A double Mannich approach to the synthesis of substituted piperidones - Application to the synthesis of substituted E-ring analogues of methyllycaconitine

Article abstract of DOI:10.1016/j.tet.2010.06.084

The double Mannich reaction of acyclic α,γ-substituted β-keto esters and bis(aminol) ethers gives substituted 3,5-substituted-4- piperidones with high levels of diastereoselectivity. These piperdiones can be easily transformed into substituted E-ring analogues of the delphinium alkaloid methyllycacotine.

Full text of DOI:10.1016/j.tet.2010.06.084

Tetrahedron 66 (2010) 7179e7191
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A double Mannich approach to the synthesis of substituted
piperidonesdapplication to the synthesis of substituted
E-ring analogues of methyllycaconitine
*
Yinman Chan, Jared Balle, J. Kevin Sparrow, Peter D.W. Boyd, Margaret A. Brimble, David Barker
Department of Chemistry, University of Auckland, 23 Symonds St, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The double Mannich reaction of acyclic
a
,g
-substituted
b
-keto esters and bis(aminol) ethers gives
Received 22 April 2010
Received in revised form 14 June 2010
Accepted 28 June 2010
substituted 3,5-substituted-4-piperidones with high levels of diastereoselectivity. These piperdiones can
be easily transformed into substituted E-ring analogues of the delphinium alkaloid methyllycacotine.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 3 July 2010
Keywords:
Mannich reaction
4-Piperidones
Multicomponent reaction
Methyllycacontine
1. Introduction
OMe
OMe
OR
Methyllycaconitine 1 is the major toxic component in Delphin-
ium brownii and was first discovered by Manske in 1938.1 The
methyllycaconitine 1 core structure contains a piperidine (E) ring
and a 2-[2-(S)-methylsuccinimido]benzoate ester, which together
are believed to form a homocholine motif, which mimics the en-
dogenous ligand, acetylcholine.2 The primary mode of action of
methyllycaconitine 1 is via competitive blockade at the nicotinic
acetylcholine receptors (nAChRs). Structure-activity studies on
methyllycaconitine 1 have shown that both a tertiary amine in the
piperidine E-ring and the N-substituted anthranilate ester moiety
are essential for potent pharmacological activity.2,3 Many groups,4
including our own, have synthesised analogues of these alkaloids
with some groups focussing specifically on the synthesis of piper-
idine E-ring analogues 2 (Fig. 1).5 There are, however, very few
examples of poly substituted piperidine E-ring analogues5,6 with
most focussing on altering the aromatic anthranilate moiety and
the N-substituent on a mono-substituted piperidine ring. Func-
tionalised piperidines and piperidones are also important in-
termediates in the synthesis of numerous other bioactive alkaloids
and pharmaceuticals.7
OH
N
MeO
O
O
OH
OMe
Et
Et
O
N
N
2
R=
E-ring
RO
1
Figure 1. Methyllycaconitine (1) and typical E-ring analogue 2.
There are few methods for the synthesis of 3,4,5-substituted
piperidines,8 with many recent strategies for the synthesis of
substituted piperidines aimed particularly at the synthesis of
2-substitued9 and 2,4- and 2,6-disubstitued10 piperidines. We
herein report the synthesis of substituted E-ring analogues of
methyllycaconitine beginning with a double Mannich reaction of
acyclic b-keto esters to form the substituted piperidine ring.
2. Results and discussion
The Lewis-acid catalysed double Mannich reaction of bis-aminol
ethers 3 with cyclic b
-keto esters11 and cyclic ketones,12 to give
3-azabicyclononanes, has been shown to give greatly improved
yields when compared to classical double Mannich conditions.
When classical, acidic or basic, double Mannich conditions are
* Corresponding author. E-mail address: d.barker@auckland.ac.nz (D. Barker).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.084

7180
Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
Table 1
Synthesis of substituted 4-piperidones
O
O
O
R
R
R
CO2Et
R
MeSiCl3
OEt
EtO
N
R
OEt
R
R
N
R
Me CN, r.t.
4a-l
5a-q
3a-e
Entry
1
b
-keto ester
Bis(aminol)ether
Product
Yield %
0
O
O
O
CO2Et
EtO
N
OEt
3a
OEt
N
O
4a
5a
O
O
Me
CO2Et
Et
2
3
4
3a
0
90
82
OEt
N
O
4b
5b
O
O
Me
CO2Et
3a
OEt
Me
N
4c
5c
O
Me
EtO
Ph
N
OEt
3b
CO2Et
4c
N
5d
Ph
O
N
Me
CO2Et
EtO
Ph
N
OEt
3c
5
6
4c
86
85
5e
Ph
O
N
O
O
CO2Et
3b
OEt
O
Et
O
5f
4d
Ph
O
Me
Me
Me
7
8
9
3a
3a
3a
CO2Et
60
63
65
OEt
Me
N
O
4e
5g
O
O
Me
Et
Et
CO2Et
OEt
Me
N
O
4f
5h
O
O
Me
CO2Et
OEt
Me
N
4g
5i
O
O
O
Me
10
11
3a
3a
CO2Et
88
76
OEt
Me
N
O
N
4h
5j
O
O
Me
CO2Et
OEt
Me
4i
5k

Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
7181
Table 1 (continued)
Entry
b
-keto ester
Bis(aminol)ether
Product
Yield %
O
Me
EtO
EtO
N
Me
OEt
3d
CO2Et
12
13
4i
80
79
N
5l
Me
O
O
O
N
3a
3c
OEt
3e
Et
CO2Et
OEt
OEt
N
Et
4j
5m
O
N
O
O
Me
Me
Me
Me
14
15
CO2Et
51
59
Me Me
4k
5n
O
Me
CO2Et
Me
Me
4k
N
5o
Ph
applied to form piperidones reactions only occur with
diesters and even then occur in low yields.13 We previously
reported14 that the double Mannich of acyclic
-keto esters pro-
ceeds to give 4-piperidones only when there is a substituent at the
-position. When -keto esters, such as 4a and 4b, with two acidic
protons at the -position are employed none of the desired piper-
idones 5a/b are produced and only polymeric material is obtained
(Table 1, entries 1 and 2). However, reaction of ethyl 2-methyl-
acetoacetate 4c and ethyl 2-ethylacetoacetate 4d with bis(aminol)
ethers 3aec gives 3,3-disubstituted 4-piperidones 5cef in 82d90%
yields (Table 1, entries 3e6).
b
,
b
0-keto
the subsequently modified compounds, 8f, was found to be suitable
for X-ray crystallographic analysis (see below).
b
For the synthesis of E-ring analogues of methyllycacontine we
chose to functionalise piperidones 5c, 5gek and 5n, which all have
the same N-butyl substituent, with altered substitution at the
5-position in the piperidine ring. Our route from piperidones to
E-ring analogues of methyllycacontine began with reduction of
the ketone with NaBH4 to give piperidols 6. In the case of
3,3,5-trisubstituted-4-piperidones 5gek the reduction was com-
pletely stereoselective giving piperidols 6aee in 93e98% yield
(Scheme 1). The 4-hydroxy group in piperidols 6aee was syn to
the 3-ethoxycarbonyl group, resulting from axial hydride attack,
antiperiplanar to the axial ester group.21 Reduction of the di-
substituted piperidones 5c and tetrasubstituted piperidones 5n
was not stereoselective, giving a 2:1 and 1:1 inseparable mixtures
of diastereomers, respectively. We therefore decided to abandon
working with these mixtures and carry on with only piperidols
6aee.22
With piperidols 6aee in hand, the next step was to methylate
the 4-hydroxy group, using NaH and three equivalents of iodo-
methane in THF, to give methyl ethers 7aee in 68e94% yields.
Extended reactions times of 3 days were required and we found the
use of a sealed tube significantly increased the yield of the desired
ether 7aee, whilst heating the reaction or adding further equiva-
lents of iodomethane both led to reduced yields.
5-Allylpiperidol 6e was also alkylated with allyl bromide,
using the same conditions, to give allyl ether 7f in 71% yield.
Ring closing metathesis of diene 7f, using the 10 mol % of first
generation Grubbs’ catalyst in DCM, gave piperidine 7g in 64%
yield. Piperidine 7g contains an appended seven-membered
ether ring, which also mimics sections of the B and F rings of
methyllycacontine.
Lithium aluminium hydride reduction of ethyl esters 7aee,g
afforded neopentyl-like alcohols 8aef in 92e98% yields. After pu-
rification bicyclic alcohol 8f solidified to give crystals suitable for
X-ray crystallographic analysis (Fig. 2). The crystal structure shows
a trans-fused seven-membered ring and a syn arrangement be-
tween the 3-methyl and 5-substituent, thus confirming the
a
b
a
In order to prepare E-ring analogues with further substitution
required synthesis of a,g-substituted b-keto esters. Esters 4e and
4j were prepared from the Claisen condensation of ethyl pro-
pionate and ethyl butyrate, respectively,15 whilst esters 4f/g/k
were prepared from the dianion alkylation16 of 4c. We found that
2-methyl-4-phenyl substituted ester 4h was best prepared from
the Blaise reaction17 between benzyl cyanide and ethyl 2-bromo-
propionate as other methods18 gave less satisfactory results. The
a
,
g,g-trisubstituted b-keto ester 4k was prepared from the titanium
tetrachloride mediated cross-Claisen condensation19 of isobutyryl
chloride and ethyl propionate.
3,3,5-Trisubstituted-4-piperidones 5gem (Table 1, entries
7e13) were produced in good yields (60e88%) whilst 3,3,5,5-tet-
rasubstituted-4-piperidones 5n and 5o (Table 1, entries 14 and 15)
were produced in 51% and 59% yields, respectively. The synthesis of
4-piperidones with a large variety of N-substitution can therefore
be achieved by altering the bis(aminol) ethers, which are easily
synthesised from a range of primary amines.11,20 The reaction also
accommodates varying sizes of alkyl or aryl substituents on the
b
-keto ester, with little difference in the yield of the piperidone 5
produced. In all cases trialled only a single diastereoisomer of
piperidone 5 was formed and analysis of coupling constants and
NOE interactions in the 1H NMR indicated the conformation of
these piperidones to have an axial 3-ester group.14 In the case of
3,3,5-trisubstituted-4-piperidones 5gem, the 3- and 5- alkyl sub-
stituents were both in equatorial positions.14 The relative stereo-
chemistry of these piperidones was later confirmed when one of

7182
Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
R1O
O
N
HO
Me
Me
CO2Et
Me
CO2Et
R
R
R
a
b
CO2Et
N
N
5g
6a,
7a
, R = Me
R = Me
, R = R1 = Me
5h, R = Et
5i, R = Pr
6b, R = Et
7b, R = Et, R1 = Me
6c, R = iPr
7c, R = iPr, R1 = Me
i
1
5j
6d
7d
, R = Ph
, R = CH2CH=CH2
, R = Ph
, R = Ph, R = Me
5k
6e,
7e
R = CH2CH=CH2
, R = CH2CH=CH2, R1 = Me
, R = R1 = CH2CH=CH2
7f
c
7g, R/R1= -CH2CH=CH-CH2-
R1O
R
R1O
R
Me
Me
d
e
OH
O
O
O
O
N
N
N
1
, R = R1 = Me
8a
9a
, R = R = Me
, R = Et, R1 = Me
8b
9b, R = Et, R1 = Me
9c, R = Pr, R1 = Me
9d
i
8c, R = iPr, R1 = Me
8d, R = Ph, R1 = Me
, R = Ph, R1 = Me
8e, R = CH2CH=CH2, R1 = Me
, R = CH2CH=CH2, R1 = Me
9e
1
1
9f
8f
, R/R = -CH2CH=CH-CH2-
, R/R = -CH2CH=CH-CH2-
Scheme 1. Synthesis of substituted E-ring analogues of methyllycaconitine. Reagents: (a) NaBH4, 1:1 THF/H2O; 6a 98%, 6b 94%, 6c 98%, 6d 98%, 6e 93%; (b) NaH, THF 1 h then, for
7ae7e MeI and for 7f CH2]CHCH2Br; 7a 68%, 7b 94%, 7c 79%, 7d 93%, 7e 87%, 7f 81%; (c) 10 mol % first generation Grubbs’ catalyst, DCM, 64%; (d) LiAlH4, THF, 8a 98%, 8b 95%, 8c
92%, 8d 94%, 8e 96%, 8f 98%; (e) 2-(2-methyl maleimido)benzoate acid, DCC, DMAP, MeCN, 9a 57%, 9b 62%, 9c 55%, 9d 74%, 9e 77%, 9f 64%.
stereoselectivity of both the double Mannich reaction and ketone
reduction. Esterification of alcohols 8aef with 2-(2-methyl mal-
eimido)benzoate acid using our previously reported conditions23
afforded esters 9aef in 55e77% yields. Overall, use of this four-
step sequence affords substituted E-ring analogues of MLA 9aef in
good yields from piperidones 5iem.
g-substituted b-keto esters 4 to give 3,3,5-trisubstituted-4-piper-
idones 5. These synthetic analogues 9aef contain the key structural
features of methyllycaconitine 1, namely the presence of a homo-
choline motif derived from a tertiary amine, embedded within
a piperidine ring, together with a benzoate ester side chain and
may provide access to more effective inhibitors of nicotinic ace-
tylcholine receptors.
4. Experimental section
4.1. General methods and materials
Reactions were monitored by TLC, using pre-coated silica gel TLC
plates obtained from Merck. Flash chromatography was carried out
on silica gel (Riedel-de Haën, particle size 0.032e0.063 mm).
Retention times (Rf) were determined using the stated solvent
mixture for column chromatography. Melting point determinations
were performed on an ElectrothermalÒ melting point apparatus. 1H
NMR and 13C NMR spectra were recorded on Bruker Avance DRX
300 MHz or 400 MHz spectrometers at ambient temperatures.
Chemical shifts
d are expressed in parts per million and coupling
constants J are reported in hertz. TMS served as internal standard
(
d
¼0 ppm) for 1H NMR, and CDCl3 served as internal standard
(d
¼77.0 ppm) for 13C NMR. In addition, 1He1H-COSY and 1He13C-
HSQC correlation spectra were used for the complete assignment of
the proton and carbon resonances. 1He1H-NOESY NMR spectra
were recorded in special cases. The NMR spectroscopic data for the
benzoate esters analogues 9aef of methyllycaconitine were
assigned using the following descriptors: piperidine ring system
(two primes 00), anthranilate ring (no primes) and methyl mal-
eimido ring (one prime 0). Infrared spectra were recorded on
a PerkineElmer spectrum one FT-IR spectrometer either as a thin
film between NaCl plates or neat on an ATR system and are reported
as cmꢀ1. Ethyl acetoacetate 4a, ethyl 2-methylacetoacetate 4c and
ethyl 2-ethylacetoacetate 4d were purchased and used without
additional purification. The previously reported compounds, ethyl
Figure 2. ORTEP diagram, with numbering (50% probability thermal ellipsoids) of 8f.
The major form of the disordered n-butyl group eC12 to C16 is shown. Dashed lined
indicate the OeH/N hydrogen bonds between the two enantiomers in the asym-
metric unit.
3. Conclusion
In summary, the successful syntheses of six substituted E-ring
analogues 9aef of methyllycaconitine 1 have been achieved, with
the key step being a stereoselective double Mannich reaction of a,

Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
7183
3-oxohexanoate 4b, ethyl 2-methyl-3-oxohexanoate 4f and ethyl
2-methyl-3-oxo-hept-6-enoate 4i were prepared using general
procedure A in 59, 61 and 91% yields, respectively. Ethyl 2-methyl-
3-oxopentanoate 4e and ethyl 2-ethyl-3-oxohexanoate 4j were
prepared using the method of Yoshizawa et.al.15 Bis(aminol)ethers
3aee11,20 and 2-(3-methyl-2,5-dioxo-2,5-dihydropyrrol-1-yl)ben-
zoic acid24 were prepared using reported methods.
oil. Rf¼0.5; dH (300 MHz; CDCl3) 1.23 (3H, t, J¼7.1 Hz, OCH2CH3),
1.30 (3H, d, J¼7.2 Hz, 2-CH3), 3.62 (1H, q, J¼7.2 Hz, 2-H), 3.83 (2H, s,
PhCH2CO), 4.14 (2H, q, J¼7.1 Hz, OCH2CH3), 7.18e7.34 (5H, m, Ph).
The 1H NMR data obtained was in agreement with that reported in
the literature.25
4.2.3. Ethyl 2,4-dimethyl-3-oxopentanoate 4k. Isobutyryl chloride
(72 mmol, 7.67 g) was added to a stirred solution of ethyl pro-
pionate (40 mmol, 4.09 g) and 1-methylimidazole (48 mmol,
3.94 g) in dry toluene at ꢀ45 ꢁC and stirred for 20 min. Titanium
tetrachloride (132 mmol, 14.5 mL), followed by N,N-diisopropyle-
thylamine (144 mmol, 25.1 mL) were added dropwise to the re-
action mixture and stirred for 5 h at ꢀ45 ꢁC. The reaction was
quenched with deionised water 100 mL until and the aqueous layer
extracted with diethyl ether (4ꢂ40 mL). The combined organic
extracts were washed with satd NaHCO3 and brine, dried (MgSO4)
and solvent removed under reduced pressure to give the crude
product, which was purified by flash chromatography (14:1 hexane,
ethyl acetate) to afford the title compound 4k (2.90 g, 42%) as a pale
yellow oil; Rf ¼0.7; IR (NaCl) nmax 2977, 2939, 2877 (CH), 1745
(COO), 1715 (C]O), 1467, 1376, 1245, 1197, 1098, 1016; dH (300 MHz;
CDCl3) 1.10 (6H, dd, J¼4.34, 1.55 Hz, CH(CH3)2), 1.23 (3H, t,
J¼7.13 Hz, OCH2CH3), 1.30 (3H, d, J¼7.21 Hz, 2-CH3), 2.76e2.86 (1H,
m, 4-H), 3.66 (1H, q, J¼7.09 Hz, 2-H), 4.15 (2H, q, J¼7.14 Hz,
OCH2CH3); dC (75 MHz; CDCl3) 13.0 (OCH2CH3), 14.0 (2-CH3), 18.1
(1ꢂCH(CH3)2), 18.5 (1ꢂCH(CH3)2), 40.1 (C-4), 50.8 (C-2), 61.2
(OCH2CH3), 170.6 (C-1), 209.8 (C-3); m/z (EIþ) 172 (Mþ, 16%), 129
(22), 127 (10), 102 (11), 74 (25), 71 (90), 56 (17), 43 (100); found
[Mþ] 172.10981. C9H16O3 requires 172.10994.
4.2. General procedure A: synthesis of
-keto esters 4
d-substituted
b
A suspension of sodium hydride (0.44 g, 11 mmol, 60% w/w in
oil) in dry THF (20 mL) was cooled to 0 ꢁC and either ethyl ace-
toacetate or ethyl 2-methylacetoacetate (10 mmol) was added
dropwise and the mixture stirred for 25 min. n-Butyllithium (1.4 M,
7.5 mL, 10.5 mmol) was added dropwise over a 15 min period then
stirred at 0 ꢁC for a further 25 min. A solution of alkylhalide
(11 mmol) in dry THF (2 mL) was added dropwise and the resulting
solution was stirred at room temperature overnight. The reaction
was quenched with aqueous HCl (3.3 M, 6 mL) and diethyl ether
(15 mL) added. The organic phase was separated and the aqueous
phase was further extracted with diethyl ether (4ꢂ8 mL). The
combined organic extracts were washed with water until neutral,
dried (MgSO4) and solvents were removed under reduced pressure
to give the crude product, which was purified by distillation or flash
chromatography (hexane, ethyl acetate) to afford the title
compound.
4.2.1. Ethyl 2,5-dimethyl-3-oxohexanoate 4g. Prepared using gen-
eral procedure A from ethyl 2-methylacetoacetate 4c (40 mmol,
5.77 g) and 2-iodopropane (44 mmol, 7.48 g) with purification by
flash chromatography (9:1 hexane, ethyl acetate) to afford the title
compound 4h (4.17 g, 56%) as a pale yellow oil; Rf¼0.4; IR (NaCl)
nmax 2960, 2874 (CH), 1746 (CO2R), 1715 (C]O), 1469, 1455, 1367,
1248, 1195; dH (300 MHz; CDCl3) 0.89 (6H, dd, J¼6.6, 2.1 Hz, CH
(CH3)2), 1.24 (3H, t, J¼7.1 Hz, OCH2CH3), 1.30 (3H, d, J¼7.2 Hz,
2-CH3), 2.11e2.20 (1H, m, 5-H), 2.39 (2H, d, J¼8.7 Hz, 4-H), 3.46 (1H,
q, J¼7.1 Hz, 2-H), 4.15 (2H, q, J¼7.3 Hz, OCH2CH3); dC (75 MHz;
CDCl3) 12.6 (2-CH3), 14.0 (OCH2CH3), 22.4 (CH(CH3)2), 24.1 (C-5),
50.2 (C-4), 53.2 (C-2), 61.2 (OCH2CH3), 170.5 (C-1), 205.4 (C-3); m/z
(EIþ) 186 (Mþ, 5%), 141 (4), 129 (7), 102 (14), 85 (100), 74 (12), 57
(84), 41 (18); found [Mþ] 186.12505. C10H18O3 requires 186.12559.
4.3. General procedure B: synthesis of 4-piperidones 5
Methyltrichlorosilane (2.24 g, 15 mmol) was added dropwise to
a mixture of
b-keto ester 4 (10 mmol) and bis-aminol ether 3
(12 mmol) in dry acetonitrile (30 mL) then stirred at room tem-
perature for 20 h. The reaction was then quenched with aqueous
satd NaHCO3 until basic, extracted with ethyl acetate (3ꢂ30 mL),
dried (MgSO4), concentrated in vacuo to give the crude product,
which was purified by flash chromatography (hexane, ethyl ace-
tate) to afford the title compound.
4.3.1. Ethyl 1-butyl-3-methyl-4-oxopiperidine-3-carboxylate 5c. Pre-
pared using general procedure B from b-keto ester 4c (6.3 mmol,
4.2.2. Ethyl 2-methyl-3-oxo-4-phenylbutanoate 4h. Zinc dust (8.17 g,
125 mmol) was activated by sequential addition, stirring for 5 min
and removal, by syringe, of each of 3 M HCl (100 mL), deionised
water (100 mL), ethanol (100 mL) and ether (2ꢂ100 mL), followed
by drying in vacuo. The activated zinc dust was suspended in dry
THF (120 mL) and heated under reflux with stirring, 20 drops of
ethyl 2-bromopropanoate was added and the mixture heated fur-
ther, developing a slight green colour upon successful initiation
(ca. 60 min.). 2-Phenylacetonitrile (2.93 g, 25.0 mmol) was added in
one portion then ethyl 2-bromopropanoate (10.0 g, 55.2 mmol)
was added drop-wise over 1 h. The reaction mixture was heated for
a further 10 min, cooled, diluted with THF (360 mL) and quenched
with aqueous K2CO3 (50%, 52.0 mL). Rapid stirring for 10 min
caused the mixture to separate into two layers, the organic layer
was decanted and the aqueous layer was further extracted with THF
(2ꢂ95 mL). The combined THF fractions were then stirred with 10%
HCl (50 mL) at room temperature for 45 min before being con-
centrated in vacuo. The remaining aqueous mixture was diluted
with dichloromethane (290 mL) and washed with satd NaHCO3
(195 mL). The organic phase was separated before being dried over
MgSO4, filtered, evaporated in vacuo to give the crude product,
which was purified by flash chromatography (9:1 hexane, ethyl
acetate, 9:1) to afford the title compound 4i (5.17 g, 94%) as a yellow
0.91 g) and bis(aminol)ether 3a (7.5 mmol, 1.43 g) with purification
by flash chromatography (3:1 hexane, ethyl acetate) to afford the
title compound 5c (1.37 g, 90%) as a yellow oil; Rf ¼0.25; IR (NaCl)
nmax, 2936, 2873 (CH), 1732 (COO), 1722 (C]O), 1458, 1378, 1129
(CN); dH (300 MHz; CDCl3) 0.89 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3),
1.20 (3H, s, 3-CH3), 1.23 (3H, t, J¼7.1 Hz, OCH2CH3), 1.28e1.40 (2H,
m, NCH2CH2CH2CH3), 1.41e1.50 (2H, m, NCH2CH2CH2CH3), 2.10 (1H,
d, J¼11.5 Hz, 2A-H), 2.26e2.50 (4H, m, NCH2CH2CH2CH3 and 6-CH2),
2.86e3.04 (2H, m, 5-CH2), 3.45 (1H, dd, J¼11.5, 2.9 Hz, 2B-H), 4.12
(2H, m, OCH2CH3); dC (75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 14.1
(OCH2CH3), 17.9 (3-CH3), 20.2 (NCH2CH2CH2CH3), 29.2
(NCH2CH2CH2CH3), 40.4 (C-5), 56.5 (NCH2CH2CH2CH3), 60.8 (C-3),
61.4 (OCH2CH3), 62.2 (C-6), 62.8 (C-2), 173.0 (COO), 207.9 (C-4); m/z
(ESIþ) 242 (MHþ, 100%); found [MHþ] 242.17597. C13H24NO3 re-
quires 242.17562.
4.3.2. Ethyl 1-benzyl-3-methyl-4-oxopiperidine-3-carboxylate 5d. Pre-
pared using general procedure B from b-keto ester 4c (6.3 mmol,
0.91 g) and bis(aminol)ether 3b (7.6 mmol, 1.69 g) with purification
by flash chromatography (2:1 hexane, ethyl acetate) to afford the
title compound 5d (1.43 g, 82%) as a pale yellow oil; Rf ¼0.4; dH
(300 MHz; CDCl3) 1.21 (3H, s, 3-CH3), 1.24 (3H, t, J¼7.1 Hz,
OCH2CH3), 2.15 (1H, d, J¼11.4 Hz, 2A-H), 2.35e2.45 (2H, m, 6-CH2),

7184
Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
2.85e3.07 (2H, m, 5-CH2), 3.47 (1H, dd, J¼11.4, 2.7 Hz, 2B-H), 3.59
(2H, m, NCH2Ph), 4.19 (2H, m, OCH2CH3) and 7.20e7.34 (5H, m, Ph).
The 1H NMR data obtained was in agreement with that reported in
the literature.26
m, NCH2CH2CH2CH3), 1.86 (1H, p, J¼5.4 Hz, 1ꢂ5-CH2CH3), 1.95
(1H, dd, J¼8.6, 1.0 Hz, 2A-H), 1.98 (1H, t, J¼8.5 Hz, 6A-H), 2.29e2.50
(2H, m, NCH2CH2CH2CH3), 2.73e2.81 (1H, m, 5-H), 3.10e3.15 (1H,
m, 6B-H), 3.57 (1H, dd, J¼8.6, 2.2 Hz, 2B-H), 4.15e4.25 (2H, m,
OCH2CH3); dC (100 MHz; CDCl3) 11.6 (5-CH2CH3), 13.9 (OCH2CH3
and NCH2CH2CH2CH3), 17.8 (3-CH3), 19.7 (5-CH2CH3), 20.4
(NCH2CH2CH2CH3), 29.2 (NCH2CH2CH2CH3), 50.1 (C-5), 56.8 (C-3),
56.9 (NCH2CH2CH2CH3), 60.4 (C-6), 61.1 (OCH2CH3), 63.0 (C-2),
173.0 (COO), 207.62 (C-4); m/z (EIþ) 269 (Mþ, 7%), 254 (1), 238 (3),
226 (100), 224 (8), 196 (16), 154 (7), 84 (18), 69 (29), 41 (57); found
[Mþ] 269.19918. C15H27NO3 requires 269.19909.
4.3.3. Ethyl 5-methyl-4-oxo-1-(3-phenylpropyl)-piperidine-3-carboxy-
late 5e. Prepared using general procedure B from b-keto ester 4c
(6.9 mmol, 1.00 g) and bis(aminol)ether 3c (8.3 mmol, 2.10 g) with
purification by flash chromatography (3:1 hexane, ethyl acetate) to
afford the title compound 5e (1.80 g, 86%) as a pale yellow oil; Rf
¼0.3; IR (NaCl) nmax 2996, 2934, 2810 (CH),1732 (COO),1717 (C]O),
1378, 1251, 1136 (CN); dH (400 MHz; CDCl3) 1.21 (3H, s, 3-CH3), 1.22
(3H, t, J¼7.0 Hz, OCH2CH3), 1.75 (2H, m, NCH2CH2CH2Ph), 1.95 (1H,
d, J¼11.4 Hz, 2A-H), 1.97 (1H, t, J¼10.91 Hz, 6A-H), 2.22 (2H, t,
J¼7.1 Hz, NCH2CH2CH2Ph), 2.38e2.60 (4H, m, 6-CH2 and
NCH2CH2CH2Ph), 2.86e3.03 (2H, m, 5-CH2), 3.49 (1H, dd, J¼11.4,
3.1 Hz, 2B-H), 4.20 (2H, q, J¼7.0 Hz, OCH2CH3), 7.14e7.29 (5H, m,
Ph); dC (100 MHz; CDCl3) 14.1 (OCH2CH3), 17.9 (3-CH3), 28.8
(NCH2CH2CH2Ph), 33.5 (NCH2CH2CH2Ph), 40.2 (C-5), 56.9
(NCH2CH2CH2Ph), 60.1 (C-3), 61.3 (OCH2CH3), 61.9 (C-6), 62.9 (C-2),
125.6 (AreC), 128.2 (AreC), 128.6 (AreC), 142.6 (AreC) 173.0 (COO),
207.8 (C-4); m/z (ESIþ) 326 (MNaþ, 100%); found [Mþ] 303.18341.
C18H25NO3 requires 303.18344.
4.3.7. Ethyl (3R
*
,5R
*
)-1-butyl-5-isopropyl-3-methyl-4-oxopiperidine-
-keto
3-carboxylate 5i. Prepared using general procedure B from
b
ester 4g (1.9 mmol, 0.35 g) and bis(aminol)ether 3a (2.3 mmol,
0.43 g) in dry acetonitrile (20 mL) with purification by flash chro-
matography (9:1 hexane, ethyl acetate) to afford the title com-
pound 5i (0.33 g, 65%) as a pale yellow oil; Rf ¼0.4; IR (NaCl) nmax
2958, 2935, 2873, 2809 (CH), 1721, 1721 (COO), 1715 (C]O), 1464,
1456, 1377, 1366, 1248, 1132, 1022 (CeN); dH (300 MHz; CDCl3) 0.85
(3H, d, J¼6.9 Hz, 1ꢂCH(CH3)2), 0.91 (3H, t, J¼7.2 Hz,
NCH2CH2CH2CH3), 0.95 (3H, d, J¼6.9 Hz, 1ꢂCH(CH3)2), 1.19 (3H, s,
3-CH3), 1.23 (3H, t, J¼7.1 Hz, OCH2CH3), 1.27e1.37 (2H, m,
NCH2CH2CH2CH3), 1.39e1.52 (2H, m, NCH2CH2CH2CH3), 1.91 (1H, d,
J¼11.5 Hz, 2A-H), 2.05 (1H, t, J¼11.34 Hz, 6A-H), 2.15 (1H, sex,
J¼6.8 Hz, CH(CH3)2), 2.26e2.49 (2H, m, NCH2CH2CH2CH3), 2.67 (1H,
p, J¼6.0 Hz, 5-H), 3.05e3.12 (1H, m, 6B-H), 3.54 (1H, dd, J¼11.5,
4.0 Hz, 2B-H), 4.10e4.23 (2H, m, OCH2CH3); dC (75 MHz; CDCl3) 14.0
(NCH2CH2CH2CH3 and OCH2CH3), 17.9 (3-CH3), 19.0 (CH(CH3)2),
20.5 (NCH2CH2CH2CH3), 21.3 (CH(CH3)2), 25.0 (CH(CH3)2), 29.3
(NCH2CH2CH2CH3), 54.6 (C-5), 57.0 (C-3), 57.2 (NCH2CH2CH2CH3),
57.5 (C-6), 61.2 (OCH2CH3), 62.9 (C-2), 173.1 (COO), 207.3 (C-4); m/z
(EIþ) 284 (MHþ, 47%), 266 (6), 252 (4), 240 (100), 210 (15), 152 (4),
85 (18), 57 (32); found [MHþ] 284.22275. C16H30NO3 requires
284.22257.
4.3.4. Ethyl 1-benzyl-3-ethyl-4-oxopiperidine-3-carboxylate 5f. Pre-
pared using general procedure B from b-keto ester 4d (6.3 mmol,
1.00 g) and bis(aminol)ether 3b (7.6 mmol, 1.70 g) with purification
by flash chromatography (4:1 hexane, ethyl acetate) to afford the
title compound 5f (1.55 g, 85%) as a pale yellow oil; Rf¼0.3. dH
(300 MHz; CDCl3) 0.82 (3H, t, J¼7.1 Hz, 3-CH2CH3), 1.24 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.75 (2H, q, J¼7.1 Hz, 3-CH2CH3), 2.19 (1H, d,
J¼11.5 Hz, 2A-H), 2.39e2.45 (2H, m, 6-CH2), 2.86e3.09 (2H, m,
5-CH2), 3.48 (1H, d, J¼11.6 Hz, 2B-H), 3.53 (2H, s, NCH2Ph), 4.20 (2H,
m, OCH2CH3) and 7.15e7.31 (5H, m, Ph). The 1H NMR data obtained
were in agreement with that reported in the literature.27
4.3.5. Ethyl 1-butyl-3,5-dimethyl-4-oxopiperidine-3-carboxylate 5g. Pre-
4.3.8. Ethyl (3R
*
,5R
*
)-1-butyl-3-methyl-4-oxo-5-phenylpiperidine-3-
-keto
pared using general procedure B from
b-keto ester 4e (9.5 mmol,
carboxylate 5j. Prepared using general procedure B from b
1.51 g) and bis(aminol)ether 3a (11.4 mmol, 2.16 g) with purifica-
tion by flash chromatography (9:1 hexane, ethyl acetate) to afford
the title compound 5g (1.46 g, 60%) as a pale yellow oil; Rf ¼0.3; IR
(NaCl) nmax 2959, 2934, 2873, 2808 (CH), 1730 (COO), 1719 (C]O),
1457, 1378, 1251, 1135 (CN); dH (300 MHz; CDCl3) 0.90 (3H, t,
J¼7.2 Hz, NCH2CH2CH2CH3), 1.00 (3H, d, J¼6.5 Hz, 5-CH3), 1.20 (3H,
s, 3-CH3), 1.23 (3H, t, J¼7.1 Hz, OCH2CH3), 1.28e1.39 (2H, m,
NCH2CH2CH2CH3), 1.41e1.51 (2H, m, NCH2CH2CH2CH3), 1.95 (1H, d,
J¼11.5 Hz, 2A-H), 1.97 (1H, t, J¼10.9 Hz, 6A-H), 2.26e2.47 (2H, m,
NCH2CH2CH2CH3), 2.89e3.01 (1H, m, 5-H), 3.03e3.10 (1H, m, 6B-H),
3.54 (1H, dd, J¼11.5, 3.1 Hz, 2B-H), 4.17 (2H, q, J¼7.1 Hz, OCH2CH3);
dC (75 MHz; CDCl3) 11.6 (5-CH3), 13.9 (NCH2CH2CH2CH3), 14.0
(OCH2CH3), 17.9 (3-CH3), 20.4 (NCH2CH2CH2CH3), 29.2
(NCH2CH2CH2CH3), 43.2 (C-5), 56.8 (NCH2CH2CH2CH3), 56.8 (C-3),
61.2 (OCH2CH3), 62.2 (C-6), 63.2 (C-2), 173.1 (COO), 208.1 (C-4); m/z
(EIþ) 362 (Mþ, 100%), 256 (16), 212 (65), 178 (23), 154 (11), 122 (4),
100 (12); found [Mþ] 256.19112. C14H26NO3 requires 256.19127.
ester 4h (4.5 mmol, 1.0 g) and bis(aminol)ether 3a (9.0 mmol,
1.70 g) with purification by flash chromatography (14:1 hexane,
ethyl acetate) to afford the title compound 5j (1.26 g, 88%) as a pale
yellow oil. Rf ¼0.5; IR (neat) nmax 3030 (CeH, Ph), 2958, 2933, 2871,
2809, 2775 (CeH), 1718 (COO, C]O), 1603 (C]C) 1498, 1456, 1377,
1302, 1245, 1208, 1192, 1175, 1125, 1107, 1046, 1018 (CeN); dH
(300 MHz; CDCl3) 0.92 (3H, t, J¼7.3 Hz, NCH2CH2CH2CH3), 1.28 (3H,
s, 3-CH3), 1.31 (3H, t, J¼7.1 Hz, OCH2CH3), 1.36 (2H, m,
NCH2CH2CH2CH3), 1.50 (2H, p, J¼7.3 Hz, NCH2CH2CH2CH3), 2.19
(1H, d, J¼11.6 Hz, 2A-H), 2..44 (2H, m, NCH2CH2CH2CH3), 2.57 (1H,
dd, J¼12.0, 11.0 Hz, 6A-H), 3.25 (1H, m, 6B-H), 3.66 (1H, dd, J¼11.6,
3.2 Hz, 2B-H), 4..25 (3H, m, 5-H, OCH2CH3), 7.13e7.16 (5H, m, Ph); dC
(75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 14.1 (OCH2CH3), 18.0
(3-CH3), 20.4 (NCH2CH2CH2CH3), 29.2 (NCH2CH2CH2CH3), 55.6
(C-5), 56.8 (NCH2CH2CH2CH3), 57.0 (C-3), 61.3 (OCH2CH3), 61.5
(C-6), 63.3 (C-2), 127.2 (Ph), 128.3 (Ph), 129.1 (Ph), 136.3 (Ph), 173.0
(COO), 205.1 (C-4); m/z (EIþ, %) 318 (MHþ, 9%), 272 (100), 254 (16),
244 (28), 226 (11), 214 (1), 199 (2), 187 (16), 159 (7), 154 (8), 126 (9);
found [MHþ] 318.2061. C19H28NO3 requires 318.2069.
4.3.6. Ethyl (3R
*
,5R
*
)-1-butyl-5-ethyl-3-methyl-4-oxopiperidine-3-
-keto
carboxylate 5h. Prepared using general procedure B from
b
ester 4f (29 mmol, 5 g) and bis(aminol)ether 3a (35 mmol, 6.60 g)
with purification by flash chromatography (9:1 hexane, ethyl ace-
tate) to afford the title compound 5h (4.93 g, 63%) as a pale yellow
oil; Rf ¼0.4; IR (NaCl) nmax 2960, 2935, 2874, 2807, 2773 (CH), 1720
(C]O and COO), 1457, 1377, 1246, 1203 (CeN), 1134, 1021; dH
(400 MHz; CDCl3) 0.88e0.95 (6H, m, 5-CH2CH3, NCH2CH2CH2CH3),
1.12e1.19 (1H, m, 1ꢂ5-CH2CH3), 1.21 (3H, s, 3-CH3), 1.24e1.29 (3H,
m, OCH2CH3), 1.31e1.38 (2H, m, NCH2CH2CH2CH3), 1.45e1.53 (2H,
4.3.9. Ethyl (3R
*
,5R
*
)-5-allyl-1-butyl-3-methyl-4-oxopiperidine-3-car-
boxylate 5k. Prepared using general procedure B from
b
-keto ester
4i (2 g, 10.9 mmol) and bis(aminol)ether 3a (21.8 mmol, 4.13 g)
with purification by flash chromatography (14:1 hexane, ethyl ac-
etate) to afford the title compound 5k (2.33 g, 76%) as a pale yellow
oil. Rf ¼0.4; IR (neat) nmax 3076 (]CH2, ]CHe), 2979, 2957, 2933,
2872, 2807, 2773 (CeH), 1716 (COO, C]O), 1641 (C]C), 1466, 1455,
1377, 1366, 1300, 1270, 1241, 1173, 1110, 1097, 1020 (CeN); dH

Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
7185
(300 MHz; CDCl3) 0.90 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.20 (3H,
s, 3-CH3), 1.24 (3H, t, J¼7.1 Hz, OCH2CH3), 1.33 (2H, m,
NCH2CH2CH2CH3), 1.46 (2H, m, NCH2CH2CH2CH3), 1.87e2.00 (3H,
m, 2A-H, 5-CHAHBCH]CH2 and 6A-H), 2.36 (2H, m,
NCH2CH2CH2CH3), 2.59 (1H, dtt, J¼14.7, 5.6, 1.5 Hz, 5-CHAHBCH]
CH2), 2.94 (1H, m, 5-H), 3.10 (1H, m, 6B-H), 3.55 (1H, dd, J¼11.5,
3.1 Hz, 2B-H), 4.18 (2H, dq, J¼7.1, 2.1 Hz, OCH2CH3), 5.02 (2H, m,
5-CH2CH]CH2), 5.76 (1H, m, 5-CH2CH]CH2); dC (75 MHz; CDCl3)
13.9 (CH2CH2CH2CH3), 14.0 (OCH2CH3), 17.8 (3-CH3), 20.4
(NCH2CH2CH2CH3), 29.2 (NCH2CH2CH2CH3), 31.1 (5-CH2CH]CH2),
47.8 (C-5), 56.8 (NCH2CH2CH2CH3), 56.9 (C-3), 60.2 (C-6), 61.2
(OCH2CH3), 63.0 (C-2), 116.3 (5-CH2CH]CH2), 135.9 (5-CH2CH]
CH2), 173.0 (COO), 207.1 (C-4); m/z (EIþ, %) 282 (MHþ, 14%), 236
(100), 208 (86), 190 (8), 166 (7), 154 (12), 126 (28), 112 (1), 100 (6);
found [MH]þ 282.2069. C16H28NO3 requires 282.2069.
(OCH2CH3), 18.4 (3-CH3), 19.9 (1ꢂ5-(CH3)2), 20.1 (C-3), 20.2
(NCH2CH2CH2CH3), 20.3 (1ꢂ5-(CH3)2), 32.0 (NCH2CH2CH2CH3), 37.0
(C-6), 50.2 (NCH2CH2CH2CH3), 54.2 (C-5), 54.2 (C-2), 61.1
(OCH2CH3), 172.7 (COO), 212.9 (C-4); m/z (EIþ, %) 270 (Mþ, 100%),
198 (3), 139 (3), 98 (6), 86 (7), 84 (7), 71 (14), 43 (37); found [Mþ]
270.20699. C15H28NO3 requires 270.20692.
4.3.13. Ethyl 1-(3-phenylpropyl)-3,5,5-trimethyl-4-oxopiperidine-3-
carboxylate 5o. Prepared using general procedure B from b-keto
ester 4k (5.8 mmol, 1.00 g) and bis(aminol)ether 3c (6.9 mmol,
1.75 g) with purification by flash chromatography (9:1 hexane,
ethyl acetate) to afford the title compound 5o (1.14 g, 59%) as a pale
yellow oil; Rf ¼0.6; IR (NaCl) nmax 2934, 2879 (CH), 1732 (COO), 1716
(C]O), 1470, 1380, 1242, 1015 (CeN); dH (300 MHz; CDCl3) 1.02 and
1.05 (2ꢂ3H, d, J¼6.8 Hz, 5-(CH3)2), 1.23 (3H, t, J¼7.1 Hz, OCH2CH3),
1.39 (3H, s, 3-CH3), 1.75 (2H, m, NCH2CH2CH2Ph), 2.23 (2H, t,
J¼7.1 Hz, NCH2CH2CH2Ph), 2.68 (2H, t, J¼7.3 Hz, NCH2CH2CH2Ph),
2.86 (2H, m, 6-H), 2.91 (2H, m, 2-H), 4.16 (2H, m, OCH2CH3); dC
(75 MHz; CDCl3) 14.1 (OCH2CH3), 18.3 (3-CH3), 19.8 (1ꢂ5-(CH3)2),
20.1 (C-3), 20.5 (1ꢂ5-(CH3)2), 28.9 (NCH2CH2CH2Ph), 33.5
(NCH2CH2CH2Ph), 37.1 (C-6), 54.6 (C-5), 54.7 (C-2), 56.9
(NCH2CH2CH2Ph), 61.0 (OCH2CH3), 125.6 (AreC), 128.0 (AreC),
128.5 (AreC), 142.6 (AreC), 172.9 (COO), 213.0 (C-4); m/z (ESIþ, %)
332 (MHþ, 100%); found [MHþ] 332.22249. C20H30NO3 requires
332.22257.
4.3.10. Ethyl (3R
*
,5R
*
)-5-allyl-1,5-dimethyl-4-oxopiperidine-3-carboxy-
late 5l. Prepared using general procedure B from
b-keto ester 4i
(1.0 g, 10.9 mmol) and bis(aminol)ether 3d (6.83 mmol, 0.8 g) with
purification by flash chromatography (2:1 hexane, ethyl acetate) to
afford the title compound 5l (1.0 g, 80%) as a pale yellow oil. Rf ¼0.2;
IR (neat) nmax 2936, 2774 (CeH), 1720 (COO, C]O), 1640 (C]C),
1466, 1455, 1248, 1195, 1097, 1021 (CeN); dH (300 MHz; CDCl3)
1.21e1.26 (6H, m, 3-CH3 and OCH2CH3), 1.90e2.03 (3H, m, 2A-H,
5-CHAHBCH]CH2 and 6A-H), 2.31 (3H, s, NCH3), 2.59 (1H, m, 5-
CHAHBCH]CH2), 2.93 (1H, m, 5-H), 3.08 (1H, m, 6B-H), 3.47 (1H, dd,
J¼14.2, 4.0 Hz, 2B-H), 4.20 (2H, m, OCH2CH3), 5.03 (2H, m,
5-CH2CH]CH2), 5.74 (1H, m, 5-CH2CH]CH2); dC (75 MHz; CDCl3)
13.8 (OCH2CH3), 17.6 (3-CH3), 31.2 (5-CH2CH]CH2), 46.8 (NCH3),
47.9 (C-5), 57.0 (C-3), 59.3 (C-6), 61.5 (OCH2CH3), 62.8 (C-2), 116.4
(5-CH2CH]CH2), 136.2 (5-CH2CH]CH2), 173.7 (COO), 208.0 (C-4);
m/z (ESIþ, %) 240 (MHþ, 100%), 208 (32), 115 (1), 100 (6); found
[MH]þ 240.15983. C13H21NO3 requires 240.15996.
4.4. General procedure C: synthesis of 4-hydroxypiperidines 6
A solution of piperidone 5 (10 mmol) in THF (40 mL) was added
to a solution of sodium borohydride (0.19 g, 5 mmol) in THF (40 mL)
and deionised water (40 mL). The mixture was stirred for 30 min at
0 ꢁC, then stirred for 3 h at room temperature. The reaction was
quenched with 2 M NaOH and extracted with diethyl ether
(3ꢂ100 mL). The combined organic extracts were washed with
brine, dried (MgSO4) and concentrated in vacuo to give the crude
product, which was purified by flash chromatography (hexane,
ethyl acetate) to afford the title compound.
* *
4.3.11. Ethyl (3R ,5R )-1-tert-butyl-3,5-diethyl-4-oxopiperidine-3-car-
boxylate 5m. Prepared using general procedure B from
b
-keto ester
4j (5.9 mmol, 1.1 g) and bis(aminol)ether 3e (7.7 mmol, 1.22 g) with
purification by flash chromatography (3:1 hexane, ethyl acetate) to
afford the title compound 5m (1.3 g, 79%) as a pale yellow oil; Rf
¼0.4; IR (NaCl) nmax 2962, 2874, 2773 (CH), 1719 (C]O and COO),
1200 (CeN); dH (400 MHz; CDCl3) 0.89 (3H, t, J¼7.9 Hz, 5-CH2CH3),
0.93 (3H, t, J¼8.0 Hz, 3-CH2CH3), 1.24 (9H, s, NC(CH3)3), 1.11e1.23
(1H, m, 1ꢂ5-CH2CH3), 1.27 (3H, m, OCH2CH3), 1.54 (2H, m, 3-
CH2CH3), 1.87 (1H, m, 1ꢂ5-CH2CH3), 1.98 (1H, t, J¼8.9 Hz, 6A-H),
2.06 (1H, dd, J¼8.7, 1.0 Hz, 2A-H), 2.69 (1H, m, 5-H), 3.27e3.32 (1H,
m, 6B-H), 3.66 (1H, dd, J¼8.7, 2.0 Hz, 2B-H), 4.15e4.23 (2H, m,
OCH2CH3); dC (100 MHz; CDCl3) 9.30 (3-CH2CH3), 11.8 (5-CH2CH3),
14.2 (OCH2CH3), 19.8 (5-CH2CH3), 24.1 (3-CH2CH3), 26.4 (NC(CH3)3),
51.2 (C-5), 53.2 (NC(CH3)3), 56.3 (C-3), 60.7 (C-6), 60.9 (OCH2CH3),
61.6 (C-2), 174.9 (COO), 208.4 (C-4); m/z (ESI) 284 (Mþ, 100%), 272
(50), 226 (M-C4H9, 15); found [MHþ] 284.2220. C16H30NO3 requires
269.2223.
4.4.1. Ethyl (3R ,4S
* *
,5R )-1-butyl-3,5-dimethyl-4-hydroxypiperidine-
*
3-carboxylate 6a. Prepared using general procedure C from piper-
idone 5g (5.6 mmol, 1.4 g) and sodium borohydride (2.8 mmol,
0.11 g) with purification by flash chromatography (4:1 hexane,
ethyl acetate) to afford the title compound 6a (1.41 g, 98%) as a pale
yellow oil; Rf ¼0.5; IR (NaCl) nmax 3519 (OH), 2956, 2932, 2873,
2805, 2765 (CH), 1708 (COO), 1466, 1376, 1327, 1252, 1216 (CeN),
1140, 1068 (CeO); dH (300 MHz; CDCl3) 0.86 (3H, t, J¼7.1 Hz,
NCH2CH2CH2CH3), 0.97 (3H, d, J¼6.5 Hz, 5-CH3), 1.22e1.28 (8H, m,
3-CH3, OCH2CH3, NCH2CH2CH2CH3), 1.30e1.44 (2H, m,
NCH2CH2CH2CH3), 1.61 (1H, d, J¼11.5 Hz, 2A-H), 1.64 (1H, t, J¼11.1,
6A-H), 1.90e2.01 (1H, m, 5-H), 2.08e2.31 (2H, m, NCH2CH2CH2CH3),
2.69 (1H, t, J¼11.2 Hz, 4-H), 2.73e2.79 (1H, m, 6B-H), 3.26 (1H, dd,
J¼11.5, 5.2 Hz, 2B-H), 3.36 (1H, d, J¼11.2 Hz, OH), 4.14 (2H, q,
J¼7.1 Hz, OCH2CH3); dC (75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3),
14.0 (OCH2CH3), 20.4 (NCH2CH2CH2CH3), 21.3 (3-CH3), 29.2
(NCH2CH2CH2CH3), 36.3 (C-5), 47.9 (C-3), 57.4 (NCH2CH2CH2CH3),
60.4 (OCH2CH3), 61.7 (C-6), 62.1 (C-2), 81.9 (C-4), 177.4 (COO); m/z
(CIþ) 258 (Mþ, 64%), 240 (3), 214 (100), 168 (12), 140 (5), 84 (10);
found [M]þ 258.20681. C14H28NO3 requires 258.20692.
4.3.12. Ethyl 1-butyl-3,5,5-trimethyl-4-oxopiperidine-3-carboxylate
5n. Prepared using general procedure B from
b-keto ester 4k
(5.7 mmol, 0.96 g) and bis(aminol)ether 3a (6.7 mmol, 1.27 g) with
purification by flash chromatography (9:1 hexane, ethyl acetate) to
afford the title compound 5n (0.77 g, 51%) as a pale yellow oil; Rf
¼0.6; IR (NaCl) nmax 2961, 2933, 2874 (CH), 1738, 1732 (COO), 1713
(C]O), 1470, 1463, 1456, 1380, 1242, 1109, 1015 (CeN); dH
(300 MHz; CDCl3) 0.85 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.03 and
1.05 (2ꢂ3H, d, J¼6.7 Hz, 5-(CH3)2), 1.24 (3H, t, J¼7.1 Hz, OCH2CH3),
1.22e1.40 (4H, m, NCH2CH2CH2CH3 and NCH2CH2CH2CH3), 1.38
(3H, s, 3-CH3), 2.53 (2H, t, J¼6.9 Hz, NCH2CH2CH2CH3), 2.86 (2H, t,
J¼6.7 Hz, 6-H), 2.91 (2H, d, J¼1.5 Hz, 2-H), 4.16 (2H, q, J¼10.7 Hz,
OCH2CH3); dC (75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 14.0
4.4.2. Ethyl (3R ,4S
* *
,5R )-1-butyl-5-ethyl-4-hydroxy-3-methylpiper-
*
idine-3-carboxylate 6b. Prepared using general procedure C from
piperidone 5h (0.74 mmol, 0.2 g) and sodium borohydride
(0.37 mmol, 140 mg) with purification by flash chromatography
(4:1 hexane, ethyl acetate) to afford the title compound 6b (0.19 g,
94%) as a pale yellow oil; Rf ¼0.4; IR (NaCl) nmax 3518 (OH), 2960,
2933, 2874, 2804, 2765 (CH), 1708 (COO), 1465, 1378, 1324, 1248,

7186
Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
1238, 1215 (CN), 1139, 1067 (CeO); dH (300 MHz; CDCl3) 0.87 (3H, t,
J¼7.1 Hz, NCH2CH2CH2CH3), 0.88 (3H, t, J¼7.5 Hz, 5-CH2CH3), 1.06
(1H, p, J¼7.5 Hz, 1ꢂ5-CHACH3), 1.20e1.32 (7H, m, 3-CH3, OCH2CH3,
NCH2CH2CH2CH3), 1.35e1.42 (2H, m, NCH2CH2CH2CH3), 1.57 (1H, d,
J¼11.5 Hz, 2A-H), 1.61 (1H, t, J¼11.0 Hz, 6A-H), 1.71e1.79 (1H, m,
5-H), 1.87e1.96 (1H, m, 1ꢂ5-CHBCH3), 2.09e2.36 (2H, m,
NCH2CH2CH2CH3), 2.77 (1H, t, J¼11.1 Hz, 4-H), 2.90 (1H, dt, J¼11.0,
3.4 Hz, 6B-H), 3.27 (1H, dd, J¼11.5, 2.5, 2B-H), 3.38 (1H, d, J¼11.8 Hz,
OH), 4.15 (2H, q, J¼7.1 Hz, OCH2CH3); dC (100 MHz; CDCl3) 11.4
(5-CH2CH3), 14.0 (OCH2CH3, NCH2CH2CH2CH3), 20.5 (NCH2-
CH2CH2CH3), 21.4 (3-CH3), 23.14 (5-CH2CH3), 29.2 (NCH2CH2-
CH2CH3), 42.6 (C-5), 47.9 (C-3), 57.6 (NCH2CH2CH2CH3), 59.2 (C-6),
60.5 (OCH2CH3), 61.8 (C-2), 80.4 (C-4), 177.4 (COO); m/z (EIþ) 271
(Mþ 7%), 256 (3), 228 (100), 226 (6), 182 (12), 149 (20), 124 (11), 84
(21), 69 (29), 57 (47), 43 (46), 41 (61); found [M]þ 271.21512.
C15H29NO3 requires 271.21474.
piperidone 5k (5.3 mmol, 1.50 g) and sodium borohydride
(6.4 mmol, 0.24 g) with purification by flash chromatography (9:1
hexane, ethyl acetate) to afford the title compound 6e (1.41 g, 93%)
as a yellow oil. Rf ¼0.35; IR (neat) nmax 3511 (OeH), 3076 (]CH2, ]
CHe), 2959, 2931, 2873, 2803, 2766 (CeH),1705 (COO),1640 (C]C),
1466, 1414, 1377, 1317, 1299, 1275, 1237, 1208 (CeN), 1145, 1112,
1095, 1069. 1038, 1024, 992 (CeO); dH (300 MHz; CDCl3) 0.89 (3H, t,
J¼7.1 Hz, NCH2CH2CH2CH3), 1.27 (3H, t, J¼7.1 Hz, OCH2CH3), 1.27
(3H, s, 3-CH3), 1.29e1.42 (4H, m, NCH2CH2CH2CH3), 1.62 (1H, d,
J¼11.7 Hz, 2A-H), 1.64 (1H, t, J¼11.2 Hz, 6A-H), 1.79e2.04 (2H, m,
5-CHAHBCH]CH2 and 5-H), 2.23 (2H, m, NCH2CH2CH2CH3), 2.67
(1H, m, 5-CHAHBCH]CH2), 2.79e2.90 (2H, m, 4-H and 6B-H), 3.29
(1H, dd, J¼11.7, 2.6 Hz, 2B-H), 3.46 (1H, d, J¼10.7 Hz, 4-OH), 4.17
(2H, q, J¼7.1 Hz, OCH2CH3), 5.02 (2H, m, 5-CH2CH]CH2), 5.79 (1H,
m, 5-CH2CH]CH2); dC (75 MHz; CDCl3) 14.0 (NCH2CH2CH2CH3,
OCH2CH3), 20.5 (NCH2CH2CH2CH3), 21.3 (3-CH3), 29.2 (NCH2-
CH2CH2CH3), 34.9 (5-CH2CH]CH2), 40.8 (C-5), 57.8 (NCH2CH2-
CH2CH3), 59.2 (C-6), 60.5 (OCH2CH3), 61.8 (C-2), 79.9 (C-4), 116.0
(5-CH2CH]CH2), 136.8 (5-CH2CH]CH2), 177.4 (COO); m/z (EIþ, %)
284 (MHþ, 53%), 266 (100), 238 (38), 224 (14), 210 (23), 194 (39),
181 (40), 153 (23), 135 (19), 107 (14); found [MHþ] 284.2214.
C16H30NO3 requires 284.2226.
4.4.3. Ethyl (3R
*
,4S
*
,5R )-1-butyl-4-hydroxy-5-isopropyl-3-methylpiper-
*
idine-3-carboxylate 6c. Prepared using general procedure C using
piperidone 5i (3.9 mmol,1.05 g) and sodium borohydride (1.9 mmol,
75 mg) with purification by flash chromatography (4:1 hexane, ethyl
acetate) to afford the title compound 6c (1.07 g, 98%) as a pale yellow
oil; Rf ¼0.5; IR (NaCl) nmax 3514 (OH), 2957, 2933, 2873, 2807 (CH),
1708 (COO),1465,1245,1216,1135 (CeO),1068 (CeN); dH (300 MHz;
CDCl3) 0.83 (3H, d, J¼7.1 Hz, 1ꢂ CH(CH3)2), 0.87 (3H, t, J¼7.2 Hz,
NCH2CH2CH2CH3), 0.88e0.97 (2H, m, NCH2CH2CH2CH3), 0.93 (3H, d,
J¼7.2 Hz,1ꢂCH(CH3)2),1.25 (3H, t, J¼7.1 Hz, OCH2CH3),1.26 (3H, s, 3-
CH3), 1.32e1.45 (2H, m, NCH2CH2CH2CH3), 1.54 (1H, d, J¼11.5 Hz, 2A-
H), 1.70 (1H, d, J¼11.3 Hz, 6A-H), 1.79e1.88 (1H, m, 5-H), 2.03e2.34
(3H, m, CH(CH3)2, NCH2CH2CH2CH3), 2.70e2.75 (1H, m, 6B-H), 3.00
(1H, d, J¼10.5 Hz, 4-H), 3.26 (1H, dd, J¼11.5, 3.4 Hz, 2B-H), 3.72e3.74
(1H, m, OH), 4.14 (2H, qd, J¼7.1, 1.7 Hz, OCH2CH3); dC (100 MHz;
CDCl3) 14.0 (OCH2CH3, NCH2CH2CH2CH3), 16.8 (1ꢂCH(CH3)2), 20.5
(NCH2CH2CH2CH3), 20.9 (3-CH3), 21.5 (1ꢂCH(CH3)2), 25.6 (CH
(CH3)2), 29.2 (NCH2CH2CH2CH3), 45.6 (C-5), 47.8 (C-3), 54.4 (C-6),
57.8 (NCH2CH2CH2CH3), 60.4 (OCH2CH3), 61.7 (C-2), 77.6 (C-4), 177.5
(COO); m/z (CIþ) 286 (MHþ, 15%), 242 (65), 200 (100), 100 (23), 86
(21), 58 (33); found [MH]þ 286.23857. C16H32NO3 requires
286.23822.
* *
4.4.6. Reduction of piperidone 5n to give ethyl (3R ,4S )-1-butyl-4-
hydroxy-3,5,5-trimethylpiperidine-3-carboxylate and ethyl (3R
*
,4R )-
*
1-butyl-4-hydroxy-3,5,5-trimethylpiperidine-3-carboxylate. Prepared
using general procedure C from piperidone 5n (0.33 mmol, 90 mg)
and sodium borohydride (0.17 mmol, 6 mg) with purification by
flash chromatography (4:1 hexane, ethyl acetate) to afford the title
compounds (82 mg, 91%) as a pale yellow oil as a mixture of in-
separable diastereomers, where denotes signals from the second
*
diastereomer; Rf ¼0.4; IR (NaCl) nmax 3522 (OH), 2954, 2931, 2920,
2867, 2782, 2766 (CH), 1707 (COO), 1465, 1372, 1313, 1265, 1234,
1210 (CN), 1122, 1097 (CeO);dH (300 MHz; CDCl3) 0.82e0.96
(2ꢂ9H, m, 2ꢂC(CH3)2, 2ꢂC(CH3)2
CH2CH3), 1.08 (3H, s, 3-CH3
), 1.20 (3H, s, 3-CH3), 1.23 (3H, t, J¼7.1 Hz,
OCH2CH3), 1.24 (3H, t, J¼6.3 Hz, OCH2CH3), 1.28e1.34 (2ꢂ2H, m,
NCH2CH2CH2CH3, NCH2CH2CH2CH3
), 1.35e1.43 (2ꢂ2H, m, NCH2-
CH2CH2CH3, NCH2CH2CH2CH3
), 2.58e2.48 (2ꢂ2H, m, NCH2-
CH2CH2CH3, NCH2CH2CH2CH3 ), 2.78
), 2.64 (1H, d, J¼10.5 Hz, 6-H
(1H, d, J¼12.4 Hz, 6-H), 2.97 (2H, d, J¼4.8 Hz, 2-H ), 3.01 (2H, d,
J¼5.1 Hz, 2-H), 3.49 (1H, d, J¼4.0 Hz, 4-H ), 3.81 (1H, d, J¼5.5 Hz, 4-
H), 4.06e4.16 (2ꢂ3H, m, OCH2CH3, OCH2CH3, OH, OH ); dC (75 MHz;
CDCl3) 13.8e14.1 (OCH2CH3, OCH2CH3, NCH2CH2CH2CH3, NCH2-
CH2CH2CH3), 16.8 (3-CH3 ), 18.5 (1ꢂ5-(CH3)2),
), 16.9 (1ꢂ5-(CH3)2
20.2 (NCH2CH2CH2CH3 ), 22.0 (1ꢂ5-
), 20.4 (3-CH3), 21.3 (1ꢂ5-(CH3)2
(CH3)2), 29.6 (C-3 ), 30.9 (C-3), 31.8 (NCH2CH2CH2CH3), 31.9
(NCH2CH2CH2CH3), 48.7 (C-5 ), 49.7 (NCH2CH2CH2CH3), 50.0 (C-5),
50.1 (NCH2CH2CH2CH3), 56.3 (C-2 , C-6 ), 56.7 (C-2, C-6), 60.5
(OCH2CH3), 60.6 (OCH2CH3), 81.0 (C-4 ), 82.3 (C-4), 175.9 (COO ),
*
, NCH2CH2CH2CH3, NCH2CH2-
*
*
*
*
*
*
*
4.4.4. Ethyl(3R
*
,4S
*
,5R
*
)-1-butyl-4-hydroxy-3-methyl-5-phenylpiperidine-
*
3-carboxylate 6d. Prepared using general procedure C from piper-
idone 5j (6.0 mmol, 1.90 g) and sodium borohydride (7.2 mmol,
0.272 g) with purification by flash chromatography (9:1 hexane,
ethyl acetate) to afford the title compound 6d (1.88 g, 98%) as
a yellow oil. Rf ¼0.4; IR (neat) nmax 3522 (OeH), 3028 (CeH, Ph),
2955, 2392, 2872, 2805, 2767 (CeH), 1705 (COO), 1603 (C]C), 1497,
1466, 1455, 1415, 1377, 1325, 1299, 1245, 1211 (CeN), 1145, 1132,
1093, 1068, 1023, 983 (CeO); dH (300 MHz; CDCl3) 0.89 (3H, t,
J¼7.1 Hz, NCH2CH2CH2CH3), 1.26e1.47 (4H, m, NCH2CH2CH2CH3),
1.31 (3H, t, J¼7.1 Hz, OCH2CH3), 1.36 (3H, s, 3-CH3), 1.83 (1H, d,
J¼11.6 Hz, 2A-H), 2.10 (1H, t, J¼11.4 Hz, 6A-H), 2.28 (2H, m,
NCH2CH2CH2CH3), 2.92 (1H, m, 6B-H), 3.22 (1H, m, 5-H), 3.39 (1H,
dd, J¼11.6, 2.5 Hz, 2B-H), 3.41 (1H, m, 4-OH), 3.45 (1H, m, 4-H), 4.22
(2H, q, J¼7.1 Hz, OCH2CH3), 7.18e7.34 (5H, m, Ph); dC (75 MHz;
CDCl3) 13.9 (NCH2CH2CH2CH3), 14.0 (OCH2CH3), 20.4 (NCH2-
CH2CH2CH3), 21.3 (3-CH3), 29.2 (NCH2CH2CH2CH3), 48.1 (C-3), 48.5
(C-5), 57.2 (NCH2CH2CH2CH3), 60.6 (OCH2CH3), 61.8 (C-6), 62.1
(C-2), 79.2 (C-4), 126.6 (Ph), 128.1 (Ph), 128.4 (Ph), 141.2 (Ph), 177.1
(COO); m/z (EIþ, %) 320 (MHþ, 7%), 302 (59), 292 (1), 274 (41), 256
(3), 246 (15), 228 (60), 217 (5), 204 (1), 189 (10), 171 (100), 161 (3),
143 (91), 128 (27); found [MHþ] 320.2214. C19H30NO3 requires
320.2226.
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
176.3 (COO); m/z (Clþ) 272 (Mþ, 6%), 270 (13), 228 (12), 173 (42), 172
(41), 129 (24), 127 (30), 86 (81), 83 (51), 71 (100); found [M]þ
272.22222. C15H30NO3 requires 272.22257.
4.5. General procedure D: synthesis of 4-alkoxypiperidines 7
To a solution of 4-hydroxypiperidine 6 (1 mmol) in dry THF
(10 mL) was added dropwise to a suspension of sodium hydride
(80 mg, 2 mmol, 60% w/w in oil) in dry THF (10 mL) and stirred for
1 h at room temperature, iodomethane or allyl bromide (3 mmol)
was added dropwise and the mixture stirred in a well sealed flask
(preferably a Teflon sealed pressure tube) for 3 days at room tem-
perature. The reaction was quenched with deionised water (30 mL)
and the resulting aqueous mixture extracted with ethyl acetate
(4ꢂ25 mL). The combined organic extracts were washed with
brine, dried (MgSO4), concentrated in vacuo to give the crude
4.4.5. Ethyl (3R
*
,4S
*
,5R
*
)-5-allyl-1-butyl-4-hydroxy-3-methylpiper-
idine-3-carboxylate 6e. Prepared using general procedure C from

Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
7187
product, which was purified by flash chromatography (hexane,
ethyl acetate) to afford the title compound.
(62), 83 (96); found [MH]þ 300.25301. C17H34NO3 requires
300.25387.
* * *
4.5.1. Ethyl (3R ,4S ,5R )-1-butyl-3,5-dimethyl-4-methoxypiperidine-
4.5.4. Ethyl (3R
*
,4S
*
,5R )-1-butyl-4-methoxy-3-methyl-5-phenyl-
*
3-carboxylate 7a. Prepared using general procedure D from alcohol
6a (6.3 mmol, 1.62 g) and iodomethane (18.9 mmol, 1.19 mL) with
purification by flash chromatography (9:1 hexane, ethyl acetate) to
afford the title compound 7a (1.71 g, 68%) as a pale yellow oil; Rf
¼0.4; IR (NaCl) nmax 2956, 2928, 2872, 2825 (CH), 1744 (COO), 1465,
1375, 1260, 1237, 1188 (CeN), 1105, 1095 (CeO); dH (300 MHz;
CDCl3) 0.85 (3H, t, J¼7.1 Hz, NCH2CH2CH2CH3), 0.97 (3H, d,
J¼6.4 Hz, 5-CH3), 1.19e1.29 (8H, m, 3-CH3, OCH2CH3, NCH2-
CH2CH2CH3), 1.31e1.41 (2H, m, NCH2CH2CH2CH3), 1.65e1.78 (3H,
m, 2A-H, 5-H, 6A-H), 2.08e2.30 (2H, m, NCH2CH2CH2CH3),
2.42e2.47 (1H, m, 4-H), 2.67e2.73 (1H, m, 6B-H), 3.04 (1H, dd,
J¼11.4, 2.2 Hz, 2B-H), 3.47 (3H, s, OCH3), 4.06e4.17 (2H, m,
OCH2CH3); dC (75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 14.2
(OCH2CH3), 16.6 (5-CH3), 20.4 (NCH2CH2CH2CH3), 21.5 (3-CH3),
29.2 (NCH2CH2CH2CH3), 34.0 (C-5), 48.9 (C-3), 57.3
(NCH2CH2CH2CH3), 59.7 (OCH2CH3), 60.9 (C-6), 62.2 (C-2), 62.3
(OCH3), 91.8 (C-4), 173.9 (COO); m/z (Clþ) 272 (Mþ, 80%), 240 (4),
228 (100), 210 (2), 185 (5), 166 (6), 124 (3); found [M]þ 272.22228.
C15H30NO3 requires 272.22257.
piperidine-3-carboxylate 7d. Prepared using general procedure D
from alcohol 6d (5.1 mmol, 1.63 g) and iodomethane (15.3 mmol,
0.96 mL) with purification by flash chromatography (9:1 hexane,
ethyl acetate) to afford the title compound 7d (1.59 g, 93%) as
a yellow oil. Rf ¼0.3; IR (neat) nmax 3086, 3060, 3028 (CeH, Ph),
2955, 2931, 2873, 2818, 2767 (CeH), 1736 (COO), 1602 (C]C), 1494.
1465, 1454, 1365, 1311, 1276, 1249 (CeN), 1198, 1187, 1147, 1127,
1095, 1020 (CeO); dH (300 MHz; CDCl3) 0.88 (3H, t, J¼7.2 Hz,
NCH2CH2CH2CH3), 1.24 (3H, s, 3-CH3), 1.27 (3H, t, J¼7.5 Hz,
OCH2CH3), 1.30 (2H, sext, J¼7.1 Hz, NCH2CH2CH2CH3), 1.41 (2H, p,
J¼6.7 Hz, NCH2CH2CH2CH3), 1.99 (1H, d, J¼11.5 Hz, 2A-H),
2.20e2.39 (3H, m, NCH2CH2CH2CH3 and 6A-H), 2.88 (1H, ddd,
J¼11.4, 4.5, 2.1 Hz, 6B-H), 2.97 (3H, s, 4-OCH3), 3.03 (1H, d, J¼9.5 Hz,
4-H), 3.13 (1H, dd, J¼11.5, 2.1 Hz, 2B-H), 3.66 (1H, td, J¼9.5, 4.5 Hz,
5-H), 4.12e4.23 (2H, m, OCH2CH3), 7.18e7.41 (5H, m, Ph); dC
(75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 14.2 (OCH2CH3), 20.3
(NCH2CH2CH2CH3), 21.4 (3-CH3), 29.2 (NCH2CH2CH2CH3), 44.9
(C-5), 48.9 (C-3), 57.3 (NCH2CH2CH2CH3), 59.3 (C-6), 59.8
(OCH2CH3), 61.4 (OeCH3), 62.0 (C-2), 90.2 (C-4), 126.4 (Ph), 128.1
(Ph),128.5 (Ph),141.9 (Ph),173.7 (COO); m/z (EIþ, %) 334 (MHþ,13%),
302 (100), 288 (10), 274 (23), 256 (2), 228 (46), 217 (6), 189 (8), 171
(56), 143 (47), 128 (10); found [MHþ] 334.2375. C20H32NO3 requires
334.2382.
4.5.2. Ethyl (3R
*
,4S
*
,5R )-1-butyl-5-ethyl-4-methoxy-3-methylpiper-
*
idine-3-carboxylate 7b. Prepared using general procedure D from
alcohol 6b (3.3 mmol, 0.90 g) and iodomethane (10.0 mmol,
0.63 mL) with purification by flash chromatography (9:1 hexane,
ethyl acetate) to afford the title compound 7b (0.89 g, 94%) as a pale
yellow oil; Rf ¼0.45; IR (NaCl) nmax 2958, 2929, 2873, 2820 (CH),
1738 (COO), 1463, 1368, 1240 (CeN), 1108, 1094, 1027 (CeO); dH
(400 MHz; CDCl3) 0.86 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 0.91 (3H,
t, J¼7.5 Hz, 5-CH2CH3), 1.10e1.19 (1H, m, 5-CHACH3), 1.22 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.25e1.31 (2H, m, NCH2CH2CH2CH3), 1.27 (3H,
s, 3-CH3), 1.33e1.41 (2H, m, NCH2CH2CH2CH3), 1.64 (1H, s, 5-
CHBCH3), 1.70e1.80 (1H, m, 6-H), 1.85 (1H, d, J¼11.5 Hz, 2A-H),
2.12e2.35 (3H, m, 5-H, NCH2CH2CH2CH3), 2.60 (1H, d, J¼8.5 Hz, 4-
H), 2.76 (1H, d, J¼8.3 Hz, 6B-H), 2.97 (1H, d, J¼11.5 Hz, 2B-H), 3.43
(3H, s, OCH3), 4.07e4.17 (2H, m, OCH2CH3); dC (100 MHz; CDCl3)
11.8 (5-CH2CH3), 14.0 (NCH2CH2CH2CH3), 14.2 (OCH2CH3), 20.5
(NCH2CH2CH2CH3), 21.6 (3-CH3), 23.7 (5-CH2CH3), 29.2
(NCH2CH2CH2CH3), 40.4 (C-5), 48.7 (C-3), 57.5 (NCH2CH2CH2CH3),
57.7 (C-6), 59.8 (OCH2CH3), 61.3 (C-2), 61.4 (OCH3), 90.0 (C-4), 174.2
(COO); m/z (Clþ) 286 (Mþ, 100%), 254 (5), 242 (72), 240 (6), 180 (4);
found [M]þ 286.23775. C16H32NO3 requires 286.23822.
4.5.5. Ethyl (3R
*
,4S
*
,5R )-5-allyl-1-butyl-4-methoxy-3-methylpiper-
*
idine-3-carboxylate 7e. Prepared using general procedure D from
alcohol 6e (0.7 mmol, 0.20 g) and iodomethane (2.1 mmol, 0.12 mL)
with purification by flash chromatography (9:1 hexane, ethyl ace-
tate) to afford the title compound 7e (0.184 g, 87%) as a yellow oil. Rf
¼0.4; IR (neat) nmax 3076 (]CH2, ]CHe), 2956, 2931, 2874, 2821,
2760 (CeH), 1737 (COO), 1640 (C]C), 1466, 1366, 1312, 130, 1271,
1239 (CeN), 1187, 1151, 1133, 1107, 1090, 1053, 1027, 992, 971 (CeO);
dH (300 MHz; CDCl3) 0.87 (3H, t, J¼7.1 Hz, NCH2CH2CH2CH3), 1.24
(3H, t, J¼7.1 Hz, OCH2CH3), 1.29 (3H, s, 3-CH3), 1.29e1.43 (4H, m,
NCH2CH2CH2CH3), 1.77e1.98 (3H, m, 6A-H, 2A-H and 5-CHAHBCH]
CH2), 2.12e2.43 (3H, m, NCH2CH2CH2CH3 and 5-H), 2.51 (1H, m,
5-CHAHBCH]CH2), 2.65 (1H, d, J¼8.5 Hz, 4-H), 2.72 (1H, ddd,
J¼11.2, 4.0, 1.5 Hz, 6B-H), 2.99 (1H, dd, J¼11.4, 1.5 Hz, 2B-H), 2.45
(3H, s, 4-OCH3), 4.14 (2H, m, OCH2CH3), 5.02 (2H, m, 5-CH2CH]
CH2), 5.79 (1H, m, 5-CH2CH]CH2); dC (75 MHz; CDCl3) 13.9
(NCH2CH2CH2CH3), 14.2 (OCH2CH3), 20.4 (NCH2CH2CH2CH3), 21.6
(3-CH3), 29.2 (NCH2CH2CH2CH3), 35.6 (5-CH2CH]CH2), 38.3 (C-5),
48.8 (C-3), 57.5 (NCH2CH2CH2CH3 and C-6), 59.8 (OCH2CH3), 61.3
(C-2), 61.6 (4-OCH3), 89.3 (C-4), 115.9 (5-CH2CH]CH2), 137.1
(5-CH2CH]CH2), 174.0 (COO); m/z (EIþ, %) 298 (MHþ, 29%), 266
(100), 252 (15), 238 (18), 224 (11), 211 (3), 192 (11), 181 (34),168 (5),
153 (18), 135 (17), 117 (4), 100 (6); found [MHþ] 298.2381.
C17H32NO3 requires 298.2382.
4.5.3. Ethyl (3R
*
,4S
*
,5R )-1-butyl-5-isopropyl-4-methoxy-3-methyl-
*
piperidine-3-carboxylate 7c. Prepared using general procedure D
from alcohol 6c (6.0 mmol, 1.70 g) and iodomethane (17.9 mmol,
1.14 mL) with purification by flash chromatography (9:1 hexane,
ethyl acetate) to afford the title compound 7c (1.47 g, 79%) as a pale
yellow oil; Rf ¼0.5; IR (NaCl) nmax 2957, 2928, 2871, 2818 (CH), 1738
(COO), 1464, 1367, 1268, 1239 (CeN), 1136, 1106, 1094 (CeO); dH
(300 MHz; CDCl3) 0.85 (3H, t, J¼6.3 Hz, NCH2CH2CH2CH3), 0.87 (3H,
d, J¼7.2 Hz, 1ꢂCH(CH3)2), 0.97 (3H, d, J¼6.6 Hz, 1ꢂCH(CH3)2),
1.19e1.28 (2H, m, NCH2CH2CH2CH3),1.21 (3H, t, J¼7.1 Hz, OCH2CH3),
1.28 (3H, s, 3-CH3), 1.31e1.42 (2H, m, NCH2CH2CH2CH3), 1.80 (1H, d,
J¼11.4 Hz, 2A-H), 1.93 (1H, d, J¼10.9 Hz, 6A-H), 2.07e2.30 (4H, m,
5-H, CH(CH3)2, NCH2CH2CH2CH3), 2.60 (1H, d, J¼10.9 Hz, 6B-H),
2.85 (1H, d, J¼8.4 Hz, 4-H), 2.95 (1H, dd, J¼11.4, 1.6 Hz, 2B-H), 3.43
(3H, s, OCH3), 4.05e4.16 (2H, m, OCH2CH3); dC (75 MHz; CDCl3) 14.0
(NCH2CH2CH2CH3), 14.2 (OCH2CH3), 20.5 (NCH2CH2CH2CH3), 21.6
(3-CH3, CH(CH3)2), 21.8 (CH(CH3)2), 25.5 (CH(CH3)2), 29.3
(NCH2CH2CH2CH3), 43.9 (C-5), 48.8 (C-3), 53.3 (C-6), 57.9
(NCH2CH2CH2CH3), 59.8 (OCH2CH3), 61.3 (OCH3), 61.4 (C-2), 86.4
(C-4), 174.2 (COO); m/z (Clþ) 300 (MHþ, 34%), 256 (100), 254 (6), 85
4.5.6. Ethyl (3R
*
,4S
*
,5R )-5-allyl-4-(allyloxy)-1-butyl-3-methylpiper-
*
idine-3-carboxylate 7f. Prepared using general procedure D using
alcohol 6e (3.5 mmol, 1.0 g) and allyl bromide (11 mmol, 1.85 g)
with purification by flash chromatography (9:1 hexane, ethyl
acetate) to afford the title compound 7f (0.81 g, 71%) as a pale
yellow oil. Rf ¼0.6; IR (neat) nmax 3075 (]CH2, ]CHe), 2957,
2935, 2875, 2807, 2764 (CeH), 1736 (COO), 1639 (C]C), 1466,
1427, 1407, 1366, 1350, 1309, 1299 (CeN), 1272, 1238, 1202, 1172,
1154, 1131, 1106, 1081, 1052, 1026, 992 (CeO); dH (300 MHz;
CDCl3) 0.88 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.24 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.24e1.44 (4H, m, NCH2CH2CH2CH3), 1.29
(3H, s, 3-CH3), 1.85e2.04 (3H, m, 6A-H, 2A-H, 5-CHAHBCH]CH2),
2.13e2.37 (3H, m, NCH2CH2CH2CH3 and 5-H), 2.47 (1H, m, 5-

7188
Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
CHAHBCH]CH2), 2.68 (1H, dd, J¼11.3, 2.9 Hz, 6B-H), 2.89 (1H, d,
J¼7.7 Hz, 4-H), 2.95 (1H, dd, J¼11.4, 1.3 Hz, 2B-H), 4.06 (2H, m, 4-
OCH2CH]CH2), 4.13 (2H, q, J¼7.1 Hz, OCH2CH3), 5.02 (2H, m, 5-
CH2CH]CH2), 5.10 (1H, dq, J¼10.4, 1.5 Hz, 4-OCH2CH]CHAHB),
5.23 (1H, dq, J¼17.2, 1.5 Hz, 4-OCH2CH]CHAHB), 5.78 (1H, m, 5-
CH2CH]CH2), 5.91 (1H, m, 4-OCH2CH]CH2); dC (75 MHz; CDCl3)
13.9 (NCH2CH2CH2CH3), 14.2 (OCH2CH3), 20.4 (NCH2CH2CH2CH3),
21.8 (3-CH3), 29.2 (NCH2CH2CH2CH3), 35.8 (5-CH2CH]CH2), 38.4
(C-5), 48.6 (C-3), 56.9 (C-6), 57.6 (NCH2CH2CH2CH3), 59.8
(OCH2CH3), 60.8 (C-2), 74.2 (4-OCH2CH]CH2), 86.6 (C-4), 116.0
(4-OCH2CH]CH2), 116.1 (5-CH2CH]CH2), 135.2 (4-OCH2CH]
CH2), 137.3 (5-CH2CH]CH2), 174.2 (COO); m/z (EIþ, %) 324 (MHþ,
21%), 296 (2), 278 (9), 266 (100), 238 (12), 224 (8), 192 (8), 181
(29), 153 (13), 135 (9), 121 (2); found [MHþ] 324.2535. C19H34NO3
requires 298.2539.
(2H, m, NCH2CH2CH2CH3),1.37e1.45 (2H, m, NCH2CH2CH2CH3),1.52
(1H, t, J¼11.3 Hz, 6A-H), 1.88 (1H, dd, J¼11.6, 2.0 Hz, 2A-H),
2.15e2.25 (3H, m, 5-H, NCH2CH2CH2CH3), 2.54 (1H, d, J¼10.6 Hz,
4-H), 2.81 (1H, dd, J¼11.6, 2.5 Hz, 2B-H), 2.93e2.99 (1H, m, 6B-H),
3.49 (3H, s, OCH3), 3.59 (1H, d, J¼10.7 Hz,1ꢂOCHAOH), 3.81 (1H, dd,
J¼10.7, 2.0 Hz, 1ꢂCHBOH), 5.49 (1H, s, OH); dC (75 MHz; CDCl3) 11.2
(NCH2CH2CH2CH3), 13.9 (5-CH3), 20.5 (NCH2CH2CH2CH3), 22.6
(3-CH3), 29.1 (NCH2CH2CH2CH3), 39.7 (C-3), 41.4 (C-5), 57.7
(NCH2CH2CH2CH3), 57.9 (C-6), 62.5 (OCH3), 64.4 (C-2), 68.9
(OCH2OH), 91.4 (C-4); m/z (ESI) found [MNa]þ 258.19383.
C13H27NO2Na requires 252.19395.
4.6.2. (3S
*
,4S
*
,5R )-(1-Butyl-5-ethyl-4-methoxy-3-methylpiperidin-
*
3-yl)methanol 8b. Prepared using general procedure E from ester
7b (0.56 mmol, 0.16 g) with purification by flash chromatography
(4:1 hexane, ethyl acetate) to afford the title compound 8b (0.13 g,
95%) as a colourless oil; Rf ¼0.2; IR (NaCl) nmax 3443, 3289 (OH),
2955, 2872, 2828 (CH), 1463, 1455, 1372, 1180, 1106 (CeN), 1091,
1044 (CeO); dH (300 MHz; CDCl3) 0.84 (3H, s, 3-CH3), 0.87 (3H, t,
J¼7.2 Hz, 5-CH2CH3), 0.94 (3H, d, J¼6.4 Hz, NCH2CH2CH2CH3),
1.22e1.34 (4H, m, 5-CH2CH3, NCH2CH2CH2CH3), 1.37e1.44 (2H, m,
NCH2CH2CH2CH3), 1.57 (1H, t, J¼11.4 Hz, 6A-H), 1.91 (1H, dd,
J¼12.0, 1.9 Hz, 2A-H), 2.20 (2H, td, J¼14.4, 1.9 Hz, NCH2
CH2CH2CH3), 2.28e2.40 (1H, m, 5-H), 2.48 (1H, d, J¼10.6 Hz, 4-H),
2.79e2.84 (2H, m, 2B-H, 6B-H), 3.52 (3H, s, OCH3), 3.60 (1H, d,
J¼10.8 Hz, 1ꢂCHAOH), 3.81 (1H, dd, J¼10.8, 1.9 Hz, 1ꢂCHBOH), 5.48
(1H, s, OH); dC (75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 16.8 (5-
4.5.7. Ethyl (5aR
*
,9R
*
,9aS
*
)-7-butyl-9-methyl-2,5,5a,6,7,8,9,9a-octa-
hydrooxepino[3,2-c]pyridine-9-carboxylate 7g. To
a
dry, stirred
suspension of bis(tricyclohexylphosphine)benzylideneruthenium
(IV) chloride (51 mg, 0.062 mmol) in dry dichloromethane (40 mL)
under an atmosphere of argon at room temperature, was added
diene 7f (200 mg, 0.62 mmol). After stirring for 1.5 h the solvent
was removed in vacuo to give the crude product, which was puri-
fied by flash chromatography (9:1 hexane, ethyl acetate) afforded
the title compound 7g (0.12 g, 64%) as a yellow oil. Rf ¼0.5; IR (NaCl)
nmax 3017 (]CH2, ]CHe), 2957, 2932, 2871, 2821, 2764 (CeH),
1737, (COO), 1716 (C]C), 1464, 1393, 1374, 1322, 1299 (CeN), 1256,
1231, 1215, 1193, 1138, 1104, 1090, 1070, 1049, 1029 (CeO); dH
(300 MHz; CDCl3) 0.87 (3H, t, J¼7.1 Hz, NCH2CH2CH2CH3), 1.23 (3H,
t, J¼7.1 Hz, OCH2CH3), 1.23e1.43 (4H, m, NCH2CH2CH2CH3), 1.65
(1H, t, J¼11.0 Hz, 6A-H), 1.70 (1H, d, J¼11.3 Hz, 8A-H), 1.90 (1H, m,
5-HA), 2.09e2.21 (2H, m, 5-HB and NCHAHBCH2CH2CH3), 2.28 (1H,
m, NCHAHBCH2CH2CH3), 2.67 (1H, m, 5a-H), 2.80 (1H, ddd, J¼11.1,
4.6, 2.5 Hz, 6B-H), 2.90 (1H, d, J¼11.1 Hz, 6B-H), 3.14 (1H, dd, J¼11.3,
2.5 Hz, 8B-H), 3.91 (1H, d, J¼13.9 Hz, 2-HA), 4.12 (2H, q, J¼7.1 Hz,
OCH2CH3), 4.48 (1H, m, 2-HB), 5.86e5.87 (2H, m, 3-H and 4-H); dC
(75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3), 14.2 (OCH2CH3), 20.3
(NCH2CH2CH2CH3), 21.2 (9-CH3), 29.2 (NCH2CH2CH2CH3), 33.3
(C-5), 36.6 (C-5a), 48.7 (C-9), 57.2 (NCH2CH2CH2CH3), 59.8
(OCH2CH3), 60.7 (C-6), 68.3 (C-2), 92.5 (C-9a), 130.9 and 131.33 (C-3
and C-4), 173.6 (COO); m/z (EIþ, %) 296 (MHþ, 36%), 278 (6), 242 (1),
222 (100), 196 (10), 180 (25), 164 (6), 150 (41), 135 (7), 126 (43), 119
(29), 100 (9), 91 (4); found [MHþ] 296.2213. C17H30NO3 requires
296.2226.
CH2CH3),
20.5
(NCH2CH2CH2CH3),
22.5
(3-CH3),
29.1
(NCH2CH2CH2CH3), 29.7 (5-CH2CH3), 35.2 (C-5), 39.7 (C-3), 57.5
(NCH2CH2CH2CH3), 60.7 (C-6), 62.5 (OCH3), 64.7 (C-2), 68.9
(CH2OH), 93.0 (C-4). m/z (ESI) found [MNa]þ 266.20901.
C14H29NO2Na requires 266.20960.
4.6.3. (3S
*
,4S
*
,5R )-(1-Butyl-5-isopropyl-4-methoxy-3-methylpiper-
*
idin-3-yl)methanol 8c. Prepared using general procedure E from es-
ter 7c (3.5 mmol, 1.04 g) with purification by flash chromatography
(4:1 hexane, ethyl acetate) to afford the title compound 8c (0.82 g,
92%) as a colourless oil; Rf ¼0.3; IR (NaCl) nmax 3436 (OH), 2955, 2942,
2898, 2822 (CH), 1464, 1455,1353, 1180, 1116 (CeN), 1086, 1077, 1065
(CeO); dH (400 MHz; CDCl3) 0.82 (3H, d, J¼7.9 Hz, 1ꢂCH(CH3)2), 0.86
(3H, s, 3-CH3), 0.87 (3H, t, J¼7.1 Hz, NCH2CH2CH2CH3), 0.95 (3H, d,
J¼7.1 Hz, 1ꢂCH(CH3)2), 1.21e1.31 (2H, m, NCH2CH2CH2CH3),
1.38e1.43 (2H, m, NCH2CH2CH2CH3),1.64 (1H, t, J¼11.6 Hz, 6A-H), 7.61
(1H, dd, J¼11.9, 1.6 Hz, 2A-H), 2.16e2.25 (4H, m, 5-H, CH(CH3)2,
NCH2CH2CH2CH3), 2.78e2.81 (3H, m, 2B-H, 4-H, 6B-H), 3.50 (3H, s,
OCH3), 3.59 (1H, d, J¼10.7 Hz, 1ꢂCHAOH), 3.81 (1H, dd, J¼10.7,1.9 Hz,
1ꢂCHBOH), 6.01 (1H, s, OH); dC (100 MHz; CDCl3) 13.9
(NCH2CH2CH2CH3), 16.0 (1ꢂCH(CH3)2), 20.6 (NCH2CH2CH2CH3), 21.4
(1ꢂCH(CH3)2),22.9(3-CH3),25.5(CH(CH3)2),29.2(NCH2CH2CH2CH3),
39.6 (C-3), 44.4 (C-5), 52.9 (NCH2CH2CH2CH3), 57.9 (C-6), 62.1 (OCH3),
64.4 (C-2), 68.9 (CH2OH), 87.9 (C-4); m/z (Clþ) 258 (MHþ, 87%), 226
(7), 214 (100), 196 (9), 182 (8), 88 (12); found [MH]þ 258.24293.
C15H32NO2 requires 258.24330.
4.6. General procedure E: synthesis of 3-hydroxymethyl-
piperidines 8
Lithium aluminium hydride (38 mg, 1 mmol) was added to
a solution of piperidine 3-carboxylate ethyl ester 7 (0.5 mmol) in
dry THF (10 mL) and the mixture stirred for 2 h at room tempera-
ture. The reaction was quenched with deionised water (5 mL), fil-
tered through Celite and the aqueous mixture layer extracted with
ethyl acetate (3ꢂ10 mL). The combined organic layers were dried
(MgSO4), concentrated in vacuo to give the crude product, which
was purified by flash chromatography (hexane, ethyl acetate) to
afford the title compound.
4.6.4. ((3S
*
,4S
*
,5R )-1-Butyl-4-methoxy-3-methyl-5-phenyl-
*
piperidin-3-yl)methanol 8d. Prepared using general procedure E
from ester 7d (1.2 mmol, 0.4 g) with purification by flash chroma-
tography (9:1 hexane, ethyl acetate) to afford the title compound
8d (0.33 g, 94%) as a yellow oil. Rf ¼0.3; IR (NaCl) nmax 3463, 3263
(OeH), 3030 (CeH, Ph), 2954, 2931, 2871, 2823, 2775 (CeH), 1601
(C]C), 1495, 1467, 1454, 1375, 1361, 1332, 1318, 1269, 1232 (CeN),
1174, 1127, 1102, 1080, 1044, 1019, 988, 967 (CeO); dH (300 MHz;
CDCl3) 0.89 (3H, t, J¼7.3 Hz, NCH2CH2CH2CH3), 0.91 (3H, s, 3-CH3),
1.31 (2H, sext, J¼7.3 Hz, NCH2CH2CH2CH3), 1.45 (2H, p, J¼7.3 Hz,
NCH2CH2CH2CH3), 2.13 (1H, d, J¼12.0 Hz, 2A-H), 2.16 (1H, t,
J¼12.1 Hz, 6A-H), 2.28 (2H, td, J¼7.4, 1.6 Hz, NCH2CH2CH2CH3), 2.92
4.6.1. (3S
*
,4S
*
,5R )-(1-Butyl-3,5-dimethyl-4-methoxypiperidin-3-yl)
*
methanol 8a. Prepared using general procedure E from ester 7a
(5.9 mmol, 1.6 g) with purification by flash chromatography (4:1
hexane, ethyl acetate) to afford the title compound 8a (1.32 g, 98%)
as a colourless oil; Rf ¼0.4; IR (NaCl) nmax 3439, 3291 (OH), 2958,
2926, 2858, 2828 (CH), 1463, 1455, 1376, 1177 (CeN), 1105, 1087,
1048 (CeO); dH (300 MHz; CDCl3) 0.83 (3H, s, 3-CH3), 0.87 (3H, t,
J¼8.6 Hz, 5-CH3), 0.88 (3H, t, J¼9.5 Hz, NCH2CH2CH2CH3), 1.23e1.31

Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
7189
(3H, s, 4-OCH3), 2.92e3.00 (2H, m, 2B-H, 4-H), 3.10 (2H, d,
J¼10.8 Hz, 6B-H), 3.53 (1H, m, 5-H), 3.72 (1H, d, J¼10.9 Hz, 3-
CHAHBOH), 3.93 (1H, dd, J¼10.9 Hz, 2.12 Hz, 3-CHAHBOH),
7.20e7.36 (5H, m, Ph); dC (75 Hz; CDCl3) 13.9 (NCH2CH2CH2CH3),
20.5 (NCH2CH2CH2CH3), 22.3 (3-CH3), 29.1 (NCH2CH2CH2CH3), 39.7
(C-3), 46.9 (C-5), 57.5 (NCH2CH2CH2CH3), 59.8 (C-6), 61.3 (4-OCH3),
64.8 (C-2), 69.0 (3-CH2OH), 90.9 (C-4), 126.7 (Ph), 128.3 (Ph), 141.9
(Ph); m/z (EIþ, %) 292 (MHþ, 32%), 274 (1), 260 (100), 242 (2), 157
(3), 138 (4), 117 (7); found [MHþ] 292.2272. C18H30NO2 requires
292.2277.
using direct methods (SHELXS-97). The asymmetric unit con-
sisted of a hydrogen bonded pair of optical isomers of 8f. Non-
hydrogen atoms were refined anisotropically (SHELXL-97) and H
atoms were refined using
a
riding model, with CeH
¼0.93e0.97 Å and Uiso(H)¼1.2Ueq(C), 1.5Ueq(methyl C) or
1.5Ueq(O). The n-butyl group eC13eC14eC15eC16 is disordered
with a minor component eC13aeC14aeC15aeC16a of 0.187. For
this butyl group EADP constraints between corresponding atoms
were applied. The deposition number for compound 8f is CCDC-
773732.
Crystallographic data for 8f: C30H54N2O4 (MW¼506.06), colour-
4.6.5. ((3S
*
,4S
*
,5R )-5-Allyl-1-butyl-4-methoxy-3-methylpiperidin-
*
less fragment (0.45ꢂ0.29ꢂ0.12 mm3), monoclinic, P21/c, a¼9.2699
3-yl)methanol 8e. Prepared using general procedure E from ester
7e (2.7 mmol, 0.8 g) with purification by flash chromatography (9:1
hexane, ethyl acetate) to afford the title compound 8e (0.67 g, 96%)
as a yellow oil. Rf ¼0.25; IR (neat) nmax 3419, 3277 (OeH), 3074 (]
CH2, ]CHe), 2955, 2930, 2872, 2826, 2768 (CeH), 1639 (C]C),
1467, 1457, 1440, 1369, 1316, 1267, 1246 (CeN), 1176, 1154, 1132,
1102, 1083, 1043, 1020, 992, 965, 939 (CeO); dH (300 MHz; CDCl3)
0.87 (3H, s, 3-CH3), 0.89 (3H, t, J¼7.3 Hz, NCH2CH2CH2CH3), 1.29
(2H, sext, J¼7.3 Hz, NCH2CH2CH2CH3), 1.43 (2H, p, J¼7.3 Hz,
NCH2CH2CH2CH3), 1.57 (1H, t, J¼11.4 Hz, 6A-H), 1.79 (1H, dt, J¼13.8,
8.9 Hz, 5-CHAHBCH]CH2), 1.93 (1H, dd, J¼11.6, 2.1 Hz, 2A-H), 2.23
(2H, m, NCH2CH2CH2CH3), 2.38 (1H, m, 5-H), 2.56 (1H, m,
5-CHAHBCH]CH2), 2.60 (1H, d, J¼10.8 Hz, 4-H), 2.85 (1H, dd,
J¼11.6, 2.5 Hz, 2B-H), 2.93 (1H, ddd, J¼11.4, 4.4, 2.5 Hz, 6B-H), 3.53
(3H, s, 4-OCH3), 3.61 (1H, d, J¼10.6 Hz, 3-CHAHBOH), 3.85 (1H, dd,
J¼10.6, 2.1 Hz, 3-CHAHBOH), 5.03 (2H, m, 5-CH2CH]CH2), 5.78 (1H,
m, 5-CH2CH]CH2); dC (75 MHz; CDCl3) 13.9 (NCH2CH2CH2CH3),
20.5 (NCH2CH2CH2CH3), 22.6 (3-CH3), 29.1 (NCH2CH2CH2CH3), 35.8
(5-CH2CH]CH2), 39.6 (C-5), 57.6 (NCH2CH2CH2CH3), 58.1 (C-6),
62.5 (4-OCH3), 64.5 (C-2), 68.8 (3-CH2OH), 91.0 (C-4). 116.2 (5-
CH2CH]CH2), 136.5 (5-CH2CH]CH2); m/z (EIþ, %) 256 (MHþ, 17%),
238 (2), 224 (100), 206 (11), 182 (12), 164 (18), 150 (3), 140 (22), 124
(4), 100 (3); found [MHþ] 256.2266. C15H30NO2 requires 256.2277.
(3) Å, b¼22.3936 (7) Å, c¼14.2246 (5) Å,
b
¼98.418 (2)ꢁ, V¼2921.02
(17) Å3, Z¼4, Dcalcd¼1.152 Mg/m3,
m
(Mo K
a
)¼0.075 mmꢀ1. Mea-
reflections¼6924
sured
reflections¼36,883,
independent
(Rint¼0.0594), number of parameters¼344. Final R indices [I>2
s(I)],
R1¼0.0470, wR2¼0.1132, goodness-of-fit on F2¼1.032.
4.7. General procedure F: synthesis of anthranilate esters 9
To a solution of 3-hydroxymethyl-piperidine 8 (1 mmol) in dry
acetonitrile (20 mL) were added 2-(3-methyl-2,5-dioxo-2,5-dihy-
dro-1H-pyrrol-1-yl)benzoic acid24 (462 mg, 2 mmol), DMAP
(12 mg, 0.1 mmol) and DCC (412 mg, 2 mmol) and the resulting
mixture stirred for 7 h at room temperature. The mixture was then
filtered through Celite and solvent removed in vacuo and residue
dissolved in ethyl acetate (30 mL), washed with satd NaHCO3,
washed with brine, dried (MgSO4) and concentrated in vacuo to
give the crude product, which was purified by flash chromatogra-
phy (hexane, ethyl acetate) to afford the title compound.
4.7.1. (3S
*
,4S
*
,5R )-(1-Butyl-3,5-dimethyl-4-methoxypiperidin-3-
*
yl)methyl 2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ben-
zoate 9a. Prepared using general procedure F from alcohol 8a
(0.57 mmol, 0.13 g) with purification by flash chromatography (1:1
hexane, ethyl acetate) to afford the title compound 9a (0.14 g, 57%)
as a yellow oil; Rf ¼0.35; IR (NaCl) nmax 2955, 2933, 2860, 2821
(CH), 2118, 1718 (COO, C]O), 1645 (C]C), 1602, 1494, 1452, 1394,
1261, (CeN), 1138, 1122, 1090 (CeO); dH (300 MHz; CDCl3) 0.79
(3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 0.88 (3H, d, J¼6.4 Hz, 500-CH3),
1.01 (3H, s, 300-CH3), 1.15e1.29 (2H, m, NCH2CH2CH2CH3), 1.31e1.38
(2H, m, NCH2CH2CH2CH3), 1.53e1.56 (2H, m, 200A-H, 600A-H),
1.75e1.84 (1H, m, 500-H), 2.12 (3H, d, J¼1.4 Hz, 30-CH3), 2.41 (1H, d,
J¼10.6 Hz, 400-H), 2.75 (1H, d, J¼11.0 Hz, 200B-H), 2.83 (1H, d,
J¼11.7 Hz, 600B-H), 3.45 (3H, s, OCH3), 4.26 (1H, d, J¼10.4 Hz,
CHAO2C), 4.54 (1H, d, J¼10.4 Hz, CHBO2C), 6.45e6.48 (1H, m, 40-H),
7.21e7.24 (1H, m, 6-H), 7.44e7.48 (1H, m, 5-H), 7.55e7.61 (1H, m,
4-H), 8.04 (1H, t, J¼7.5 Hz, 3-H); dC (75 MHz; CDCl3) 11.1 (30-CH3),
13.9 (NCH2CH2CH2CH3), 16.3 (500-CH3), 20.4 (NCH2CH2CH2CH3),
21.3 (300-CH3), 29.1 (NCH2CH2CH2CH3), 34.3 (C-500), 40.5 (C-300),
57.36 (NCH2CH2CH2CH3), 60.1 (C-600), 61.0 (C-200), 62.4 (OCH3), 66.7
(CH2O2C), 92.7 (C-400), 127.8 (C-40), 128.4 (C-1), 128.7 (C-5), 130.3
(C-6), 131.1 (C-3), 131.7 (C-2), 132.8 (C-4), 146.0 (C-30), 164.5 (COO),
169.7 (C-50), 170.7 (C-20); m/z (FABþ) 443 (MHþ, 20%), 307 (21), 214
(16), 165 (3), 154 (100), 120 (11); found [MHþ] 443.25485.
C25H35N2O5 requires 443.25460.
4.6.6. ((5aR
*
,9S
*
,9aS )-7-Butyl-9-methyl-2,5,5a,6,7,8,9,9a-octahy-
*
drooxepino[3,2-c]pyridin-9-yl)methanol 8f. Prepared using general
procedure E from ester 7g (0.34 mmol, 0.10 g) with purification by
flash chromatography (9:1 hexane, ethyl acetate) to afford the title
compound 8f (84 mg, 98%) as a pale yellowcrystals. Mp 52e53 ꢁC; Rf
¼0.3; IR (neat) nmax 3175 (OeH), 3028 (]CH2, ]CHe), 2957, 2917,
2871, 2850, 2814, 2771, 2732, 2671 (CeH), 1470, 1461, 1447, 1398,
1370,1341,1315,1275,1261,1242 (CeN),1211,1192,1170,1129,1079,
1047, 1028, 1003 (CeO); dH (300 MHz; CDCl3) 0.84 (3H, s, 9-CH3),
0.90 (3H, t, J¼7.5 Hz, NCH2CH2CH2CH3), 1.31 (2H, sext, J¼7.5 Hz,
NCH2CH2CH2CH3),1.46 (2H, p, J¼7.5 Hz, NCH2CH2CH2CH3),1.64 (1H,
t, J¼11.4 Hz, 6A-H), 1.93 (1H, m, 5-HA), 1.97 (1H, dd, J¼11.5, 1.0 Hz,
8A-H), 2.16 (1H, m, 5-HB), 2.24 (2H, m, NCH2CH2CH2CH3), 2.43e2.56
(1H, m, 5a-H), 2.81e2.92 (2H, m, 6B-H and 8B-H), 2.99 (1H, d,
J¼10.1 Hz, 9a-H), 3.60 (1H, d, J¼10.8 Hz, 9-CHAHBOH), 3.85 (1H, dd,
J¼10.8, 2.36 Hz, 9-CHAHBOH), 3.98 (1H, d, J¼14.6 Hz, 2-HA), 4.40 (1H,
m, 2-HB), 5.84e5.86 (2H, m, 3-H and 4-H); dC (75 MHz; CDCl3) 13.9
(NCH2CH2CH2CH3), 20.5 (NCH2CH2CH2CH3), 21.8 (9-CH3), 29.1
(NCH2CH2CH2CH3), 34.0 (C-5), 37.9 (C-5a), 39.4 (C-9), 57.6
(NCH2CH2CH2CH3), 59.6 (C-6), 65.0 (C-8), 68.2 (9-CH2OH), 92.3
(C-2),130.9 and 131.2 (C-3 and C-4); m/z (EIþ, %) 254 (MHþ, 47%), 236
(22), 204 (12),194 (8),182 (34),164 (100),150 (26),140 (89),124 (91),
105 (48), 98 (21), 91 (24); found [MHþ] 254.2111. C15H28NO2 requires
254.2120.
4.7.2. (3S
*
,4S
*
,5R )-(1-Butyl-5-ethyl-4-methoxy-3-methylpiperidin-
*
3-yl)methyl 2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ben-
zoate 9b. Prepared using general procedure F from alcohol 8b
(0.58 mmol, 0.14 g) with purification by flash chromatography (1:1
hexane, ethyl acetate) to afford the title compound 9b (0.16 g, 62%)
as a yellow oil; Rf ¼0.6; IR (neat) nmax 2959, 2932, 2860, 2828, 2806
(CH), 2118, 1715 (COO, C]O), 1645 (C]C), 1602, 1494, 1455, 1394,
1259, (CeN), 1138, 1091 (CeO); dH (400 MHz; CDCl3) 0.82 (3H, t,
J¼7.3 Hz, NCH2CH2CH2CH3), 0.88 (3H, t, J¼7.3 Hz, 500-CH3), 1.05 (3H,
4.6.7. X-ray crystal structure of ((5aR
*
,9S
*
,9aS )-7-butyl-9-methyl-
*
2,5,5a,6,7,8,9,9a-octahydrooxepino[3,2-c]pyridin-9-yl)methanol 8f. The
single crystal X-ray diffraction data were collected on a Bruker
Smart APEX-2 CCD diffractometer using graphite mono-
chromated Mo K
a radiation at 93 K. The structure was solved

7190
Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
s, 300-CH3), 1.22e1.32 (2H, m, NCH2CH2CH2CH3), 1.33e1.42 (2H, m,
NCH2CH2CH2CH3), 1.53 (1H, d, J¼11.7 Hz, 200A-H), 1.55 (1H, t,
J¼11.5 Hz, 600A-H), 1.66e1.77 (3H, m, 500-H, 500-CH2CH3), 2.14 (3H, s,
30-CH3), 2.14e2.30 (2H, m, NCH2CH2CH2CH3), 2.50 (1H, d,
J¼10.4 Hz, 400-H), 2.84 (1H, dd, J¼11.7, 1.7 Hz, 200B-H), 2.93 (1H, d,
J¼11.5 Hz, 600B-H), 3.47 (3H, s, OCH3), 4.28 (1H, d, J¼10.4 Hz,
1ꢂCHACOO), 4.60 (1H, d, J¼10.4 Hz, 1ꢂCHBCOO), 6.48 (1H, d,
J¼1.8 Hz, 40-H), 7.28 (1H, dd, J¼7.9, 1.0, 6-H), 7.47 (1H, td, J¼7.6,
1.2 Hz, 5-H), 7.61 (1H, td, J¼7.7, 1.6 Hz, 4-H), 8.06 (1H, dd, J¼7.9,
1.3 Hz, 3-H); dC (100 MHz; CDCl3) 11.0 (30-CH3), 11.2 (500-CH3), 13.8
(NCH2CH2CH2CH3), 20.3 (NCH2CH2CH2CH3), 21.32 (300-CH3), 23.2
(500-CH2CH3), 29.2 (NCH2CH2CH2CH3), 40.4 (C-300), 40.6 (C-500), 57.5
(NCH2CH2CH2CH3), 58.2 (C-600), 59.8 (C-200), 66.8 (CH2O2C), 91.2
(C-400), 127.8 (C-40), 128.4 (C-1), 128.9 (C-5), 130.3 (C-6), 131.0 (C-3),
131.8 (C-2), 132.þ8 (C-4), 145.9 (C-30), 164.4 (COO), 169.6 (C-50), 170.6
(C-20); m/z (FAB ) 457 (MHþ, 100%), 413 (12), 314 (13), 286 (3), 214
(23), 120 (11); found [MHþ] 457.27109. C26H37N2O5 requires
457.27025.
(NCH2CH2CH2CH3), 40.6 (C-300), 46.3 (C-500), 57.4 (NCH2-
CH2CH2CH3), 60.2 (C-600), 60.3 (C-200), 61.7 (400-OCH3), 66.7 (300-
CH2COO), 90.9 (C-400), 126.7 (500-Ph), 127.9 (C-40), 128.2 (500-Ph),
128.5 (C-1), 128.8 (C-5), 130.5 (C-6), 131.2 (C-3), 132.0 (C-2), 132.9
(C-4), 141.7 (500-Ph), 146.1 (C-30), 164.6 (COO), 169.8 (C-50), 170.8
(C-20); m/z (EIþ, %) 505 (MHþ, 14%), 473 (17), 274 (15), 242 (11), 214
(100), 186 (1), 157 (4), 138 (1); found [MHþ] 505.2691. C31H38N2O5
requires 505.2703.
4.7.5. ((3S
*
,4S
*
,5R )-5-Allyl-1-butyl-4-methoxy-3-methylpiperidin-
*
3-yl)methyl 2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ben-
zoate 9e. Prepared using general procedure F from alcohol 8e
(0.78 mmol, 0.20 g) with purification by flash chromatography (9:1
hexane, ethyl acetate) to afford the title compound 9e (0.252 g,
77%) as a viscous yellow oil. Rf ¼0.2; IR (neat) nmax 3075 (]CH2, ]
CHe), 2957. 2928, 2864, 2832, 2803, 2757 (CeH), 1785, 1709 (COO,
C]O), 1643 (C]C), 1602, 1579, 1536, 1493, 1466, 1454, 1391, 1293,
1258 (CeN), 1209, 1195, 1177, 1165, 1136, 1106, 1085, 1045 (CeO); dH
(300 MHz; CDCl3) 0.82 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.06 (3H,
s, 300-CH3), 1.24 (2H, sext, J¼7.2 Hz, NCH2CH2CH2CH3), 1.35 (2H, p,
J¼7.2 Hz, NCH2CH2CH2CH3), 1.55 (1H, d, J¼1.7 Hz, 600A-H), 1.63 (1H,
d, J¼12.7 Hz, 200A-H), 1.72e1.89 (2H, m, 500-CHAHBCH]CH2, 500-H),
2.11e2.31 (5H, m, NCH2CH2CH2CH3 and 30-CH3), 2.43e2.50 (1H, m,
500-CHAHBCH]CH2), 2.54 (1H, d, J¼10.2 Hz, 400-H), 2.81e2.89 (2H,
m, 200B-H and 600B-H), 3.49 (3H, s, 400-OCH3), 4.30 (1H, d, J¼10.3 Hz,
300-CHAHBOOC), 4.58 (1H, d, J¼10.4 Hz, 300-CHAHBOOC), 5.01 (2H, m,
500-CH2CH]CH2), 5.75 (1H, m, 500-CH2CH]CH2), 6.49 (1H, q,
J¼1.8 Hz, 40-H), 7.29 (1H, dd, J¼7.9, 1.2 Hz, 6-H), 7.48 (1H, td, J¼7.7,
1.4 Hz, 5-H), 7.62 (1H, td, J¼7.7, 1.6 Hz, 4-H), 8.06 (1H, dd, J¼7.8,
1.5 Hz, 3-H); dC (75 MHz; CDCl3) 11.2 (30-CH3), 13.9 (NCH2-
CH2CH2CH3), 20.5 (NCH2CH2CH2CH3), 21.5 (300-CH3), 29.3 (NCH2-
CH2CH2CH3), (500-CH2CH]CH2), 35.3 (NCH2CH2CH2CH3), 39.0
(C-500), 57.6 (NCH2CH2CH2CH3), 58.5 (C-600), 60.2 (C-200), 62.5 (400-
OCH3), 66.9 (300-CH2COO), 91.1 (C-400), 116.1 (500-CH2CH]CH2), 127.9
(C-40), 128.5 (C-5), 130.5 (C-6), 131.2 (C-3), 131.9 (C-2), 132.9 (C-4),
136.6 (500-CH2CH]CH2),146.1 (C-30),164.6 (COO),169.8 (C-50),170.8
(C-20); m/z (EIþ, %) 469 (MHþ, 16%), 437 (21), 238 (15), 214 (100),
206 (16), 186 (1), 164 (3), 138 (2); found [MHþ] 469.2692.
C27H37N2O5 requires 469.2703.
4.7.3. (3S
*
,4S
*
,5R )-(1-Butyl-5-isopropyl-4-methoxy-3-methylpiper-
*
idin-3-yl)methyl 2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)
benzoate 9c. Prepared using general procedure F from alcohol 8c
(0.54 mmol, 0.14 g) with purification by flash chromatography (1:1
hexane, ethyl acetate) to afford the title compound 9c (0.14 g, 55%)
as a yellow oil; Rf ¼0.4; IR (neat) nmax 2958, 2932, 2873, 2825 (CH),
1716 (COO, C]O), 1645 (C]C), 1602, 1495, 1454, 1394, 1259 (CeN),
1107, 1095 (CeO); dH (400 MHz; CDCl3) 0.79 (3H, t, J¼9.6 Hz,
NCH2CH2CH2CH3), 0.81 (3H, d, J¼9.4 Hz, 1ꢂCH(CH3)2), 0.92 (3H, d,
J¼9.4 Hz, 1ꢂCH(CH3)2), 1.05 (3H, s, 300-CH3), 1.14e1.26 (2H, m,
NCH2CH2CH2CH3), 1.27e1.39 (2H, m, NCH2CH2CH2CH3), 1.46 (1H, d,
J¼15.5 Hz, 200A-H), 1.55e1.74 (2H, m, 5-H, 600A-H), 1.93e2.27 (3H, m,
CH(CH3)2, NCH2CH2CH2CH3), 2.12 (3H, d, J¼2.5 Hz, 30-CH3),
2.72e2.82 (3H, m, 200B-H, 400-H, 600B-H), 3.45 (3H, s, OCH3), 4.25 (1H,
d, J¼13.9 Hz, CHAO2C), 4.59 (1H, d, J¼13.9 Hz, CHBO2C), 6.46 (1H, d,
J¼2.4 Hz, 40-H), 7.26 (1H, dd, J¼10.4, 1.5 Hz, 6-H), 7.45 (1H, td,
J¼10.2, 1.7 Hz, 5-H), 7.59 (1H, td, J¼10.2, 2.1 Hz, 4-H), 8.04 (1H, dd,
J¼10.4, 2.0 Hz, 3-H); dC (100 MHz; CDCl3) 10.9 (30-CH3), 13.8
(NCH2CH2CH2CH3), 16.16 (1ꢂCH(CH3)2), 20.4 (NCH2CH2CH2CH3),
21.3 (1ꢂCH(CH3)2), 21.6 (300-CH3), 25.0 (CH(CH3)2), 29.2
(NCH2CH2CH2CH3), 40.4 (C-300), 43.6 (C-500), 53.1 (C-600), 57.8
(NCH2CH2CH2CH3), 59.9 (C-200), 61.9 (OCH3), 66.83 (CH2O2C), 87.7
(C-400), 127.8 (C-40), 128.3 (C-1), 128.6 (C-5), 130.3 (C-6), 131.0 (C-3),
131.7 (C-2), 132.8 (C-4þ), 146.0 (C-30), 164.6 (COO), 169.6 (C-50),
170.64 (C-20); m/z (FAB ) 471 (MHþ, 100%), 439 (8), 427 (31), 328
(12), 240 (12), 214 (50), 196 (3); found [MHþ] 471.28601.
C27H39N2O5 requires 471.28590.
4.7.6. ((5aR,9S,9aS)-7-Butyl-9-methyl-2,5,5a,6,7,8,9,9a-octahydroox-
epino[3,2-c]pyridin-9-yl)methyl 2-(3-methyl-2,5-dioxo-2,5-dihydro-
1H-pyrrol-1-yl)benzoate 9f. Prepared using general procedure F
from alcohol 8f (0.20 mmol, 50 mg) with purification by flash
chromatography (9:1 hexane, ethyl acetate) to afford the title
compound 9f (59 mg, 64%) as a viscous yellow oil. Rf ¼0.3; IR (neat)
nmax 3096 (]CH), 2953, 2764 (CeH), 1785, 1707 (COO, C]O), 1645
(C]C), 1602, 1579, 1536, 1493, 1454, 1293, 1259 (CeN), 1209, 1177,
1135, 1106,1085,1044,1033 (CeO); dH (300 MHz; CDCl3) 0.81 (3H, t,
J¼7.2 Hz, NCH2CH2CH2CH3), 1.04 (3H, s, 900-CH3), 1.25 (2H, sext,
J¼7.2 Hz, NCH2CH2CH2CH3), 1.37 (2H, p, J¼7.2 Hz, NCH2CH2-
CH2CH3), 1.55 (1H, d, J¼11.6 Hz, 8A00-H), 1.62 (1H, t, J¼11.0, 6A00-H),
1.78e1.99 (2H, m, 5a00-H and 500-HA), 2.04e2.30 (6H, m, 500-HB, 30-
CH3 and NCH2CH2CH2CH3), 2.76 (1H, d, J¼11.0 Hz, 6B00-H), 2.91 (1H,
dd, J¼11.6, 2.8 Hz, 8B00-H), 2.92 (1H, d, J¼9.5 Hz, 9a00-H), 3.91 (1H, d,
J¼14.0 Hz, 200-HA), 4.25 (1H, m, 200-HB), 4.29 (1H, d, J¼10.5 Hz, 900-
OCHAHBOOC), 4.61 (1H, d, J¼10.5 Hz, 900-OCHAHBOOC), 5.83e5.85
(2H, m, 300-H and 400-H), 6.51 (1H, q, J¼1.8 Hz, 40-H), 7.30 (1H, dd,
J¼8.0, 0.9 Hz, 6-H), 7.49 (1H, td, J¼7.6, 1.2 Hz, 5-H), 7.64 (1H, td,
J¼7.6, 1.4 Hz, 4-H), 7.08 (1H, dd, J¼7.6, 1.4 Hz, 3-H), dC (75 MHz;
CDCl3) 11.1 (30-CH3), 13.9 (NCH2CH2CH2CH3), 20.4 (NCH2CH2-
CH2CH3), 20.8 (900-CH3), 29.3 (NCH2CH2CH2CH3), 33.3 (C-500), 37.3
(C-5a00), 57.5 (NCH2CH2CH2CH3), 60.1 (C-600), 60.2 (C-800), 66.9
(900-CH2OOC), 68.4 (C-200), 93.0 (C-9a00), 127.8 (C-40), 128.9 (C-5),
130.3 (C-6), 131.0 (C-3), 131.5 (C-300 and C-400), 133.2 (C-4), 146þ.2
(C-30), 164.6 (COO), 169.7 (C-50), 170.8 (C-20); m/z (EIþ, %) 467 (MH ,
4.7.4. ((3S
*
,4S
*
,5R )-1-Butyl-4-methoxy-3-methyl-5-phenyl-
*
piperidin-3-yl)methyl 2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-
1-yl)benzoate 9d. Prepared using general procedure F from alcohol
8d (0.24 mmol, 70 mg) with purification by flash chromatography
(9:1 hexane, ethyl acetate) to afford the title compound 9d (89 mg,
74%) as a yellow foam. Rf ¼0.4; IR (neat) nmax 3067 (]CHe), 3028
(CH, Ph), 2953, 2928, 2867, 2814, 2760 (CeH), 1784, 1711 (COO, C]
O), 1643 (C]C), 1602, 1582, 1493, 1466, 1452, 1393, 1293, 1256
(CeN), 1209, 1176, 1136, 1102, 1083, 1042 (CeO); dH (300 MHz;
CDCl3) 0.81 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.10 (3H, s, 300-CH3),
1.26 (2H, sext, J¼7.2 Hz, NCH2CH2CH2CH3), 1.37 (2H, p, J¼7.2 Hz,
NCH2CH2CH2CH3), 1.74 (1H, d, J¼11.6 Hz, 200A-H), 2.18 (4H, m, 30-CH3
and 600A-H), 2.28 (2H, m, NCH2CH2CH2CH3), 2.87 (3H, s, 400-OCH3),
2.91e4.04 (4H, m, 6B00-H, 2B00-H, 500-H and 400-H), 4.36 (1H, d,
J¼10.2 Hz, 300-CHAHBO), 4.75 (1H, d, J¼10.5 Hz, 300-CHAHBO), 6.50
(1H, q, J¼1.8 Hz, 40-H), 7.19e7.33 (6H, m, 500-Ph and 6-H), 7.49 (1H,
td, J¼7.6, 1.3 Hz, 5-H), 7.64 (1H, td, J¼7.6, 1.5 Hz, 4-H), 8.09 (1H, dd,
J¼7.8, 1.5 Hz, 3-H); dC (75 MHz; CDCl3) 11.2 (30-CH3), 13.9
(NCH2CH2CH2CH3), 20.4 (NCH2CH2CH2CH3), 21.3 (300-CH3), 29.3

Y. Chan et al. / Tetrahedron 66 (2010) 7179e7191
7191
6%), 236 (13), 214 (100), 186 (2), 158 (1); found [MHþ] 467.2543.
C27H35N2O5 requires 467.2546.
Knop, J.; Malmberg, A.; McDermott, J. S.; Nguyen, H. Q.; Springer, S. K.; Waldon,
D.; Woodin, K.; McDonough, S. I. Bioorg. Med. Chem. Lett. 2008, 18, 5209.
8. (a) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu, P.-F. Chem.d
Eur. J. 2010, 16, 3922; (b) Clarke, P. A.; Zaytsev, A. V.; Whitwood, A. C. Synthesis
2008, 3530; (c) Sales, M.; Charette, A. B. Org. Lett. 2005, 7, 5773.
Acknowledgements
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We wish to thank the University of Auckland for supporting this
research.
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