Switching the stereochemical outcome of 6- endo - Trig cyclizations; Synthesis of 2,6- cis -6-substituted 4-oxopipecolic acids

Article abstract of DOI:10.1021/jo3022583

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-l-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-l-pipecolic acids to the corresponding 4-hydroxy-l-pipecolic acids was also performed.

Full text of DOI:10.1021/jo3022583

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Switching the Stereochemical Outcome of 6-Endo-Trig Cyclizations;
Synthesis of 2,6-Cis-6-Substituted 4‑Oxopipecolic Acids
Mark Daly,† Alastair A. Cant,† Lindsay S. Fowler,† Graham L. Simpson,‡ Hans Martin Senn,†
and Andrew Sutherland*,†
†WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, United Kingdom
‡GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
S
* Supporting Information
ABSTRACT: A base-mediated 6-endo-trig cyclization of
readily accessible enone-derived α-amino acids has been
developed for the direct synthesis of novel 2,6-cis-6-
substituted-4-oxo-L-pipecolic acids. A range of aliphatic and
aryl side chains were tolerated by this mild procedure to give
the target compounds in good overall yields. Molecular
modeling of the 6-endo-trig cyclization allowed some insight as
to how these compounds were formed, with the enolate
intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving
force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic
acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed.
enone side chain for the preparation of 2,6-trans-6-substituted
4-oxo-L-pipecolic acids (Scheme 1a).16 The stereochemical
outcome of the 6-endo-trig cyclization was rationalized by a
Zimmerman−Traxler chairlike transition state17 that placed
both the R group and the N-substituent in a pseudoequatorial
position. To switch the stereochemical outcome of this 6-endo-
trig cyclization and gain access to 2,6-cis-6-substituted-4-oxo-L-
pipecolic acids, a more direct, intramolecular aza-Michael
reaction was proposed (Scheme 1b). Without a substituent on
the amine, it was believed an alternative chairlike reacting
conformer in which the R-group and methyl ester moieties
both occupy a pseudoequatorial position would now control
the cyclization. Herein, we now report the development of a
one-pot, deprotection/base-mediated 6-endo-trig cyclization to
give 2,6-cis-6-substituted 4-oxo-L-pipecolic acids. The facile
stereoselective reduction of these compounds to the corre-
sponding (4R)-hydroxypipecolic acid analogues is also
described.
INTRODUCTION
■
The cyclic nonproteinogenic α-amino acid L-pipecolic acid (1)
is metabolized from L-lysine via several putative pathways.1 As
well as being found in plants and fungi, it has a functional role
in the mammalian central nervous system in a manner similar
to γ-aminobutyric acid (GABA).2,3 L-Pipecolic acid 1 is also a
component of several pharmacologically active compounds
including the antitumor antibiotic sandramycin4 and the
immunosuppressive agents rapamycin5 and FK506.6 Analogues
incorporating an oxygen atom, particularly at the 4-position,
such as 4-oxo-L-pipecolic acid (2) or (2S,4R)-4-hydroxypipe-
colic acid (3) are also biologically and medicinally important.
For example, 4-oxo-L-pipecolic acid (2) is a key structural
element of the cyclic hexadepsipeptide antibiotic virginamycin
S1 (4),7 while (2S,4R)-4-hydroxypipecolic acid 3, isolated from
the leaves of Calliandra pittieri and Strophantus scandeus,8 is a
constituent of the synthetic HIV protease inhibitor palinavir 5
(Figure 1).9
As these compounds are of significant pharmacological and
medicinal importance, methods for their asymmetric synthesis
has received considerable attention.10 For example, Occhiato
and co-workers demonstrated the synthesis of (2S,4R)-4-
hydroxypipecolic acid (3) using a palladium-catalyzed methox-
ycarbonylation of a 4-alkoxy-substituted δ-valerolactam-derived
vinyl triflate as the key step,11 while the research group of
Haufe showed that a (2S,6R)-6-tert-butyl-4-oxopipecolic amide
could be formed via an acid-mediated cascade from a 2-
fluorovinyl imidazolidinone.12 Our own research efforts have
focused on developing stereoselective approaches for the less
well-known 6-substituted 4-oxo- and 4-hydroxypipecolic
acids,13−15 and recently, we reported a one-pot, reductive
amination/6-endo-trig cyclization of α-amino acids bearing an
RESULTS AND DISCUSSION
■
To study the scope of the 6-endo-trig cyclization, a range of aryl
and alkyl substituted α-amino acid derived enones were
prepared in four steps from L-aspartic acid 6 (Scheme 2).16,18
Initially, 6 was converted under standard conditions and in
quantitative yield to N-trityl L-aspartate dimethyl ester 7.
Regioselective reaction of the β-methyl ester of 7 with 2.2 equiv
of the lithium anion of dimethyl methylphosphonate gave
exclusively β-ketophosphonate ester 8 in 84% yield.19 Horner−
Wadsworth−Emmons reaction of 8 under mild conditions with
Received: October 17, 2012
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of Enone-Derived α-Amino Acids
Table 1. Optimization of the 6-Endo-Trig Cyclization
Figure 1. L-Pipecolic acid (1) and oxygenated analogues.
Scheme 1. 6-Endo-Trig Cyclization of Enone-Derived α-
Amino Acids
entry
base
solvent
temp (°C)
time (h)
yield (%)
1
2
3
n-BuLi
THF
−78
65
rt
24
24
48
18
18
0
0
LiHMDS
Na2CO3
Na2CO3
EtN(iPr)2
THF
CH2Cl2
MeOH
MeOH
0
a
4
a
rt
41
85
5
rt
a
Reactions were performed as one-pot, two-step procedures.
methanol (cf. entry 3) seemed crucial for successful cyclization
of enone 9. Following this observation, the one-pot, two-step
procedure was investigated using neutral organic bases. Optimal
a range of aldehydes gave solely the E-enones 9−19 in 58−96%
yield.
results were achieved using Hunig’s base (entry 5), which gave
̈
20 and 21 very cleanly in 85% yield and with the same
diastereomeric ratio as noted above. The main product, cis-
diastereomer 20, was easily isolated in 56% yield using flash
column chromatography.
The phenyl-derived E-enone 9 was selected as the model
substrate for discovery and optimization of the key cyclization
step (Table 1). Initially, conversion to the corresponding 4-oxo-
L-pipecolic acids 20 and 21 was performed as a two-pot process.
The trityl protecting group was removed under acidic
conditions, and on basic workup the amine was isolated in
quantitative yield. Attempted intramolecular aza-Michael
reaction with strong bases such as n-butyllithium (entry 1) or
lithium hexamethyldisilazane (entry 2) gave highly complex
mixtures of polar compounds with no cyclized products
detected. Using sodium carbonate in dichloromethane and
milder reaction conditions returned only the starting amine
(entry 3). A one-pot procedure was next attempted with
sodium carbonate added to the reaction mixture after the
deprotection step was deemed complete (entry 4). This gave
cyclized products 20 and 21 in 41% yield over the two steps
and in a diastereoselective ratio of 75:25, respectively.20
Enhanced solvation of the base using the more polar solvent,
The scope and stereoselectivity of the one-pot deprotection/
6-endo-trig cyclization was then investigated using E-enones
10−19 (Table 2). On workup of all of these reactions, the
diastereomeric ratio of the cis- and trans-products was recorded
using the 1H NMR spectrum of the crude material, and this was
followed by isolation of the major cis-diasteromer by flash
column chromatography. In general, the 6-endo-trig cyclization
of enones with alkyl side chains or electron-rich aromatic
groups proceeded very cleanly giving the major cis-diaster-
eomers in good isolated yields (54−68%) over the two steps.
Slightly lower yields (37−51%) were observed for enones with
electron-deficient aromatic groups.
In all cases, the cis-diastereomers were formed as the major
product in good diastereoselectivity. To rule out formation of
these compounds via a reversible process, the 85:15 cis/trans-
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differences. We therefore use only the results for formation of
20 (R = Ph) in the discussion below. The 6-endo-trig cyclization
(Figure 2) proceeds through a transition state (TS) with a
partially formed N−C bond (1.90 Å) and a planar, delocalized
Cβ−Cα−C(O) moiety, in which the C−C bond lengths have
equalized to 1.41 Å. Moreover, compared to the reactant,
electron density has been shifted from the nitrogen onto the
carbonyl-oxygen, increasing its negative partial charge. The
immediate product of the cyclization is the zwitterionic
ammonioenolate ZI; subsequent tautomerization and intra-
molecular neutralization afford the 2,6-cis-substituted 4-
oxopipecolic acid derivative P. The free-energy profile of the
reaction (calculated for 298 K, 1 bar) shows a relatively high
activation energy of 108 kJ mol−1 for the cyclization. The free-
energy barrier includes a sizable entropic contribution of
−TΔ⧧S = 18 kJ mol−1 due to the loss of conformational
flexibility in the delocalized system. The formation of ZI is
endergonic by 94 kJ mol−1. However, formation of the final
product P is exergonic by −24 kJ mol−1 relative to the reactant.
The initial addition step in forming ZI is therefore an
equilibrium, shifted strongly to the reactant side. However,
subsequent tautomerization/neutralization which is kinetically
facile, is energetically highly favorable and irreversible,
providing the driving force for product formation. This
corroborates the experimental finding that the cyclized
products cannot undergo reversible ring-opening under the
reaction conditions.
Table 2. Scope of the 6-Endo-Trig Cyclization
Having developed a rapid approach for the preparation of
2,6-cis-6-substituted 4-oxo-L-pipecolic acid analogues, we
wished to show that these compounds could be reduced
stereoselectively to give the naturally occurring (4R)-hydroxyl
moiety. Initially, various borohydride reagents were screened
for the reduction of ketone 24.12,13,21 L-Selectride showed no
reduction, while sodium borohydride and sodium cyanobor-
ohydride both gave the (4R)- and (4S)-alcohols in excellent
diastereoselectivity (91:9) but in moderate yields (52% and
60%, respectively). Optimal results were achieved using sodium
triacetoxyborohydride which gave the (4R)- and (4S)-alcohols
in similar diastereoselectivity (93:7) but in a much higher 87%
yield (Scheme 3). Using sodium triacetoxyborohydride, several
other ketones were also reduced in excellent diastereoselectivity
giving alcohols 33−37 in yields ranging from 63−100%.
To complete the synthesis of the parent 2,6-cis-6-substituted
4-hydroxypipecolic acids, several pipecolic esters (32−34 and
36) bearing alkyl and aryl side chains were subjected to
hydrolysis at 100 °C in 6 M hydrochloric acid. This gave the
corresponding pipecolic acids in good to excellent yields (62−
99%) (Scheme 4).
a
Isolated yields of cis-product over two steps.
CONCLUSIONS
In summary, a one-pot, two-step procedure involving
deprotection and a Hunig’s base mediated 6-endo-trig
mixture of cyclized products formed from enone 18 were
resubjected to the cyclization reaction conditions over an
extended period of time (5 days). However, inspection of the
reaction mixture at regular intervals during this period using 1H
NMR spectroscopy, showed no change in the ratio of
diastereomers. This suggested that the 6-endo-trig cyclization
of the enones proceeded under kinetic control. In order to
obtain further insight into the mechanism and energetics of the
cyclization step, we performed quantum-chemical calculations.
The calculations were done at the DFT level (M06-2X/def2-
TZVP+) and included a polarizable-continuum model of the
methanol solvent. To probe substituent effects, we studied the
reaction for formation of compounds 20 (R = Ph), 22 (R =
isobutyl), and 26 (R = 4-BrPh). However, we found only minor
■
̈
cyclization of α-amino acids bearing an enone side chain has
been developed leading to the formation of 2,6-cis-6-substituted
4-hydroxypipecolic acid derivatives in good overall yields. The
stereochemical outcome of this cyclization can be rationalized
by a Zimmerman−Traxler chairlike transition state where both
the enone side chain and ester moieties adopt pseudoequatorial
positions. The compounds formed from this process have
potential for further functionalization, and we have demon-
strated one aspect of this by converting these compounds to
the corresponding (4R)-hydroxyl derivatives by a stereo-
selective reduction with sodium triacetoxyborohydride. Work
C
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Figure 2. Free-energy profile (at 298 K, 1 bar) and optimized structures of the transition state and zwitterionic intermediate for the Michael
addition/cyclization reaction. Energies and structures calculated at M06-2X/def2-TZVP+/PCM(MeOH) level.
Scheme 3. Stereoselective Reduction of 4-Oxopipecolic
Esters
Scheme 4. Synthesis of 4-Hydroxypipecolic Acids
received. All dry solvents were purified using a solvent purification
system. All reactions were performed under an atmosphere of argon
unless otherwise mentioned. Brine refers to a saturated solution of
sodium chloride. Flash column chromatography was performed using
silica gel 60 (35−70 μm). Aluminum-backed plates precoated with
silica gel 60F254 were used for thin-layer chromatography and were
visualized with a UV lamp or by staining with potassium
permanganate. 1H NMR spectra were recorded on a NMR
spectrometer at either 400 or 500 MHz and data are reported as
follows: chemical shift in ppm relative to tetramethylsilane as the
internal standard, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet or overlap of nonequivalent resonances,
integration). 13C NMR spectra were recorded on a NMR spectrometer
at either 101 or 126 MHz and data are reported as follows: chemical
shift in ppm relative to tetramethylsilane or the solvent as internal
standard (CDCl3, δ 77.0 ppm or CD3OD, δ 44.0 ppm), multiplicity
with respect to proton (deduced from DEPT experiments, C, CH,
is currently underway to demonstrate the use of these
compounds as general building blocks for the preparation of
more complex systems.
EXPERIMENTAL SECTION
■
The synthesis of compounds 7−10, 12, 14−17, and 19 has been
already described in the literature.18,19 All reagents and starting
materials were obtained from commercial sources and used as
D
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CH2 or CH3). Infrared spectra were recorded on a FTIR 410
spectrometer; wavenumbers are indicated in cm−1. Mass spectra were
recorded using electron impact, chemical ionization or fast atom
bombardment techniques. HRMS spectra were recorded using a dual-
focusing magnetic analyzer mass spectrometer. Melting points are
uncorrected. Optical rotations were determined as solutions irradiating
with the sodium D line (λ = 589 nm) using a polarimeter. [α]D values
are given in units 10−1 deg cm2 g−1.
1H) ppm; 13C NMR (101 MHz, CDCl3) δ 45.9 (CH2), 52.1 (CH3),
53.7 (CH), 71.3 (C), 123.9 (CH), 126.6 (3 × CH), 127.8 (7 × CH),
128.8 (6 × CH), 130.2 (C), 134.4 (CH), 139.4 (CH), 145.8 (3 × C),
151.2 (CH), 151.7 (CH), 174.4 (C), 197.0 (C) ppm; MS m/z 477
(MH+, 38), 399 (12), 243 (100), 233 (14), 215 (5), 165 (21), 132
(11), 104 (4), 83 (20); HRMS (FAB) calcd for C31H29N2O3 (MH+),
477.2178, found 477.2180.
Methyl (2S,6R)-4-Oxo-6-phenylpiperidine-2-carboxylate
(20). To a solution of methyl (2S,5E)-2-(tritylamino)-4-oxo-6-
phenylhex-5-enoate (9) (0.06 g, 0.13 mmol) in methanol (10 mL)
at room temperature was added 2 M hydrochloric acid (2.5 mL). The
reaction mixture was stirred for 1 h and then diluted with water (5
mL), and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was added
until pH 8 was obtained. The mixture was stirred for 18 h and then
partitioned between ethyl acetate (20 mL) and brine (20 mL). The
aqueous layer was separated and extracted with ethyl acetate (20 mL).
The organic layers were combined, dried (MgSO4), filtered, and
concentrated under reduced pressure. Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded methyl (2S,6R)-4-oxo-6-phenylpiperidine-2-carboxylate (20)
(0.02 g, 56%) as a colorless oil: IR (neat) 3325, 2978, 2361, 1728,
1705, 1435, 1211, 756 cm−1; [α]25D = +43.9 (c 0.9, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 2.50−2.64 (m, 4H), 2.79 (ddd, 1H, J = 14.5, 3.5,
1.5 Hz), 3.71−3.80 (m, 4H), 3.95 (dd, 1H, J = 10.0, 4.7 Hz), 7.30−
7.43 (m, 5H) ppm; 13C NMR (101 MHz, CDCl3) δ 43.9 (CH2), 50.1
(CH2), 52.5 (CH3), 57.9 (CH), 60.2 (CH), 126.5 (2 × CH), 128.2
(CH), 128.9 (2 × CH), 141.7 (C), 171.4 (C), 206.5 (C) ppm; MS m/
z 234 (MH+, 100), 217 (2), 190 (4), 174 (12), 131 (4); HRMS (CI)
calcd for C13H16NO3 (MH+), 234.1130, found 234.1134.
Methyl (2S,6S)-4-Oxo-6-(2-methylpropyl)piperidine-2-car-
boxylate (22). The reaction was carried out as described above
using methyl (2S,5E)-2-(tritylamino)-4-oxo-8-methylnon-5-enoate
(10) (0.07 g, 0.14 mmol). Flash column chromatography (petroleum
ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine) afforded methyl
(2S,6S)-4-oxo-6-(2-methylpropyl)piperidine-2-carboxylate (22) (0.03
g, 68%) as a colorless oil: IR (neat) 3332, 2957, 1740, 1716, 1437,
1216, 751 cm−1; [α]D26 = −11.2 (c 1.1, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 0.91 (d, 3H, J = 6.4 Hz), 0.93 (d, 3H, J = 6.4 Hz), 1.31−1.39
(m, 1H), 1.46−1.53 (m, 1H), 1.69−1.80 (m, 1H), 2.03−2.16 (m, 2H),
2.38−2.45 (m, 2H), 2.69 (ddd, 1H, J = 14.3, 3.4, 2.0 Hz), 2.88−2.95
(m, 1H), 3.65 (dd, 1H, J = 12.1, 3.4 Hz), 3.78 (s, 3H) ppm; 13C NMR
(101 MHz, CDCl3) δ 22.5 (CH3), 22.8 (CH3), 24.4 (CH), 44.6
(CH2), 46.1 (CH2), 48.8 (CH2), 52.5 (CH3), 53.7 (CH), 58.0 (CH),
171.9 (C), 207.2 (C) ppm; MS m/z 214 (MH+, 100), 187 (3), 154
(6), 130 (2), 112 (2), 85 (8); HRMS (CI) calcd for C11H20NO3
(MH+), 214.1443, found 214.1446.
Methyl (2S,5E)-2-(Tritylamino)-4-oxonon-5-enoate (11).
Methyl (2S)-2-(tritylamino)-4-oxo-5-(dimethoxyphosphoryl)-
pentanoate (8) (0.39 g, 0.78 mmol) was dissolved in acetonitrile
(25 mL) at room temperature under argon. Anhydrous potassium
carbonate (0.12 g, 0.86 mmol) and butyraldehyde (0.14 mL, 1.56
mmol) were added to the solution, which was then heated at 50 °C for
96 h. The reaction mixture was allowed to cool to room temperature
and then concentrated in vacuo. The resulting residue was dissolved in
ethyl acetate (25 mL) and washed with water (25 mL). The aqueous
phase was extracted with ethyl acetate (25 mL), and the organic phases
were combined, dried (MgSO4), filtered, and concentrated under
reduced pressure. Flash column chromatography (petroleum ether/
diethyl ether 1:0 to 2:3) afforded methyl (2S,5E)-2-(tritylamino)-4-
oxonon-5-enoate (11) (0.21 g, 59%) as a yellow oil: IR (neat) 3316,
2955, 1736, 1667, 1443, 1204, 1173, 748 cm−1; [α]27D = +28.6 (c 0.5,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H, J = 7.3 Hz),
1.44−1.53 (m, 2H), 2.18 (qd, 2H, J = 7.0, 1.5 Hz), 2.65 (dd, 1H, J =
15.3, 7.1 Hz), 2.79 (dd, 1H, J = 15.3, 5.2 Hz), 2.85 (d, 1H, J = 9.8 Hz),
3.27 (s, 3H), 3.66−3.74 (m, 1H), 6.04 (dt, 1H, J = 16.0, 1.5 Hz), 6.74
(dt, 1H, J = 16.0, 7.0 Hz), 7.15−7.29 (m, 15H) ppm; 13C NMR (101
MHz, CDCl3) δ 13.7 (CH3), 21.3 (CH2), 34.5 (CH2), 44.9 (CH2),
51.9 (CH), 53.6 (CH3), 71.2 (C), 126.5 (3 × CH), 127.9 (6 × CH),
129.1 (6 × CH), 130.7 (CH), 145.8 (3 × C), 148.3 (CH), 174.6 (C),
198.0 (C) ppm; MS m/z 442 (MH+, 21), 364 (60), 243 (100), 198
(64), 165 (43), 97 (21), 56 (19); HRMS (FAB) calcd for C29H32NO3
(MH+) 442.2382, found 442.2378.
Methyl (2S,5E)-2-(Tritylamino)-6-(4-nitrophenyl)-4-oxohex-
5-enoate (13). The reaction was carried out as described above
using methyl (2S)-2-(tritylamino)-4-oxo-5-(dimethoxyphosphoryl)-
pentanoate (8) (0.30 g, 0.61 mmol), p-nitrobenzaldehyde (0.18 g,
1.21 mmol), and anhydrous potassium carbonate (0.09 g, 0.67 mmol)
in acetonitrile (25 mL). The mixture was heated to 50 °C for 24 h.
Flash column chromatography (petroleum ether/diethyl ether 1:0 to
3:7) afforded methyl (2S,5E)-2-(tritylamino)-6-(4-nitrophenyl)-4-
oxohex-5-enoate (13) (0.22 g, 69%) as an off-white solid: mp 139−
141 °C; IR (neat) 2951, 1742, 1712, 1490, 1509, 1341 cm−1; [α]25
=
D
+43.3 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.80 (dd, 1H, J
= 15.5, 6.9 Hz), 2.91 (dd, 1H, J = 15.5, 5.1 Hz), 2.95 (br s, 1H), 3.31
(s, 3H), 3.55−3.76 (m, 1H), 6.77 (d, 1H, J = 16.2 Hz), 7.17−7.32 (m,
10H), 7.41−7.53 (m, 6H), 7.66 (d, 2H, J = 8.8 Hz), 8.25 (d, 2H, J =
8.8 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ 46.2 (CH2), 52.1
(CH3), 53.7 (CH), 71.3 (C), 124.3 (CH), 126.6 (3 × CH), 128.0 (6 ×
CH), 128.8 (6 × CH), 128.9 (2 × CH), 129.6 (2 × CH), 139.9 (CH),
140.6 (C), 145.7 (3 × C), 148.6 (C), 174.3 (C), 197.0 (C) ppm; MS
m/z 543 (MNa+, 32), 443 (9), 413 (9), 351 (19), 329 (58), 243 (100),
176 (78), 154 (32); HRMS (FAB) calcd for C32H28N2O5Na (MNa+),
543.1896, found 543.1903.
Methyl (2S,6S)-4-Oxo-6-propylpiperidine-2-carboxylate
(23). The reaction was carried out as described above using methyl
(2S,5E)-2-(tritylamino)-4-oxonon-5-enoate (11) (0.10 g, 0.23 mmol).
Flash column chromatography (petroleum ether/ethyl acetate 1:0 to
3:7 with 1% triethylamine) afforded methyl (2S,6S)-4-oxo-6-
propylpiperidine-2-carboxylate (23) (0.03 g, 56%) as a colorless oil:
IR (neat) 3330, 2959, 2359, 1740, 1715, 1437, 1265, 1217, 750 cm−1;
1
[α]25 = −20.9 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 0.94
D
(t, 3H, J = 7.0 Hz), 1.36−1.63 (m, 4H), 2.05−2.21 (m, 2H), 2.39−
2.46 (m, 2H), 2.69 (dddd, 1H, J = 14.4, 3.4, 2.1, 0.6 Hz), 2.83−2.90
(m, 1H), 3.64 (dd, 1H, J = 12.2, 3.4 Hz), 3.78 (s, 3H) ppm; 13C NMR
(101 MHz, CDCl3) δ 14.0 (CH3), 18.8 (CH2), 38.9 (CH2), 44.5
(CH2), 48.4 (CH2), 52.5 (CH3), 55.6 (CH), 57.9 (CH), 171.9 (C),
207.3 (C) ppm; MS m/z 199 (M+, 22), 156 (95), 140 (97), 114 (70),
98 (96), 85 (100); HRMS (EI) calcd for C10H17NO3 (M+), 199.1208,
found 199.1212.
Methyl (2S,5E)-2-(tritylamino)-4-oxo-6-pyridin-3-ylhex-5-
enoate (18). The reaction was carried out as described above using
methyl (2S)-2-(tritylamino)-4-oxo-5-(dimethoxyphosphoryl)-
pentanoate (8) (0.20 g, 0.40 mmol), 3-pyridinecarboxaldehyde (0.08
mL, 0.80 mmol) and anhydrous potassium carbonate (0.06 g, 0.44
mmol) in acetonitrile (15 mL). The mixture was heated to 50 °C for
24 h. Flash column chromatography (petroleum ether/diethyl ether
8:2 to 6:4) afforded methyl (2S,5E)-2-(tritylamino)-4-oxo-6-pyridin-3-
ylhex-5-enoate (18) (0.17 g, 87%) as an orange oil: IR (NaCl) 3320,
3056, 2949, 1737, 1691, 1662, 1612, 1490, 1447, 1415, 1203, 1025
Methyl (2S,6S)-4-Oxo-6-(2-phenylethyl)piperidine-2-carbox-
ylate (24). The reaction was carried out as described above using
methyl (2S,5E)-2-(tritylamino)-4-oxo-8-phenyloct-5-enoate (12)
(0.15 g, 0.30 mmol). Flash column chromatography (petroleum
ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine) afforded methyl
(2S,6S)-4-oxo-6-(2-phenylethyl)piperidine-2-carboxylate (24) (0.04 g,
54%) as a white solid: mp 76−78 °C; IR (neat) 3212, 2924, 2361,
1
cm−1; [α]D = +54.3 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
2.78 (dd, 1H, J = 15.4, 7.0 Hz), 2.84−2.30 (m, 2H), 3.31 (s, 3H),
3.69−3.88 (m, 1H), 6.73 (d, 1H, J = 16.1 Hz), 7.10−7.30 (m, 9H),
7.34 (dd, 1H, J = 7.9, 4.7 Hz), 7.44 (d, 1H, J = 16.1 Hz), 7.46−7.59
(m, 6H), 7.83 (d, 1H, J = 7.9 Hz), 8.63 (d, 1H, J = 4.7 Hz), 8.74 (s,
1736, 1713, 1435, 1265, 1227, 910, 733 cm−1; [α]26 = −15.1 (c 0.6,
D
E
dx.doi.org/10.1021/jo3022583 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.82−1.97 (m, 2H), 2.16
(dd, 1H, J = 14.6, 12.2 Hz), 2.79 (ddd, 1H, J = 14.6, 3.5, 1.5 Hz), 3.77
(dd, 1H, J = 12.2, 3.5 Hz), 3.79 (s, 3H), 3.95 (dd, 1H, J = 10.2, 4.7
Hz), 5.28 (d, 1H, J = 11.0 Hz), 5.78 (d, 1H, J = 17.6 Hz), 6.72 (dd,
1H, J = 17.6, 11.0 Hz), 7.25−7.39 (m, 3H), 7.46 (s, 1H) ppm; 13C
NMR (101 MHz, CDCl3) δ 43.8 (CH2), 50.1 (CH2), 52.6 (CH3),
57.9 (CH), 60.2 (CH), 114.6 (CH2), 124.4 (CH), 125.9 (CH), 126.0
(CH), 129.1 (CH), 136.5 (CH), 138.2 (C), 142.0 (C), 171.4 (C),
206.5 (C) ppm; MS m/z 260 (MH+, 100), 225 (16), 172 (12), 113
(12), 81 (26), 69 (42); HRMS (CI) calcd for C15H18NO3 (MH+),
260.1287, found 260.1281.
Methyl (2S,6R)-4-Oxo-6-(naphthalen-2-yl)piperidine-2-car-
boxylate (29). The reaction was carried out as described above
using methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(naphthalen-2-yl)hex-5-
enoate (17) (0.15 g, 0.29 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded methyl (2S,6R)-4-oxo-6-(naphthalen-2-yl)piperidine-2-car-
boxylate (29) (0.055 g, 66%) as a white solid: mp 115−117 °C; IR
(neat) 3325, 2953, 2360, 1736, 1712, 1435, 1248, 1211, 820, 750
cm−1; [α]25D = +36.9 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ
2.64−2.72 (m, 4H), 2.86 (ddd, 1H, J = 14.5, 3.5, 1.3 Hz), 3.82 (s, 3H),
3.85 (dd, 1H, J = 12.1, 3.5 Hz), 4.15 (dd, 1H, J = 9.3, 5.4 Hz), 7.47−
7.57 (m, 3H), 7.84−7.90 (m, 4H) ppm; 13C NMR (126 MHz, CDCl3)
δ 43.9 (CH2), 50.1 (CH2), 52.6 (CH3), 58.0 (CH), 60.3 (CH), 124.5
(CH), 125.3 (CH), 126.2 (CH), 126.4 (CH), 127.7 (CH), 127.9
(CH), 128.7 (CH), 133.2 (C), 133.4 (C), 139.1 (C), 171.4 (C), 206.4
(C) ppm; MS m/z 284 (MH+, 100), 243 (7), 224 (2), 182 (2), 156
(2); HRMS (CI) calcd for C17H18NO3 (MH+), 284.1287, found
284.1287.
(ddd, 1H, J = 14.4, 11.7, 0.9 Hz), 2.44 (ddd, 1H, J = 14.4, 12.2, 0.9
Hz), 2.48 (ddd, 1H, J = 14.4, 2.9, 2.0 Hz), 2.70 (ddd, 1H, J = 14.4, 3.4,
2.0 Hz), 2.73−2.77 (m, 2H), 2.86−2.91 (m, 1H), 3.63 (dd, 1H, J =
12.2, 3.4 Hz), 3.79 (s, 3H), 7.19−7.33 (m, 5H) ppm; 13C NMR (101
MHz, CDCl3) δ 30.3 (CH2), 38.3 (CH2), 44.5 (CH2), 48.4 (CH2),
52.5 (CH3), 55.2 (CH), 57.9 (CH), 126.2 (CH), 128.5 (2 × CH),
128.6 (2 × CH), 141.1 (C), 171.8 (C), 206.8 (C) ppm; MS m/z 262
(MH+, 100), 202 (9), 156 (4), 135 (5), 113 (4), 91 (5), 85 (11);
HRMS (CI) calcd for C15H20NO3 (MH+), 262.1443, found 262.1444.
Methyl (2S,6R)-4-Oxo-6-(4-nitrophenyl)piperidine-2-carbox-
ylate (25). The reaction was carried out as described above using
methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(4-nitrophenyl)hex-5-enoate
(13) (0.15 g, 0.29 mmol). Flash column chromatography (petroleum
ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine) afforded methyl
(2S,6R)-4-oxo-6-(4-nitrophenyl)piperidine-2-carboxylate (25) (0.03 g,
37%) as a white solid: mp 121−123 °C; IR (neat) 3347, 2955, 2361,
1721, 1605, 1520, 1350, 1219 cm−1; [α]26D = +62.9 (c 1.4, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 2.39 (dd, 1H, J = 14.6, 11.8 Hz), 2.49−
2.58 (m, 3H), 2.76 (ddd, 1H, J = 14.6, 3.2, 1.9 Hz), 3.69−3.76 (m,
4H), 4.03 (dd, 1H, J = 11.8, 3.0 Hz), 7.55 (d, 2H, J = 8.8 Hz), 8.17 (d,
2H, J = 8.8 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ 43.7 (CH2),
49.8 (CH2), 52.7 (CH3), 57.7 (CH), 59.4 (CH), 124.2 (2 × CH),
127.5 (2 × CH), 147.8 (C), 148.8 (C), 171.1 (C), 205.1 (C) ppm; MS
m/z 279 (MH+, 100), 249 (7), 219 (10), 203 (2), 177 (2); HRMS
(CI) calcd for C13H15N2O5 (MH+) 279.0981, found 279.0975.
Methyl (2S,6R)-4-Oxo-6-(4-bromophenyl)piperidine-2-car-
boxylate (26). The reaction was carried out as described above
using methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(4-bromophenyl)hex-5-
enoate (14) (0.18 g, 0.32 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded methyl (2S,6R)-4-oxo-6-(4-bromophenyl)piperidine-2-car-
boxylate (26) (0.04 g, 39%) as a white solid: mp 166−168 °C dec;
Methyl (2S,6R)-4-Oxo-6-(pyridin-3-yl)piperidine-2-carboxy-
late (30). The reaction was carried out as described above using
methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(pyridin-3-yl)hex-5-enoate
(18) (0.14 g, 0.30 mmol). Flash column chromatography (petroleum
ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine) afforded methyl
(2S,6R)-4-oxo-6-(pyridine-3-yl)piperidine-2-carboxylate (30) (0.03 g,
43%) as an off-white solid: mp 123−125 °C; IR (neat) 3264, 2924,
1713, 1435, 1227, 718 cm−1; [α]26D = +34.8 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 2.50 (dd, 1H, J = 14.3, 11.2 Hz) 2.53−2.58 (m,
1H), 2.60 (dd, 1H, J = 13.6, 12.2 Hz), 2.79 (ddd, 1H, J = 14.3, 3.5, 1.8
Hz), 3.74−3.78 (m, 4H), 4.00 (dd, 1H, J = 11.2, 3.5 Hz), 7.31 (dd,
1H, J = 7.8, 4.2 Hz), 7.78 (d, 1H, J = 7.8 Hz), 8.56 (d, 1H, J = 4.2 Hz),
8.63 (s, 1H) ppm; 13C NMR (126 MHz, CDCl3) δ 43.8 (CH2), 49.6
(CH2), 52.6 (CH3), 57.7 (CH), 57.8 (CH), 123.8 (CH), 134.2 (CH),
137.2 (C), 148.4 (CH), 149.7 (CH), 171.1 (C), 205.5 (C) ppm; MS
m/z 234 (M+, 8), 175 (69), 133 (22), 86 (95), 84 (95), 49 (100);
HRMS (EI) calcd for C12H14N2O3 (M+), 234.1004, found 234.1005.
Methyl (2S,6R)-4-Oxo-6-(3′-nitrobiphen-4-yl)piperidine-2-
carboxylate (31). The reaction was carried out as described above
using methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(3′-nitrobiphen-4-yl)-
hex-5-enoate (19) (0.11 g, 0.18 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded methyl (2S,6R)-4-oxo-6-(3′-nitrobiphen-4-yl)piperidine-2-
carboxylate (31) (0.033 g, 51%) as a yellow oil: IR (neat) 3325,
IR (neat) 3327, 2954, 1721, 1435, 1250, 1227, 787 cm−1; [α]27
=
D
+29.9 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.46 (ddd, 1H, J
= 14.5, 11.6, 0.8 Hz), 2.51−2.56 (m, 2H), 2.59 (ddd, 1H, J = 14.5,
11.6, 0.8 Hz), 2.79 (ddd, 1H, J = 14.5, 3.0, 2.0 Hz), 3.75 (dd, 1H, J =
11.6, 3.0 Hz), 3.79 (s, 3H), 3.92 (dd, 1H, J = 11.6, 3.0 Hz), 7.30 (d,
1
2H, J = 8.4 Hz), 7.50 (d, 2H, J 8.4 Hz) ppm; H NMR (126 MHz,
CDCl3) δ 43.8 (CH2), 50.0 (CH2), 52.6 (CH3), 57.8 (CH), 59.6
(CH), 122.0 (C), 128.3 (2 × CH), 132.0 (2 × CH), 140.8 (C), 171.3
(C), 206.0 (C) ppm; MS m/z 314 (MH+, 100), 252 (3), 234 (8), 167
(2), 113 (5); HRMS (CI) calcd for C13H1581BrNO3 (MH+) 314.0216,
found 314.0219.
Methyl (2S,6R)-4-Oxo-6-(4-methoxyphenyl)piperidine-2-car-
boxylate (27). The reaction was carried out as described above using
methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(4-methoxyphenyl)hex-5-
enoate (15) (0.05 g, 0.10 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded methyl (2S,6R)-4-oxo-6-(4-methoxyphenyl)piperidine-2-car-
boxylate (27) (0.02 g, 56%) as a colorless oil: IR (neat) 3317, 2955,
2361, 1743, 1713, 1512, 1250, 1219, 756 cm−1; [α]25D = +38.4 (c 1.1,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 2.52−2.55 (m, 3H), 2.59
2924, 1721, 1528, 1350, 1219, 733 cm−1; [α]26 = +41.2 (c 1.0,
D
1
(dd, 1H, J = 14.4, 12.2 Hz), 2.78 (dd, 1H, J = 14.4, 3.3 Hz), 3.75 (dd,
1H, J = 12.2, 3.3 Hz), 3.78 (s, 3H), 3.81 (s, 3H), 3.90 (dd, 1H, J = 8.2,
6.7 Hz), 6.90 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz) ppm; 13C
NMR (101 MHz, CDCl3) δ 43.9 (CH2), 50.2 (CH2), 52.5 (CH3),
55.3 (CH3), 57.9 (CH), 59.7 (CH), 114.2 (2 × CH), 127.7 (2 × CH),
133.9 (C), 159.4 (C), 171.4 (C), 206.6 (C) ppm; MS m/z 263 (M+,
53), 204 (25), 161 (100), 134 (28), 84 (32), 49 (33); HRMS (EI)
calcd for C14H17NO4 (M+), 263.1158, found 263.1161.
CHCl3); H NMR (500 MHz, CDCl3) δ 2.55 (dd, 1H, J = 14.2, 11.2
Hz), 2.61 (ddd, 1H, J = 14.2, 3.6, 1.9 Hz), 2.62 (dd, 1H, J = 14.5, 12.2
Hz), 2.82 (ddd, 1H, J = 14.5, 3.3, 1.8 Hz), 3.77−3.82 (m, 4H), 4.03
(dd, 1H, J = 11.2, 3.6 Hz), 7.53−7.56 (m, 2H), 7.59−7.65 (m, 3H),
7.91 (ddd, 1H, J = 8.0, 1.6, 1.0 Hz), 8.20 (ddd, 1H, J = 8.0, 2.0, 1.0
Hz), 8.44 (t, 1H, J = 2.0 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ
43.9 (CH2), 50.0 (CH2), 52.5 (CH3), 58.9 (CH), 59.8 (CH), 121.9
(CH), 122.2 (CH), 127.4 (2 × CH), 127.6 (2 × CH), 129.8 (CH),
132.9 (CH), 138.5 (C), 142.2 (C), 142.2 (C), 148.8 (C), 171.3 (C),
206.1 (C) ppm; MS m/z 354 (M+, 30), 295 (91), 252 (100), 84 (32),
49 (30); HRMS (EI) calcd for C19H18N2O5 (M+), 354.1216, found
354.1210.
Methyl (2S,4R,6S)-4-Hydroxy-6-(2-phenylethyl)piperidine-2-
carboxylate (32). To a solution of methyl (2S,6S)-4-oxo-6-(2-
phenylethyl)piperidine-2-carboxylate (24) (0.05 g, 0.19 mmol) in
tetrahydrofuran (10 mL) at room temperature was added sodium
triacetoxyborohydride (0.05 g, 0.23 mmol) and the reaction stirred for
Methyl (2S,6R)-4-Oxo-6-(3-ethenylphenyl)piperidine-2-car-
boxylate (28). The reaction was carried out as described above
using methyl (2S,5E)-2-(tritylamino)-4-oxo-6-(3-ethenylphenyl)hex-5-
enoate (16) (0.15 g, 0.30 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded methyl (2S,6R)-4-oxo-6-(3-ethenylphenyl)piperidine-2-car-
boxylate (28) (0.035 g, 45%) as a colorless oil: IR (neat) 3321,
2953, 2359, 1740, 1717, 1437, 1219, 802 cm−1; [α]26D = +58.7 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 2.50−2.57 (m, 2H), 2.61
F
dx.doi.org/10.1021/jo3022583 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
48 h. The mixture was quenched with 2 M hydrochloric acid (5 mL)
and then partitioned between a saturated solution of sodium hydrogen
carbonate (15 mL) and ethyl acetate (15 mL). The organic phase was
separated, washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded the desired product 32 (0.04 g, 87%) as a colorless oil: IR
(C) ppm; MS m/z 261 (M+, 42), 202 (100), 159 (21), 130 (12), 83
(78); HRMS (EI) calcd for C15H19NO3 (M+), 261.1365, found
261.1364.
Methyl (2S,4R,6R)-4-Hydroxy-6-(naphthalen-2-yl)piperidine-
2-carboxylate (36). The reaction was carried out as described above
using methyl (2S,6R)-4-oxo-6-(naphthalen-2-yl)piperidine-2-carboxy-
late (29) (0.07 g, 0.24 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 1:0 to 3:7 with 1% triethylamine)
afforded the desired product 36 (0.07 g, 100%) as a white solid: mp
109−111 °C; IR (neat) 3275, 2361, 1728, 1431, 1223, 1123, 1049, 826
cm−1; [α]D25 = +25.3 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.53 (dd, 1H, J = 11.5, 8.4 Hz), 1.58 (dd, 1H, J = 11.9, 8.4 Hz), 2.17−
2.22 (m, 1H), 2.41−2.47 (m, 1H), 3.57 (dd, 1H, J = 11.9, 2.6 Hz),
3.75 (s, 3H), 3.84 (dd, 1H, J = 11.5, 2.3 Hz), 3.87−3.93 (m, 1H),
7.43−7.51 (m, 3H), 7.80−7.84 (m, 4H) ppm; 13C NMR (126 MHz,
CDCl3) δ 37.6 (CH2), 43.2 (CH2), 52.3 (CH3), 57.5 (CH), 59.2
(CH), 69.3 (CH), 125.1 (CH), 125.2 (CH), 125.8 (CH), 126.1 (CH),
127.6 (CH), 127.9 (CH), 128.3 (CH), 133.0 (C), 133.4 (C), 140.5
(C), 172.6 (C) ppm; MS m/z 286 (MH+, 100), 266 (17), 226 (4), 209
(2), 155 (2), 95 (3); HRMS (CI) calcd for C17H20NO3 (MH+)
286.1443, found 286.1444.
Methyl (2S,4R,6R)-4-Hydroxy-6-(3′-nitrobiphen-4-yl)-
piperidine-2-carboxylate (37). The reaction was carried out as
described above using methyl (2S,6R)-4-oxo-6-(3′-nitrobiphen-4-
yl)piperidine-2-carboxylate (31) (0.008 g, 0.02 mmol). Flash column
chromatography (petroleum ether/ethyl acetate 1:0 to 3:7 with 1%
triethylamine) afforded the desired product 37 (0.008 g, 100%) as a
yellow oil: IR (neat) 3344, 2924, 2359, 1734, 1532, 1349, 1213, 668
cm−1; [α]26D = +15.2 (c 3.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.53 (q, 1H, J = 11.8 Hz), 1.54 (q, 1H, J = 11.8 Hz), 1.61 (br s, 1H),
2.18 (dquint, 1H, J = 11.8, 2.3 Hz), 2.46 (dquint, 1H, J = 11.8, 2.3 Hz),
3.57 (dd, 1H, J = 11.8, 2.6 Hz), 3.77 (s, 3H), 3.75−3.81 (m, 1H),
3.86−3.95 (m, 1H), 7.50−7.55 (m, 2H), 7.58−7.64 (m, 3H), 7.91
(ddd, 1H, J = 7.7, 1.6, 1.0 Hz), 8.20 (ddd, 1H, J = 8.2, 2.2, 1.0 Hz),
8.45 (t, 1H, J = 1.9 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ 37.6
(CH2), 43.2 (CH2), 52.3 (CH3), 57.4 (CH), 58.7 (CH), 69.3 (CH),
121.9 (CH), 122.0 (CH), 127.3 (2 × CH), 127.6 (2 × CH), 129.7
(CH), 132.9 (CH), 138.0 (C), 142.5 (C), 143.6 (C), 148.7 (C), 172.4
(C) ppm; MS m/z 357 (MH+, 6), 307 (48), 282 (3), 189 (5), 164
(14), 138 (100), 81 (5); HRMS (CI) calcd for C19H21N2O5 (MH+)
357.1450, found 357.1456.
(2S,4R,6S)-4-Hydroxy-6-(2-phenylethyl)piperidine-2-carbox-
ylic Acid (38). Methyl (2S,4R,6S)-4-hydroxy-6-(2-phenylethyl)-
piperidine-2-carboxylate (32) (0.06 g, 0.22 mmol) was dissolved in
6 M hydrochloric acid (5 mL) and heated to 100 °C for 48 h. The
reaction mixture was cooled and concentrated under reduced pressure
to afford a white solid. This was washed with acetone then dried under
reduced pressure to afford the desired product 38 (0.04 g, 62%) as a
white solid: mp 219−221 °C dec; IR (neat) 3408, 2921, 1757, 1453,
1184, 1066, 751, 699 cm−1; [α]26D = +50.3 (c 0.1, MeOH); 1H NMR
(500 MHz, CD3OD) δ 1.38 (q, 1H, J = 12.8 Hz), 1.59 (q, 1H, J = 12.8
Hz), 1.90−1.98 (m, 1H), 2.10−2.16 (m, 1H), 2.33−2.36 (m, 1H),
2.52−2.55 (m, 1H), 2.67−2.73 (m, 1H), 2.78−2.84 (m, 1H), 3.23−
3.27 (m, 1H), 3.88−3.94 (m, 1H), 4.06 (dd, 1H, J = 11.5, 2.1 Hz),
7.18−7.31 (m, 5H) ppm; 13C NMR (101 MHz, CD3OD) δ 32.3
(CH2), 35.8 (2 × CH2), 37.6 (CH2), 56.0 (CH), 57.1 (CH), 66.3
(CH), 127.5 (CH), 129.4 (2 × CH), 129.8 (2 × CH), 141.6 (C),
170.6 (C) ppm; MS m/z 249 (M+, 9), 226 (7), 204 (100), 160 (25),
144 (92), 126 (33), 117 (22), 91 (81); HRMS (EI) calcd for
C14H19NO3 249.1365, found 249.1368.
(neat) 3330, 2946, 2360, 1739, 1436, 1262, 1213, 700 cm−1; [α]29
=
D
−2.2 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.99 (q, 1H, J =
11.2 Hz), 1.26 (q, 1H, J = 11.8 Hz), 1.65−1.81 (m, 2H), 1.94−1.99
(m, 1H), 2.22−2.28 (m, 1H), 2.49−2.56 (m, 1H), 2.58−2.70 (m, 2H),
3.30 (dd, 1H, J = 11.8, 2.7 Hz), 3.60−3.69 (m, 4H), 7.10−7.23 (m,
5H) ppm; 13C NMR (126 MHz, CDCl3) δ 32.2 (CH2), 38.2 (CH2),
38.5 (CH2), 41.5 (CH2), 52.2 (CH3), 53.6 (CH), 57.2 (CH), 68.9
(CH), 125.9 (CH), 128.3 (2 × CH), 128.5 (2 × CH), 141.7 (C),
172.9 (C) ppm; MS m/z 263 (M+, 8), 204 (100), 187 (12), 158 (49),
140 (28), 91 (57), 82 (16); HRMS (EI) calcd for C15H21NO3 (M+),
263.1521, found 263.1519.
Methyl (2S,4R,6S)-4-Hydroxy-6-(2-methylpropyl)piperidine-
2-carboxylate (33). The reaction was carried out as described above
using methyl (2S,6S)-6-(2-methylpropyl)-4-oxopiperidine-2-carboxy-
late (22) (0.033 g, 0.13 mmol). Flash column chromatography
(DCM/methanol 19:1 with 1% triethylamine) afforded the desired
product 33 (0.021 g, 63%) as a colorless oil: IR (neat) 3329, 2955,
2360, 1735, 1437, 1264, 1213, 1160 cm−1; [α]26 = −11.4 (c 1.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.89 (d, 3H, J = 6.4 Hz), 0.91
(d, 3H, J = 6.4 Hz), 0.99 (dt, 1H, J = 11.8, 11.2 Hz), 1.24−1.30 (m,
1H), 1.31 (td, 1H, J = 11.8, 11.3 Hz), 1.36−1.44 (m, 1H), 1.65−1.80
(m, 3H), 1.97 (dquint, 1H, J = 12.1, 2.2 Hz), 2.31 (dquint, 1H, J =
11.8, 2.2 Hz), 2.59−2.66 (m, 1H), 3.38 (dd, 1H, J = 11.8, 2.7 Hz), 3.70
(tt, 1H, J = 11.3, 4.5 Hz), 3.73 (s, 3H) ppm; 13C NMR (126 MHz,
CDCl3) δ 22.5 (CH3), 22.9 (CH3), 24.4 (CH), 38.6 (CH2), 42.1
(CH2), 45.9 (CH2), 52.0 (CH2), 52.1 (CH), 57.3 (CH), 69.0 (CH),
172.8 (C) ppm; MS m/z 216 (MH+, 48), 198 (34), 158 (65), 156
(100), 140 (32), 112 (37), 80 (18); HRMS (CI) calcd for C11H22NO3
(MH+), 216.1600, found 216.1597.
Methyl (2S,4R,6R)-4-Hydroxy-6-(4-methoxyphenyl)-
piperidine-2-carboxylate (34). The reaction was carried out as
described above using methyl (2S,6R)-6-(4-methoxyphenyl)-4-oxopi-
peridine-2-carboxylate (27) (0.03 g, 0.13 mmol). Flash column
chromatography (petroleum ether/ethyl acetate 1:0 to 3:7 with 1%
triethylamine) afforded the desired product 34 (0.03 g, 96%) as a
colorless oil: IR (neat) 3333, 2926, 2363, 1738, 1612, 1514, 1245,
1034, 831 cm−1; [α]25D = +16.4 (c 0.9, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.47 (dd, 1H, J = 11.5, 5.0 Hz), 1.52 (dd, 1H, J = 11.8, 5.5
Hz), 2.08−2.12 (m, 1H), 2.38−2.42 (m, 1H), 3.52 (dd, 1H, J = 11.8,
2.6 Hz), 3.64 (dd, 1H, J = 11.5, 2.5 Hz), 3.74 (s, 3H), 3.80 (s, 3H),
3.79−3.88 (m, 1H), 6.85−6.88 (m, 2H), 7.29−7.32 (m, 2H) ppm; 13C
NMR (101 MHz, CDCl3) δ 37.6 (CH2), 43.1 (CH2), 52.2 (CH3),
55.3 (CH3), 57.5 (CH), 58.5 (CH), 69.3 (CH), 113.9 (2 × CH),
128.0 (2 × CH), 135.2 (C), 159.0 (C), 172.5 (C) ppm; MS m/z 266
(MH+, 100), 248 (30), 234 (6), 206 (4), 178 (3), 158 (3), 130 (2);
HRMS (CI) calcd for C14H20NO4 (MH+), 266.1392, found 266.1396.
Methyl (2S,4R,6R)-4-Hydroxy-6-(3-ethenylphenyl)-
piperidine-2-carboxylate (35). The reaction was carried out as
described above using methyl (2S,6R)-4-oxo-6-(3-ethenylphenyl)-
piperidine-2-carboxylate (28) (0.015 g, 0.06 mmol). Flash column
chromatography (petroleum ether/ethyl acetate 1:0 to 3:7 with 1%
triethylamine) afforded the desired product 35 (0.01 g, 76%) as a
colorless oil: IR (neat) 3320, 2924, 2360, 1735, 1437, 1216, 1013, 910,
802 cm−1; [α]26 = +27.3 (c 0.6, CHCl3); 1H NMR (400 MHz,
(2S,4R,6S)-4-Hydroxy-6-(2-methylpropyl)piperidine-2-car-
boxylic Acid (39). The reaction was carried out as described above
using methyl (2S,4R,6S)-4-hydroxy-6-(2-methylpropyl)piperidine-2-
carboxylate (33) (0.029 g, 0.084 mmol). This gave the desired
product 39 (0.027 g, 99%) as a white solid: mp 247−249 °C; IR
(neat) 3362, 2926, 2074, 1732, 1117, 972 cm−1; [α]25D = −2.4 (c 2.5,
D
CDCl3) δ 1.52 (q, 2H, J = 11.8 Hz), 1.60−2.00 (br s, 1H), 2.14
(dquint, 1H, J = 11.8, 2.3 Hz), 2.43 (dquint, 1H, J = 11.8, 2.3 Hz), 3.54
(dd, 1H, J = 11.8, 2.2 Hz), 3.70 (dd, 1H, J = 11.8, 2.3 Hz), 3.75 (s,
3H), 3.87 (tt, 1H, J = 11.8, 2.3 Hz), 5.25 (dd, 1H, J 10.9, 0.4 Hz), 5.76
(dd, 1H, J = 17.6, 0.4 Hz), 6.71 (dd, 1H, J = 17.6, 10.9 Hz), 7.26−7.32
(m, 2H), 7.34 (dt, 1H, J = 7.1, 1.7 Hz), 7.43 (s, 1H) ppm; 13C NMR
(126 MHz, CDCl3) δ 37.6 (CH2), 43.1 (CH2), 52.2 (CH3), 57.5
(CH), 59.1 (CH), 69.4 (CH), 114.1 (CH2), 124.7 (CH), 125.4 (CH),
126.3 (CH), 128.7 (CH), 136.7 (CH), 137.9 (C), 143.3 (C), 172.4
1
MeOH); H NMR (500 MHz, CD3OD) δ 0.96 (d, 3H, J = 6.1 Hz),
1.00 (d, 3H, J = 6.1 Hz), 1.27−1.40 (br m, 1H), 1.54−1.66 (br m,
3H), 1.72−1.83 (br m, 1H), 2.24 (br d, 1H, J = 13.4 Hz), 2.53 (br d,
1H, J = 12.5 Hz), 3.24−3.34 (br m, 1H), 3.90−3.98 (br m, 1H), 4.04
G
dx.doi.org/10.1021/jo3022583 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(br d, 1H, J = 12.5 Hz) ppm; 13C NMR (126 MHz, CD3OD) δ 21.9
(CH3), 23.7 (CH3), 25.4 (CH), 35.9 (CH2), 38.1 (CH2), 43.0 (CH2),
55.1 (CH), 57.4 (CH), 66.4 (CH), 170.6 (C) ppm; MS m/z 202
(MH+, 100), 184 (25), 100 (41); HRMS (CI) calcd for C10H20NO3,
202.1443, found 202.1445.
ACKNOWLEDGMENTS
■
We are grateful to the EPSRC (studentships to M.D. and
L.S.F.), GlaxoSmithKline, and the Scottish Funding Council for
financial support.
(2S,4R,6R)-4-Hydroxy-6-(4-methoxyphenyl)piperidine-2-car-
boxylic Acid (40). The reaction was carried out as described above
using methyl (2S,4R,6R)-4-hydroxy-6-(4-methoxyphenyl)piperidine-2-
carboxylate (34) (0.03 g, 0.11 mmol). This gave the desired product
40 (0.02 g, 67%) as a white solid: mp 173−175 °C dec; IR (neat)
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■
3323, 2926, 1732, 1612, 1518, 1254, 1182, 1022, 831 cm−1; [α]29
=
D
−21.0 (c 1.0, MeOH); 1H NMR (400 MHz, CD3OD) δ 1.74 (q, 1H, J
= 12.8 Hz), 1.94 (q, 1H, J = 12.8 Hz), 2.24−2.27 (m, 1H), 2.60−2.63
(m, 1H), 3.82 (s, 3H), 4.07−4.11 (m, 1H), 4.22−4.24 (m, 1H), 4.34−
4.36 (m, 1H), 7.02 (d, 2H, J = 8.4 Hz), 7.45 (d, 2H, J = 8.8 Hz) ppm;
13C NMR (101 MHz, CD3OD) δ 35.4 (CH2), 39.3 (CH2), 55.9
́
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(CH3), 57.8 (CH), 59.5 (CH), 66.9 (CH), 115.6 (2 × CH), 128.6
(C), 130.2 (2 × CH), 162.2 (C), 170.4 (C) ppm; MS m/z 251 (M+,
42), 234 (19), 206 (100), 179 (28), 163 (74), 135 (62), 91 (18);
HRMS (EI) calcd for C13H17NO4 (M+), 251.1158, found 251.1156.
(2S,4R,6R)-4-Hydroxy-6-(naphthalen-2-yl)piperidine-2-car-
boxylic Acid (41). The reaction was carried out as described above
using methyl (2S,4R,6R)-4-hydroxy-6-(naphthalen-2-yl)piperidine-2-
carboxylate (36) (0.06 g, 0.21 mmol). This gave the desired product
41 (0.05 g, 70%) as a white solid: mp 203−205 °C dec; IR (neat)
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3327, 2951, 1744, 1622, 1410, 1213, 1055, 814 cm−1; [α]27 = +10.1
D
(c 1.1, MeOH); 1H NMR (400 MHz, CD3OD) δ 1.86 (q, 1H, J = 13.0
Hz), 2.08 (q, 1H, J = 12.8 Hz), 2.39−2.41 (m, 1H), 2.67−2.70 (m,
1H), 4.17−4.23 (m, 1H), 4.37 (dd, 1H, J = 13.0, 2.6 Hz), 4.64 (dd,
1H, J = 12.8, 1.9 Hz), 7.54−7.58 (m, 2H), 7.66 (dd, 1H, J = 8.5, 1.4
Hz), 7.91 (dd, 1H J = 6.1, 3.4 Hz), 7.95 (dd, 1H, J = 6.1, 3.4 Hz), 7.99
1
(d, 1H, J = 8.5 Hz), 8.07 (br s, 1H) ppm; H NMR (101 MHz,
CD3OD) δ 35.5 (CH2), 39.6 (CH2), 58.0 (CH), 60.1 (CH), 66.9
(CH), 125.6 (CH), 128.0 (CH), 128.3 (CH), 128.3 (CH), 128.9
(CH), 129.3 (CH), 130.3 (CH), 134.2 (C), 134.7 (C), 135.1 (C),
170.4 (C) ppm; MS m/z 271 (M+, 25), 226 (100), 205 (36), 183 (40),
155 (48), 128 (21), 91 (14); HRMS (EI) calcd for C16H17NO3 (M+),
271.1209, found 271.1205.
Computational Details. All calculations were done with the
program Gaussian 0922 using the M06-2X exchange-correlation
functional,23 which has been shown23,24 to provide accurate results
for main-group thermochemistry and activation barriers. The def2-
TZVP basis set,25 which affords results close to the basis-set limit for
density-functional theory, was augmented for all atoms by one diffuse
basis function per valence orbital. The exponents of the additional
functions were derived from the existing ones according to a simple
geometric progression (even-tempered). We refer to the augmented
set as def2-TZVP+. All calculations included the effects of the
methanol solvent at the level of the IEF-PCM polarizable continuum
model as implemented in Gaussian 09. Default parameters for SCF
and geometry convergence were used. The nature of stationary points
was verified by the appropriate number of imaginary frequencies,
obtained from analytical second derivatives. Thermochemical data
were calculated within the standard rigid-rotor/harmonic-oscillator
framework at 298 K, 100 kPa.
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Org. Chem. 2010, 75, 222. (b) Purkayastha, N.; Haufe, G. Synlett 2010,
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ASSOCIATED CONTENT
■
S
* Supporting Information
NOE data for compounds 32−37 and, H and 13C NMR
1
(19) Rudisill, D. E.; Whitten, J. P. Synthesis 1994, 851.
(20) In an attempt to improve the diastereoselective outcome of the
6-endo-trig cyclization, a temperature screen was implemented. While
lower temperatures (e.g., −20 °C) gave a slight improvement (from
75:25 to 80:20), the level of conversion to the cyclized products was
significantly reduced (only 10% conversion after 18 h). As such, it was
deemed considerably more efficient to perform these reactions at
room temperature.
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Andrew.Sutherland@glasgow.ac.uk.
(21) For some examples of studies on the stereoselective reduction of
4-oxopipecolic acid derivatives, see: (a) Golubev, A.; Sewald, N.;
Burger, K. Tetrahedron Lett. 1995, 36, 2037. (b) Marin, J.; Didierjean,
Notes
The authors declare no competing financial interest.
H
dx.doi.org/10.1021/jo3022583 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
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P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
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