Divergent synthetic strategy leading to structurally diverse pyrrolidines and piperidines from common γ-aminoalkyl butenolide and aldehyde precursors

Article abstract of DOI:10.1021/jo0614487

Condensation between aldehydes and the secondary amino function of 5-(aminoalkyl)furan-2(5H)-ones, obtained by the silyloxyfuran dienolate addition to imine-type derivatives, produces either aminoalkylbenzotriazoles or 1,2,3,4-tetrahydropyridines. The former can be reduced with SmI₂ to generate α-aminoalkyl radicals that are trapped by the α,β-unsaturated lactone moiety yielding substituted pyrrolidines diastereoselectively, while catalytic hydrogenation of the latter affords isomeric piperidine analogues. Alternatively, SmI₂-promoted reduction of tetrahydropyridines in the presence of acid also leads to intermediate α-aminoalkyl radicals that participate in inter- or intramolecular olefin addition reactions. Further manipulation of the lactone functionality in various ways gives access to a number of interesting derivatives based upon either a pyrrolidine or a piperidine structural motif. As a result, a high degree of structural diversity is obtained in a few steps starting from a common set of simple materials.

Full text of DOI:10.1021/jo0614487

Divergent Synthetic Strategy Leading to Structurally Diverse
Pyrrolidines and Piperidines from Common γ-Aminoalkyl
Butenolide and Aldehyde Precursors†
Jose´ M. Aurrecoechea,* Rube´n Suero, and Esther de Torres
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, UniVersidad del Pa´ıs Vasco,
Apartado 644, 48080 Bilbao, Spain
jm.aurrecoechea@ehu.es
ReceiVed July 12, 2006
Condensation between aldehydes and the secondary amino function of 5-(aminoalkyl)furan-2(5H)-ones,
obtained by the silyloxyfuran dienolate addition to imine-type derivatives, produces either aminoalkyl-
benzotriazoles or 1,2,3,4-tetrahydropyridines. The former can be reduced with SmI2 to generate
R-aminoalkyl radicals that are trapped by the R,â-unsaturated lactone moiety yielding substituted
pyrrolidines diastereoselectively, while catalytic hydrogenation of the latter affords isomeric piperidine
analogues. Alternatively, SmI2-promoted reduction of tetrahydropyridines in the presence of acid also
leads to intermediate R-aminoalkyl radicals that participate in inter- or intramolecular olefin addition
reactions. Further manipulation of the lactone functionality in various ways gives access to a number of
interesting derivatives based upon either a pyrrolidine or a piperidine structural motif. As a result, a high
degree of structural diversity is obtained in a few steps starting from a common set of simple materials.
SCHEME 1. Vinylogous Mannich Reaction of
Silyloxyfurans I
Introduction
The aminoalkyl-substituted furan-2(5H)-one substructure
present in amines IVa,b (Scheme 1) has attracted particular
attention not only for being present in natural products1 but also
for the synthetic applications of their derivatives, which have
recently found extensive use in the synthesis of natural
products.2 As indicated in Scheme 1, compounds IVa,b are
commonly accessible by Mannich-type reactions.
For synthetic applications, the formation of IV is often
followed at some stage by manipulation of the R,â-unsaturated
γ-lactone moiety, which may commonly undergo reduction,l,2f,g
oxidation,2a-e or nucleophilic conjugate addition2h reactions. On
the other hand, the corresponding conjugate radical additions3
to IV or derivatives thereof are unprecedented. It was initially
envisaged that the strategic combination of a vinylogous
Mannich reaction and an intramolecular addition of R-ami-
noalkyl radicals4 VII, derived from amines IVb and aldehydes
V through the intermediacy of benzotriazoles VI,5 would provide
a conveniently rapid and practical access to pyrrolofuranone
† Dedicated to the memory of Professor Marcial Moreno-Man˜as.
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46, 5795-5797. (b) Blanco, P.; Busque´, F.; de March, P.; Figueredo, M.;
Font, J.; Sanfeliu, E. Eur. J. Org. Chem. 2004, 48-53. (c) Salim, A. A.;
Garson, M. J.; Craik, D. J. J. Nat. Prod. 2004, 67, 54-57. (d) Honda, T.;
Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett. 2004, 6, 87-89. (e) Alibe´s,
R.; Ballbe´, M.; Busque´, F.; de March, P.; Elias, L.; Figueredo, M.; Font, J.
Org. Lett. 2004, 6, 1813-1816. (f) Ohsaki, A.; Ishiyama, H.; Yoneda, K.;
Kobayashi, J. Tetrahedron Lett. 2003, 44, 3097-3099. (g) Takayama, H.;
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10.1021/jo0614487 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/07/2006
J. Org. Chem. 2006, 71, 8767-8778
8767

Aurrecoechea et al.
SCHEME 2. Divergent Strategy for the Preparation of
3-Hydroxypyrrolidines and 3-Hydroxypiperidines from
Amines IV and Aldehydes V
derivatives IX (Scheme 2).6-9 Different combinations of readily
incorporated substituents R1, R2, and R3, along with various
manipulations of the lactone functionality in bicycles IX, would
then be expected to lead to structurally diverse 3-hydroxypyr-
rrolidines XI, as suggested in Scheme 2. During the course of
work directed to this end, it was found that, depending on
reaction conditions, condensation between IVb and V could be
directed either toward the formation of benzotriazole derivatives
VI or toward cyclic enamines X,10,11 and, therefore, the
corresponding synthesis of piperidines XII and XIII became
an additional goal of this work. Thus, similar to the preparation
of XI, manipulation of the lactone moiety could be expected to
provide 3-hydroxypiperidines XII, whereas the presence of an
enamine-type double bond in X would provide an opportunity
for the additional introduction of functionality at a piperidine
R-position, leading to XIII. In this manner, a divergent strategy
emerged that would give access to a range of structurally diverse
pyrrolidines and piperidines XI-XIII in a few steps starting
from common materials IVb and V (Scheme 2). Products IX-
XIII are worthy synthetic targets. Thus, the basic skeleton of
IX is present in natural products,12 besides serving as a precursor
of 3-azaprostaglandins, a type of 3-hydroxypyrrolidine with
potential in the treatment of glaucoma.13,14 The basic pyrrolidine-
diol and -aminoalcohol substructures of XI (X ) CH2OH, CH2-
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NHR4) are found in natural products with a wide range of
biological activities,15 while many other 3-hydroxy-pyrrolidines
and -piperidines are also found as structural components of
compounds with interesting biological profiles.16 This paper
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Gorgojo, J. M.; Saornil, C. J. Org. Chem. 2005, 70, 9640-9643.
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C. Y. H.; Bueno, M. A.; Rodrigues, A. Curr. Org. Chem. 2005, 9, 419-
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Yoshida, N.; Shiro, M.; Morita, H. J. Org. Chem. 2002, 67, 2283-2286.
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8768 J. Org. Chem., Vol. 71, No. 23, 2006

Synthetic Strategy for Pyrrolidines and Piperidines
SCHEME 3. Preparation of 5-Aminomethylbutenolide 4a
(7b/8b) diastereomeric ratio was obtained in the case of the
six-membered analogue. Acidic removal of the Boc-protecting
group afforded the free amines 9 and 10, which needed to be
handled with care. Thus, they have a tendency to epimerize,20
particularly in the absence of solvent, and this is also ac-
companied by gradual decomposition.21 Nevertheless, we have
been able to isolate pyrrolidine 9a in 84% yield and characterize
it as the partially epimerized material. On the other hand, amines
9b,c and 10b were best manipulated as a partially evaporated
CH2Cl2 solution obtained after workup of the mixture derived
from the deprotection step. As a consequence, yields for
subsequent reactions are always referred to Boc-protected
amines 7b,c and 8b as the starting point. Stereochemical
assignments for amines 7-10 relied on crystallographic data
previously reported for the Boc-derivatives 7a-c17a and were
further supported by independent spectroscopic studies per-
formed on their derived cyclization products described herein
(vide infra and Supporting Information).
a Reagents and conditions: (a) n-BuLi, MOMCI, THF, -78 °C f rt.
(b) TMSOF, TMSOTf, CH2Cl2, -78 °C. (c) TFA, CH2Cl2, 0 °C f rt.
SCHEME 4. Preparation of Cyclic Amines 9 and 10a
The SmI2-mediated one-electron reduction of condensation
adducts derived from aldehydes, secondary amines, and ben-
zotriazole4 has become a practical method for generation of
R-aminoalkyl radicals capable of radical cyclization, as shown
by the corresponding reports on the preparation of cyclopentyl-
amines,22a pyrrolidines,22b-e and piperidines.22f At the outset,
the possibility of applying this methodology using amines 4, 9,
or 10 raised some concerns. For example, in the R-aminoalkyl
radicals VII, the delocalization of the single electron into the
nitrogen lone pair would give some π character to the C-N
bond,23 and its cyclization into the bicyclic or tricyclic arrange-
ment (with formation of an endocyclic C-N bond) could be
hindered as a result of strain development. Another point of
concern was stereocontrol in the formation of pyrrolidines of
type IX. While the relative configuration at C-3 and C-4 (5-
hexenyl radical numbering) is already set during preparation
of the amines (vide supra) and a cis-fusion between the
pyrrolidine and lactone rings is readily expected based on
thermodynamic considerations, control of the 1,5-relative ster-
eochemistry would be defined in the radical cyclization step.
Related R-aminoalkyl radical cyclizations have been shown to
give preferentially 1,5-syn relationships in agreement with the
Beckwith-Houk model;24 however, in the present case, this
would lead to apparently severely congested polysubstituted all-
syn bicyclic or tricyclic systems.
a Reagents and conditions: (a) t-Butyldimethylsilyloxyfuran (TBSOF),
TMSOTf, CH2Cl2, -80 °C. (b) TMSOTf, CH2Cl2, -25 f -5 °C (for 9a)
or TFA, CH2Cl2, 0 °C f rt (for 9b,c, and 10b).
Results and Discussion
(A) Radical Cyclizations. Amines of general structure IVb
were prepared using the vinylogous Mannich reaction2 between
silyloxyfurans of type I and Boc-protected R-alkoxyamines II
(P ) Boc), followed by hydrolysis of the N-protecting group
(Schemes 1, 3, and 4). Thus, coupling between 2 and trimeth-
ylsilyloxyfuran (TMSOF) was carried out using trimethylsilyl-
triflate (TMSOTf) as a promoter resulting in the formation of
the corresponding 5-(aminomethyl)furan-2(5H)-one, 3, that was
isolated in good yields (Scheme 3). Formation of a regioisomer
5 was also observed in this reaction as a result of competitive
R-alkylation.17 Deprotection under acidic conditions afforded
the free amine 4 in quantitative yield from 3. A more direct
preparation of amine 4 has been reported starting from TMSOF
and a triazine derivative acting as a synthetic equivalent of
benzylmethyleneamine.18 However, the alternative indirect route
depicted in Scheme 3 was preferred because it allowed us to
conveniently store multigram quantities of the more stable
N-Boc protected derivative 3 and deprotection afforded an
essentially pure crude free amine 4 that could be used without
purification.
The possibility of preparing bicyclic and tricyclic systems
of type 13 was explored first. In that event, treatment of 4, 9,
(20) For a related report see ref 1b.
(21) For a report describing spontaneous deamination upon formation
of 5-aminoalkylbutenolides, see: Piper, S.; Risch, N. ARKIVOC 2003, 86-
92.
Cyclic protected amines 7 and 8 were similarly obtained
following a literature procedure17a (Scheme 4).19 A high
diastereoselectivity favoring isomer 7 was observed, which is
in line with previous reports.17a Thus, five- and seven-membered
protected amines 7a and 7c, respectively, were isolated as single
diastereoisomers after column chromatography, whereas a 5:1
(22) (a) Aurrecoechea, J. M.; Lo´pez, B.; Ferna´ndez, A.; Arrieta, A.;
Coss´ıo, F. P. J. Org. Chem. 1997, 62, 1125-1135. (b) Aurrecoechea, J.
M.; Ferna´ndez, A.; Gorgojo, J. M.; Saornil, C. Tetrahedron 1999, 55, 7345-
7362. (c) Katritzky, A. R.; Feng, D. M.; Qi, M.; Aurrecoechea, J. M.; Suero,
R.; Aurrekoetxea, N. J. Org. Chem. 1999, 64, 3335-3338. (d) Suero, R.;
Gorgojo, J. M.; Aurrecoechea, J. M. Tetrahedron 2002, 58, 6211-6221.
(e) Bustos, F.; Gorgojo, J. M.; Suero, R.; Aurrecoechea, J. M. Tetrahedron
2002, 58, 6837-6842. (f) Katritzky, A. R.; Luo, Z.; Fang, Y.; Feng, D.;
Ghiviriga, I. J. Chem. Soc., Perkin Trans. 2 2000, 1375-1380.
(23) (a) Schubert, S.; Renaud, P.; Carrupt, P. A.; Schenk, K. HelV. Chim.
Acta 1993, 76, 2473-2489. (b) Armstrong, D. A.; Rauk, A.; Yu, D. K. J.
Am. Chem. Soc. 1993, 115, 666-673. (c) Wayner, D. D. M.; Clark, K. B.;
Rauk, A.; Yu, D.; Armstrong, D. A. J. Am. Chem. Soc. 1997, 119, 8925-
8932. (d) Jansen, T. L.; Trabjerg, I.; Rettrup, S.; Pagsberg, P.; Sillesen, A.
Acta Chem. Scand. 1999, 53, 1054-1058.
(17) For other cases of competing R-alkylation, see: (a) de Oliveira, M.
C. F.; Silva-Santos, L.; Pilli, L. A. Tetrahedron Lett. 2001, 42, 6995-
6997. (b) Ref 2h.
(18) Ha, H.-J.; Kang, K.-H.; Ahn, Y.-G.; Oh, S.-J. Heterocycles 1997,
45, 277-286.
(19) For other reported preparations of these compounds, see: (a) Suh,
Y.-G.; Kim, S.-H.; Jung, J.-K.; Shing, D.-Y. Tetrahedron Lett. 2002, 43,
3165-3167. (b) Pichon, M.; Figade`re, B.; Cave, A. Tetrahedron Lett. 1996,
37, 7963-7966.
(24) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941. (b) Spellmeyer, D. C.; Houk, K. M. J. Org. Chem. 1987, 52, 959-
974.
J. Org. Chem, Vol. 71, No. 23, 2006 8769

Aurrecoechea et al.
SCHEME 5. Preparation of Pyrrolofuranones 13 from 4, 9,
or 10 and a Formaldehyde Equivalenta
SCHEME 6. Preparation of Pyrrolofuranones 16 from
Amine 4 and Aldehydesa
a Reagents and conditions: (a) RCHO, Bt-H, 4 Å MS, CH2Cl2, rt. (b)
SmI2, t-BuOH, THF, -78 °C f rt.
a Reagents and conditions: (a) N-Hydroxymethylbenzotriazole, 4 Å MS,
CH2Cl2, rt. (b) SmI2, t-BuOH, THF, -78 °C f rt.
TABLE 2. Preparation of Pyrrolofuranones 16 from Amine 4 and
Aldehydes
TABLE 1. Preparation of Bicyclic Pyrrolidines 13
major diastereoisomer
16
X
Y
yield (dr)a
1
16a
16b
16b
16c
16d
16e
n-Pr
H
71 (94:6)b
2
(CH2)2Arc
(CH2)2Arc
(CH2)4CO2Me
i-Pr
H
H
H
H
Ph
47d
3e
4
84 (91:9)
66 (94:6)f,g
84 (83:17)
44 (61:39)g
5
6
H
a Yield (%) of isolated purified products. Unless otherwise indicated,
diastereoisomer ratios were measured in the crude products. b Tetrahydropy-
ridine 17a was isolated in 6% yield. c Ar ) 3,4-dimethoxyphenyl. d Tet-
rahydropyridine 17b was isolated in 9% yield. e Benzene was used as the
solvent in the formation of adduct 14. f Tetrahydropyridine 17c was isolated
in 6% yield. g Isomer ratio determined from the isolated purified products.
NMR spectra of the crude benzotriazole adducts that already
showed signals associated to the other epimer.
The same cyclization conditions were applied successfully
to benzotriazole adducts derived from aldehydes other than
formaldehyde. Thus, starting from amine 4, the corresponding
pyrrolofuranones 16 were obtained in a process which, overall,
represented the intramolecular aminoalkylation of an R,â-
unsaturated lactone (Scheme 6, Table 2). The reaction proceeded
with both good yields and good stereoselectivities for aliphatic
aldehydes, while benzaldehyde gave poorer results (entry 6).
The use of aldehydes containing an unsubstituted methylene
unit R to the carbonyl group (entries 1-4), in addition to the
expected pyrrolidines 16, led to the isolation of small amounts
(6-9%) of tetrahydropyridines 17. These six-membered side
a Isolated yield (%) of pure products for three steps starting from 3, 7,
or 8. b The corresponding product (13b) was formed, as determined by 1H
NMR, but could not be conveniently isolated and purified. c Yield was
corrected for epimerization.
or 10 with commercial N-hydroxymethylbenzotriazole (a sur-
rogate for benzotriazole and formaldehyde) afforded the cor-
responding condensation adducts 11, which were directly treated
with excess SmI2/t-BuOH to afford pyrrolidine lactones 13
(Scheme 5 and Table 1) in good overall yields, which are given
for three steps starting from N-Boc derivatives 3, 7, or 8.
Therefore, starting from a furanone dienolate of type I, the
combination of a vinylogous Mannich reaction and SmI2-
promoted intramolecular conjugate aminomethylation gives
ready access to fused bicyclic or tricyclic systems with remark-
able ease. As expected, only cis-fused lactones were obtained,
and this was confirmed by the observation of strong NOEs
between the lactone bridgehead protons. The same technique
served to confirm the relative configuration of the stereogenic
center adjacent to nitrogen in tricyclic 13c-e (see Supporting
Information). The reaction of piperidine 9b afforded, besides
13c, small amounts of a minor product that was identified as
epimer 13d on the basis of spectroscopic data. Product 13d
arises from epimerization of the starting amine 9b, the extent
products originated during formation of benzotriazole adducts
14, as shown by the presence of the characteristic enamine
proton resonance at δ ∼ 6.0 in the 1H NMR spectrum of crude
adducts 14. The generation of enamines 17 from amine 4 and
aldehydes was found to be dependent on the solvent used in
the condensation step leading to 14. Thus, CH2Cl2 as solvent
promoted their formation, whereas benzene largely suppressed
it, as shown by comparison between entry 2 and entry 3 (Table
2). Incidentally, the improved isolated yield of 16b in entry 3
is mainly due to a notably simplified chromatographic purifica-
tion in the absence of 17b. Details on the independent formation
of 17 from 4 and aldehydes will be discussed later on in this
paper (vide infra).
1
of which was estimated to be about 10% from the H NMR
spectrum of the crude cyclization mixture. The identity of 13d
was further confirmed by starting the condensation/cyclization
sequence from epimeric amine 10b. In this manner, 13d was
obtained (49%) along with 13c (16%), confirming the facile
epimerization of these amines, as previously noted in the
literature.20 That epimerization was taking place before cycliza-
Pyrrolofuranones 16a-d derived from aliphatic aldehydes
formed with good levels of stereoselectivity (Table 2). Improved
1
tion was corroborated by inspection of the corresponding H
8770 J. Org. Chem., Vol. 71, No. 23, 2006

Synthetic Strategy for Pyrrolidines and Piperidines
SCHEME 7. Preparation of a Tricyclic Pyrrolidine with
Four Contiguous Stereocentersa
control of the 1,5-relative stereochemistry (5-hexenyl radical
numbering) was observed in these reactions when compared to
related cyclizations starting either from the all-carbon substituted
hex-5-enyl radical25 or from the simple acyclic 2-azahex-5-enyl
radicals22b analogously activated with EWG on the alkene
moiety. The radical ring closure produced only two pyrrolidine
products that were diastereomeric at the newly created stereo-
genic center adjacent to N; in addition, a cis-ring fusion was
observed in all cases, as expected. The major diastereoisomers
of products 16a-d derived from aliphatic aldehydes (X ) alkyl)
presented in these cases an all-syn relationship between the
pyrrolidine methine hydrogens. Therefore, this reaction succeeds
in producing a rather congested stereoisomer in an overall
preparatively useful yield, and this stereochemical outcome can
be rationalized within the framework of the Beckwith-Houk
model for radical cyclizations.24 According to this model, the
major product derived from radical 15 in a kinetically controlled
cyclization would form through a chairlike transition state of
type 18 where the R substituent occupies a pseudo-equatorial
a Reagents and conditions: (a) Bt-H, 4 Å MS, CH2Cl2, rt. (b) SmI2,
t-BuOH, THF, -78 °C f rt.
SCHEME 8. Reaction of Amine 9c with Butyraldehydea
a Reagents and conditions: (a) n-PrCHO, Bt-H, 4 Å MS, CH2Cl2, rt.
(b) SmI2, t-BuOH, THF, -78° f rt.
SCHEME 9. Preparation of Tetrahydropyridines 17 from
Amines 4 or 9 and Aldehydesa
position. As noticed previously,22e for a 2-azahex-5-enyl radical,
this arrangement would be expected to place the N-substituent
in a pseudo-axial position in order to allow for some interaction
between the unpaired electron and the N lone pair during
cyclization. Therefore, further steric congestion would be
expected involving the N-Bn unit, making the observed stere-
ochemistry all the more remarkable. In apparent support of the
model, radicals 15 derived from aldehydes with linear aliphatic
chains gave the highest stereoselectivities (up to ∼16:1, entries
1-4), whereas R-branching resulted in a somewhat reduced
diastereoisomer ratio (entry 5), and this effect was more
noticeable for R ) Ph (entry 6), derived from an aromatic
aldehyde, which produced a major isomer with a 1,5-anti
relationship (5-hexenyl radical numbering). However, it is not
clear whether in this latter case the stereochemical preference
results from kinetic control or is, rather, the consequence of
the reversible cyclization of a particularly stable benzylic
R-aminoalkyl radical.26-28
a Reagents and conditions: 4 Å MS, CH2Cl2, rt.
7). This stereochemical assignment is in line with the results
reported above and was supported by NOE studies (see
Supporting Information).
In contrast, only a complex mixture of products was obtained
when butyraldehyde was used in combination with piperidine
9b, and the similar use of azepane 9c (Scheme 8) afforded a
mixture of tetrahydropyridine 17g and its reduction product 20g
in low yields instead of the expected pyrrolidine product. While
tetrahydropyridine 17g was a reasonable product given the above
precedents, the formation of 20g was intriguing, and this reaction
was investigated further. The corresponding results will be
discussed below in the context of the preparation and applica-
tions of tetrahydropyridine derivatives.
To summarize this part of the work, the intramolecular
aminoalkylation of γ-butenolides can be effected through the
intermediacy of R-aminoalkyl radicals derived from amines IVb
and aldehydes V, and this provides a viable strategy to prepare
pyrrolofuranones of general structure IX with very good control
of the relative stereochemistry of up to four contiguous
stereogenic centers. In terms of scope, the use of aldehydes
RCHO where R * H appears to be restricted to amines IVb
unsubstituted at C-2 (R2 ) H), whereas the use of formaldehyde
is of a more general application.
The similar radical cyclizations starting from cyclic amine
substrates 9 were much less successful. Thus, starting from
pyrrolidine 9a and butyraldehyde, application of the above
sequence afforded the corresponding cyclized tricyclic product
19 as a single diastereoisomer containing four contiguous
stereocenters, albeit in only moderate chemical yield (Scheme
(25) Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62, 7418-
7429.
(B) Formation of Cyclic Enamines. Tetrahydropyridines 17
(Scheme 9) are interesting compounds containing a basic
bicyclic enamine substructure that can be found in naturally
occurring alkaloids of the Corynanthe type.29 Results discussed
above indicated formation of 17 to be a facile process already
(26) The trans-selectivity observed in cyclizations of benzylic radicals
has usually been explained by postulating a reversible cyclization22b,27 so
that the product ratios would be a reflection of their thermodynamic
stabilities. However, this explanation has been challenged, and some
experimental evidence for a kinetic origin of the product distribution, based
on dilution studies, has been alternatively offered.28
(27) (a) Walling, C.; Cioffari, A. J. Am. Chem. Soc. 1972, 94, 6064-
6069. (b) Taber, D. F.; Wang, Y.; Pahutski, T. F. J. J. Org. Chem. 2000,
65, 3861-3863.
(29) (a) Takayama, H.; Kurihara, M.; Kitajima, M.; Said, I. M.; Aimi,
N. J. Org. Chem. 1999, 64, 1772-1773. (b) Takayama, H.; Kurihara, M.;
Kitajima, M.; Said, I. M.; Aimi, N. Tetrahedron 2000, 56, 3145-3151.
(28) Miranda, L. D.; Zard, S. Z. Chem. Commun. 2001, 1068-1069.
J. Org. Chem, Vol. 71, No. 23, 2006 8771

Aurrecoechea et al.
TABLE 3. Preparation of Tetrahydropyridines 17 from Amines 4
or 9 and Aldehydes
SCHEME 10. Mechanistic Proposals for Formation and
SmI2-Promoted Reduction of 17
4, 9
R1
R2
R3
17 (yield)a
4
4
4
4
9a
9b
9c
Bn
Bn
Bn
Bn
H
H
H
H
Et
17a (73)
17b (100)c
17c (78)
CH2Arb
(CH2)3CO2Me
(CH2)2CHdCHYd
17d (81)e
17e (42)
(CH2)3
(CH2)4
(CH2)5
Et
Et
Et
17f (42)f,g
17g (68)e,f
a Percent yield (%) of isolated, purified product. b Ar ) 3, 4-dimethox-
yphenyl. c Yield of crude product. d (E)-Isomer. Y ) CO2Et. e Prepared
under refluxing conditions. f Two-step yield starting from N-Boc derivatives
7b or 7c. g Corrected for epimerization.
at room temperature. Furthermore, subsequent manipulation of
the functionality present in 17 would allow the rapid synthesis
of structurally diversified polysubstituted piperidine derivatives
from readily available amine and aldehyde building blocks.
Therefore, the condensation between amines 4 or 9 and R-unsub-
stituted aldehydes was studied as a new entry into the synthesis
of hydroxypiperidine derivatives under very mild reaction
conditions.10 Related direct condensations leading to 1,2,3,4-
tetrahydropyridine formation via spirocyclization have been
described starting from 3-(aminoethyl)cyclohex-2-enones and
arylacetaldehydes under harsh conditions;30 more recently, we
have reported an application to alkaloid synthesis using a simpler
acyclic amine under refluxing conditions.11 In the present case,
it was found that by using amines 4 or 9 and representative
aldehydes, tetrahydropyridines 17 were produced in good yields
as single stereoisomers under milder reaction conditions (Scheme
9, Table 3). As expected, cis-fused lactones were formed in all
cases. These compounds were somewhat unstable to chromato-
graphic conditions, and some mass loss was observed. Thus,
the low yield of enamine 17e appears to be associated to its
chromatographic instability, as suggested by the substantially
improved yield of its derived piperidine obtained by catalytic
hydrogenation of the crude enamine product (vide infra). The
preparation of enamine 17f, on the other hand, was complicated
by partial epimerization (about 10%) of the starting amine 9b
(vide supra), and the corresponding epimeric tetrahydropyridine
product had to be separated by column chromatography,
similarly resulting in a diminished yield.
of formation of 17 via intermolecular enamine conjugate addi-
tion, we treated amine 4 with the enamine derived from butanal
and piperidine.34 After 16 h at room temperature, only trace
amounts of 17a had formed, if at all, in a very complex reac-
tion mixture, probably indicating that formation of the key C-C
bond of 17 takes place intramolecularly. This conclusion appears
to be further supported by the efficient formation of 17d (Table
3) from an aldehyde containing an R,â-unsaturated carbonyl
unit, a functionality that would have been expected to interfere
had the conjugate addition step taken place intermolecularly.
As mentioned above, the formation of 17g from azepane 9c,
butyraldehyde, and benzotriazole was examined in more detail.
Thus, the 1H NMR spectrum of the crude condensation product
revealed the presence of free benzotriazole together with some
tetrahydropyridine 17g and a product tentatively assigned the
structure 23g [R1 and R2 ) (CH2)5; R3 ) Et in Scheme 10b].
Attempted separation of the mixture by flash chromatography
afforded only 17g in overall yields that ranged from 64 to 84%
depending on the particular run. The identity of the benzotriazole
derivative 23g was established after mixing 17g with benzo-
triazole in CDCl3 at room temperature, whereupon formation
The ease of formation of enamines 17 is remarkable. Presum-
ably, acyclic enamines 22 are involved (Scheme 10a), and these
are accessed from the aldehyde and secondary amine starting
materials either directly, as in Scheme 9, or, alternatively, by par-
tial elimination31 of adducts 21 when condensations are carried
out in the presence of benzotriazole (Scheme 10a). Ring closure
of 22 to cyclic enamine 17 has precedent in the intramolecular
enamine endocyclic addition to an R,â-unsaturated carbonyl
derivative found in a key step of the synthesis of karachine from
berberine32 and in some related reactions starting from activated
enaminone-type substrates.33 In any case, to check the possibility
1
of a 17g/23g mixture was immediately observed by H NMR,
in an approximately 1:1 ratio that did not change over time.
This behavior appears to be general,35a as treatment of tetrahy-
dropyridine 17a with benzotriazole also led to the formation of
a similar mixture where diastereomeric adducts 23a (R1 ) Bn;
R2 ) H; R3 ) Et in Scheme 10b) presented characteristic sets
of resonances at δ 8.08-8.14 and δ 5.28-5.74 corresponding
(30) Grewe, R.; Arpe, H. J.; Petersen, E. Liebigs Ann. Chem. 1962, 653,
97-104.
(31) The preparation of enamines from simple R-(dialkylamino)alkyl-
benzotriazoles upon treatment with NaH has been reported: (a) Katritzky,
A. R.; Long, Q. H.; Lue, P.; Jozwiak, A. Tetrahedron 1990, 46, 8153-
8160. (b) Katritzky, A. R.; Long, Q. H.; Lue, P. Tetrahedron Lett. 1991,
32, 3597-3600.
(32) Stevens, R. V.; Pruitt, J. R. J. Chem. Soc., Chem. Commun.
1983, 1425.
(33) Kucklaender, U.; Ulmer, P.; Zerta, G. Chem. Ber. 1989, 122, 1493-
1498.
(34) Norman, M. H.; Heathcock, C. H. J. Org. Chem. 1988, 53,
3370-3371.
8772 J. Org. Chem., Vol. 71, No. 23, 2006

Synthetic Strategy for Pyrrolidines and Piperidines
to benzotriazole ring and aminal-type protons, respectively.35b
An additional interesting observation was made when a presum-
ably similar mixture of 17g and 23g, obtained from 17g and
benzotriazole in THF, was treated with SmI2/t-BuOH. A slow
reaction took place that eventually led, after 14 days, to the
isolation of piperidine 20g [R1 and R2 ) (CH2)5; R3 ) Et in
Scheme 10b; see also Scheme 8] in a 46% yield. The formation
of 20g implies the intermediacy of an R-aminoalkyl radical
24,4,22 which is further reduced to the organosamarium 25 or,
alternatively, abstracts a H atom from the solvent (Scheme 10b).
This outcome was somewhat surprising since, in the absence
of efficient radical traps (e.g., electron-deficient alkenes), 24
would instead be expected to dimerize to afford a vicinal
diamine.36 It is likely that steric congestion around the radical
center slows down dimerization so that other processes (e.g.,
H abstraction or reduction) become competitive. While this
reaction does not have preparative value, it opens, nevertheless,
the very interesting possibility of further building up of
molecular complexity by combining condensations between
amines of type 4 or 9 and aldehydes with radical chemistry at
the piperidine 2-position through R-aminoalkyl radicals derived
from cyclic enamines 17. The application of these ideas will
be demonstrated in the section that follows.
SCHEME 11. Intermolecular Radical Functionalization of
Enamine 17aa
(C) Derivatization of Cyclization Products. The possibility
of generating synthetically useful R-aminoalkyl radicals from
enamines 17 was explored with ethyl derivative 17a. Thus,
treatment of 17a with excess benzotriazole and SmI2, at room
temperature, in the presence of acrylonitrile, afforded coupling
product 26a, accompanied by two other diastereoisomers, in
good overall yield (81%; Scheme 11). The relative configuration
of the major diastereoisomer 26a was assigned on the basis of
spectroscopic studies (see Supporting Information) and is seen
to follow the trend observed in the formation of piperidine 20g
(Scheme 8), with enamine protonation taking place from the
less hindered side of the double bond. The resulting stereogenic
center then directs the subsequent radical-alkene coupling so
that the new C-C bond is preferentially formed anti to the Et
substituent. The formation of 26 is readily interpreted in terms
of formation of an iminium ion 27 (in equilibrium with a
benzotriazole adduct 23a; see Scheme 10)35b upon enamine
protonation, followed by one-electron transfer, trapping of the
resulting nucleophilic R-aminoalkyl radical 28 with the electron-
deficient olefin, further reduction to an enolate-type intermediate,
and protonation. Lowering the temperature with benzotriazole
as the protonating agent resulted in sluggish reactions. On the
other hand, the coupling reaction could alternatively be per-
formed at lower temperatures using TFA to first generate cation
27, followed by treatment with SmI2, acrylonitrile, and t-butanol
from -78 °C to room temperature. Formation of coupling
product 26 under these conditions confirmed the proposed
reaction pathway, and, furthermore, a better stereoselectivity
(∼87:13 dr) was observed. However, about 50% of the starting
enamine was recovered in this case. It is likely that intermediate
R-aminoalkyl radical 28 partially undergoes â-H elimination37
to regenerate enamine 17a. Apparently, in the presence of an
a Reagents and conditions: (a) SmI2, benzotriazole, acrylonitrile, THF,
rt.
excess of a protonating agent (e.g., benzotriazole), effective
recycling of enamine 17a back to iminium ion 27 takes place,
eventually resulting in complete reactions. The use of excess
TFA also led to complete consumption of the starting material;
however, the isolated yields of 26 never exceeded 50%, and
reactions were noticeably less clean. In any case, the overall
reaction is unusual in that it achieves the stereoselective coupling
of an electron-deficient alkene to the enamine R-position by
performing a double polarity inversion, first by conversion of
a nucleophilic enamine into an electron-deficient iminium ion
and then by reduction of this to a nucleophilic R-aminoalkyl
radical. This also appears to represent the first example of the
use of an enamine as a starting material to perform an
R-aminoradical C-C coupling.38,39
A suitably modified tetrahydropyridine 17d was used to
exemplify the possibility of doing an analogous intramolecular
coupling to an electron-deficient alkene (Scheme 12). As
previously shown in Scheme 9 and Table 3, tetrahydropyridine
17d was available in good yield by condensation between amine
4 and the functionalized aldehyde ethyl (E)-7-oxohept-2-
enoate.22a,40 Generation of an R-aminoalkyl radical 31 and
cyclization were triggered by simultaneous treatment with
(38) The generation of R-aminoalkyl radicals from enamines by addition
of electrophilic radicals has been reported: (a) Renaud, P. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 433-434. (b) Renaud, P.; Bjo¨rup, P.; Carrupt, P.
A.; Schenk, K.; Schubert, S. Synlett 1992, 211-213. (c) Schubert, S.;
Renaud, P.; Carrupt, P. A.; Schenk, K. HelV. Chim. Acta 1993, 76, 2473-
2489.
(39) A related SmI2-mediated intermolecular coupling with electron-
deficient alkenes has been reported using nitrones as starting materials: (a)
Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem., Int. Ed. 2003,
42, 2265-2268. (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229-
231. (c) Masson, G.; Zeghida, W.; Cividino, P.; Py, S.; Vallee, Y. Synlett
2003, 1527-1529. (d) Desvergnes, S.; Py, S.; Valle´e, Y. J. Org. Chem.
2005, 70, 1459-1462. (e) Cardona, F.; Goti, A. Angew. Chem., Int. Ed.
2005, 44, 7832-7835.
(35) (a) The addition of benzotriazole to enamines has been reported:
Katritzky, A. R.; Jurczyk, S.; Rachwal, B.; Rachwal, S.; Shcherbakova, I.;
Yannakopoulou, K. Synthesis 1992, 1295-1298. (b) Katritzky, A. R.;
Yannakapoulou, K.; Kuzmierkiewicz, W.; Aurrecoechea, J. M.; Palenik,
G. J.; Koziol, A. E.; Szczesniak, M.; Skarjune, R. J. Chem. Soc., Perkin
Trans. 1 1987, 2673-2679.
(36) Aurrecoechea, J. M.; Ferna´ndez-Acebes, A. Tetrahedron Lett. 1992,
33, 4763-4766.
(40) Nishida, A.; Kawahara, N.; Nishida, M.; Yonemitsu, O. Tetrahedron
1996, 52, 9713-9734.
(37) Ripa, L.; Hallberg, A. J. Org. Chem. 1998, 63, 84-91.
J. Org. Chem, Vol. 71, No. 23, 2006 8773

Aurrecoechea et al.
SCHEME 12. Intramolecular Radical Cyclization from an
Enamine Precursora
product, with formation of ester 33, took place leading to poor
results in terms of yields and stereoselectivity. Conducting the
reaction at 60 psi largely avoided formation of 33 (3%), and
20f was isolated in excellent yield as a single stereoisomer
(Table 4).
The lactone moiety fused to either a pyrrolidine or a
piperidine offered further opportunities for structural diversifica-
tion (Scheme 14). For example, LAH reduction of 16a and 20a
at 0 and -78 °C, respectively, led to the corresponding diols
34a,b. Alternatively, performing the reduction of 16a at -78
°C allowed the stereocontrolled preparation of lactol 35,
containing functionality that has participated in Wittig-type
reactions leading to biologically active 2-azaprostaglandins from
closely related analogues.13,14 Lactol 35 can be alternatively
elaborated into aminals 36 and then aminoalcohol 37 in high
yields. Finally, lactone aminolysis under mild conditions41
provided piperidine-based amides 38a and 38b in excellent
yields (Scheme 14). A similar transformation was attempted
starting from pyrrolidine 16a; however, even after prolonged
reaction times, conversions were only in the order of 50%, and
upon attempted isolation, the presumed amide product reverted
back to the starting lactone.
a Reagents and conditions: (a) SmI2, benzotriazole, THF, rt.
SCHEME 13. Catalytic Hydrogenation of Enamines 17a
Conclusion. The strategic combination of a vinylogous
Mannich reaction and either a radical- or an enamine-type ring
closure provides expeditious entries into pyrrolidine- and
piperidine-type structures, respectively, from a common set of
simple amine and aldehyde building blocks. Structural diversity
can be directly incorporated at three ring positions based on
the choice of starting materials while subsequent manipulation
of the lactone and enamine functionalities in the cyclization
products introduces further diversification via either conventional
procedures or novel radical-mediated enamine-alkene coupling.
The compounds, thus obtained, are related to materials with
interesting biological profiles.
a Reagents and conditions: (a) H2, 10% Pd/C, EtOH, rt.
TABLE 4. Preparation of Piperidines 20 from Enamines 17
17
R1
R2
R3
20
yielda (dr)
17a
17b
17c
17e
17f
17g
Bn
Bn
Bn
(CH2)3
(CH2)4
(CH2)5
H
H
H
Et
20a
20b
20c
20e
20f
20g
77b (90:10)
75b,d (90:10)
95 (94:6)
62b (92:8)
88f,g
CH2Arc
(CH2)3Ye
Et
Et
Et
94 (99:1)
a Percent yield (%) of isolated, purified product. b Yield for two steps
starting from amine 4 or 9a, as appropriate. c Ar ) 3,4-dimethoxyphenyl.
d Yield of isolated major isomer alone. e Y ) CO2Me. f Hydrogenation
conducted at 60 psi. Also isolated was ethyl ester 33 (3%). g A single isomer
was isolated.
Experimental Section
General Reductive Cyclization Procedures. In a typical
experiment, a mixture of amine 4 or 9a (1.00 mmol), the appropriate
aldehyde (1.00 mmol), benzotriazole (0.119 g, 1.00 mmol), and 4
Å molecular sieves (0.50 g) in CH2Cl2 (or THF or benzene, as
indicated; 12 mL) was stirred at rt for 14 h. Alternatively,
N-(hydroxymethyl)benzotriazole (0.149 g, 1.00 mmol) was used
as a substitute for formaldehyde and benzotriazole. In any case,
the resulting suspension was filtered over Celite, the solid residue
was washed with CH2Cl2 (2 × 10 mL), and the solution was
evaporated to dryness to yield the crude adduct 11 or 14. Without
further manipulation the adduct was dissolved with t-BuOH (0.19
mL, 2.00 mmol) in THF (20 mL), and the resulting solution was
added dropwise over 30 min to a solution of SmI2 (ca. 0.1 M in
THF, 31 mL, 3.08 mmol) at -78 °C. The mixture was stirred at
-78 °C for an additional 30 min and allowed to warm to room
temperature. After further stirring for 2 h, the reaction mixture was
quenched with a 1:1 mixture of saturated K2CO3 solution and water
(50 mL). After separation, the aqueous layer was extracted with
EtOAc (3 × 50 mL), and the combined organic extracts were
washed with brine (20 mL) and dried (Na2SO4). The residue after
evaporation was purified by flash column chromatography in silica
gel saturated with Et3N to yield pyrrolidines 13, 16, and 19 as oils.
For reactions that employed amines 9b,c or 10b, the following
integrated procedure, starting from carbamates 7b,c, or 8b, was
used: In a typical experiment, TFA (1.31 mL, 17.0 mmol) was
benzotriazole and SmI2 at room temperature, as described above
for the intermolecular coupling. This resulted in formation of
the expected tricyclic product 32, that was obtained in good
yield (Scheme 12). Therefore, the partial goal of increasing
structural complexity considerably, in just two steps, is readily
achieved with this simple reaction sequence, but for synthetic
applications, the very low observed diastereoselectivity will
diminish the appeal of this novel procedure.
Cyclic products of general types IX and X (see Scheme 2),
besides being variable at R1, R2, and R3, contain functionality
that offered different possibilities to introduce structural diversity
around the pyrrolidine and tetrahydropyridine core. For example,
tetrahydropyridines 17 turned out to be excellent substrates for
the stereocontrolled preparation of substituted piperidines under
catalytic hydrogenation conditions. Thus, in all cases, polysub-
stituted piperidines 20 were obtained in excellent yields (Scheme
13, Table 4). Some enamines (17a,b,e) were used in a crude
form, and this proved advantageous as reflected by overall two-
step yields of 20a,b,e (Table 4) that were comparable or even
higher than those of the purified enamines. In general, enamines
17 underwent efficient hydrogenation under a 1 atm hydrogen
pressure. However, in the case of 17f, the reaction was sluggish,
and competitive lactone ring-opening of the hydrogenated major
(41) Liu, W.; Xu, D. D.; Repic, O.; Blacklock, T. J. Tetrahedron Lett.
2001, 42, 2439-2441.
8774 J. Org. Chem., Vol. 71, No. 23, 2006

Synthetic Strategy for Pyrrolidines and Piperidines
SCHEME 14. Lactone Transformations in Cyclization Productsa
a Reagents and conditions: (a) LAH, THF, 0 °C (for 34a). (b) LAH, THF, -78 °C (for 34b and 35). (c) RNH2, NaBH3CN, ZnCl2, MeOH, rt. (d) LAH,
THF, 0 °C f rt. (e) RNH2, sodium 2-ethylhexanoate, THF, rt.
added dropwise over a solution of protected amine 7b,c, or 8b (1.00
mmol) in CH2Cl2 (12 mL) at 0 °C. After stirring for 15 min, the
reaction mixture was allowed to reach room temperature and stirred
further 90 min. The solution was washed with saturated K2CO3
solution (10 mL), and the aqueous phase was extracted with CH2-
Cl2 (2 × 10 mL). The combined organic layers were washed with
brine (5 mL), and dried (MgSO4). The solvent was partially
evaporated to an approximate volume of 12 mL, and the resulting
solution of amine 9b,c, or 8b in CH2Cl2 was used according to the
general reductive cyclization procedure described above. Structural
information, yields, and diastereomeric ratios of all compounds
prepared according to these procedures are collected in Schemes
5-7 and Tables 1 and 2. Purification and separation details, as
well as characterization data, are provided in the Supporting
Information.
was added dropwise to a solution of 17a (0.083 g, 0.32 mmol),
benzotriazole (0.114 g, 0.96 mmol), and acrylonitrile (42 µL, 0.64
mmol) in THF (1 mL) at room temperature at such a rate as to
allow for the disappearance of the SmI2 characteristic blue color
before the next drop was added. The addition was continued until
the blue color persisted (at that point approximately 8.8 mL, 2.8
equiv, had been consumed). The reaction mixture was poured over
a saturated K
2CO3 solution (15 mL). After separation, the aqueous
layer was extracted with EtOAc (3 × 15 mL), and the combined
organic layers were washed with brine (6 mL) and dried (Na2SO4).
The residue after evaporation was purified by flash column
chromatography (silica gel saturated with Et3N, 50:48:2 hexanes/
EtOAc/Et3N) to yield 26 (81 mg, 81%) as a 17:68:15 diastereomeric
mixture. The isomers were separated by HPLC (µ-Bondapak-NH2,
10 µ, 19 mm ×15 cm; 65:35 hexanes/EtOAc; 10 mL/min). Data
1
General Procedures for Tetrahydropyridine Formation. In
a typical experiment, a mixture of amine 4 or 9a (1.00 mmol), the
appropriate aldehyde (1.00 mmol), and 4 Å molecular sieves (2.00
g) in CH2Cl2 (12 mL) was stirred at room temperature for 14 h.
The solid was filtered out and washed with CH2Cl2 (3 × 5 mL).
The crude after solvent evaporation was elaborated, as indicated
in the Supporting Information for the individual cases, to afford
tetrahydropyridines 17. For reactions that employed amines 9b or
9c, the following integrated procedure, starting from protected
amines 7b or 7c, was used: In a typical experiment, TFA (1.31
mL, 17.0 mmol) was added dropwise over a solution of protected
amine 7b or 7c (1.00 mmol) in CH2Cl2 (12 mL) at 0 °C. After
stirring for 15 min, the reaction mixture was allowed to reach room
temperature and stirred further for 90 min. The solution was washed
with saturated K2CO3 solution (10 mL), and the aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers
were washed with brine (5 mL) and dried (MgSO4). The solvent
was partially evaporated to an approximate volume of 12 mL, and
the resulting solution of amine 9b or 9c in CH2Cl2 was used
according to the general procedure described above. Structural
information and yields of all compounds prepared according to these
procedures are collected in Scheme 9 and Table 3. Purification and
separation details, as well as characterization data, are provided in
the Supporting Information.
for the less polar isomer 26b: tR ) 8 min; H NMR (500 MHz,
CDCl3) δ 0.93 (t, J ) 7.3 Hz, 3H), 1.46-1.56 (m, 3H), 1.80-1.85
(m, 1H), 1.96-2.02 (m, 1H), 2.41-2.47 (m, 4H), 2.66 (td, J )
9.5, 4.0 Hz, 1H), 2.73 (dd, J ) 17.5, 8.0 Hz, 1H), 2.80 (dd, J )
15.0, 4.0 Hz, 1H), 3.19 (dd, J ) 15.0, 4.0 Hz, 1H), 3.54 (d, J )
13.6 Hz, 1H), 3.84 (d, J ) 13.6 Hz, 1H), 4.50 (dt, 1H, J ) 5.4, 3.9
Hz), 7.26-7.36 (m, 5H); 13C NMR (75.4 MHz, CDCl3) δ 9.2 (CH3),
13.5 (CH2), 22.3 (CH2), 25.9 (CH2), 35.5 (CH2), 35.9 (CH), 36.8
(CH), 49.0 (CH2), 53.8 (CH2), 59.4 (CH), 77.2 (CH), 119.9 (C),
127.4 (CH), 128.6 (CH), 138.4 (C), 176.6 (C); MS (EI) m/z (%)
312 (M), 259 (18), 258 (base), 91 (37); HRMS calcd for
C19H24N2O2, 312.1838; found, 312.1830. Data for the major isomer
1
26a: tR ) 9 min; H NMR (250 MHz, CDCl3) δ 0.94 (t, J ) 7.0
Hz, 3H), 1.07-1.26 (m, 1H), 1.62-1.71 (m, 2H, H-6, 1 CH-CH3),
1.94-2.04 (m, 2H), 2.37-2.57 (m, 5H, 1 H-9, 2 H-4, CH2-CN),
2.61-2.69 (m, 1H, H-7), 2.88-3.03 (m, 2H, H-5, 1 H-9), 3.57 (d,
J ) 13.5 Hz, 1H), 3.75 (d, J ) 13.6 Hz, 1H), 4.57-4.66 (m, 1H,
H-1), 7.23-7.36 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 11.6
(CH3), 13.5 (CH2), 23.3 (CH2), 24.4 (CH2), 28.8 (CH2), 34.3 (CH),
38.3 (CH), 49.3 (CH2), 55.6 (CH2), 57.9 (CH), 76.7 (CH), 119.6
(C), 127.5 (CH), 128.3 (CH), 128.6 (CH), 137.8 (C), 176.4 (C);
IR (neat) ν 2240 (CN), 1770 (CdO) cm-1; MS (EI) m/z (%) 312
(M, 2), 259 (17), 258 (base), 91 (67); HRMS calcd for C19H24N2O2,
312.1838; found, 312.1834. Data for the more polar isomer (26c):
1
Procedure for Enamine-Alkene Intermolecular Reductive
Coupling. Preparation of 8-Benzyl-7-(2-cyanoethyl)-6-ethyl-2-
oxa-8-azabiciclo[3.4.0]nonan-3-one (26). SmI2 (0.1 M in THF)
tR ) 10 min; H NMR (250 MHz, CDCl3; from a 93:7 mixture
with 26a) δ 0.89 (t, J ) 7.3 Hz, 3H), 0.95-1.17 (m, 1H), 1.69-
1.80 (m, 4H), 2.04-2.30 (m, 2H), 2.39-2.53 (m, 2H), 2.71 (dd, J
J. Org. Chem, Vol. 71, No. 23, 2006 8775

Aurrecoechea et al.
) 17.2, 6.9 Hz, 1H), 2.81-2.94 (m, 2H), 3.21 (d, J ) 15.9 Hz,
1H), 3.81 (d, J ) 13.3 Hz, 1H), 4.02 (d, J ) 13.1 Hz, 1H), 4.33
(br s, 1H), 7.26-7.31 (m, 5H); 13C NMR (62.9 MHz, CDCl3; from
a 1:1 mixture with 26a) δ 11.0 (CH3), 14.3 (CH2), 20.6 (CH2),
22.5 (CH2), 33.0 (CH), 36.2 (CH2), 36.7 (CH), 44.0 (CH2), 54.2
(CH), 59.3 (CH2), 77.8 (CH), 120.0 (C), 127.4 (CH), 128.4 (CH),
129.1 (CH), 139.1 (C), 176.6 (C); GC/MS tR ) 20.0 min, MS (EI)
m/z (%) 312 (M), 258 (24), 126 (11), 106 (31), 105 (38), 91 (base),
77 (23); HRMS calcd for C19H24N2O2, 312.1838; found, 312.1852;
tR ) 20.5 min, MS (EI) m/z (%) 312 (M), 258 (12), 106 (48), 105
(52), 91 (base), 77 (37); HRMS calcd for C19H24N2O2, 312.1838;
found, 312.1852.
calcd for C21H27NO4, 357.1940; found, 357.1945. Data for 32e: tR
) 25 min; H NMR (300 MHz, CDCl3) δ 1.22 (t, J ) 7.1 Hz,
1
overlapped with signals from another proton, total 4H), 1.64-1.90
(m. 2H), 2.02-2.11 (m, 1H), 2.21-2.29 (m, 3H), 2.45-2.73 (m,
4H), 2.75-2.78 (m, 2H), 2.95 (d, J ) 13.8 Hz, 1H), 3.05 (d, J )
13.8 Hz, 1H), 4.06-4.14 (m, 3H), 4.47-4.49 (m, 1H), 7.20-7.31
(m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 14.2 (CH3), 28.0 (CH2),
30.5 (CH2), 34.5 (CH), 34.5 (CH2), 39.2 (CH), 40.2 (CH), 41.0
(CH2), 52.9 (CH2), 58.3 (CH2), 60.4 (CH2), 69.6 (CH), 78.2 (CH),
127.1 (CH), 128.2 (CH), 128.4 (CH), 138.6 (C), 172.4 (C), 177.6
(C); IR (neat) ν 1770 (CdO), 1730 (CdO) cm-1; MS (EI) m/z
(%) 357 (M, 5), 242 (71), 97 (12), 91 (base), 85 (272), 83 (12), 71
(18), 57 (30), 55 (19); HRMS calcd for C21H27NO4, 357.1940;
found, 357.1926.
Procedure for Enamine-Alkene Intramolecular Reductive
Coupling. Preparation of Ethyl (3aR*,8bR*)-(5-Benzyl-2-oxo-
decahydro-3-oxa-5-aza-as-indacen-6-yl)acetate (32). SmI2 (0.1
M in THF) was added dropwise to a solution of 17d (0.100 g, 0.28
mmol) and benzotriazole (0.100 g, 0.84 mmol) in THF (5.6 mL)
at room temperature at such a rate as to allow for the disappearance
of the SmI2 characteristic blue color before the next drop was added.
The addition was continued until the blue color persisted (at that
point approximately 9 mL, 3.2 equiv, had been consumed). The
reaction mixture was poured over a saturated K2CO3 solution (20
mL). After separation, the aqueous layer was extracted with EtOAc
(3 × 20 mL), and the combined organic layers were washed with
brine (10 mL) and dried (Na2SO4). The residue after evaporation
was purified by flash column chromatography (silica gel saturated
with Et3N, 70:28:2 hexanes/EtOAc/Et3N) and HPLC (µ-Bondapak-
NH2, 10 µ, 19 mm × 15 cm; 85:15 hexanes/EtOAc; 10 mL/min)
to yield 32 (67 mg, 66%) as a 42:37:6 (two isomers):15 diastere-
omeric mixture. Further separation by HPLC provided samples of
some of the individual isomers. Characterization data are given in
order of elution. Data for 32a: tR ) 12 min; 1H NMR (250 MHz,
CDCl3) δ 1.24 (t, J ) 7.1 Hz, 3H), 1.38-1.45 (m, 1H), 1.67-1.72
(m, 2H), 1.93-2.27 (m, 5H), 2.30-2.41 (m, 1H), 2.64-2.89 (m,
4H), 3.11-3.20 (m, 2H), 3.97 (d, J ) 13.9 Hz, 1H), 4.11 (q, J )
7.1 Hz, 2H), 4.68 (dd, J ) 15.1, 8.2 Hz, 1H), 7.26-7.32 (m, 5H);
13C NMR (62.9 MHz, CDCl3) δ 14.2 (CH3), 28.3 (CH2), 28.9 (CH2),
33.6 (CH2), 33.8 (CH2), 37.7 (CH), 38.0 (CH), 39.3 (CH), 51.5
(CH2), 59.2 (CH2), 60.4 (CH2), 67.4 (CH), 78.0 (CH), 127.3 (CH),
128.5 (CH), 137.9 (C), 173.6 (C), 176.9 (C); IR (neat) ν 1770 (Cd
O), 1730 (CdO) cm-1; MS (EI) m/z (%) 357 (M, 6), 242 (82), 91
(base), 71 (13), 57 (29), 55(16); HRMS calcd for C21H27NO4,
357.1940; found, 357.1942. Data for isomer 32b (from a 9:1 mixture
with 32a): tR ) 13 min; 1H NMR (250 MHz, CDCl3) δ 1.24 (t, J
) 7.1 Hz, 4H), 1.52-2.54 (m, 9H), 2.69-3.13 (m, 5H), 4.03-
4.16 (m, 3H), 4.51-4.60 (m, 1H), 7.26-7.30 (m, 5H); 13C NMR
(62.9 MHz, CDCl3) δ 14.2 (CH3), 24.6 (CH2), 27.3 (CH2), 27.4
(CH2), 34.6 (CH2), 34.8 (CH), 36.8 (CH), 38.9 (CH), 53.7 (CH2),
59.4 (CH2), 60.4 (CH2), 64.5 (CH), 77.5 (CH), 127.3 (CH), 128.4
(CH), 137.5 (C), 173.4 (C), 176.5 (C); IR (neat) ν 1780 (CdO),
1730 (CdO) cm-1; MS (EI) m/z (%) 357 (M, 8), 243 (12), 242
(base), 91 (72); HRMS calcd for C21H27NO4, 357.1940; found,
357.1931. Data for a 2:3 32c/32d mixture: tR ) 16 min; 1H NMR
(500 MHz, CDCl3) δ 1.26 (t, J ) 7.3 Hz, 4H), [1.48-1.95 (m,
3H), 2.00-2.80 (m), 2.90-2.97 (m), 3.01 (dd, J ) 13.3, 5.1 Hz)
3.08 (dd, J ) 12.6, 6.3 Hz) (total 10H)], [3.19 (d, J ) 12.5 Hz),
3.41 (d, J ) 13.6 Hz) (total 1H)], [3.93 (d, J ) 13.6 Hz), 4.03 (d,
J ) 12.4 Hz) (total 1H)], 4.10-4.16 (m, 2H), 4.52 (dd, J ) 11.5,
6.0 Hz), 4.55-4.60 (m, 1H), 7.25-7.31 (m, 5H); 13C NMR (125.7
MHz, CDCl3) δ 14.3 (CH3), 25.7 (CH2), 27.6 (CH2), 29.1 (CH2),
29.9 (CH2), 34.5 (CH2), 35.0 (CH), 36.6 (CH), 37.2 (CH), 37.4
(CH), 38.4 (CH), 40.2 (CH2), 41.2 (CH2), 43.5 (CH), 49.3 (CH2),
54.1 (CH2), 58.3 (CH2), 58.9 (CH2), 60.5 (CH2), 66.9 (CH), 67.6
(CH), 76.3 (CH), 76.8 (CH), 127.2 (CH), 127.4 (CH), 128.4 (CH),
128.5 (CH), 128.6 (CH), 128.8 (CH), 138.4 (C), 138.8 (C), 172.4
(C), 172.7 (C), 176.6 (C), 176.8 (C); GC/MS tR ) 19.7 min, MS
(EI) m/z (%) 357 (M, 9), 243 (11), 242 (73), 91 (base); HRMS
calcd for C21H27NO4, 357.1940; found, 357.1945; tR ) 20.2 min,
MS (EI) m/z (%) 357 (M, 9), 243 (12), 242 (77), 91 (base); HRMS
General Hydrogenation Procedure. In a typical experiment,
H2 was bubbled through a suspension of 17 (2.00 mmol) and 10%
Pd/C (0.028 g) in absolute ethanol (24 mL), and the mixture was
stirred under a H2 atmosphere (1 atm) at room temperature for 2-24
h. The catalyst was filtered off over Celite and the solid residue
was washed with CH2Cl2 (3 × 10 mL). The crude after evaporation
was purified by flash column chromatography to afford piperidines
20. Structural information, yields, and diastereomeric ratios of all
compounds prepared according to this procedure are collected in
Scheme 13 and Table 4. Purification and separation details, as well
as characterization data, are provided in the Supporting Information.
(3R*,4R*,5S*)-1-Benzyl-4-(2′-hydroxyethyl)-5-propylpyrro-
lidin-3-ol (34a). A solution of 16a (50 mg, 0.19 mmol) in THF
(3.0 mL) was added dropwise to a stirred suspension of LAH (9
mg, 0.23 mmol) in THF (2.5 mL) at 0 °C. The reaction mixture
was allowed to reach room temperature, stirred further for 14 h,
and then quenched at 0 °C with 1 M NaOH (2 mL). After allowing
the mixture to reach room temperature, CH2Cl2 (4 mL) and saturated
sodium potassium tartrate (5 mL) were added. The resulting
emulsion was vigorously stirred for 4 h, becoming a clear biphasic
liquid. After separation, the aqueous layer was extracted with CH2-
Cl2 (3 × 6 mL). The combined organic layers were dried (Na2-
SO4), and the residue after evaporation was purified by flash column
chromatography (silica gel saturated with Et3N, 18:80:2 hexanes/
EtOAc/Et3N) to yield 34a (49 mg, 98%) as an oil: 1H NMR (250
MHz, CDCl3) δ 0.94 (t, J ) 7.3 Hz, 3H), 1.31-1.60 (m, 4H), 1.67-
1.96 (m, 2H), 2.24-2.35 (m, 1H), 2.42 (dd, J ) 10.5, 5.4 Hz, 1H),
2.57-2.65 (m, 2H), 2.84 (dd, J ) 10.5, 2.2 Hz, overlapped with
br signal, total 2H), 3.25 (d, J ) 13.1 Hz, 1H), 3.64-3.81 (m,
2H), 4.06 (d, J ) 13.0 Hz, 1H), 4.20 (td, J ) 5.6, 2.2 Hz, 1H),
7.20-7.32 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 14.5 (CH3),
20.5 (CH2), 27.1 (CH2), 32.7 (CH2), 43.7 (CH), 58.9 (CH2), 60.7
(CH2), 61.7 (CH2), 65.0 (CH), 71.5 (CH), 127.0 (CH), 128.3 (CH),
128.7 (CH), 138.8 (C); IR (neat) ν 3350 (O-H) cm-1; MS (EI)
m/z (%) 262 (M, 1), 221 (18), 220 (base), 202 (1), 174 (2), 160
(2), 155 (1), 91 (82); HRMS calcd for C16H25NO2, 263.1885; found,
263.1884.
(1R*,3S*,5R*,6S*)-7-Benzyl-3-hydroxy-2-oxa-6-propyl-7-
azabicyclo[3.3.0]octane (35). A suspension of LAH (36 mg, 0.95
mmol) in THF (1.0 mL) was added dropwise to a stirred solution
of 16a (50 mg, 0.19 mmol) in THF (4.0 mL) at -78 °C. Stirring
was continued at the same temperature for 90 min, and the reaction
mixture was quenched with 1 M NaOH (2 mL) and then allowed
to reach room temperature. After diluting the mixture with CH2Cl2
(4 mL), saturated sodium potassium tartrate (6 mL) was added,
and the resulting emulsion was vigorously stirred for 14 h, resulting
in a clear biphasic liquid. After separation, the aqueous layer was
extracted with CH2Cl2 (3 × 6 mL). The combined organic layers
were dried (Na2SO4), and the residue after evaporation was purified
by flash column chromatography (silica gel saturated with Et3N,
78:20:2 hexanes/EtOAc/Et3N) to yield 35 (42 mg, 85%) as an oil:
1H NMR (500 MHz, CDCl3) δ 1.00 (t, J ) 7.3 Hz, 3H), 1.25-
1.35 (m, 1H), 1.42-1.55 (m, 2H), 1.83-1.94 (m, 2H, 1 H-1′, 1
H-4), 1.97 (dd, J ) 11.0, 4.8 Hz, 1H, H-8), 2.02 (d, J ) 13.6 Hz,
1H, 1 H-4), 2.22 (ddd, J ) 10.9, 6.8, 4.0 Hz, 1H, H-6), 2.86 (dt,
8776 J. Org. Chem., Vol. 71, No. 23, 2006

Synthetic Strategy for Pyrrolidines and Piperidines
J ) 10.0, 7.2 Hz, 1H, H-5), 2.93 (d, J ) 11.0 Hz, 1H, H-8), 3.07
(d, J ) 12.7 Hz, 1H), 4.17 (d, J ) 12.7 Hz, 1H), 4.60 (dd, J ) 7.2,
4.8 Hz, 1H, H-1), 5.24 (d, J ) 4.6 Hz, 1H, H-3), 7.14-7.33 (m,
6H); 13C NMR (125.8 MHz, CDCl3) δ 14.4 (CH3), 19.3 (CH2),
31.0 (CH2), 35.0 (CH2, C-4), 42.9 (CH, C-5), 56.8 (CH2, PhCH2),
61.6 (CH2, C-8), 66.1 (CH, C-6), 79.8 (CH, C-1), 97.9 (CH, C-3),
127.4 (CH), 128.6 (CH), 128.8 (CH), 137.1 (C); IR (neat) ν 3180
(O-H) cm-1; MS (EI) m/z (%) 261 (M, 1), 260 (2), 219 (16), 218
(base), 160 (3), 146 (4), 120 (7), 110 (3), 91 (80); HRMS calcd for
C16H23NO2, 261.1729; found, 261.1724.
(91), 162 (15); HRMS (FAB) calcd for C26H39N2O3 (M + 1),
427.2961; found, 427.2949.
(3R*,4R*,5S*)-1-Benzyl-5-ethyl-4-(2-hydroxyethyl)piperidin-
3-ol (34b). The procedure described above for the preparation of
35 was followed starting from 20a. The crude product was purified
by flash column chromatography (silica gel saturated with Et3N,
98:2 EtOAc/Et3N) to yield 34b (82%) as an oil: 1H NMR (250
MHz, CDCl3, 50 °C) δ 0.84 (t, J ) 7.3 Hz, 3H), 1.28-1.46 (m,
2H), 1.50-1.62 (m, 2H), 1.69-1.83 (m, 1H), 1.87-1.95 (m, 1H),
2.06-2.56 (m, 6H), 3.46 (d, J ) 13.1 Hz, 1H), 3.59 (d, J ) 13.1
Hz, overlapped with other signals, total 2H), 3.72-3.84 (m, 2H),
7.20-7.31 (m, 5H); 13C NMR (62.9 MHz, CDCl3, 45 °C) δ 12.3
(CH3), 22.5 (CH2), 26.9 (CH2), 40.6 (CH), 40.6 (CH), 54.5 (CH2),
57.0 (CH2), 62.3 (CH2), 62.7 (CH2), 69.9 (CH), 127.0 (CH), 128.2
(CH), 129.0 (CH), 138.2 (C); IR (neat) ν 3360 (O-H) cm-1; MS
(EI) m/z (%) 263 (M, 11), 262 (6), 246 (6), 202 (15), 172 (17),
120 (21), 91 (base); HRMS calcd for C16H25NO2, 263.1885; found,
263.1882.
(3′S*,4′R*,5′R*)-N-Benzyl-2-(1-benzyl-3-ethyl-5-hydroxypip-
eridin-4-yl)acetamide (38a). A mixture of 20a (100 mg, 0.39
mmol), BnNH2‚HCl (140 mg, 0.98 mmol), and sodium 2-ethyl-
hexanoate (227 mg, 1.36 mmol) in THF (2.0 mL) was stirred for
5 days under Ar. Brine (2.0 mL) and EtOAc (4.0 mL) were added,
and the mixture was stirred 5 min. After separation, the aqueous
layer was extracted with EtOAc (2 × 2 mL), and the combined
organic layers were dried (Na2SO4). The residue after evapora-
tion was purified by flash column chromatography (silica gel
saturated with Et3N, 18:80:2 hexanes/EtOAc/Et3N) to yield 38a (132
mg, 92%) as an oil: 1H NMR (250 MHz, CDCl3, 50 °C) δ 0.82 (t,
J ) 7.3 Hz, 3H), 1.32-1.44 (m, 2H), 1.59-1.70 (m, 1H), 2.09-
2.18 (m, 2H), 2.32-2.51 (m, 4H), 2.60 (dd, J ) 11.2, 3.4 Hz,
overlapped with br signal, total 2H), 3.47 and 3.55 (2 d, J ) 13.1
Hz, 2H), 3.84 (dt, J ) 7.3, 3.6 Hz, 1H), 4.39 and 4.46 (2 dd, J )
14.7, 5.7 Hz, 2H), 6.02 (br s, 1H), 7.19-7.36 (m, 10H); 13C NMR
(62.9 MHz, CDCl3, 45 °C) δ 12.4 (CH3), 22.6 (CH2), 32.3 (CH2),
39.2 (CH), 40.1 (CH), 43.8 (CH2), 54.8 (CH2), 57.2 (CH2), 62.7
(CH2), 69.6 (CH), 127.0 (CH), 127.4 (CH), 127.7 (CH), 128.2 (CH),
128.6 (CH), 128.9 (CH), 138.4 (C), 173.6 (C); IR (neat) ν 3290
(NsH), 3290 (OsH), 1640 (CdO), 1560 (NsCO) cm-1; MS (EI)
m/z (%) 366 (M, 1), 348 (38), 257 (11), 200 (77), 168 (9), 134 (4),
120 (7), 91 (base); HRMS calcd for C23H30N2O2, 366.2307; found,
366.2290.
(1R*,3R*,5R*,6S*)- and (1R*,3S*,5R*,6S*)-7-Benzyl-3-(3,4-
dimethoxyphenethylamino)-6-propyl-2-oxa-7-azabicyclo[3.3.0]-
octane (36). A mixture of NaBH3CN (6 mg, 0.10 mmol) and ZnCl2
(7 mg, 0.05 mmol) in MeOH (0.5 mL) was stirred for 1 h at room
temperature and was added dropwise to a stirred solution of 35
(26 mg, 0.10 mmol) and homoveratrylamine (0.07 mL, 0.40 mmol)
in MeOH (1.0 mL). The reaction mixture was stirred for 40 h at
room temperature, diluted with CH2Cl2 (5 mL), and poured over
saturated K2CO3 solution (5 mL). After separation, the aqueous
layer was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic layers were washed with brine (2 mL) and dried (Na2SO4).
The residue after evaporation was purified by flash column
chromatography (silica gel saturated with Et3N, 78:20:2 hexanes/
EtOAc/Et3N) to yield 36 (38 mg, 90%, 3:1 dr): 1H NMR (250
MHz, CDCl3) δ 0.94 and 0.98 (2 t, J ) 7.1 Hz, total 3H), 1.21-
1.56 (m, 4H), 1.70-2.27 (m, 5H), 2.46-3.15 (m, 7H), 3.84-3.86
(4 s, 6H), 4.02 (d, J ) 13.3 Hz, 1H) and 4.06 (d, J ) 12.5 Hz, 1H,
total 1H), 4.40 (dd, J ) 7.3, 5.4 Hz) and 4.50 (dd, J ) 7.7, 5.8 Hz,
total 1H), 4.73 (dd, J ) 6.7, 2.4 Hz) and 4.92 (t, J ) 5.6 Hz, total
1H), 6.62-6.81 (m, 3H), 7.18-7.34 (m, 5H); 13C NMR (62.9 MHz,
CDCl3) δ 14.5 (CH3), 14.6 (CH3), 19.6 (CH2), 19.6 (CH2), 31.1
(CH2), 31.6 (CH2), 32.5 (CH2), 32.9 (CH2), 36.4 (CH2), 36.7 (CH2),
43.7 (CH), 44.4 (CH), 47.3 (CH2), 48.3 (CH2), 55.7 (CH3), 55.8
(CH3), 57.0 (CH2), 57.5 (CH2), 61.9 (CH2), 62.4 (CH2), 66.2 (CH),
66.5 (CH), 78.2 (CH), 79.3 (CH), 92.0 (CH), 111.0 (CH), 111.2
(CH), 111.8 (CH), 120.4 (CH), 120.5 (CH), 126.6 (CH), 127.0 (CH),
128.1 (CH), 128.3 (CH), 128.5 (CH), 129.1 (CH), 132.5 (C), 133.1
(C), 138.7 (C), 139.2 (C), 147.1 (C), 147.3 (C), 148.6 (C), 148.8
(C); IR (neat) ν 3260 (N-H) cm-1; MS (FAB) m/z (%) 425 (M +
1, base), 424 (M, 23), 423 (74), 244 (83); HRMS calcd for
C26H37N2O3 (M + 1), 425.2804; found, 425.2797.
(3R*,4R*,5S*)-1-Benzyl-4-[2-(3,4-dimethoxyphenethylamino)-
ethyl]-5-propylpyrrolidin-3-ol (37). A solution of 36 (19 mg, 0.045
mmol) in THF (1.0 mL) was added dropwise to a stirred suspension
of LAH (2 mg, 0.054 mmol) in THF (1.0 mL) at 0 °C. The reaction
mixture was allowed to reach room temperature, stirred further for
40 h, and then quenched at 0 °C with 1 M NaOH (1 mL). After
allowing the mixture to reach room temperature, CH2Cl2 (2 mL)
and saturated sodium potassium tartrate (2 mL) were added. The
resulting emulsion was vigorously stirred for 4 h, becoming a clear
biphasic liquid. After separation, the aqueous layer was extracted
with CH2Cl2 (3 × 2 mL), and the combined organic layers were
dried (Na2SO4). The residue after evaporation was purified by flash
column chromatography (silica gel saturated with Et3N, 98:2 CH2-
Cl2/Et3N and then 95:3:2 CH2Cl2/MeOH/Et3N) and then dissolved
in CH2Cl2 (2 mL), and the solution was washed with 1 M NaOH
(0.5 mL) to yield 37 (17 mg, 90%) as an oil: 1H NMR (250 MHz,
CDCl3) δ 0.91 (t, J ) 7.1 Hz, 3H), 1.25-1.78 (m, 8H), 2.10-2.22
(m, 1H), 2.49-2.93 (m, 9H), 3.32 (d, J ) 13.3 Hz, 1H), 3.85 and
3.85 (2 s, 6H), 3.99 (d, J ) 13.3 Hz, 1H), 4.18 (td, J ) 5.7, 3.8
Hz, 1H), 6.70-6.81 (m, 3H), 7.18-7.32 (m, 5H); 13C NMR (125.8
MHz, CDCl3) δ 14.6 (CH3), 20.4 (CH2), 24.8 (CH2), 32.8 (CH2),
35.7 (CH2), 46.2 (CH), 48.4 (CH2), 51.0 (CH2), 55.9 (CH3), 55.9
(CH3), 59.2 (CH2), 60.3 (CH2), 65.4 (CH), 71.0 (CH), 111.4 (CH),
112.0 (CH), 120.6 (CH), 126.7 (CH), 128.1 (CH), 128.6 (CH), 132.1
(C), 139.9 (C), 147.5 (C), 149.0 (C); IR (neat) ν 3300 (N-H, O-H)
cm-1; MS (FAB) m/z (%) 427 (M + 1, 97), 426 (M, 14), 275 (24),
262 (10), 246 (base), 226 (33), 201 (41), 184 (36), 172 (13), 165
(3′S*,4′R*,5′R*)-2-(1-Benzyl-3-ethyl-5-hydroxypiperidin-4-yl)-
N-phenethylacetamide (38b). A mixture of 20a (100 mg, 0.39
mmol), Ph(CH2)2NH2‚HCl (155 mg, 0.98 mmol), and sodium
2-ethylhexanoate (227 mg, 1.36 mmol) in THF (2.0 mL) was stirred
for 6 days under Ar, and the mixture was poured over a saturated
K2CO3 solution (4.0 mL). After separation, the aqueous layer was
extracted with EtOAc (3 × 5 mL), and the combined organic layers
were dried (Na2SO4). The residue after evaporation was purified
by flash column chromatography (silica gel saturated with Et3N,
18:80:2 hexanes/EtOAc/Et3N) to yield 38b (142 mg, 96%) as an
oil: 1H NMR (250 MHz, CDCl3, 50 °C) δ 0.81 (t, J ) 7.3 Hz,
3H), 1.21-1.45 (m, 2H), 1.57-1.68 (m, 1H), 1.90-2.11 (m, 2H),
2.28-2.41 (m, 4H), 2.60 (dd, J ) 11.2, 3.3 Hz, 1H), 2.80 (t, J )
7.0 Hz, 2H), 3.32 (br s, 1H), 3.43-3.58 (m, 4H), 3.77-3.82 (m,
1H), 5.88 (br s, 1H), 7.16-7.31 (m, 10H); 13C NMR (62.9 MHz,
CDCl3, 45 °C) δ 12.3 (CH3), 22.6 (CH2), 32.0 (CH2), 35.6 (CH2),
39.1 (CH), 40.1 (CH), 40.7 (CH2), 54.6 (CH2), 57.0 (CH2), 62.6
(CH2), 69.5 (CH), 126.4 (CH), 127.0 (CH), 128.2 (CH), 128.6 (CH),
128.7 (CH), 128.9 (CH), 138.2 (C), 138.8 (C), 173.8 (C); IR (neat)
ν 3380 (OsH, NsH), 1640 (CdO), 1560 (NsCO) cm-1; MS (EI)
m/z 380 (M, 1), 362 (38), 271 (19), 214 (12), 200 (base), 168 (5),
134 (6), 120 (6), 105 (11), 91 (93); HRMS calcd for C24H32N2O2,
380.2464; found, 380.2469.
Acknowledgment. Financial support by Ministerio de Edu-
cacio´n y Ciencia (CTQ2004-04901) and UniVersidad del Pa´ıs
J. Org. Chem, Vol. 71, No. 23, 2006 8777

Aurrecoechea et al.
19, 20, and 33, stereochemical elucidation details, and copies of
1H NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Vasco (9/UPV00041.310-14471/2002 and fellowship to R.S.)
is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and characterization data for compounds 2-5, 7-9, 13, 16, 17,
JO0614487
8778 J. Org. Chem., Vol. 71, No. 23, 2006