Enantioselective synthesis of cis-(2S,3R)- and trans-(2S,3S)- piperidinedicarboxylic acids using domino: Allylic acetate and Ireland-Claisen rearrangements and Michael addition as the key steps

Article abstract of DOI:10.1016/j.tetasy.2011.04.015

An enantioselective synthesis of (2S,3R)-piperidine-2,3-dicarboxylic acid and (2S,3S)-piperidine-2,3-dicarboxylic acid is described. This synthesis was mainly based on a δ-amino acid formation via a domino reaction: allylic acetate rearrangement, stereose

Full text of DOI:10.1016/j.tetasy.2011.04.015

Tetrahedron: Asymmetry 22 (2011) 872–880
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Tetrahedron: Asymmetry
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Enantioselective synthesis of cis-(2S,3R)- and trans-(2S,3S)-piperidinedicarb-
oxylic acids using domino: allylic acetate and Ireland-Claisen rearrangements
and Michael addition as the key steps
Narciso M. Garrido a, , M. Rosa Sánchez a, David Díez a, Francisca Sanz b, Julio G. Urones a
⇑
a Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
b Servicio de Rayos X, Facultad de Ciencias Químicas Universidad de Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective synthesis of (2S,3R)-piperidine-2,3-dicarboxylic acid and (2S,3S)-piperidine-2,3-
dicarboxylic acid is described. This synthesis was mainly based on a d-amino acid formation via a domino
reaction: allylic acetate rearrangement, stereoselective Ireland-Claisen rearrangement and asymmetric
Michael addition protocol from a Baylis–Hillman adduct, in which the cinnamaldehyde double bond is
a masked carboxylic functionality, and a cerium(IV) ammonium nitrate promoted monodebenzylation.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 March 2011
Accepted 15 April 2011
Available online 12 June 2011
Dedicated with respect and affection to
Professor Carmen Nájera in the occasion of
her 60th birthday
1. Introduction
I (Scheme 1) using chiral lithium amide (R)-6 to afford d-aminoac-
ids II, which can be transformed to piperidines III. When benzalde-
Excitatory amino acids are recognized to mediate synaptic exci-
tation and therefore nerve signal transmission in the mammalian
central nervous system by binding to the excitatory amino acids
receptor.1 Modulation of the excitatory amino acids receptors
seems to be implicated in several neurological disorders such as
Huntington’s chorea, Alzheimer disease and epilepsy.2 It is known
that glutamic and aspartic acids are the major excitatory neuro-
transmitters and their receptor complexes are pharmacologically
hyde was used as the starting material in the Baylis–Hillman
reaction, we proved the application of the methodology toward
the enantioselective synthesis of (+)-L-733,060 and (+)-CP-99,994.7
In order to further demonstrate the versatility of this methodol-
ogy to obtain homochiral piperidinedicarboxylic derivatives by
using cinammaldehyde as a starting material carrying a masked
carboxylic functionality, the enantioselective synthesis of cis- and
trans-piperidine dicarboxylic acid was undertaken.
characterized by their affinities for N-methyl-
acid, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid and
trans-1-aminocyclopentyl-1,3-dicarboxylic acid. The N-methyl-
-aspartic acid receptor has been the most studied and the synthe-
sis of N-methyl- -aspartic acid analogues constitutes an active area
D-aspartic acid, kainic
a
2. Results and discussion
D
Our synthetic strategy (Scheme 2) started with the Baylis–
Hillman adduct 3 from cinnamaldehyde,8 which was prepared
according to a literature procedure.9 The resulting secondary hy-
droxyl group was protected as its acetyl derivative 4 by reaction
with AcCl and Et3N. This compound was treated with CsF to give
the acetate isomer 5.
D
of investigation. Some of these restricted analogues are cis- and
trans-2,3-piperidine dicarboxylic acids (see Fig. 1).
Due to their pharmacological importance, various methods
have been developed to synthesize piperidine dicarboxylic acids.3
Davies et al.3f synthesized these compounds and studied their
structure–activity relationships. The racemate of the trans-isomer
When acetate 4 was treated with lithium amide (R)-6, we ob-
tained monoaddition compound,
was used and appeared to be an N-methyl-D
-aspartic acid agonist.4
(aR,3E,5E)-3-[(N-benzyl-N-
a-methylbenzylamino)-methyl]-6-phenyl-hex-3,5-dien-2-one (18%),
The cis-isomer was resolved and it was observed that both enanti-
omers present an antagonist activity. The (2R,3S)-absolute config-
uration was assigned to the most active enantiomer, that is, the
levorotatory one.
and di-addition compounds 7 (3%) and (ꢀ)-8 (3%), and neither of
the desired acids during the domino reaction. All similar Baylis–
Hillman adducts coming from aromatic aldehyde gave a mixture
of di-addition and acid derivatives. The acids were always in a low-
er yield than when the rearranged acetates were used.5 When
product 5 was treated with lithium amide10 (R)-6, we obtained
compounds 7, (ꢀ)-8, (ꢀ)-9 and (ꢀ)-10 as shown in Scheme 3.
The selectivity achieved here (7:4) is not in agreement with the
reported good results obtained with Baylis–Hillman adducts from
Recently, we have demonstrated5 a novel domino reaction:
stereoselective Ireland-Claisen rearrangement6 and asymmetric
Michael addition. A protocol starting from Baylis–Hillman adducts
⇑
Corresponding author. Fax: +34 923 294574.
E-mail address: nmg@usal.es (N.M. Garrido).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.015

N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
Ph
873
Ph
R3
R1
COOR2
Ph
N
Li
R1
Ph
N
COOR2
COOH
R1
N
H
(R)-6
OAc
I
II
III
Scheme 1.
OH
HOOC
HOOC
HOOC
HOOC
CHO
Ph
a
COOMe
COOMe
Ph
Ph
+
N
H
N
H
3
COOMe
trans-(2S,3S)-piperidine
dicarboxylic acid 1
cis-(2S,3R)-piperidine
dicarboxylic acid 2
b
Figure 1.
OAc
COOMe
OAc
Ph
c
5
4
Scheme 2. Reagents and conditions: (a) DABCO, rt, 6d, 66%; (b) AcCl, Et3N, 0 °C,
86%; (c) CsF, PhCH2N+Et3Clꢀ, 93%.
aromatic aldehydes. Here probably due to the bulky lithium amide
in the ester enolate transition state, the styryl group is in a confor-
mation that forces the carboxylate into a position partially avoiding
anti protonation in the tandem reaction. The mixture of acids is eas-
ily isolable by basic extraction and can be resolved as single diaste-
reoisomers by column chromatography (see Section 4).
The stereochemistry of the products from the domino reaction
is in accordance with the accepted model of addition of a chiral
amide to a-substituted a
,b-unsaturated esters,10,11 and was further
demonstrated by the X-ray analysis of one of the derivatives (vide
infra).
We have previously shown direct access to d-lactams from the
related d-aminoacid7 by a one-pot hydrogenolysis-cyclization.
However, cerium(IV) ammonium nitrate12 promotes a monodeb-
enzylation while keeping intact the masked carboxylic double
bond. So, d-amino acid (ꢀ)-9 was treated with cerium(IV) ammo-
nium nitrate to give product (+)-11 in 98% yield. Cyclization of acid
(+)-11 with DIPEA, EDCI and hydroxybenzotriazole hydrate affor-
ded the corresponding amide (+)-12 (Scheme 4).
When lactam (+)-12 was submitted to cleavage of the vinyl
group by ozonolysis followed by oxidative degradation of the
resulting ozonide in Me2S, the aldehyde (+)-13 was obtained. The
product crystallizes easily from EtOAc/hexane. X-ray structure
analysis13 of the derivative (+)-13 (Fig. 2) confirmed it as the
Figure 2. X-ray crystal structure of (+)-(2S,3S,aR)-13.
trans-isomer; the intermolecular interactions of the molecules
are shown in Figure 3. The newly formed stereogenic center was
determined to be (2S,3S), and the structure took a boat conforma-
tion with the C2 and C3 substituents at axial positions.14 The axial
orientation is because of the minimization of A(2,3) allylic strain be-
tween the N-(a
-methyl-benzyl) and the axial formyl units.15 This is
in accordance with the coupling constant for H2 at 4.20 (1H, br s)
and H3 at (1H, ddd, J = 6.8, 5.1 and 1.9), where JH2,H3 = 1.9 Hz,
which is consistent with the H2–C2–C3–H3 dihedral angle 84.7°
taken from the crystal structure.16
Ph
N
7, 8%
N
Ph
COOMe
Ph
N
Ph
COOMe
Ph
Ph
Ph
N
Li
(R)-6
Ph
N
Ph
N
Ph
COOMe
OAc
Ph
(-)-8, 8%
Ph
Ph
THF, -78ºC
5
Ph
Ph
Ph
N
Ph
COOMe
COOMe
Ph
(-)-9, 44%
Ph
(-)-10, 26%
COOH
COOH
Scheme 3.

874
N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
Table 1
Intermolecular interactions for compound (+)-(2S,3S,
a
R)-13
D–Hꢁ ꢁ ꢁA
D–H (Å)
Hꢁ ꢁ ꢁA (Å)
Dꢁ ꢁ ꢁA (Å)
D–Hꢁ ꢁ ꢁA (o)
C11–H11ꢁ ꢁ ꢁO1
C17–H17ꢁ ꢁ ꢁO2
C8–H8Aꢁ ꢁ ꢁO4
C3–H3Bꢁ ꢁ ꢁO1
C6–H6ꢁ ꢁ ꢁO4
0.93
0.96
0.96
0.97
0.98
2.659
2.419
2.488
2.641
2.586
3.412(1)
3.419(2)
3.447(3)
3.439(1)
3.422(1)
138
161
133
149
143
(+)-17 gave the expected final aminodiacid (+)-1 as the hydro-
chloride, ½a 2D0
ꢂ
¼ þ18:6 (c 0.62, HCl 6 M) {lit.3e
½
a 2D0
ꢂ
¼ þ16:6 (c
1.60, HCl 6 M)}.
Using the same method, we obtained the cis-(2S,3R)-piperidine
dicarboxylic acid from d-amino acid (ꢀ)-10 (Scheme 5). Hence,
d-amino acid (ꢀ)-10 was treated with CAN to give the monodeben-
zylation product (+)-18 in 96% yields. Cyclization of acid (+)-18 led
to the corresponding amide (+)-19. Conversion of lactam (+)-19
into cis-piperidine dicarboxylic acid was performed by the follow-
ing sequence of reactions: (a) cleavage of the vinyl group by ozon-
olysis followed by oxidative degradation of the resulting ozonide in
Me2S; (b) oxidation of the resulting aldehyde with NaClO2; (c)
esterification of the carboxylic acid (+)-21 with TMSCHN2; (d)
reduction from amide (+)-22 to amine (ꢀ)-23 with BH3ꢁTHF; (e)
deprotection of amine group with H2, Pd/C and finally; (f) hydroly-
sis of esters with HCl 3 M to obtain the cis-piperidine dicarboxylic
Figure 3. Intermolecular interactions for (+)-(2S,3S,aR)-13.
In the crystal structure, each molecule is involved in five types
of intermolecular C–Hꢁ ꢁ ꢁO interactions (Table 1), which are repre-
sented in Figure 3. The neighboring molecules are connected by
two types of intermolecular C11–H11ꢁ ꢁ ꢁO1 (dotted orange lines)
and C17–H17ꢁ ꢁ ꢁO2 (dotted light blue lines) interactions, which
lead to infinite molecular chains running along the [0 1 0] direc-
tion. These zigzag chains are joined to each other along the a axis
by three types of intermolecular C8–H8Aꢁ ꢁ ꢁO4 (dotted yellow
lines), C3–H3Bꢁ ꢁ ꢁO1 (dotted red lines) and C6–H6ꢁ ꢁ ꢁO4 (dotted
violet lines) hydrogen bonds (dotted yellow lines).
acid (+)-2, ½a 2D0
ꢂ
¼ þ2:8 (c 0.75, HCl 6 M) {lit.3f
½
a 2D0
ꢂ
¼ þ4:2 (c 1.00,
HCl 6 M)}.
3. Conclusions
Oxidation of the resulting aldehyde with NaClO2 gave the cor-
responding carboxylic acid (+)-14. Dimethylester (+)-15 was ob-
tained by esterification of compound (+)-14 with TMSCHN2.
Reduction of amide (+)-15 to amine (ꢀ)-16 was performed with
a large excess of BH3ꢁTHF complex.17 Compound (ꢀ)-16, when
treated with H2 and Pd/C, led to aminodiacid ester (+)-17. We
In conclusion, by using a cinnamaldehyde Baylis–Hillman ad-
duct in an efficient domino reaction: allylic acetate rearrangement,
stereoselective Ireland-Claisen rearrangement and asymmetric
Michael addition, we obtained ready access to d-aminoacids (ꢀ)-
9 and (ꢀ)-10, from which biological amino diacids (+)-(2S,3S)-1
and (+)-(2S,3R)-2 were synthesized in eight steps in 21% and 4%
overall yields, respectively. The key step of the synthesis is the
CAN selective monodebenzylation of the initial adducts (+)-11
and (+)-18 while keeping intact the double bond (masked carbox-
observed
a JH2,H3 = 8.0 Hz, which was in agreement with a
trans-diequatorial conformation of the ester substituent within
C2 and C3. Finally, acidic hydrolysis of the aminodiacid ester
MeOOC
b
Ph
N
Ph
COOMe
Ph
NH
a
COOMe
COOH
Ph
N
O
O
Ph
Ph
COOH
Ph
Ph
(+)-11
(+)-12
(-)-9
c
MeOOC
MeOOC
MeOOC
d
e
MeOOC
N
O
HOOC
N
O
OHC
N
Ph
Ph
(+)-15
(+)-14
(+)-13
f
MeOOC
MeOOC
HOOC
g
h
MeOOC
N
MeOOC
(+)-17
N
HOOC
(+)-1
N
H
H
(-)-16
Ph
Scheme 4. Reagents and conditions: (a) cerium(IV) ammonium nitrate, AcCN/H2O, 98%; (b) DIPEA, EDCI, hydroxybenzotriazole hidrate, DMF, 87%; (c) (1) O3, CH2Cl2; (2)
Me2S, 94%; (d) NaClO2, NaH2PO4, t-BuOH, 2-methyl-2-butene, 82%; (e) TMSCHN2, benzene/MeOH: 1/1, 67%; (f) BH3ꢁTHF, THF, 73%; (g) H2, Pd/C, AcOH, 67%; (h) HCl 3 M,
D,
96%.

N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
875
MeOOC
Ph
Ph
N
Ph
COOMe
Ph
NH
a
b
COOMe
COOH
N
O
O
Ph
Ph
COOH
Ph
Ph
(+)-18
(+)-19
(-)-10
c
MeOOC
MeOOC
MeOOC
e
d
MeOOC
N
O
HOOC
N
O
OHC
N
Ph
Ph
(+)-22
(+)-21
(+)-20
f
MeOOC
MeOOC
HOOC
h
g
MeOOC
N
MeOOC
N
HOOC
N
H
H
Ph
(-)-23
(+)-24
(+)-2
Scheme 5. Reagents and conditions: (a) CAN, AcCN/H2O, 96%; (b) DIPEA, EDCI, hydroxybenzotriazole hydrate, DMF, 48%; (c) (1) O3, CH2Cl2; (2) Me2S, 89%; (d) NaClO2,
NaH2PO4, t-BuOH, 2-methyl-2-butene, 50%; (e) TMSCHN2, benzene/MeOH: 1/1, 98%; (f) BH3ꢁTHF, THF, 40%; (g) H2, Pd/C, AcOH, 61%; (h) HCl 3 M, , 81%.
D
ylic functionality) of the styryl derivative, which provides the for-
myl group upon ozonolysis. Importantly, the analogue series of
reactions using the enantiomer of lithium amide (S)-6 in the dom-
ino reaction step will allow simple access to the enantiomer of the
aforementioned compounds. Taking into account the multifunc-
tionality present in the formyl derivatives (+)-13 and (+)-20, fur-
ther work is currently underway in our laboratory to develop
different piperide derivatives.
24.97 mmol) and stirred for 8 days at rt. The reaction mixture
was dissolved in CH2Cl2 and washed with HCl 2 M and saturated
aqueous NaCl, dried over Na2SO4 and concentrated. The residue
was purified on silica gel, eluting with hexane/EtOAc: 95/5 to pro-
vide 3.3 g of 3 (66%). IR (film)
m
(cmꢀ1) 3600, 3200, 3100, 2840,
2350, 1710, 1690, 1650, 1600, 1450, 1410, 1050, 800, 700; 1H
NMR (200 MHz, CDCl3) 3.62 (1H, s, OH), 3.73 (3H, s, COOCH3),
5.16 (1H, d, J = 6.2 Hz, H-3), 5.94 (1H, s, H-10A), 6.27 (1H, dd,
J = 15.8 and 6.2 Hz, H-4), 6.30 (1H, s, H-10B), 6.66 (1H, d,
J = 15.8 Hz, H-5), 7.20–7.38 (5H, m, ArH), 13C NMR (50 MHz, CDCl3)
52.2 (CH3, COOCH3), 71.7 (CH, C-3), 125.9 (CH2, C-10), 126.9 (CH,
C-4), 128.0–129.7 (CH ꢃ 5, Ar), 131.8 (CH, C-5), 136.8 (C, Cipso),
141.8 (C, C-2), 167.0 (C, COOCH3); HRMS (EI) C13H14O3, M+ requires
218.0941; found 218.0967.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3 and D2O
at 200 and 400 MHz (1H) or 50 and 100 MHz (13C) on Varian 200
VX and BRUKER DRX 400 instruments, respectively. Multiplicities
were determined by DEPT experiments. IR spectra were registered
using a BOMEM 100 FTIR spectrophotometer. Optical rotations
were determined using a Perkin–Elmer 241 polarimeter in a
1 dm cell and are given in units of 10ꢀ1 deg cm2 gꢀ1. Concentra-
tions are quoted in g per 100 mL. The electron impact (EI) mass
spectra were run on a VG-TS 250 spectrometer using a 70 eV ion-
izing voltage. HRMS were recorded using a VG Platform (Fisons)
spectrometer using chemical ionization (ammonia as gas) or fast
atom bombardment (FAB) techniques. Thin layer chromatography
(TLC) was performed on aluminum sheets coated with 60 F254 sil-
ica. Sheets were visualized using iodine, UV light or 1% aqueous
KMnO4 solution. Column chromatography (was performed with
Merck Silica Gel 60 (70–230 mesh). Reactions were carried out un-
der an atmosphere of argon in dry glassware where noted with
magnetic stirring. Yields refer to isolated yield of analytically pure
material solvents and reagents were generally distilled prior to use.
Elemental analysis was performed by the microanalysis service of
the ‘Servicio de Análisis Iónico’, Universidad de Salamanca.
4.3. (E)-Methyl-3-acetoxy-2-methylene-5-phenyl-pent-4-enoate
4
To a solution of 3 (1.5 g, 7.01 mmol) in THF were added Et3N
(3.9 mL, 28.04 mmol) and AcCl (2 mL, 28.09 mmol) at 0 °C. After
2 h, H2O was added and the resulting solution was extracted with
EtOAc. The organic layer was washed with H2O and brine, dried
over Na2SO4 and concentrated. The residue was purified on silica
gel, eluting with hexane/EtOAc: 9/1 to provide 1.9 g of 4 (86%). IR
(film)
m
(cmꢀ1) 3100, 2840, 1742, 1439, 1371, 1276, 1230, 1149,
1023, 967; 1H NMR (200 MHz, CDCl3) 2.12 (3H, s, OCCH3), 3.78
(3H, s, COOCH3), 5.94 (1H, s, H-10A), 6.18 (1H, d, J = 7.0 Hz, H-3),
6.27 (1H, dd, J = 14.4 and 7.0 Hz, H-4), 6.33 (1H, s, H-10B), 6.50
(1H, d, J = 14.4 Hz, H-5), 7.25–7.41 (5H, m, ArH); 13C NMR
(50 MHz, CDCl3) 21.5 (CH3, OCCH3), 52.3 (CH3, COOCH3), 72.2 (CH,
C-3), 125.5 (CH, C-4), 126.6 (CH2, C-10), 127.0–128.8 (CH ꢃ 5, Ar),
133.9 (CH, C-5), 136.3 (C, Cipso), 139.2 (C, C-2), 165.7 (C, COOCH3),
169.8 (C, OCCH3); HRMS (EI) C15H16O4, M+ requires 260.1021;
found 260.1029.
4.4. (2E,4E)-Methyl-2-acetoxymethyl-5-phenyl-penta-2,4-
4.2. (E)-Methyl-3-hydroxy-2-methylene-5-phenyl-pent-4-
dienoate 5
enoate 3
To a solution of 4 (1.1 g, 4.03 mmol) in THF was added CsF (0.6 g,
4.03 mmol) and benzyltriethylammonium chloride (3.7 mg,
To a solution of cinnamaldehyde (2.9 mL, 22.70 mmol) with
methyl acrylate (2.3 mL, 24.97 mmol) was added DABCO (2.8 g,

876
N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
00
00
0
0
0.16 mmol) at rt. After 3 days, the reaction mixture was then filtered
through CeliteÒ, washed with CH2Cl2 and concentrated. The residue
was purified on silica gel, eluting with hexane/EtOAc: 9/1 to provide
(C, Cipso a), 140.5 (C, Cipso ), 142.0 (C, Cipso a), 144.6 (C, Cipso ), 174.6
(C, COOCH3); HRMS (EI) C43H47N2O2, M+ requires 623.3631; found
623.3651, ½a 2D0
ꢂ
¼ ꢀ15:2 (c 1.30, CHCl3). Compound (ꢀ)-9: 1H NMR
980 mg of 5 (93%). IR (film)
m
(cmꢀ1) 3100, 2955, 1738, 1712, 1624,
(400 MHz, CDCl3) 1.43 (3H, d, J = 6.8 Hz, C(a)Me), 2.02–2.26 (4H, m,
1466, 1369, 1280, 1233, 1099, 1025, 979; 1H NMR (400 MHz, CDCl3)
2.08 (3H, s, OCCH3), 3.81 (3H, s, COOCH3), 5.04 (2H, s, –CH2OAc), 6.97
(1H, d, J = 15.2 Hz, H-5), 7.22 (1H, dd, J = 15.2 and 11.4 Hz, H-4),
7.31–7.52 (5H, m, ArH), 7.57 (1H, d, J = 11.4 Hz, H-3); 13C NMR
(50 MHz, CDCl3) 21.2 (CH3, OCCH3), 52.3 (CH3, COOCH3), 58.3 (CH2,
–CH2OAc), 123.0 (CH, C-4), 125.1 (C, C-2), 127.8–129.7 (CH ꢃ 5, Ar),
136.1 (C, Cipso), 143.0 (CH, C-3), 144.6 (CH, C-5), 167.5 (C, COOCH3),
171.1 (C, OCCH3); HRMS (EI) C15H16O4Na, M+ requires 283.0938;
found 283.0939.
H-2 and H-3), 2.77 (1H, dt, J = 10.8 and 2.8 Hz, H-4), 3.43 (1H, dt,
J = 5.6 and 2.8 Hz, H-5), 3.47 (3H, s, COOCH3), 3.73 (1H, AB, JAB
13.8 Hz, NCHHBPh), 3.93 (1H, AB, JAB = 13.8 Hz, NCHAHPh), 4.12
(1H, q, J = 6.8 Hz, C( )H), 6.37–6.40 (2H, m, H-6 and H-7), 7.22–
7.44 (15H, m, ArH), 10.04 (1H, s, COOH); 13C NMR (50 MHz, CDCl3)
15.5 (CH3, C( )Me), 24.8 (CH2, C-3), 31.9 (CH2, C-2), 49.4 (CH, C-4),
50.9 (CH2, NCH2Ph), 51.7 (CH3, COOCH3), 56.5 (CH, C( )), 61.9 (CH,
C-5), 126.7 (CH, C-6), 127.2–128.9 (CH ꢃ 15, Ar), 133.2 (CH, C-7),
=
a
a
a
00
0
137.3 (C, Cipso), 140.6 (C, Cipso ), 144.1 (C, Cipso ), 174.8 (C, COOCH3),
179.2 (C, COOH); ½a D20
¼ ꢀ76:3 (c 1.11, CHCl3). Compound (ꢀ)-10:
ꢂ
4.5. (2S,3R,
amino)-2-[(N-benzyl-N-
phenyl-pent-4-enoate 7, (2R,3R,
N- -methylbenzylamino)-2-[(N-benzyl-N-
methylbenzylamino)-methyl]-5-phenyl-pent-4-enoate (ꢀ)-8,
(4S,5R, R,E)-5-(N-benzyl-N- -methylbenzylamino)-4-
methoxycarbonyl-7-phenyl-hept-6-enoic acid (ꢀ)-9 and
(4R,5R, R,E)-5-(N-benzyl-N- -methylbenzylamino)-
a
R,a0R,E)-Methyl-3-(N-benzyl-N-
-methylbenzylamino)-methyl]-5-
R,a0R,E)-methyl-3-(N-benzyl-
a
-methylbenzyl-
IR (film) m
(cmꢀ1) 3027, 2948, 1735, 1709, 1494, 1449, 1205, 1159,
a
900, 800; 1H NMR (400 MHz, CDCl3) 1.43 (3H, d, J = 6.8 Hz,
C( )Me), 1.55–1.61 (1H, m, H-3A), 1.74–1.76 (1H, m, H-3B), 2.00–
a
a
a
a-
2.25 (2H, m, H-2), 2.84 (1H, td, J = 10.2 and 3.4 Hz, H-4), 3.48
(3H, s, COOCH3), 3.59 (1H, t, J = 10.2 Hz, H-5), 3.65 (1H, AB,
JAB = 13.9 Hz, NCHHBPh), 3.91 (1H, AB, JAB = 13.9 Hz, NCHAHPh),
a
a
4.22 (1H, q, J = 6.8 Hz, C(
H-6), 6.40 (1H, d, J = 15.9 Hz, H-7), 7.19–7.40 (15H, m, ArH), 10.04
(1H, s, COOH); 13C NMR (50 MHz, CDCl3) 15.9 (CH3, C(
)Me), 25.0
(CH2, C-3), 31.5 (CH2, C-2), 48.6 (CH, C-4), 50.3 (CH2, NCH2Ph),
51.4 (CH3, COOCH3), 55.5 (CH, C( )), 63.0 (CH, C-5), 126.5–129.0
(CH ꢃ 15, Ar), 126.4 (CH, C-6), 134.0 (CH, C-7), 136.6 (C, Cipso),
a)H), 6.20 (1H, dd, J = 15.9 and 10.2 Hz,
a
a
4-methoxycarbonyl-7-phenyl-hept-6-enoic acid (ꢀ)-10
a
At first, 7.4 mL of n-BuLi was added dropwise to a stirred solu-
a
tion of (R)-N-benzyl-N-
THF at ꢀ78 °C under an Ar atmosphere and the resulting solution
stirred for 30 min prior to the addition of solution of
a-methylbenzylamine (2.6 g, 12.5 mmol) in
00
0
139.8 (C, Cipso ), 144.1 (C, Cipso ), 174.0 (C, COOCH3), 177.8 (C,
a
5
COOH); HRMS (EI)
C
30H34NO4, M+ requires 472.2481; found
¼ ꢀ74:7 (c 0.96, CHCl3).
(856 mg, 3.3 mmol) in THF at ꢀ78 °C. After the reaction time, sat-
urated aqueous NH4Cl solution was added and the resulting solu-
tion warmed to rt, partitioned between DCM and brine, dried
over Na2SO4 and the organic layer concentrated in vacuo. This res-
idue was partitioned between DCM and 10% citric acid solution.
The organic layer was washed with brine, dried and concentration
followed by flash chromatography on silica gel gave 684 mg of (ꢀ)-
9 (44%), 404 mg of (ꢀ)-10 (26%), 170 mg of 7 (8%) and 170 mg of
(ꢀ)-8 (8%). Moreover the crude of reaction can be dissolved in
ether and extracted with NaOH aq. (1 M) (3 ꢃ 50 mL). The aqueous
phase was acidified (pH ffi 3) and extracted with ether. The usual
work up provided (ꢀ)-9 and (ꢀ)-10. The remaining organic layer
was washed with brine (2 ꢃ 30 mL), dried and concentrated to give
7 and (ꢀ)-8. Compound 7: 1H NMR (200 MHz, CDCl3) 1.19 (3H, d,
472.2452; ½a 2D0
ꢂ
4.6. (4S,5R,aR,E)-4-Methoxycarbonyl-5-(N-a-methylbenzyl-
amino)-7-phenyl-hept-6-enoic acid (+)-11
To a solution of (ꢀ)-9 (687 mg, 1.45 mmol) in CH3CN/H2O: 5/1
(36 mL) was added cerium(IV) ammonium nitrate (3.20 g,
5.48 mmol). After 30 min, a saturated aqueous NaHCO3 solution
was added and the resulting solution was extracted with EtOAc.
The organic layer was dried over Na2SO4. Concentration followed
by flash chromatography on silica gel (9/1 hexane/EtOAc) gave
(+)-11 (549 mg, 98%). IR (film)
1561, 1451, 1418, 1401, 1304, 1208, 1168, 751; 1H NMR
(400 MHz, CDCl3) 1.47 (3H, d, J = 6.6 Hz, C( )Me), 1.85–1.95 (1H,
m
(cmꢀ1) 3300–2364, 1735, 1619,
a
J = 6.8 Hz, C(
a
)Me), 1.36 (3H, d, J = 6.8 Hz, C(
a
)Me0), 2.19 (1H, t,
m, H-3a), 2.00–2.09 (1H, m, H-3b), 2.29–2.46 (2H, m, H-2), 2.99
(1H, dt, J = 10.8 and 5.6 Hz, H-4), 3.64 (3H, s, COOCH3), 3.72 (1H,
dd, J = 9.2 and 5.6 Hz, H-5), 4.05 (1H, q, J = 6.6 Hz, C(a)H), 6.05
J = 12.6 Hz, H-10A), 2.73 (1H, dd, J = 12.6 and 3.2 Hz, H-10B), 3.10
(1H, ddd, J = 12.6, 9.2 and 3.2 Hz, H-2), 3.20 (3H, s, COOCH3), 3.21
(1H, AB, JAB = 13.4 Hz, NCHHBPh), 3.30 (1H, t, J = 9.2 Hz, H-3), 3.50
(1H, AB, JAB = 14.2 Hz, NCHHBPh0), 3.66 (1H, AB, JAB = 13.4 Hz,
(1H, dd, J = 16.0 and 9.2 Hz, H-6), 6.47 (1H, d, J = 16.0 Hz, H-7),
7.19–7.37 (10H, m, ArH); 13C NMR (50 MHz, CDCl3) 21.4 (CH3,
NCHAHPh), 3.85 (1H, q, J = 6.8 Hz, C(
a
)H0), 3.98 (1H, AB,
)H), 6.26 (2H,
C(a)Me), 25.0 (CH2, C-3), 33.0 (CH2, C-2), 48.2 (CH, C-4), 52.1
JAB = 14.2 Hz, NCHAHPh0), 4.06 (1H, q, J = 6.8 Hz, C(
a
(CH3, COOCH3), 56.2 (CH, C(
a
)), 60.9 (CH, C-5), 126.2 (CH, C-6),
m, H-4 and H-5), 7.16–7.35 (25H, m, ArH); HRMS (EI) C43H47N2O2,
126.9–129.0 (CH ꢃ 10, Ar), 134.9 (CH, C-7), 136.4 (C, Cipso), 143.0
M+ requires 623.3630; found 623.3617. Compound (ꢀ)-8: IR (film)
(C, Cipso ), 174.5 (C, COOCH3), 177.6 (C, COOH); HRMS (EI)
0
m
(cmꢀ1) 3026, 2970, 2944, 1736, 1494, 1451, 1433, 1371, 1237,
C
23H28NO4, M+ requires 382.2013; found 382.2021; ½a 2D0
¼ þ14:3
ꢂ
1204, 1164, 1129, 1074, 1028, 973; 1H NMR (400 MHz, CDCl3)
(c 0.47, CHCl3).
1.27 (3H, d, J = 6.8 Hz, C(a)Me), 1.36 (3H, d, J = 6.8 Hz, C(a
)Me0),
2.28 (1H, dd, J = 13.0 and 3.0 Hz, H-10A), 2.76 (1H, t, J = 13.0 Hz, H-
10B), 2.86 (1H, ddd, J = 13.0, 10.1 and 3.0 Hz, H-2), 3.25 (1H, AB,
4.7. (2R,3S,aR,E)-Methyl-6-oxo-1-(N-a-methylbenzyl)-2-styryl-
piperidine-3-carboxylate (+)-12
JAB = 13.6 Hz, NCHHBPh), 3.45 (1H, t, J = 10.1 Hz, H-3), 3.51 (3H, s,
COOCH3), 3.52 (1H, AB, JAB = 13.6 Hz, NCHAHPh), 3.72 (1H, AB,
To a solution of (+)-11 (540 mg, 1.4 mmol) in DMF (10 mL),
DIPEA (0.49 mL, 2.83 mmol), hydroxybenzotriazole hydrate
(421 mg, 3.12 mmol) and 1-ethyl-3-[3-dimethylaminopropyl)car-
bodiimide (598 mg, 3.12 mmol) were added and stirred for 15 h
at rt. The reaction mixture was concentrated in vacuo and then
H2O was added. The resulting solution was extracted with EtOAc.
The organic layer was washed with water, brine and dried over
Na2SO4. Concentration followed by flash chromatography on silica
gel (8/2 hexane/EtOAc) gave (+)-12 (449 mg, 87%). IR (film)
JAB = 14.2 Hz, NCHHBPh0), 3.75 (1H, AB, JAB = 14.2 Hz, NCHAHPh0),
3.79 (1H, q, J = 6.8 Hz, C(a a)H), 5.84
)H0), 4.14 (1H, q, J = 6.8 Hz, C(
(1H, dd, J = 15.8 and 10.1 Hz, H-4), 6.25 (1H, d, J = 15.8 Hz, H-5),
7.39–7.16 (25H, m, ArH); 13C NMR (50 MHz, CDCl3) 15.7 (CH3,
C(
(CH3, COOCH3), 52.1 (CH2, NCH2Ph0), 55.2 (CH2, NCH2Ph), 58.5
(CH, C(
)0), 61.2 (CH, C(
)), 62.1 (CH, C-3), 126.6–129.0 (CH ꢃ 25,
Ar), 129.3 (CH, C-5), 133.4 (CH, C-4), 137.1 (C, Cipso), 140.2
a a
)Me0), 16.6 (CH3, C( )Me), 49.7 (CH, C-2), 50.0 (CH2, C-10), 51.4
a
a

N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
877
m
(cmꢀ1) 3029, 2951, 1735, 1636, 1450, 1437, 1411, 1362, 1307,
1226, 1208, 1170; 1H NMR (400 MHz, CDCl3) 1.52 (3H, d,
J = 7.2 Hz, C( )Me), 2.04–2.09 (2H, m, H-4), 2.53 (1H, ddd,
4.10. (2S,3S,
piperidine-2,3-dicarboxylate (+)-15
aR)-Dimethyl-6-oxo-1-(N-a-methylbenzyl)-
a
J = 18.4, 7.2 and 4.1 Hz, H-5a), 2.64 (1H, dd, J = 7.0 and 4.1 Hz, H-
3), 2.77 (1H, ddd, J = 18.4, 9.2 and 8.2 Hz, H-5b), 3.35 (3H, s,
COOCH3), 4.34 (1H, dt, J = 7.0 and 1.6 Hz, H-2), 6.03 (1H, q,
To a solution of (+)-14 (47 mg, 0.15 mmol) in benzene (0.5 mL)/
MeOH (0.5 mL) was added TMSCHN2 2 M in Et2O (0.09 mL,
0.18 mmol). The mixture was stirred at room temperature for
15 min. The volatiles were removed under reduced pressure. Puri-
fication by crystallization in Et2O provided 32 mg of (+)-15 (67%).
J = 7.2 Hz, C(
(1H, d, J = 16.0 Hz, H-20), 7.26–7.37 (10H, m, ArH); 13C NMR
(50 MHz, CDCl3) 17.5 (CH3, C( )Me), 18.8 (CH2, C-4), 29.4 (CH2, C-
a
)H), 6.19 (1H, dd, J = 16.0 and 7.0 Hz, H-10), 6.40
a
IR (film)
1364, 1306, 1270, 1207, 1080, 1001, 717; 1H NMR (400 MHz,
CDCl3) 1.38 (3H, d, J = 7.3 Hz, C( )Me), 1.82–1.90 (1H, m, H-4a),
m
(cmꢀ1) 3051, 2980, 2949, 1748, 1637, 1447, 1406,
5), 44.7 (CH, C-3), 52.2 (CH, C(a)), 52.2 (CH3, COOCH3), 56.3 (CH,
C-2), 126.7–129.0 (CH ꢃ 10, Ar), 130.8 (CH, C-10), 132.1 (CH, C-20),
a
0
136.1 (C, Cipso), 140.3 (C, Cipso ), 169.9 (C, C-6), 172.1 (C, COOCH3);
2.08–2.13 (1H, m, H-4b), 2.51 (1H, ddd, J = 18.0, 7.9 and 3.5 Hz,
HRMS (EI) C23H25NO3Na, M+ requires 386.1727; found 386.1715;
H-5a), 2.69 (1H, ddd, J = 18.0, 9.3 and 8.0 Hz, H-5b), 2.91 (1H, dt,
a 2D0
ꢂ
¼ þ22:7 (c 1.41, CHCl3).
J = 5.2 and 2.3 Hz, H-3), 3.21 (3H, s, COOCH3), 3.80 (3H, s, COOCH3 ),
0
½
4.31 (1H, dd, J = 2.3 and 1.2 Hz H-2), 6.11 (1H, q, J = 7.3 Hz, C(
a)H),
4.8. (2S,3S, R)-Methyl-2-formyl-6-oxo-1-(N-a-methylbenzyl)-
a
7.24–7.35 (5H, m, ArH); 13C NMR (50 MHz, CDCl3) 15.5 (CH3,
piperidine-3-carboxylate (+)-13
C(
C(
a
a
)Me), 19.4 (CH2, C-4), 29.0 (CH2, C-5), 41.2 (CH, C-3), 50.8 (CH,
)), 52.4 (CH3, COOCH3), 53.2 (CH3, COOCH3 ), 56.0 (CH, C-2),
0
Into a solution of (+)-12 (350 mg, 0.96 mmol) in CH2Cl2 (20 mL)
at ꢀ78 °C was bubbled a gaseous O3 stream until the mixture was
saturated (solution turned blue). Then, the solution was treated
with a gaseous O2 and Ar stream. Next, Me2S (1.27 mL, 17.35 mmol)
was added at ꢀ78 °C and stirred for 15 min. The reaction mixture
was warmed to rt and then Na2SO3 was added. The resulting solu-
tion was extracted with CH2Cl2 and the organic layer was washed
with brine, dried over Na2SO4 and concentrated. Purification by
crystallization in EtOAc/hexane provided 261 mg of (+)-13 (94%).
127.9–128.6 (CH ꢃ 5, Ar), 140.0 (C, Cipso), 170.2 (C, C-6), 170.9 (C,
COOCH3), 172.7 (C, COOCH03); HRMS (EI) C17H21NO5Na, M+ requires
342.1312; found 342.1315; ½a D20
ꢂ
¼ þ92:6 (c 1.02, CHCl3).
4.11. (2S,3S,aR)-Dimethyl-1-(N-a-methylbenzyl)-piperidine-2,3-
dicarboxylate (ꢀ)-16
To a solution of (+)-15 (90 mg, 0.28 mmol) in THF (7 mL) at 0 °C
was added BH3ꢁTHF 1 M in THF (1.13 mL, 1.13 mmol). The mixture
reaction was stirred under an atmosphere of argon at 0 °C for 4 h.
The reaction was quenched with MeOH. The resulting solution was
stirred for 40 min and then the volatiles were removed under re-
duced pressure (ꢃ3). The solution was acidified with HCl
(pH ffi 3) and extracted with EtOAc three times. The combined or-
ganic phase was washed with saturated aqueous NaHCO3, dried
over Na2SO4 and concentrated. The residue was purified on silica
gel, eluting with hexane/EtOAc: 9/1 to provide 63 mg of (ꢀ)-16
Mp = 184–188 °C; IR (film)
1647, 1452, 1378, 1260, 1176, 1084, 1026, 800; 1H NMR
(400 MHz, CDCl3) 1.47 (3H, d, J = 7.2 Hz, C( )Me), 1.81 (1H, dq,
m
(cmꢀ1) 3447, 2961, 2926, 2853, 1734,
a
J = 14.3 and 7.0 Hz, H-4a), 2.06–2.15 (1H, m, H-4b), 2.24 (1H, dt,
J = 17.4 and 7.0 Hz, H-5a), 2.67 (1H, ddd, J = 17.4, 7.6 and 7.0 Hz,
H-5b), 3.14 (1H, ddd, J = 7.0, 5.1 and 1.9 Hz, H-3), 3.23 (3H, s,
COOCH3), 4.20 (1H, br s, H-2), 6.15 (1H, q, J = 7.2 Hz, C(
7.35 (5H, m, ArH), 9.69 (1H, s, CHO); 13C NMR (50 MHz, CDCl3)
17.0 (CH3, C( )Me), 19.6 (CH2, C-4), 30.0 (CH2, C-5), 38.7 (CH, C-3),
50.7 (CH, C( )), 52.6 (CH3, COOCH3), 62.3 (CH, C-2), 128.0–128.8
a)H), 7.23–
a
a
(73%). IR (film)
1172, 1145, 1093, 1023, 801; 1H NMR (400 MHz, CDCl3) 1.28
(3H, d, J = 6.6 Hz, C( )Me), 1.25–1.40 (1H, m, H-5a), 1.58–1.67
m
(cmꢀ1) 2961, 1737, 1451, 1435, 1261, 1206,
(CH ꢃ 5, Ar), 139.5 (C, Cipso), 170.5 (C, C-6), 171.3 (C, COOCH3),
199.7 (CH, CHO); HRMS (EI) C16H19NO4Na, M+ requires 312.1206;
found 312.1217; Anal. requires: C, 66.42; H, 6.62; N, 4.84. Found:
a
(2H, m, H-4a and H-5b), 1.95–1.99 (1H, m, H-4b), 2.33–2.37 (1H,
m, H-6a), 2.55 (1H, td, J = 12.2 and 3.3 Hz, H-6b), 3.12 (1H, q,
C, 66.45; H, 6.58; N, 4.76; ½a D20
ꢂ
¼ þ65:9 (c 0.78, CHCl3).
J = 4.3 Hz, H-3), 3.76 (3H, s, COOCH3), 3.78 (3H, s, COOCH3 ), 3.96
0
(1H, q, J = 6.6 Hz, C(
a
)H), 4.35 (1H, d, J = 4.3 Hz, H-2), 7.18–7.32
4.9. (2S,3S,
a
R)-6-Oxo-1-(N-
a
-methylbenzyl)-piperidine-2,3-
(5H, m, ArH); 13C NMR (50 MHz, CDCl3) 18.9 (CH3, C(
a)Me), 23.0
dicarboxylic acid 3-methyl ester (+)-14
(CH2), 23.7 (CH2), 43.7 (CH, C-3), 45.4 (CH2, C-6), 51.8 (CH3,
0
COOCH3), 52.1 (CH3, COOCH3 ), 60.4 (CH, C(a)), 61.0 (CH, C-2),
To solution of (+)-13 (240 mg, 0.83 mmol) in t-BuOH
a
126.9–128.4 (CH ꢃ 5, Ar), 146.4 (C, Cipso), 173.6 (C, COOCH3),
(19.9 mL) and 2-methyl-2-butene (5.3 mL) was slowly added an
aqueous solution of NaH2PO4 (1.4 g) in NaClO2 (3.2 mL). The mix-
ture was stirring at room-temperature for 15 min. The volatiles
were removed under reduced pressure, after which H2O was
added. The solution was acidified (pH acid) and extracted with
EtOAc three times. The combined organic phase was washed with
water and brine, dried over Na2SO4 and concentrated. Purification
173.8 (C, COOCH30 ); HRMS (EI) C17H23NO4Na, M+ requires
328.1519; found 328.1527; ½a D20
¼ ꢀ3:6 (c 1.07, CHCl3).
ꢂ
4.12. (2S,3S)-Dimethyl-piperidine-2,3-dicarboxylate (+)-17
To a solution of (ꢀ)-16 (38 mg, 0.13 mmol) in AcOH glacial
(1 mL) was added Pd–C (10%) (40% in weight) and the mixture
was stirred under H2 (50 psi) at rt for 42 h. The reaction mixture
was then filtered through CeliteÒ and silica gel, washed with
CH2Cl2 and MeOH and concentrated. The residue was dissolved
in CH2Cl2 and washed with NaHCO3 10% and H2O. The organic layer
was dried over Na2SO4, filtered and concentrated. Chromatography
on silica gel eluting hexane/EtOAc: 9/1 provided 17 mg of (+)-17
by crystallization in Et2O gave 207 mg of (+)-14 (82%). IR (film)
m
(cmꢀ1) 3500–3400, 2952, 1736, 1592, 1452, 1407, 1384, 1363,
1309, 1258, 1208, 1175, 1078, 1049, 996; 1H NMR (400 MHz,
CDCl3) 1.48 (3H, d, J = 7.3 Hz, C(a)Me), 1.92–2.02 (1H, m, H-4a),
2.09–2.15 (1H, m, H-4b), 2.62 (1H, ddd, J = 18.2, 8.1 and 3.1 Hz,
H-5a), 2.77 (1H, dt, J = 18.2 and 8.9 Hz, H-5b), 3.07 (1H, dt, J = 4.9
and 2.5 Hz, H-3), 3.20 (3H, s, COOCH3), 4.36 (1H, br s, H-2), 6.13
(67%). IR (film)
m
(cmꢀ1) 3500–3100, 2952, 2859, 1737, 1437,
(1H, q, J = 7.3 Hz, C(
(50 MHz, CDCl3) 15.5 (CH3, C(
C-5), 40.8 (CH, C-3), 51.6 (CH, C(
a
)H), 7.26–7.36 (5H, m, ArH); 13C NMR
1360, 1328, 1263, 1206, 1159, 1127, 1039, 1018; 1H NMR
(400 MHz, CDCl3) 1.61–1.71 (2H, m), 1.98–2.06 (2H, m), 2.08 (1H,
br s, NH), 2.61–2.71 (2H, m, H-3 and H-6a), 3.07 (1H, dtd,
J = 12.4, 3.7 and 0.9 Hz, H-6b), 3.65 (1H, d, J = 9.4 Hz, H-2), 3.69
a)Me), 18.9 (CH2, C-4), 28.5 (CH2,
a)), 52.4 (CH3, COOCH3), 56.0
(CH, C-2), 128.0–128.7 (CH ꢃ 5, Ar), 139.5 (C, Cipso), 171.1 (C, C-6),
172.5 (C, COOCH3), 173.3 (C, COOH); HRMS (EI) C16H19NO5Na, M+
(3H, s, COOCH3), 3.72 (3H, s, COOCH3 ); 13C NMR (50 MHz, CDCl3)
0
requires 328.1155; found 328.1149; ½a D20
ꢂ
¼ þ110:7 (c 0.84, CHCl3).
24.3 (CH2), 27.3 (CH2), 44.5 (CH, C-3), 45.1 (CH2, C-6), 52.2 (CH3,

878
N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
0
COOCH3), 52.6 (CH3, COOCH3 ), 59.5 (CH, C-2), 171.0 (C, COOCH3),
172.0 (C, COOCH03); HRMS (EI) C9H16NO4, M+ requires 202.1074;
C
½ ꢂ
23H25NO3Na, M+ requires 386.1727; found 386.1732;
¼ þ8:9 (c 1.34, CHCl3).
a 2D0
found 202.1072; ½a D20
¼ þ31:4 (c 1.09, CHCl3).
ꢂ
4.16. (2S,3R, R)-Methyl-2-formyl-6-oxo-1-(N-a-methylbenzyl)-
a
4.13. (2S,3S)-Piperidine-2,3-dicarboxylic acid hydrochloride
piperidine-3-carboxylate (+)-20
(+)-1
Into a solution of (+)-19 (379 mg, 1.04 mmol) in CH2Cl2 (20 mL)
at ꢀ78 °C was bubbled with a gaseous O3 stream until the mixture
was saturated (solution turned blue). Then, the solution was trea-
ted with a gaseous O2 and Ar stream. Next, H2O2 (1.91 mL,
18.77 mmol) was added at ꢀ78 °C and stirred for 15 min. The reac-
tion mixture was warmed to rt and then Na2SO3 was added. The
resulting solution was extracted with CH2Cl2 and the organic layer
was washed with brine, dried over Na2SO4 and concentrated. The
residue was purified on silica gel, eluting with hexane/EtOAc: 9/1
A solution of (+)-17 (10.1 mg, 0.05 mmol) in HCl 3 M (0.04 mL)
was refluxed for 7 hours and then concentrated under reduced
pressure. The solution was washed with Et2O and concentrated.
Chlorohydrate of the amino diacid (+)-1 was obtained as a white
solid (10 mg, 96%). Mp: 189–193 °C; 1H NMR (400 MHz, D2O)
1.53–1.70 (2H, m), 1.77–1.81 (1H, m), 1.97–2.02 (1H, m), 2.84
(1H, td, J = 10.2 and 3.8 Hz, H-3), 2.97 (1H, td, J = 13.3 and 2.9 Hz,
H-6a), 3.28–3.35 (1H, m, H-6b), 4.07 (1H, d, J = 9.9 Hz, H-2); 13C
NMR (50 MHz, D2O) 20.2 (CH2), 25.3 (CH2), 42.2 (CH, C-3), 43.4
(CH2, C-6), 57.1 (CH, C-2), 170.2 (C, COOH), 174.7 (C, COOH0); HRMS
(EI) C7H11NO4Na, M+ requires 196.0580; found 196.0596;
to provide 267 mg of (+)-20 (89%). IR (film)
1647, 1437, 1411, 1380, 1270, 1209, 1166, 1025, 733; 1H NMR
(400 MHz, CDCl3) 1.43 (3H, d, J = 7.2 Hz, C( )Me), 1.90–2.08 (2H,
m, H-4), 2.53–2.63 (3H, m, H-3 and H-5), 3.66 (3H, s, COOCH3),
4.19 (1H, d, J = 4.7 Hz, H-2), 6.16 (1H, q, J = 7.2 Hz, C( )H),
7.26–7.40 (5H, m, ArH), 9.80 (1H, s, CHO); 13C NMR (50 MHz,
CDCl3) 17.1 (CH3, C( )Me), 19.9 (CH2, C-4), 30.2 (CH2, C-5), 42.7
(CH, C-3), 50.9 (CH, C( )), 52.6 (CH3, COOCH3), 60.5 (CH, C-2),
m
(cmꢀ1) 2954, 1734,
a
½
a 2D0
ꢂ
¼ þ18:6 (c 0.62, HCl 6 M).
a
4.14. (4R,5R, R,E)-4-Methoxycarbonyl-5-(N-a-
a
methylbenzylamino)-7-phenyl-hept-6-enoic acid (+)-18
a
a
To a solution of (ꢀ)-10 (540 mg, 1.15 mmol) in AcCN/H2O: 5/1
(24 mL) was added cerium(IV) ammonium nitrate (2.51 g,
4.58 mmol). After 40 minutes, saturated aqueous NaHCO3 solution
was added and the resulting solution was extracted with EtOAc.
The organic layer was dried over Na2SO4. Concentration followed
by flash chromatography on silica gel (9:1 hexane/EtOAc) gave
127.4–129.1 (CH ꢃ 5, Ar), 139.6 (C, Cipso), 170.2 (C, C-6), 171.4 (C,
COOCH3), 199.5 (CH, CHO); HRMS (EI) C16H19NO4Na, M+ requires
312.1206; found 312.1207; ½a D20
ꢂ
¼ þ71:5 (c 0.91, CHCl3).
4.17. (2S,3R,
a
R)-6-Oxo-1-(N-
a-methylbenzyl)-piperidine-2,3-
dicarboxylic acid 3-methyl ester (+)-21
(+)-18 (429 mg, 96%). IR (film)
m
(cmꢀ1) 3500–3200, 3060, 3028,
2951, 1731, 1638, 1494, 1450, 1384, 1266, 1207, 1161, 1079,
To a solution of (+)-20 (250 mg, 0.87 mmol) in t-BuOH (20.7 mL)
and 2-methyl-2-butene (5.5 mL) was slowly added an aqueous
solution of NaH2PO4 (1.4 g) in NaClO2 (3.3 mL). The mixture was
stirred at room temperature for 15 minutes. The volatiles were re-
moved under reduced pressure, after which H2O was added. The
solution was acidified (pH acid) and extracted with EtOAc three
times. The combined organic phase was washed with water and
brine, dried over Na2SO4 and concentrated. The residue was puri-
fied on silica gel, eluting with hexane/EtOAc: 9/1 to provide
1029, 971, 737; 1H NMR (400 MHz, CDCl3) 1.39 (3H, d, J = 6.5 Hz,
C(
2.73 (1H, m, H-4), 3.68 (1H, t, J = 9.0 Hz, H-5), 3.72 (3H, s, COOCH3),
3.92 (1H, q, J = 6.5 Hz, C( )H), 5.91 (1H, dd, J = 15.8 and 9.0 Hz, H-
6), 6.45 (1H, d, J = 15.8 Hz, H-7), 7.23–7.32 (10H, m, ArH); 13C NMR
(50 MHz, CDCl3) 22.3 (CH3, C( )Me), 24.6 (CH2, C-3), 33.0 (CH2,
C-2), 50.5 (CH, C-4), 52.0 (CH3, COOCH3), 55.3 (CH, C( )), 60.5
a)Me), 1.89–2.03 (2H, m, H-3), 2.34–2.48 (2H, m, H-2), 2.65–
a
a
a
(CH, C-5), 126.8 (CH, C-6), 127.1–129.7 (CH ꢃ 10, Ar), 133.7 (CH,
C-7), 136.6 (C, Cipso), 145.1 (C, Cipso ), 174.9 (C, COOCH3), 177.9 (C,
133 mg of (+)-21 (50%). IR (film)
1743, 1591, 1453, 1277, 1209, 733; 1H NMR (400 MHz, CDCl3)
1.50 (3H, d, J = 7.2 Hz, C( )Me), 1.95–2.02 (1H, m, H-4a), 2.07–
m
(cmꢀ1) 3500–3200, 2954,
0
COOH); HRMS (EI) C23H28NO4, M+ requires 382.2013; found
382.2021; ½a 2D0
ꢂ
¼ þ26:8 (c 2.01, CHCl3).
a
2.19 (1H, m, H-4b), 2.53–2.65 (2H, m, H-5a and H-3), 2.74 (1H,
4.15. (2R,3R,aR,E)-Methyl-6-oxo-1-(N-a-methylbenzyl)-2-
ddd, J = 18.5, 8.9 and 2.9 Hz, H-5b), 3.62 (3H, s, COOCH3), 4.22
styryl-piperidine-3-carboxylate (+)-19
(1H, d, J = 3.9 Hz, H-2), 6.13 (1H, q, J = 7.2 Hz, C(
(5H, m, ArH); 13C NMR (50 MHz, CDCl3) 15.8 (CH3, C(
(CH2, C-4), 29.6 (CH2, C-5), 43.0 (CH, C-3), 52.0 (CH, C(
a
)H), 7.29–7.39
)Me), 19.0
)), 52.6
a
To a solution of (+)-18 (230 mg, 0.60 mmol) in DMF (4.30 mL),
DIPEA (0.21 mL, 1.21 mmol), hydroxybenzotriazole hydrate
(180 mg, 1.33 mmol) and 1-ethyl-3-[3-dimethylaminopropyl)car-
bodiimide (255 mg, 1.33 mmol) were added and stirred for 2 hours
at rt. The reaction mixture was concentrated in vacuo and then
H2O was added. The resulting solution was extracted with EtOAc.
The organic layer was washed with water, brine and dried over
Na2SO4. Concentration followed by flash chromatography on silica
a
(CH3, COOCH3), 56.0 (CH, C-2), 127.5–129.0 (CH ꢃ 5, Ar), 139.6 (C,
Cipso), 170.9 (C, C-6), 171.8 (C, COOCH3), 173.0 (C, COOH); HRMS
(EI) C16H19NO5Na, M+ requires 328.1155; found 328.1147;
½
a 2D0
ꢂ
¼ þ52:6 (c 1.24, CHCl3).
4.18. (2S,3R, R)-Dimethyl-6-oxo-1-(N-a-methylbenzyl)-
a
piperidine-2,3-dicarboxylate (+)-22
gel (8/2 hexane/EtOAc) gave 105 mg of (+)-19 (48%). IR (film)
m
(cmꢀ1) 3026, 2951, 1737, 1637, 1495, 1437, 1412, 1368, 1275,
To solution of (+)-21 (112 mg, 0.37 mmol) in benzene
a
1232, 1163, 1068, 1024, 752; 1H NMR (400 MHz, CDCl3) 1.52
(1.3 mL)/MeOH (1.3 mL) was added TMSCHN2 2 M in Et2O
(0.22 mL, 0.44 mmol). The mixture was stirred at room-tempera-
ture for 20 minutes. The volatiles were removed under reduced
pressure. The residue was purified on silica gel, eluting with hex-
(3H, d, J = 7.2 Hz, C(
m, H-3 and H-5), 3.58 (3H, s, COOCH3), 4.26 (1H, ddt, J = 6.9, 4.4
a)Me), 1.96–2.18 (2H, m, H-4), 2.52–2.73 (3H,
and 1.1 Hz, H-2), 6.10 (1H, q, J = 7.2 Hz, C(a)H), 6.14 (1H, dd,
J = 15.9 and 6.9 Hz, H-10), 6.35 (1H, dd, J = 15.9 and 1.1 Hz, H-20),
ane/EtOAc: 9/1 to provide 116 mg of (+)-22 (98%). IR (film) m
7.26–7.38 (10H, m, ArH); 13C NMR (50 MHz, CDCl3) 17.5 (CH3,
(cmꢀ1) 2954, 1746, 1651, 1439, 1411, 1379, 1309, 1272, 1208,
1075, 1021, 782; 1H NMR (400 MHz, CDCl3) 1.42 (3H, d,
C(a)Me), 18.8 (CH2, C-4), 30.5 (CH2, C-5), 45.3 (CH, C-3), 52.2
(CH3, COOCH3), 52.4 (CH, C(
a
)), 55.7 (CH, C-2), 126.8–129.0
J = 7.2 Hz, C(a)Me), 1.91–1.99 (1H, m, H-4a), 2.05–2.16 (1H, m, H-
4b), 2.53 (1H, dt, J = 18.3 and 9.0 Hz, H-5a), 2.63 (1H, dt, J = 13.0
and 4.8 Hz, H-3), 2.71 (1H, ddd, J = 18.3, 8.6 and 2.7 Hz, H-5b),
(CH ꢃ 10, Ar), 127.2 (CH, C-10), 133.6 (CH, C-20), 136.3 (C, Cipso),
0
140.6 (C, Cipso ), 169.9 (C, C-6), 171.5 (C, COOCH3); HRMS (EI)

N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
879
0
3.62 (3H, s, COOCH3), 3.72 (3H, s, COOCH3 ), 4.15 (1H, dd, J = 4.8 and
1.3 Hz, H-2), 6.13 (1H, q, J = 7.2 Hz, C( )H), 7.26–7.39 (5H, m, ArH);
13C NMR (50 MHz, CDCl3) 15.8 (CH3, C(
)Me), 19.5 (CH2, C-4), 30.0
)), 52.5 (CH3, COOCH3), 52.9
2.7 Hz, H-3), 3.23–3.36 (1H, m, H-6a), 3.40 (1H, q, J = 4.4 Hz,
H-6b), 4.01 (1H, d, J = 3.7 Hz, H-2); 13C NMR (50 MHz, D2O) 18.9
(CH2), 26.0 (CH2), 42.3 (CH, C-3), 44.5 (CH2, C-6), 59.9 (CH, C-2),
173.7 (C, COOH), 180.1 (C, COOH0); HRMS (EI) C7H12NO4, M+ re-
a
a
(CH2, C-5), 43.1 (CH, C-3), 51.4 (CH, C(
a
quires 174.0750; found 174.0762; ½a D20
¼ þ2:8 (c 0.75, HCl 6M).
ꢂ
0
(CH3, COOCH3 ), 56.0 (CH, C-2), 127.4–129.0 (CH ꢃ 5, Ar), 139.9 (C,
Cipso), 170.0 (C, C-6), 171.0 (C, COOCH3), 171.2 (C, COOCH03); HRMS
(EI)
C
17H21NO5Na, M+ requires 342.1312; found 342.1307;
Acknowledgments
½
a 2D0
ꢂ
¼ þ53:6 (c 1.27, CHCl3).
The authors are grateful to the FSE, Spanish MEC (CTQ2009-
11172/BQU) and Junta de Castilla y León (Spain) for financial sup-
port: (SA001A09) and excellence GR-178. The authors also thank
Dr. A. M. Lithgow for the NMR spectra and Dr. César Raposo for
the mass spectra. M.R.S.C. thanks University of Salamanca for a
FPI doctoral fellowship.
4.19. (2S,3R, R)-Dimethyl-1-(N-a-methylbenzyl)-piperidine-
2,3-dicarboxylate (ꢀ)-23
a
To a solution of (+)-22 (101 mg, 0.32 mmol) in THF (7.5 mL) at
0 °C was added BH3ꢁTHF 1 M in THF (1.26 mL, 1.26 mmol). The
mixture reaction was stirred under an atmosphere of argon at
0 °C for 1.5 hours. The reaction was quenched with MeOH. The
resulting solution was stirred for 40 minutes and then the volatiles
were removed under reduced pressure (ꢃ3). The solution was acid-
ified with HCl (pH ffi 3) and extracted with EtOAc three times. The
combined organic phase was washed with saturated aqueous
NaHCO3, dried over Na2SO4 and concentrated. The residue was
purified on silica gel, eluting with hexane/EtOAc: 9/1 to provide
References
1. Moloney, M. G. Nat. Prod. Rep. 1998, 205–219.
2. (a) Whitten, J. P.; Muench, D.; Cube, R. V.; Nyce, P. L.; Baron, B. M.; McDonald, I.
A. Bioorg. Med. Chem. Lett. 1991, 1, 441–444; (b) Herrling, P. L. In The N-Methyl-
d-Aspartic Acid Receptor; Watkins, J. C., Collingridge, G. L., Eds.; IRL Press at
Oxford Univ. Press: Oxford, UK, 1989.
3. (a) Agami, C.; Kadouri-Puchot, C.; Le Guen, V.; Vaissermann, J. Tetrahedron Lett.
1995, 36, 1657–1660; (b) Makara, G. M.; Marshall, G. R. Tetrahedron Lett. 1997,
38, 5069–5072; (c) Xue, C.-B.; He, X.; Roderick, J.; Corbett, R. L.; Decicco, C. P. J.
Org. Chem. 2002, 67, 865–870; (d) Johansen, J. E.; Christie, B. D.; Rapoport, H. J.
Org. Chem. 1981, 46, 4914–4920; (e) Agami, C.; Hamon, L.; Kadouri-Puchot, C.;
Le Guen, V. J. Org. Chem. 1996, 61, 5736–5742; (f) Davies, J.; Evans, R. H.;
Francis, A. A.; Jones, A. W.; Smith, D. A. S.; Watkins, J. C. Neurochem. Res. 1982, 7,
1119–1133.
39 mg of (ꢀ)-23 (40%). IR (film)
1261, 1240, 1196, 1147, 1087, 1038, 1019, 1000, 702; 1H NMR
(400 MHz, CDCl3) 1.37 (3H, d, J = 6.6 Hz, C( )Me), 1.39–1.50 (1H,
m
(cmꢀ1) 2951, 1740, 1452, 1434,
a
m), 1.54–1.62 (1H, m), 1.78 (1H, qd, J = 4.3 and 13.2 Hz, H-4a),
1.97 (1H, dq, J = 13.2 and 3.0 Hz), 2.52–2.55 (2H, m, H-6), 2.87
4. Olverman, H. J.; Jones, A. W.; Mewett, K. N.; Watkins, J. C. Neuroscience 1988, 26,
17–33.
5. Garrido, N. M.; García, M.; Díez, D.; Sánchez, M. R.; Sanz, F.; Urones, J. G. Org.
Lett. 2008, 10, 1687–1690.
(1H, dt, J = 12.9 and 4.5 Hz, H-3), 3.73 (6H, s, COOCH3 and
0
COOCH3 ), 3.87 (1H, q, J = 6.6 Hz, C(a)H), 4.43 (1H, d, J = 4.5 Hz,
H-2), 7.22–7.36 (5H, m, ArH); 13C NMR (50 MHz, CDCl3) 22.4
6. For reviews, see: (a) Hiersemann, M.; Nubbemeyer, U. The Claisen
Rearrangement: Methods and Applications; Wiley Interscience: Weinheim,
2007; (b) Martin Castro, A. M. Chem. Rev. 2004, 104, 2939; (c) Chai, Y.; Hong,
S.-P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905;
(d) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1847, 1996, 7;
(e) Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
(CH3, C(
a
)Me), 22.8 (CH2), 24.8 (CH2), 45.1 (CH, C-3), 45.6 (CH2,
0
C-6), 51.3 (CH3, COOCH3), 52.0 (CH3, COOCH3 ), 58.7 (CH, C(
a)),
62.4 (CH, C-2), 127.0–128.6 (CH ꢃ 5, Ar), 146.8 (C, Cipso), 172.2 (C,
COOCH3), 173.7 (C, COOCH03); HRMS (EI) C17H23NO4Na, M+ requires
328.1519; found 328.1517; ½a D20
¼ ꢀ2:0 (c 1.02, CHCl3).
ꢂ
7. Garrido, N. M.; García, M.; Sánchez, M. R.; Díez, D.; Urones, J. G. Synlett 2010,
387–390.
4.20. (2S,3R)-Dimethyl-piperidine-2,3-dicarboxylate (+)-24
8. Even though we used cinnamaldehyde as a masked carboxylic functionality,
we also tried ROOC–CHO, R = H, Et, as well. In the first case we did not obtain
the proper Baylis–Hillman adduct and in the second, it was obtained in poor
To a solution of (ꢀ)-23 (41 mg, 0.13 mmol) in glacial AcOH
(1 mL) was added Pd–C (10%) (40% in weight) and the mixture
was stirred under H2 (50 psi) at rt for 22 hours. The reaction mix-
ture was then filtered through CeliteÒ and silica gel, washed with
CH2Cl2 and MeOH and concentrated. The residue was dissolved
in CH2Cl2 and washed with NaHCO3 10% and H2O. The organic layer
was dried over Na2SO4, filtered and concentrated. Chromatography
on silica gel eluting hexane/EtOAc: 9/1 provided 16 mg of (+)-24
yield. However, when it was treated with lithium amide, we obtained
complex reaction mixture.
9. For relevant reviews see: (a) Ciganek, E. In Organic Reactions; Paquette, L. A.,
Ed.; Wiley: New York, 1997; Vol. 51, p 201; (b) Basavaiah, D.; Dharma Rao, P.;
Suguna Hymna, R. Tetrahedron 1996, 52, 8001–8062; (c) Basavaiah, D.; Rao, A.
J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891.
10. For a comprehensive review covering the scope, limitations and synthetic
applications of the use of enantiomerically pure lithium amides as homochiral
ammonia equivalents in conjugate addition reactions see: Davies, S. G.; Smith,
A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
a
(61%). IR (film)
m
(cmꢀ1) 2952, 2856, 1736, 1437, 1363, 1256,
11. (a) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Chem.
Commun. 1993, 1153–1154; (b) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1141–1147; (c) Davies, S. G.; Walters, I. A. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1129–1139.
1205, 1122, 1036, 1004; 1H NMR (400 MHz, CDCl3) 1.51–1.54
(2H, m), 1.78–1.84 (2H, m), 2.16 (1H, dq, J = 13.6 and 4.8, H-6a),
2.68–2.75 (1H, m, H-6b), 3.02–3.10 (1H, m, H-3), 3.67 (1H, d,
´
12. (a) Bull, S. D.; Davies, S. G.; Garner, A. C.; OShea, M. D. J. Chem. Soc., Perkin Trans.
J = 3.4 Hz, H-2), 3.72 (3H, s, COOCH3), 3.77 (3H, s, COOCH3 ); 13C
0
1 2001, 3281–3287; (b) Bull, S. D.; Davies, S. G.; Ferton, G.; Mulvaney, A. W.;
Prasad, R. S.; Smith, A. D. Chem. Commun. 2000, 337–338.
13. Suitable single crystals of compound (+)-13 were mounted on glass fiber for
data collection on a Bruker Kappa APEX II CCD diffractometer. Data were
NMR (50 MHz, CDCl3) 23.6 (CH2), 26.2 (CH2), 42.4 (CH, C-3), 45.5
0
(CH2, C-6), 52.1 (CH3, COOCH3), 52.3 (CH3, COOCH3 ), 59.5 (CH,
C-2), 172.7 (C, COOCH3), 173.4 (C, COOCH03); HRMS (EI) C9H16NO4,
collected at 298(2) K using Cu
technique, and were corrected for Lorentz and polarization effects. Structure
solution, refinement and data output were carried out with the SHELXTL
Ka radiation (k = 1.54178 Å) and x scan
M+ requires 202.1074; found 202.1072; ½a 2D0
¼ þ0:85 (c 1.18,
ꢂ
™
CHCl3).
program package. The structures were solved by direct methods combined
with difference Fourier synthesis and refined by full-matrix least-squares
procedures, with anisotropic thermal parameters in the last cycles of
refinement for all non-hydrogen atoms. (a) Crystal data for (+)-13:
4.21. (2S,3R)-Piperidine-2,3-dicarboxylic acid hydrochloride
(+)-2
C
16H19N1O4, M = 289.32, monoclinic, space group P21 (no. 4), a = 6.5263(3) Å,
b = 14.9350(5) Å, c = 7.7970(2) Å,
a
=
K
c
a
90, b = 100.768(2)°, V = 746.59(6) Å3,
Z = 4, Dc = 1.287 Mg/m3, m = (Cu
) = 0.761 mmꢀ1
,
F(0 0 0) = 308. 1913
A solution of (+)-24 (15 mg, 0.08 mmol) in HCl 3 M (0.12 mL)
was refluxed for 5 hours and then concentrated under reduced
pressure. The solution was washed with Et2O and concentrated.
The chlorohydrate of the amino diacid (+)-2 was obtained as white
solid (11 mg, 81%). 1H NMR (200 MHz, D2O) 1.29–1.58 (1H, m),
1.61–1.92 (2H, m), 2.03–2.20 (1H, m), 2.89 (1H, td, J = 12.8 and
reflections were collected at 5.93 ꢄ 2h ꢄ 59.82 and merged to give 1287
unique reflections (Rint = 0.0114), of which 1234 with I > 2 I were considered
r
to be observed. Final values are R = 0.0303, wR = 0.0744, GOF = 1.097, max/min
residual electron density 0.104 and ꢀ0.104 e Åꢀ3
. Crystallographic data
(excluding structure factors) for the structure reported in this paper has
been deposited at the Cambridge Crystallographic Data Centre as
supplementary material no. CCDC 818289.

880
N. M. Garrido et al. / Tetrahedron: Asymmetry 22 (2011) 872–880
14. The A(1,3) strain in N-acylpiperidines has been demonstrated to make the 2-
axial-substituted conformers more stable than the corresponding 2-equatorial
isomers: (a) Paulson, H.; Todt, K. Angew. Chem., Int. Ed. 1966, 5, 899–900; (b)
Scott, J. W.; Durham, L. J.; De Jongh, H. A. P.; Burckhardt, V.; Johnson, W. S.
Tetrahedron Lett. 1967, 2381–2386; (c) Chow, Y. L.; Colon, C. J.; Tam, J. N. S. Can.
J. Chem. 1968, 46, 2821–2825; (d) Fraser, R. R.; Grindley, T. B. Tetrahedron Lett.
1974, 4169–4172; (e) Quick, J.; Modello, C.; Humora, M.; Brennan, T. J. Org.
Chem. 1978, 43, 2705–2708; (f) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984,
106, 1010–1018.
15. Here the strain is between the substituent at the 2- and 3-positions in the
allylic amide system. For a general review concerning A(1,3) allylic strain see
reference: Johnson, F. Chem. Rev. 1968, 68, 375–413.
16. A similar pattern for coupling constant is observed for all C2 substituted-a-N-
methylbenzylpiperidone in this work, implying a similar conformation under
the same A(2,3) allylic strain effect.
17. Choi, Y. M.; Emblidge, R. W.; Kucharczyk, N.; Sofia, R. D. J. Org. Chem. 1989, 54,
1194–1198.