A convenient large-scale chiral synthesis of protected 2-substituted 4-oxo-piperidine derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00682-8

A convenient large-scale chiral synthesis of protected 2-substituted-4-oxo-piperidine derivatives is described. Hetero Diels-Alder reaction between trifluoroacetic acid-boron trifluoride activated (1-phenyl-ethylimino)acetic acid ethyl ester and 2-trimeth

Full text of DOI:10.1016/S0040-4020(02)00682-8

Tetrahedron 58 (2002) 7339–7344
A convenient large-scale chiral synthesis of protected
2-substituted 4-oxo-piperidine derivatives
b
a
c
Jesper F. Lau,a Thomas Kruse Hansen, John Paul Kilburn, Karla Frydenvang,
,
*
Daniel D. Holsworth,d Yu Ge,d Roy T. Uyeda,d Luke M. Judged and Henrik Sune Andersena
aMedicinal Chemistry Research I, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
bMedicinal Chemistry Research V, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
cDepartment of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
dDepartment of Chemistry, Ontogen Corporation, 2325 Camino Vida Roble, 92009 Carlsbad, CA, USA
Received 22 March 2002; revised 31 May 2002; accepted 20 June 2002
Abstract—A convenient large-scale chiral synthesis of protected 2-substituted-4-oxo-piperidine derivatives is described. Hetero Diels–
Alder reaction between trifluoroacetic acid–boron trifluoride activated (1-phenyl-ethylimino)acetic acid ethyl ester and 2-trimethylsilyloxy-
1,3-butadiene gave rise to a mixture of two diastereomers of 4-oxo-1-(1-phenyl-ethyl)-piperidine-2-carboxylic acid ethyl ester. Starting from
(S)-1-phenyl-ethylamine pure adduct can be obtained by crystallization of the diastereomeric mixture. Reduction of the ester group gave rise
to the corresponding hydroxymethyl analogue, which was subjected to further functional group transformations to yield the desired protected
2-aminomethyl-4-oxo-piperidine derivative without any racemization being observed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
During work on our Protein Tyrosine Phosphatase inhibitor
project1 an efficient synthetic strategy for the preparation of
protected 2-aminomethyl-4-oxo-piperidine (1) was
required. Since the piperidine nucleus is found in a high
number of natural products and biologically active com-
pounds,2 highly derivatized analogs thereof could also serve
as templates for parallel synthesis of screening libraries.
Furthermore, due to potential applications as intermediates
in conformational modifiers for physiologically active
peptides, such building blocks would be of significant
interest. In particular, this area seems to be much less
investigated relative to the corresponding proline analogs.
To our knowledge no literature procedures for the synthesis
of racemic or non-racemic 2-amino-methyl-4-oxo-piperi-
dine derivatives have been described.
4-Oxopipecolic acid 2, also an attractive building block, has
attracted much attention since it was found to be a structural
element in the cyclic peptidolactone antibiotic virginia-
mycin S1.3 A number of chiral4 and achiral5 procedures for
the synthesis of 4-oxopipecolic acid derivatives have been
reported. We found that one of the most promising
procedures for large scale synthesis was the hetero Diels–
Alder reaction between trifluoroacetic acid–boron tri-
fluoride activated (1-phenyl-ethylimino)acetic acid ethyl
ester and 2-trimethyl-silyloxy-1,3-butadiene reported by
Abraham and Stella.6 This procedure provides an easy entry
to racemic 4-oxo-1-(10-phenyl-ethyl)-piperidine-2-car-
boxylic acid ethyl ester with potential for subsequent
chiral separation7 and unlike other procedures involving
Danishefsky’s diene,8 it does not require a reduction step in
order to obtain the desired product.
In an initial attempt, benzylamine was used employing the
protocol described by Abraham and Stella.6 The resulting
reaction mixture was impure and the work-up was difficult,
due to the presence of an orange gummy material. Applying
the same reaction conditions using either (R) or (S)-a-
methylbenzylamine gave somewhat better results. We
anticipated the gummy material may be a result of poly-
merized ethylglyoxalate from incomplete formation of the
desired imine. Therefore we conducted an NMR study of
commercial ethylglyoxalate (solution in toluene). The study
showed that this was indeed the case, polymerized
ethylglyoxalate was present and thus imine formation
Keywords: piperidinones; amino acids and derivatives; Diels–Alder
reactions.
*
Corresponding author. Tel.: þ45-44434392; fax: þ45-44663450; e-mail:
jrla@novonordisk.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00682-8

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J. F. Lau et al. / Tetrahedron 58 (2002) 7339–7344
Scheme 1. (a) TFA, BF3·OEt2, 278!2308C.
would only proceed slowly with a-methylbenzylamine.
However, when ethylglyoxalate was heated in a controlled
fashion prior to reaction, imine formation with a-methyl-
benzylamine was much faster and cleaner, and the
formation of polymerized ethylglyoxalate was suppressed
to a level whereby a simple work-up yielded the crude
product sufficiently pure to allow crystallization from hot
heptane (Scheme 1).
isomers, respectively. On a small scale the two diastereo-
isomers could be separated chromatographically with
difficulty, but for an efficient large scale synthesis
chromatographic separation was not suitable. A filtration
through a short pad of silica yielded a light yellow oil
consisting of the two diastereoisomers. Addition of hot
heptane to the mixture induced crystallization of the major
diastereoisomer 3a. Starting from S-(2)-a-methylbenzyl-
amine a batch of 69 g of the pure diastereoisomer 3a was
prepared in 45% overall yield.
Once the imine formation was optimized, (1-phenylethyl-
imino)acetic acid ethyl ester prepared in situ was cooled
to 2788C. Sequential addition of TFA, BF3·Et2O and
2-trimethylsilyloxy-butadiene followed by aqueous work up
afforded a crude mixture of diastereoisomers as a pale
orange oil. TLC (in toluene–EtOAc (9:2)) showed two main
Employing the other enantiomer, R-(þ)-a-methylbenzyl-
amine, the corresponding (10R,2S )-4-oxo-1-(10-phenyl-
ethyl)-piperidine-2-carboxylic acid ethyl ester 3c could be
crystallized by the same procedure.
1
products (Rf: 0.45 and 0.38) and H NMR spectroscopy
revealed a distribution of 7:5 between the two diastereo-
X-Ray diffraction analysis was performed in order to
establish the absolute configuration of compound 3c. The
configuration of carbon C2 (S) was determined relative to
the known chiral center of carbon C11 (R ). The molecule 3c
with the observed absolute configuration is shown in Fig. 1.
The observed geometry of the molecule is as expected with
the piperidine ring adopting a chair conformation. The
substituent on the nitrogen atom (N1) is observed in an
equatorial position and the substituent on carbon atom C2 is
observed in an axial position on the piperidine ring. The
tertiary amine N1 is observed pyramidal.
In order to obtain the desired 2-aminomethyl moiety a
reduction of the ester group in 3a was necessary. Initial
attempts of protecting ketone 3a as the corresponding
1,3-dioxolane derivative using a variety of different reaction
conditions only gave poor results. In an attempt using
BF3·OEt2, the main product was the acyclic di(2-hydroxy-
ethyl) ketal. This prompted us to prepare the acyclic diethyl
ketal 4 instead. Treatment of ketone 3a with a mixture
of triethyl orthoformate and ethanol in the presence of
1.5 equiv. of p-toluene sulfonic acid yielded ketal 4 in 86%
yield after column chromatography (Scheme 2).10
Figure 1. Molecular structure (ORTEP II)9 of 3c showing the absolute
configuration and the atomic labeling. Displacement ellipsoids for non-
hydrogen atoms are drawn at the 50% probability level. Hydrogen atoms
are drawn at an arbitrary level.

J. F. Lau et al. / Tetrahedron 58 (2002) 7339–7344
7341
Scheme 2. (a) TsOH, (EtO)3CH, EtOH, 208C, (b) LiAlH4, Et2O, reflux, (c) phthalimide, Ph3P, DEAD, THF, 08C.
Interestingly, if the diastereomeric mixture consisting of
3a and 3b was subjected to ketalization via this strategy
the two diastereoisomers obtained could easily be separated
by column chromatography in EtOAc–petroleum ether,
40–608C (1:10).11
It is important to note that in all of the steps from 3a to 9 no
racemization was observed.
In summary, a practical large scale procedure for the
synthesis of protected chiral 2-substituted-4-oxo-piperidine
derivatives has been developed.
The ketal 4 was subjected to LiAlH4 reduction in diethyl
ether to give the hydroxymethyl analog 5 in 95% yield. The
crude product could be used without further purification.
Subsequent Mitsunobu12 reaction with phthalimide, diethyl
azadicarboxylate (DEAD) and triphenylphosphine yielded
the phthalimide derivative 6 in 73% yield.
3. Experimental
3.1. General
Starting materials and reagents are commercially available
1
and used without further purification. H and 13C NMR
The ketal derivative of the protected amine 6 was smoothly
deprotected with trifluoroacetic acid–water (9:1) at 08C to
give the ketone 7 in quantitative yield (Scheme 3).
spectra were recorded on a Bruker DRX300 or Bruker
AMX400 instrument. Chemical shifts (d given in ppm) are
relative to TMS as internal standard. Multiplicities are
indicated as s, singlet; d, doublet; t, triplet; dd, doublet of
doublet; m, multiplet and coupling constants are quoted in
Hertz (J values). Electrospray (ES) mass spectra and LCMS
analyses were recorded on a PE Sciex API 3000 instrument
with an HP1100 HPLC equipped with binary pump, column
compartment, diode array detector, single quadrupole mass
spectrometer detector and a C18 column (Waters Xterra MS
C-18£3 mm).
3.1.1. (10S,2R )-4-Oxo-1-(10-phenyl-ethyl)-piperidine-2-
carboxylic acid ethyl ester (3a). A 50% solution of
ethylglyoxylate in toluene (117.6 mL, 0.57 mol) was
refluxed for 30 min under nitrogen, then transferred to a
2 L three-necked round bottomed flask containing activated
Treatment of 6 with hydrazine hydrate in ethanol at room
temperature yielded the free amine 8 in 75% yield. Since
this derivative slowly decomposed, it was either used
directly or converted to the corresponding stable Boc-
protected analog 9.
To exemplify the strategy, compound 8 was acylated with
the intense UV-chromophore 4-biphenyl carboxylic acid by
using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDC) and 1-hydroxy-7-azabenzotriazole
(HOAt) as coupling reagents to give 10 in 81% yield
(Scheme 3). Subsequent hydrogenolysis using Pd/C in a
mixture of formic acid and methanol afforded the free amine
11 in 78% yield.
Scheme 3. (a) TFA–H2O (9:1), 208C, (b) NH2NH2·H2O, EtOH, 208C, (c) (Boc)2O, aq. NaHCO3–dioxane, 208C, (d) 4-biphenylcarboxylic-acid, HOAt, EDC,
DCM, 208C, (e) Pd/C, HCOOH, EtOH, 208C.

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J. F. Lau et al. / Tetrahedron 58 (2002) 7339–7344
˚
molecular sieves (3 A, 125 g) in dry DCM (1 L) at 08C.
(S )-(2)-a-methylbenzylamine (71.7 mL, 0.57 mol) was
added drop wise over 45 min, while the temperature was
kept at 08C. The mixture was stirred for 45 min and then
cooled to 2788C. TFA (45.2 mL, 0.57 mol) was added over
a period of 5 min. The mixture was stirred for an additional
5 min before BF3·Et2O (69.9 mL, 0.57 mol) was added over
5 min at 2658C. The reaction mixture was stirred for an
additional 5 min before 2-(trimethylsiloxy)-1,3-butadiene
(100 mL, 0.57 mol) was added over 10 min. After addition
the temperature was allowed to rise to 2308C and the
mixture was stirred at this temperature for 2 h. The cooling
bath was removed and water (250 mL) was added drop wise
with vigorous stirring over 10 min. The reaction mixture
was stirred for 30 min before water (300 mL) was again
added. Solid KH2PO4 was added until pH<9. The phases
were separated and the aqueous phase was extracted with
DCM (3£300 mL). The combined organic phases were
dried (MgSO4) and the solvent removed in vacuo. The
residue was dissolved in toluene (200 mL) and applied to
the top of a 6 cm silica layer in a Buchner funnel (19 cm
wide) and eluted with toluene–ethyl acetate (5:1) by
application of vacuum. The fractions containing the desired
compound as the main component (first band) were pooled
and the solvent removed in vacuo, to give about 150 g of a
pale orange oil. Heptane (300 mL) was added leading to
solidification and the volatiles were removed in vacuo.
Additional hot heptane (700 mL) was added to give a clear
pale yellow heptane phase in addition to a small amount of
an orange viscous oil on the glass surface. The heptane
phase was filtered under vacuum and left at rt whereupon
white crystals could be filtered off. The mother liquor was
left in a refrigerator overnight (48C) yielding pale orange
crystals which after filtration was recrystallized from hep-
tane (150 mL) to give a second crop of crystals. The crops
were combined to give 69 g (45%) of 3a as a white solid.
1H NMR (300 MHz, CDCl3): d 7.45–7.38 (m, 2H), 7.34–
7.15 (m, 3H), 4.23–4.05 (m, 3H), 3.79 (t, 1H, J¼5.0 Hz),
3.50 (q, 2H, J¼6.8 Hz), 3.38 (q, 2H, J¼6.8 Hz), 2.80–2.70
(m, 1H), 2.43–2.29 (m, 2H), 1.99 (dd, 1H, J¼13.6, 6.8 Hz),
1.75–1.55 (m, 2H), 1.32 (d, 3H, J¼6.8 Hz), 1.25 (d, 3H, J¼
7.0 Hz), 1.19 (t, 3H, J¼6.8 Hz), 1.12 (t, 3H, J¼6.8 Hz). IR
(KBr) 1738 cm21. LCMS: one peak, [MþH]þ¼350. Calcd
for C20H31NO4 C, 68.74; H, 8.94; N, 4.01. Found C, 68.90;
H, 9.27; N, 4.40.
3.1.3. (10S,2R )-4,4-Diethoxy-1-(10-phenyl-ethyl)-2-
hydroxymethyl-piperidine (5). 4 (36.0 g, 0.103 mol) in
dry Et2O (150 mL) was added to a stirred suspension of
LiAlH4 (5.88 g, 0.155 mol) in dry Et2O (300 mL) under N2
at such a rate that the solution gently refluxed. The reaction
mixture was stirred overnight, cooled to 08C and EtOAc
(30 mL) was added drop wise to destroy excess LiAlH4
(Caution ). After stirring for another 30 min, H2O (12 mL)
was added drop wise. After stirring for 10–15 min, the
precipitate was filtered off using celite and the filter cage
was washed with Et2O (200 mL). The filtrate was washed
with brine (100 mL) and dried (MgSO4). The solvent was
evaporated in vacuo affording 30 g (95%) of 5 as a colorless
oil.
1H NMR (300 MHz, CDCl3): d 7.38–7.19 (m, 5H), 4.18 (q,
1H, J¼6.8 Hz), 3.73–3.58 (m, 2H), 3.52–3.40 (m, 4H),
2.94–2.85 (m, 1H), 2.70–2.60 (m, 2H), 1.98–1.90 (m, 1H),
1.82–1.72 (m, 2H), 1.58–1.48 (m, 1H), 1.35 (d, 3H, J¼
6.8 Hz), 1.18 (t, 3H, J¼6.8 Hz), 1.14 (t, 3H, J¼6.8 Hz). IR
(KBr) 3446, 1055 cm21. LCMS: one peak, [MþH]þ¼308.
Calcd for C18H29NO3·1/2(H2O) C, 68.32; H, 9.56; N, 4.43.
Found C, 68.50; H, 9.61; N, 4.72.
3.1.4. (10S,2R)-4,4-Diethoxy-1-(10-phenyl-ethyl)-2-phthali-
midomethyl-piperidine (6). To a suspension of 5 (65.35 g,
0.21 mol), triphenylphosphine (61.30 g, 0.23 mol) and
phthalimide (34.4 g, 0.23 mol) in THF (700 mL) was
cooled to 08C and DEAD (36.84 mL, 0.23 mol) was
added over a period of 90 min. The reaction mixture
was stirred at 08C for another 2 h before the solvent was
removed in vacuo. The residue was dissolved in hot
toluene–hexane (3:2) (650 mL) and cooled to 08C on an ice
bath. The precipitate was filtered off and washed with
heptane. The filtrate was concentrated in vacuo and
subjected to column chromatography in toluene–EtOAc–
heptane 3:1:3. The solvent was evaporated in vacuo to
produce a viscous oil. Upon addition of light petrol ether
(500 mL), compound 6 crystallized to give 67.42 g (73%)
of colorless crystals.
1H NMR (400 MHz, CDCl3): d 7.41–7.37 (m, 2H), 7.36–
7.30 (m, 2H), 7.28–7.23 (m, 1H), 4.22–4.18 (m, 3H), 3.87
(q, 1H, J¼7.0 Hz), 2.88–2.83 (m, 2H), 2.73–2.48 (m, 2H),
2.45–2.34 (m, 1H), 2.28–2.22 (m, 1H), 1.45 (d, 3H,
J¼7.0 Hz), 1.30 (t, 3H, J¼7.0 Hz). 13C NMR (75.47 MHz,
CDCl3): 207.28, 171.31, 145.06, 128.53, 127.20, 126.95,
61.35, 60.77, 58.43, 45.04, 43.03, 40.44, 20.45, 14.33. IR
(KBr) 1727 cm21. LCMS: one peak, [MþH]þ¼276. Calcd
for C16H21NO3 C, 69.79; H, 7.69; N, 5.09. Found C, 69.48;
H, 7.82; N, 5.05.
For melting point determination a portion was recrystallized
from 2-propanol to give small colorless needles. Mp
91–928C (lit.13 99–1008C).
1H NMR (400 MHz, CDCl3): d 7.83–7.78 (m, 2H), 7.76–
7.70 (m, 2H), 7.05–6.95 (m, 3H), 6.85–6.80 (m, 2H), 4.40
(dd, 1H, J¼15.0, 10.0 Hz), 3.92 (q, 1H, J¼7.0 Hz), 3.55–
3.40 (m, 4H), 3.28 (dd, 1H, J¼18.0, 4.5 Hz), 3.23–3.17 (m,
1H), 3.08–3.00 (m, 1H), 3.00–2.92 (m, 1H), 1.91 (dd, 1H,
J¼13.5, 4.5 Hz), 1.77–1.57 (m, 3H), 1.28–1.15 (m, 9H). IR
(KBr) 1770, 1717 cm21. LCMS: one peak, [MþH]þ¼437.
Calcd for C26H32N2O4 C, 71.53; H, 7.39; N, 6.42. Found C,
71.48; H, 7.47; N, 6.43.
3.1.2. (10S,2R )-4,4-Diethoxy-1-(10-phenyl-ethyl)-piperi-
dine-2-carboxylic acid ethyl ester (4). 3a (148 g,
0.54 mol) was dissolved in a mixture of EtOH (1.0 L) and
(EtO)3CH (0.89 L, 5.38 mol) whereupon p-toluene sulfonic
acid (153 g, 0.81 mol) was added and the reaction mixture
was stirred for 16 h. The reaction mixture was neutralized
with sodium bicarbonate (to pH ca. 7–8), and extracted with
DCM (3£100 mL), dried with MgSO4 and concentrated
in vacuo. The title compound was purified by column
chromatography (SiO2, petrol ether–EtOAc 10:1) to give
12.0 g (86%) of 4 as a colorless oil.
For melting point determination a sample was recrystallized
from EtOH to give colorless needles. Mp 124–1258C.

J. F. Lau et al. / Tetrahedron 58 (2002) 7339–7344
7343
3.1.5. (10S,2R )-4-Oxo-1-(10-phenyl-ethyl)-2-phthalimido-
methyl-piperidine (7). 6 (90.37 g, 0.21 mol) was added to
TFA–H2O (9:1, 500 mL) pre-cooled to 08C, and the
reaction was stirred 3 h at 08C. The solvent was removed
in vacuo and the residue basified to pH 8 with a saturated
solution of Na2CO3. The reaction mixture was extracted
with EtOAc (3£200 mL) and dried (MgSO4). After filtration
the solvent was removed and the residue was dried in vacuo
at 408C for 2 d to yield 76.45 g (100%) of compound 7 as a
clear oil.
0.011 mol) in DCM (50 mL) was added HOAt (1.47 g,
0.011 mol) and EDC (2.06 mg, 0.011 mol). The mixture
was stirred for 20 min at rt before a solution of 8 (3.0 g,
0.01 mol) and DIPEA (1.84 mL, 0.011 mmol) in DCM
(20 mL) was added. The reaction mixture was stirred at rt
for 16 h.
The mixture was washed with aqueous NaHCO3 (50 mL),
dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified using column chromatography (SiO2,
DCM–EtOAC (4:1)) to give 3.8 g (81%) of compound 10
as an amorphous solid.
1H NMR (400 MHz, CDCl3): d 7.85–7.80 (m, 2H), 7.78–
7.70 (m, 2H), 7.15–7.07 (m, 3H), 7.20–6.95 (m, 2H), 4.00
(q, 1H, J¼7.0 Hz), 3.95–3.85 (m, 1H), 3.65–3.55 (m, 1H),
3.50–3.30 (m, 3H), 2.70 (dd, 1H, J¼14.0, 7.0 Hz), 2.55–
2.44 (m, 1H), 2.29–2.15 (m, 2H), 1.38 (d, 3H, J¼7.0 Hz).
IR (KBr) 1712 cm21. LCMS: one peak, [MþH]þ¼363.
Calcd for C22H22N2O3·1/2(H2O) C, 71.14; H, 6.24; N, 7.54.
Found C, 71.02; H, 6.12; N, 7.57.
1H NMR (400 MHz, CDCl3): d 7.82–7.78 (m, 2H), 7.68–
7.60 (m, 4H), 7.52–7.45 (m, 2H), 7.42–7.35 (m, 2H), 7.32–
7.18 (m, 4H), 6.77 (m, 1H), 4.19 (q, 1H, J¼7.0 Hz), 3.73–
3.57 (m, 2H), 3.48 (q, 4H, J¼7.0 Hz), 3.10–3.00 (m, 1H),
2.68–2.62 (m, 2H), 2.05–2.00 (m, 1H), 1.87–1.72 (m, 2H),
1.62–1.52 (m, 2H), 1.48 (d, 3H, J¼7.0 Hz), 1.22 (t, 3H, J¼
7.0 Hz), 1.80 (t, 3H, J¼7.0 Hz). IR (KBr) 1684, 1644 cm21
.
3.1.6. (10S,2R)-4,4-Diethoxy-1-(10-phenyl-ethyl)-2-amino-
methyl-piperidine (8). A mixture of 6 (5.25 g, 12.0 mmol)
and hydrazine hydrate (2.92 mL, 60 mmol) was stirred
overnight in EtOH (100 mL) at rt. The solvent was removed
in vacuo and the solid residue was extracted with Et2O
(3£50 mL). The Et2O extracts were combined and the
solvent was evaporated to yield 3.94 g (94%) of compound
8 as a colorless oil.
LCMS: one peak, [MþH]þ¼487. HRMS Calcd for
(C31H38N2O3þH)¼487.2961, Found 487.2972.
3.1.9. (2R )-Biphenyl-4-carboxylic acid [4,4-diethoxy-
piperidin-2-ylmethyl]-amide (11). To a stirred solution
of 10 (1.9 g) in EtOH (120 mL) was added formic acid
(15 mL) and Pd/C (5%, dry) (500 mg). The mixture was
stirred overnight under N2, the Pd/C was filtered off and the
volatiles evaporated in vacuo. The residue was dissolved in
DCM (150 mL) and washed with saturated NaHCO3
(2£150 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo to afford 1.17 g (78%) of compound
11 as an amorphous solid.
1H NMR (300 MHz, DMSO-d6): 7.44–7.38 (m, 2H), 7.33–
7.25 (m, 2H), 7.23–7.17 (m, 1H), 4.20 (q, 1H, J¼6.70 Hz),
3.45–3.28 (m, 2H), 2.82 (dd, 1H, J¼12.0, 6.0 Hz), 2.65 (dd,
1H, J¼12.0, 3.0 Hz), 2.60–2.48 (m, 1H), 2.35–2.2 (m, 2H),
1.90 (dt, 1H, J¼13.2, 2.8 Hz), 1.73–1.63 (m, 1H), 1.59 (dd,
1H, J¼13.2, 9.8 Hz), 1.27 (m, 1H), 1.22 (d, 3H, J¼6.8 Hz),
1.10 (t, 3H, J¼6.8 Hz), 1.07 (t, 3H, J¼7.2 Hz). LCMS: one
peak, [MþH]þ¼307.
3.1.7. (10S,2R )-4,4-Diethoxy-1-(10-phenyl-ethyl)-2-tert-
butyloxycarbonylaminomethyl-piperidine (9). 8 (1.96 g,
6.41 mmol) and di-tert-butyl dicarbonate (1.68 g, 7.69
mmol) was dissolved in a mixture of dioxane (30 mL) and
sodium bicarbonate (15 mL, 5% in water). The reaction
mixture was stirred 16 h at rt before the solvent was
removed in vacuo. The residue was separated between DCM
(30 mL) and water (50 mL). The organic phase was washed
with water (50 mL), dried (MgSO4) and concentrated in
vacuo. Purification by column chromatography (SiO2,
toluene–EtOAc–heptane (3:1:3)) afforded 1.96 g (75%)
of compound 9 as a colorless oil.
1H NMR (400 MHz, CDCl3): d 7.89–7.83 (m, 2H), 7.68–
7.58 (m, 4H), 7.50–7.43 (m, 2H), 7.42–7.36 (m, 1H), 6.80
(bt, 1H), 3.62–3.50 (m, 3H), 3.43 (q, 2H, J¼7.0 Hz), 3.37–
3.27 (m, 1H), 3.07–2.98 (m, 2H), 2.87–2.75 (m, 1H), 2.10–
1.98 (m, 2H), 1.50–1.40 (m, 2H), 1.22–1.13 (m, 6H). IR
(KBr) 1640 cm21. LCMS: one peak, [MþH]þ¼383. Calcd
for C23H30N2O3·1/3(H2O) C, 71.11; H, 7.96; N, 7.21. Found
C, 71.45; H, 7.95; N, 7.21.
3.2. Single crystal X-ray crystallographic analysis of
compound 3c
X-Ray diffraction data was collected on an Enraf–Nonius
CAD-4 diffractometer with v/2u scan mode. Copper
˚
radiation was used (l(Cu Ka)¼1.5418 A) with a graphite
monochromator. The crystal was cooled with an Enraf–
Nonius low-temperature device.
1H NMR (400 MHz, CDCl3): 7.40–7.35 (m, 2H), 7.34–
7.29 (m, 2H), 7.25–7.20 (m, 1H), 4.98 (m, 1H), 4.13 (q, 1H,
J¼7.0 Hz), 3.50–3.25 (m, 6H), 2.91–2.84 (m, 1H), 2.51–
2.46 (m, 2H), 1.92 (d, 1H, J¼13.0 Hz), 1.80–1.65 (m, 2H),
1.43 (s, 9H), 1.32 (d, 3H, J¼7.0 Hz), 1.18 (t, 3H, J¼7.0 Hz),
1.15 (t, 3H, J¼7.0 Hz). IR (KBr) 1715 cm21. LCMS: one
peak, [MþH]þ¼407. Calcd for C23H38N2O4 C, 67.95; H,
9.42; N, 6.89. Found C, 68.00; H, 9.50; N, 7.00.
Suitable single crystals were obtained from a solution of 3c
in EtOAc–heptane. The crystal (0.47£0.23£0.04 mm3)
belonged to the orthorhombic crystal system, space
group P212121 with a¼5.355(2), b¼14.6290(10), c¼
3
˚
˚
18.867(13) A, V¼1478(1) A , Z¼4, T¼122.0(5) K. Dcalc
¼
1.237 mg/m3, m(Cu Ka)¼0.687 mm21
,
umax¼74.908,
26 # h # 6; 218 # k # 18; 223 # l # 23: Of the 9224
reflections collected 3044 were unique (Rint¼0.025).
3.1.8. (10S,2R )-Biphenyl-4-carboxylic acid [4,4-diethoxy-
1-(10-phenyl-ethyl)-(-piperidin-2-ylmethyl]-amide (10).
To a solution of 4-biphenylcarboxylic acid (2.13 g,
Data reduction was performed using the program
DREADD.13 Five standard reflections were measured

7344
J. F. Lau et al. / Tetrahedron 58 (2002) 7339–7344
every 104 s and indicated a systematic decay in the intensity
of 3.9% in the course of the data collection and the data was
corrected for the decay.
3. Vanderhaeghe, H.; Parmentier, G. J. Am. Chem. Soc. 1960, 82,
4414–4422.
4. (a) Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe, J.-S.;
Grenier, L.; Guse, I. Tetrahedron 1997, 53, 15671–15680.
(b) Skiles, J. W.; Giannousis, P. P.; Fales, K. R. Bioorg. Med.
Chem. Lett. 1996, 6, 963–966. (c) Machetti, F.; Cordero, F. M.;
Sarlo, F. D.; Guarna, A.; Brandi, A. Tetrahedron Lett. 1996,
37, 4205–4208. (d) Golubev, A.; Stewald, N.; Burger, K.
Tetrahedron Lett. 1995, 36, 2037–2040. (e) Jackson, R. F. W.;
Graham, L. J.; Rettie, A. B. Tetrahedron 1994, 35,
4417–4418.
The structure was solved by direct methods,14 where all
non-hydrogen atoms were located. Subsequent difference
electron density maps reveal the positions of the hydrogen
atoms.
Structure refinement was performed by full matrix least
squares procedure based on F 2.15 Atomic positions and
anisotropic displacement parameters were refined for non-
hydrogen atoms. The position of the hydrogen atoms were
refined with fixed isotropic displacement parameters.
´
5. (a) Abraham, H.; Theus, E.; Stella, L. Bull. Soc. Chim. Belg.
1994, 103, 361–366. (b) Mu¨hlemann, P.; Hartmann, P.;
Obrecht, J.-P. Org. Synth. 1992, 71, 200. (c) Ornstein, P. L.;
Schoepp, D. D.; Arnold, M. B.; Leander, J. D.; Lodge, D.;
Paschal, J. W.; Elzey, T. J. Med. Chem. 1991, 34, 90–97.
(d) Essawi, M. Y.; Portoghese, P. S. J. Heterocycl. Chem.
1983, 20, 477–478.
Final R¼0.0298 and wR(F 2)¼0.0766 for 2968 observed
reflections ðI . 2sðIÞÞ and 245 variables. w¼1/[s 2(Fo2)þ
(0.0427P )2þ0.2551P ], P¼(Fo2þ2F2c)/3. GooF¼S¼1.066.
Structure refinement resulted in a Flack parameter16
x¼0.0(2) for the enantiomer, shown in Fig. 1. The parameter
was refined using TWIN and BASF (0.15) in SHELXL97.
Atomic scattering factors were used as implemented in
SHELXL97, which were taken from International Tables
for Crystallography.17
6. Abraham, H.; Stella, L. Tetrahedron 1992, 44, 9707–9718.
7. After this work was finished a paper describing crystallization
of 3c was published; Machetti, F.; Cordero, F. M.; Sarlo, F. D.;
Brandi, A. Tetrahedron 2001, 57, 4995–4998.
´ ´
8. Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez,
J. A. Tetrahedron 1999, 55, 7601–7612.
9. Johnson, C. K. ORTEPII; Report ORNL-5138; Oak-Ridge
National Laboratory: Tennessee, USA, 1976.
Crystallographic data (excluding structure factors) for the
structure 3c in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 181005. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
10. The crude product could be converted directly to 5 without
purification.
11. Rf: 4(S,R )¼0.7 and Rf: 4(S,S )¼0.4. In this case where the
reactions were performed on large scale we preferred to obtain
the pure diastereoisomer by crystallization.
12. Mitsunobu, O. Synthesis 1981, 1–28.
13. Blessing, R. H. Crystallogr. Rev. 1989, 22, 396–397.
Blessing, R. H. J. Appl. Crystallogr. 1989, 22, 396–397.
14. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
15. Sheldrick, G. M. SHELXL97: Program for the Refinement of
References
1. Iversen, L. F.; Andersen, H. S.; Møller, K. B.; Olsen, O. H.;
Peters, G. P.; Branner, S.; Mortensen, S. B.; Hansen, T. K.;
Lau, J.; Ge, Y.; Holsworth, D. D.; Newman, M. J.; Møller,
N. P. H. Biochemistry 2001, 40, 14812–14820.
¨
Crystal Structures; University of Gottingen: Germany, 1997.
16. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
17. International Tables for Crystallography, 1992. Tables 4.2.6.8
and 6.1.1.4.
2. MDL Drug Data Report (MDDR-3D), 1988–2001.