23 (m, 1H, CH3CH2), 1.35 [s, 9H,
(CH3)3], 1.36 (m, 1H, CH3CH2), 1.49-1.57 (m, 2H, CH3CH2, H-4),
1.70 (m, 1H, H-4), 1.81 (m, 1H, H-5), 2.01 (m, 1H, H-3), 3.39
(dap, J ) 12.0 Hz, 1H, H-6), 3.63 (dap, J ) 10.4 Hz, 1H, H-6), 5.14
(br s, 1H, H-2), 7.20-7.30 (m, 3H, ArH), 7.39 (dap, 2H, ArH); 13
C
NMR (100.6 MHz) δ 11.8 (CH3), 12.1 (CH3), 25.0 (CH3CH2), 26.0
(CH3CH2), 28.3 [(CH3)3], 30.0 (C-4), 35.0 (C-5), 36.0 (C-3), 42.5
(C-6), 58.3 (C-2), 79.2 [C(CH3)3], 126.7 (2CH), 127.8 (2CH), 129.0
(CH), 140.2 (C i), 155.4 (NCO); [R]22D -4.3 (c 0.31, MeOH); MS-
EI m/z 317 (M+, 1), 261 (100), 232 (16), 216 (60), 188 (41), 164
(38); HMRS calcd for C20H31NO2, 317.2355; found, 317.2370.
tert-Butyl (3R,5S)-5-Ethyl-1-(3-indolylacetyl)piperidine-3-
acetate (61a). A suspension of lactam 48 (1.50 g, 4.35 mmol) in
MeOH (20 mL) and 10% Pd(OH)2/C (500 mg) was hydrogenated
at room temperature and atmospheric pressure for 48 h. Then, the
mixed anhydride of pivalic acid and indole-3-acetic acid24 (1.17 g,
4.51 mmol) was added, and the mixture was shaken under a
hydrogen atmosphere at room temperature for 3 days. The catalyst
was removed by filtration, the solvent was evaporated, and the
resulting residue was chromatographed (1:4 to 4:1 EtOAc-hexane)
to afford 61a (1.51 g, 91%): IR (film) 1623, 1724 cm-1; 1H NMR
(300 MHz) δ 0.70 (t, J ) 7.5 Hz, 1.5H, CH3CH2), 0.89 (t, J ) 7.5
Hz, 1.5H, CH3CH2), 1.10 (m, 1H, CH3CH2), 1.28 (m, 1H, CH3CH2),
1.43 and 1.45 (s, 9H, [(CH3)3]), 1.14-1.54 (m, 3H, H-5, CH2CNO),
1.98-2.29 (m, 3H, H-3, CH2COO), 2.91 (dd, J ) 13.0, 8.0 Hz,
0.5H, H-2), 3.04 (m, 0.5H, H-6), 3.35-3.40 (m, 1.5H, 1H-2, 0.5H-
6), 3.56 (dd, J ) 13.0, 7.6 Hz, 0.5H, H-2), 3.67 (dd, J ) 13.8, 5.4
Hz, 0.5H, H-6), 3.84 (m, 3H, H-4, H-6), 6.99 (br s, 1H, ArH),
7.13 (m, 3H, ArH), 7.30 (m, 1H, ArH), 7.62 (m, 1H, ArH), 8.47
(br s, 1H, NH); 13C NMR (75.4 MHz, Rotamer A) δ 11.3 (CH3-
CH2), 25.1 (CH3CH2), 28.0 [(CH3)3], 29.7 (C-3), 31.0 (C-4), 33.6
(-)-20S-Dihydrocleavamine. A solution of 63a (131 mg, 0.42
mmol) in dioxane (10 mL) was added to a suspension of LiAlH4
(224 mg, 5.88 mmol) in dioxane (20 mL), and the mixture was
heated at reflux for 24 h. Then, the mixture was cooled to 0 °C,
H2O was added until the suspension turned colorless, and it was
filtered. Evaporation of the filtrate gave a residue, which was
chromatographed (1:4 EtOAc-hexane to 9:1 EtOAc-MeOH) to
afford (-)-20S-dihydrocleavamine (40 mg, 34%) and (2R)-2-(2-
ethyl-2-propenyl)-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-
b]indole (65; 20 mg, 17%). The spectral data and optical rotation
×ed[R]22 -97.0 (c 0.9 CHCl3); [R] -87.0 (CHCl3)23a×fd of our
D
synthetic (-)-20S-dihydrocleavamine were coincident with those
1
previously reported.31 65: IR (film) 3281, 2927 cm-1; H NMR
(200 MHz) δ 0.83 (m, 2H), 1.00 (t, J ) 7.5 Hz, 3H), 1.83-2.11
(m, 4H), 2.17 (d, J ) 7.5 Hz, 1H), 2.36 (m, 1H), 2.67-2.51 (m,
3814 J. Org. Chem., Vol. 71, No. 10, 2006

EnantioselectiVe Synthesis of â-Substituted Piperidines
2H), 3.15-2.90 (m, 2H), 3.25 (m, 1H), 4.24 (m, 1H), 4.72 (dm, J
) 7.0 Hz, 1H), 7.04-7.50 (m, 5H, ArH), 7.90 (br s, 1H); 13C NMR
(50.3 MHz) δ 11.3 (CH3), 16.6 (CH2), 27.6 (CH2), 33.4 (CH), 35.0
(CH2), 41.3 (CH2), 45.0 (CH2), 54.1 (CH2), 56.4 (CH), 107.1 (C),
107.7 (CH2), 109.6 (CH), 116.9 (CH), 118.2 (CH), 120.3 (2CH),
126.2 (C), 133.6 (C), 134.7 (C), 148.8 (C); MS-EI m/z 280 (M+,
28), 156 (13), 209 (100); HMRS calcd for C19H24N2, 280.1939;
found, 280.1944.
00505) and the DURSI, Generalitat de Catalunya (Grants
2001SGR-0084 and 2005SGR-0603) is gratefully acknowl-
edged. Thanks are also due to the Ministry of Science and
Technology (Spain) for a fellowship to O.L.
Supporting Information Available: Experimental details and
characterization data for all compounds reported in this manuscript
not included in the Experimental Section, tables with 13C NMR
assignments for lactams 10-46, and X-ray crystallographic data
for compounds 15b, 20b, 32a, 39, and 40b. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the Ministry of
Science and Technology (Spain)-FEDER (Project BQU2003-
(31) Wenkert, E.; Hagaman, E. W.; Kunesch, N.; Wang, N. HelV. Chim.
Acta 1976, 59, 2711.
JO060157V
J. Org. Chem, Vol. 71, No. 10, 2006 3815