The asymmetric synthesis of (3R)-N-methyl-2-oxo-[1,4′-bipiperidine]-3-acetamide in quantity

Article abstract of DOI:10.1016/S0957-4166(02)00229-X

The asymmetric synthesis of the enantiomerically pure bipiperidine core fragment of a potent dual NK₁/NK₂ antagonist is described. The utilization of a diastereoselective Michael addition employing Evans' auxiliary as the key step al

Full text of DOI:10.1016/S0957-4166(02)00229-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 939–943
The asymmetric synthesis of
(3R)-N-methyl-2-oxo-[1,4%-bipiperidine]-3-acetamide in quantity
Gregory A. Reichard,a,* James Spitler,a Ingrid Mergelsberg,b Alan Miller,c George Wong,c
Ramani Raghavan,c John Jenkins,c Tong Ganc and Andrew T. McPhaild
aChemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
bWerthenstein Chemie AG, Industriestrasse, CH-6105 Schachen, Switzerland
cChemical Process Development, Schering-Plough Research Institute, 1011 Morris Ave., Union, NJ 07083, USA
dDepartment of Chemistry, P. M. Gross Chemical Laboratory, Duke University, Durham, NC 27708, USA
Received 19 December 2001; accepted 29 April 2002
Abstract—The asymmetric synthesis of the enantiomerically pure bipiperidine core fragment of a potent dual NK1/NK2
antagonist is described. The utilization of a diastereoselective Michael addition employing Evans’ auxiliary as the key step allowed
for the preparation of the fragment on a multi-kilogram scale. © 2002 Published by Elsevier Science Ltd.
1. Introduction
2. Retrosynthetic analysis
Structural modification1 of an oxime lead structure2 has
resulted in the identification of Sch 206272 as a potent
dual NK1/NK2 antagonist that is quite active in vivo in
both guinea pig and dog.3 As part of our effort to
supply multigram quantities for a full preclinical evalu-
ation of Sch 206272, as well as to support the supply of
material for toxicological assessment of Sch 206272, an
asymmetric synthesis of (3R)-N-methyl-2-oxo-[1,4%-bi-
piperidine]-3-acetamide 1 was undertaken. The require-
ments of the synthesis were that it be short, efficient,
amenable to large scale preparation, have minimal
chromatographic purification, and provide material
with greater than 99% e.e.
The retrosynthetic analysis of amino amide 1 centered
on simplifying the piperidone ring to the corresponding
amino ester 2. This cyclization would allow for the
recovery and reuse of the chiral source. Functional
group interchange of the amine back to the nitrile
permitted the utilization of methodology developed by
Evans and co-workers,4 wherein the desired stereocen-
ter is constructed by means of a diastereoselective
Michael addition of the enolate of 4 to acrylonitrile.
We report herein the successful application of this ro-
bust methodology to prepare 1 on multi-kilogram scale.
* Corresponding author. Tel.: +1-908-740-3522; fax: +1-908-740-7305;
e-mail: gregory.reichard@spcorp.com
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00229-X

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G. A. Reichard et al. / Tetrahedron: Asymmetry 13 (2002) 939–943
3. Synthesis
amine hydrochloride 106 with N-Boc-4-piperidone in
THF utilizing sodium triacetoxyborohydride provided
the crude secondary amine 11. Cyclization of crude 11
in acetonitrile at 50°C for 72 h resulted in conversion to
lactam 12. Optimization of the cyclization of 11 to 12
for large scale was achieved in toluene at reflux for 5 h.
The methyl ester 12 was then saponified cleanly with
NaOH in toluene at 23°C. The resulting carboxylate
salt was separated from the auxiliary by extraction and
isolated by acidification, crystallization and filtration to
provide the pure protected amino acid 13 (99% e.e.) as
a white powder in 51–67% overall yield from 9 (Scheme
2).
Reaction of 3-carbomethoxypropionyl chloride with the
lithium salt of (R)-4-benzyl-2-oxazolidinone at −78°C
provided 6 as a colorless solid in 96% yield after
recrystallization from hot isopropanol. Subsequent for-
mation of the enolate of 6 with Ti(OiPr)Cl3 and diiso-
propylethylamine at 0°C for 1 h followed by the
Michael addition of acrylonitrile5 at 0°C for 20 h
provided pure nitrile 9 as a colorless crystalline solid in
60% yield (>99.5:0.5 d.r.) after recrystallization. The
absolute configuration of 9 was confirmed by X-ray
crystallographic analysis (Fig. 1, Scheme 1).
Figure 1. ORTEP drawing of 9.
Scheme 2. Reagents and conditions: (i) H2 (60 psi), 5% Pt/C
(50% wet), p-TSA, THF, 24 h; (ii) N-Boc-4-piperidone, THF,
-H2O by azeotropic distillation, then sodium triacetoxyboro-
hydride, 2 h; (iii) toluene, 110°C, 5 h; (iv) NaOH, toluene,
23°C, 16 h, 51–67% yield from 9.
Subsequent coupling of enantiomerically pure 13 with
methylamine using isobutylchloroformate followed by
deprotection of the piperidine nitrogen with trifluoro-
acetic acid proceeded cleanly to 1 without racemiza-
tion (Scheme 3).
Scheme 1. Reagents and conditions: (i) n-BuLi, 3-carbo-
methoxypropionyl chloride, 96%; (ii) Ti(OiPr)Cl3 and diiso-
propylethylamine, 0°C, 1 h, acrylonitrile, 20 h, recrystallize in
hot isopropanol, 60% yield.
Hydrogenation of the nitrile 9 with 5% PtO2 in MeOH/
CHCl3 at 45 psi provided clean reduction to the desired
amine hydrochloride, however, some reduction (17%)
of the phenyl to cyclohexyl on the chiral auxiliary was
noted. In an effort to adapt this procedure to kilo-scale,
as well as minimize the problematic auxiliary reduction,
various solvents, catalysts and catalyst loads were
screened. It was found that by hydrogenation of 9 at 60
psi in THF with 40 wt% of 5% Pt/C (50% wet) and
p-toluene sulfonic acid as a proton source, provided
clean reduction of the nitrile with minimal reduction of
the auxiliary phenyl ring. Reductive amination of
Scheme 3. Reagents and conditions: (i) triethylamine, isobutyl-
choroformate, MeNH2, THF, −20°C; (ii) trifluoroacetic acid,
THF, 82% yield from 13.
4. Summary
Thus, the asymmetric synthesis of (3R)-N-methyl-
2-oxo-[1,4%-bipiperidine]-3-acetamide
1
proceeds in
24–32% overall yield over eight steps with no

G. A. Reichard et al. / Tetrahedron: Asymmetry 13 (2002) 939–943
941
chromatography. The synthesis met our initial criteria
for being short, efficient, amenable to scale-up (over 10
kg of 1 was prepared using this route), having minimal
chromatographic separation, and providing material of
>99% e.e.
(4 L)/EtOAc (6 L). The resulting organic layer was
washed with 12.5% aqueous NH4Cl (2×4 L), followed
by saturated aqueous NaHCO3 (4 L), brine (4 L), then
dried (MgSO4) and concentrated. Trituration of the
crude product with diethyl ether (875 mL) and recrys-
tallization from hot methanol (4 mL/g; decolorize with
charcoal/silica gel (5 g/2.5 g) if needed) provided the
pure product 9 as a colorless crystalline solid (116.5 g,
338.3 mmol, 60%), mp 103–105°C. TLC (hex/EtOAc,
5. Experimental
1
5.1. Synthesis of (4R)-3-oxazolidinebutanoic acid, g,2-
dioxo-4-(phenylmethyl)-, methyl ester 6
1:1): Rf sm 0.6, Rf prod 0.5; stain: pma. H NMR (500
MHz, CDCl3): l 1.92 (m, 1H), 2.12 (m, 1H), 2.44 (t,
J=7.8 Hz, 2H), 2.55 (dd, J=4.4, 17.0 Hz, 1H), 2.81
(dd, J=9.77, 13.56 Hz, 1H), 2.93 (dd, J=10.4, 17.0 Hz,
1H), 3.32 (dd, J=3.78, 13.56 Hz, 1H), 3.68 (s, 3H), 4.16
(m, 1H), 4.23 (dd, J=2.52, 8.83 Hz, 1H), 4.30 (t,
J=8.83 Hz, 1H), 4.72 (m, 1H), 7.21 and 7.36 (m, 5H);
13C NMR (125 MHz, CDCl3): l 13.9, 14.3, 26.6, 34.2,
37.2, 37.4, 51.0, 54.5, 64.8, 65.7, 117.8, 126.5, 128.0,
128.4, 134.0, 152.4, 170.8, 172.7. HRMS calcd for
C18H21N2O5 (M+H)+ 345.1450, found 345.1460.
A solution of (R)-(+)-4-benzyl-2-oxazolidinone 7 (100
g, 563 mmol) and 1,10-phenanthroline (10 mg) in dry
THF (1.25 L; Aldrich Sure Seal) was cooled to −78°C.
n-BuLi (1.6 M in hexane, 350 mL, 350 mmol, 1 equiv.)
was added (via addition funnel at a rate such that the
internal temperature remained 5−70°C) until the reac-
tion turned brown from the phenanthroline complex
(ca. 349.5 mL). After 15 min, 3-carbomethoxypropionyl
chloride (69.5 mL, 564 mmol, 1 equiv.) was added over
10 min via syringe (the dark brown color of the reac-
tion mixture fades to light yellow with the first drop of
acid chloride). The mixture was stored for 17 h at
−78°C for convenience (reaction is complete after 15
min). The reaction mixture was allowed to warm to
room temperature then poured into EtOAc (2.5 L)/sat-
urated aqueous NH4Cl (1 L). The organic layer was
washed with saturated aqueous NH4Cl (1 L), satd
NaHCO3 (2.5 L), brine (2.5 L), dried (MgSO4) and
concentrated to give the crude product as a yellow
solid. Recrystallization from hot isopropanol (820 mL)
provided pure product 6 as a colorless crystalline solid
(157.9 g, 542 mmol, 96%), mp 90–92°C. TLC (hex/
EtOAc, 1:1): Rf sm 0.3 uv, Rf prod 0.6 uv; stain: 5%
5.3. Synthesis of (3R)-1%-[(1,1-dimethylethoxy)carbonyl]-
2-oxo-[1,4%-bipiperidine]-3-acetic acid 13
Method A: A solution of nitrile 9 (25 g, 72.6 mmol) in
CHCl3 (100 mL) in a 2 L Parr bottle was diluted with
MeOH (400 mL) and treated with PtO2 (1.25 g) and
placed on the Parr shaker @ 45 psi. After 24 h the
mixture was filtered through a pad of Celite, and the
filtrate was concentrated in vacuo. The resulting crude
amine·HCl (28.3 g) was used in the next step without
further purification. TLC (hex/EtOAc, 1:1): Rf sm 0.5
uv, Rf prod 0.0 uv; stain: pma. A solution of the crude
amine·HCl 10 (72.6 mmol) was dissolved in 1,2-
dichloroethane (500 mL) and treated with HOAc (6
mL, 105 mmol, 1.4 equiv.) followed by N-Boc-4 piperi-
done (14.6 g, 73.5 mmol, 1.01 equiv., Lancaster) fol-
lowed by NaB(OAc)3H (25.7 g, 122 mmol, 1.7 equiv.)
After stirring for 1.0 h, the crude mixture was poured
into a 4 L separatory funnel charged with CH2Cl2 (1.4
L). Saturated aqueous NaHCO3 (560 mL) was added
carefully. The aqueous layer was removed and the
organic layer washed again with saturated aqueous
NaHCO3 (560 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. The crude 11 (39.1
g) was used in the subsequent cyclization step without
further purification. TLC (EtOAc/MeOH, 95:5): Rf sm
0.0 uv, Rf prod 0.25 uv; stain: pma. A solution of the
crude amine 11 (72.6 mmol) in acetonitrile (500 mL)
was warmed to 50°C. The resulting solution was stirred
for 72 h, whereupon it was cooled and concentrated in
vacuo. The resulting crude lactam 12 (39.3 g) was used
in the following hydrolysis without further purification.
TLC (EtOAc/MeOH, 95:5): Rf sm 0.25, Rf prod 0.75;
TLC (hex/EtOAc, 1:1): Rf sm 0.0 uv, Rf prod 0.2 non
uv, phenyl oxazolidinone 0.4 uv, cyclohexyl oxazolidi-
none 0.6 non uv; stain: pma. A solution of the crude
lactam 12 (39.3 g) (containing up to 72.6 mmol of a
mixture of N-benzyl and N-methyl-cyclohexyl oxazo-
lidinones) in MeOH (150 mL), was treated with NaOH
(148 mL of 1N aqueous NaOH, 2.2 equiv.). After
stirring for 6 h at 23°C, methanol was removed in
vacuo and the resulting solution was diluted with water
1
ethanolic phosphomolybdic acid (pma). H NMR (500
MHz, CDCl3): l 2.66–2.77 (m, 1H), 3.20–3.26 (m, 1H),
3.68 (s, 3H), 4.13–4.20 (m, 1H), 4.14 (dd, J=2.9, 9.1
Hz, 1H), 4.18 (t, J=8.4 Hz, 1H), 4.62–4.65 (m, 1H),
7.16–7.31 (m, 5H). 13C NMR (125 MHz, CDCl3): l
27.1, 29.9, 36.7, 50.9, 54.1, 65.3, 126.3, 127.9, 128.4,
134.1, 152.4, 170.8. HRMS calcd for C15H18NO5 (M+
H)+ 292.1185, found 292.1195.
5.2. Synthesis of (bR,4R)-3-oxazolidinebutanoic acid, b-
(2-cyanoethyl)-g,2-dioxo-4-(phenylmethyl)-, methyl ester
9
A solution of TiCl4 (419 mL of 1 M in CH2Cl2, 419
mmol) in dry CH2Cl2 (1.35 L, Aldrich Sure Seal) was
cooled to 0°C and treated with Ti(Oi-Pr)4 (41.4 mL,
140 mmol) via syringe. After 10 min at 0°C, diisopropyl-
ethylamine (102.4 mL, 587 mmol, Aldrich Sure Seal)
was added via dry addition funnel (vacuum anhydrous
cannula transfer to dry addition funnel). After stirring
the resulting dark brown solution for 15 min, oxazolidi-
none 6 (163.2 g, 561 mmol) was added in one portion.
The solution was stirred for 1 h at 0°C whereupon
freshly distilled acrylonitrile (147 mL, 2.24 mol) was
added via dry addition funnel (vacuum anhydrous can-
nula transfer to dry addition funnel). The resulting
mixture was allowed to stand at 4°C for 18 h. The
reaction mixture was poured into 25% aqueous NH4Cl

942
G. A. Reichard et al. / Tetrahedron: Asymmetry 13 (2002) 939–943
(50 mL) and washed with EtOAc (3×200 mL) to
remove the oxazolidinone. The aqueous layer was then
acidified to pH 2 with 15% aq. HCl (4.4 M, 40 mL).
The product was extracted with CH2Cl2 (4×200 mL).
The organic layers were combined, dried (MgSO4) and
concentrated to give the pure acid as a colorless foam
(22.3 g, 65.5 mmol, 96% e.e.). Recrystallization from
hot acetone (18 mL/g reflux, filter, cool, remove ca. 300
mL solvent on rotovap, seed and sonicate, cool to
10°C, isolate by filtration with 50 mL cold acetone
wash) to give the pure product 13 as a colorless solid
(16.5 g, 48.5 mmol, 67% from 9), mp 145–147°C, >99%
e.e. by chiral HPLC: Daicel CHIRALCEL® OD
column, 85:15 hexane/isopropanol with 0.1% TFA; tR
R isomer=9.5 min; tR S-isomer=11.3 min. TLC
(EtOAc/MeOH, 95:5 w/2% HOAc): Rf sm 0.70, Rf prod
to a volume of 850 mL (contains 11, 185 g by theory,
348 mmol), divided into two portions and used in the
next step without further purification: half of the tolu-
ene solution from the previous step was heated to reflux
(about 110°C) and the progress of the ring closure
reaction was followed by HPLC (column: Prodigy 5m,
ODS Phenomenex, 250×4.6 mm, eluent: acetonitrile/
buffer (0.05 M decanesulfonic acid, pH 3) 40/60, reac-
tion time: 5 h). After complete conversion the reaction
mixture was cooled to 20–25°C and used in the next
step without further purification/work-up. Sodium
hydroxide (conc. 30% in water, 45 mL, 843 mmol)
dissolved in water (600 mL) was added to the toluene
solution from the previous step at 20–25°C and the
resulting mixture was stirred at that temperature for 16
h. After complete conversion (followed by HPLC:
column: Prodigy 5m, ODS Phenomenex, 250×4.6 mm,
eluent: acetonitrile/buffer (0.05 M decanesulfonic acid,
pH 3) 40/60) water (110 mL) was added and the phases
were split. The aqueous phase was extracted with iso-
propyl acetate (900 mL) and the combined organic
phases (toluene and isopropyl acetate phase) were kept
for recovery of (R)-(+)-4-benzyl-2-oxazolidinone 7 (see
note 1). The pH of the water phase was adjusted to 1 to
2 by the addition of HCl (200 mL, 12% in water)
during which compound 13 precipitated. Isopropyl ace-
tate (900 mL) was added and the precipitate was dis-
solved by heating the mixture to 40–45°C. The reaction
mixture was cooled to 25–30°C, the phases were split
and the water phase was discarded. The organic phase
was filtered through a filter aid (Hyflo, 4 g), concen-
trated to a volume of 360 mL, cooled to −10 to −5°C
and stirred at that temperature for 1 h. The product
was isolated by filtration, washed with isopropyl acetate
(50 mL) and dried in a vacuum oven at 40–45°C until
dry to provide 30.5 g of 13 (89.4 mmol, 51% based on
compound 9), HPLC-assay: 99.2% versus std., 99.2%
by area; enantiomeric purity (HPLC): 99% (R-isomer).
1
0.55; stain: pma. H NMR (500 MHz, CDCl3): l 1.42
(s, 9H), 1.45–1.62 (m, 4H), 1.70–1.78 (m, 1H), 1.86–2.02
(m, 2H), 1.86–2.02 (m, 1H), 2.43 (dd, J=2.3, 15.4 Hz,
1H), 2.64–2.8 (m, 4H), 3.12 (dd, J=4.7, 10.5 Hz, 1H),
3.15 (dd, J=4.5, 10.6 Hz, 1H), 3.20–3.25 (m, 1H), 4.17
(br s, 2H), 4.54–4.62 (m, 1H); 13C NMR (125 MHz,
CDCl3): l 21.2, 26.4, 27.4, 27.5, 37.2, 37.3, 41.1, 50.7,
78.8, 153.6, 171.8, 173.4. HRMS calcd for C17H29N2O5
(M+H)+ 341.2076; found 341.2082.
Method B: Compound 9 (120 g, 348 mmol) and p-tolu-
ene sulfonic acid (72 g, 378 mmol) were dissolved in
THF (1.2 L) at 20–25°C under stirring. Platinum (48 g,
5% on charcoal, 50% water wet) was suspended in 55
mL water and added. The suspension was hydro-
genated at 20–25°C in an autoclave at 4–5 bar for
about 10 h. After complete conversion (followed by
HPLC: column: Prodigy 5m, ODS Phenomenex, 250×
4.6 mm, eluent: acetonitrile/buffer (0.05 M decanesul-
fonic acid, pH 3) 40/60) the catalyst was removed by
filtration (contains compound 10 and the cyclohexyl
derivative in a ratio of 9:1) and the filtrate was used
without further purification. The filtrate (1.4 L, con-
tains 181 g, 348 mmol compound 10 by theory) was
added to N-Boc-4-piperidone (70 g, 351 mmol) and the
resulting clear solution was concentrated at 40°C/100
mbar to 275 mL. Dry THF (1.8 L) was added and the
water content was determined by Karl Fisher titration.
Subsequent reduction of the Schiff-base of compound
11 was then initiated if the water content was <0.15%
(if the water content >0.15%, the concentration/dilution
with dry THF was repeated). The solution was concen-
trated to 300 mL (contains compound 11, 184 g by
theory, 348 mmol) and added to a solution of sodium
triacetoxyborohydride (118 g, 558 mmol) in dry THF
(720 mL) over 20 min keeping the temperature at
20–30°C. After complete reaction (followed by HPLC:
column: Prodigy 5m, ODS Phenomenex, 250×4.6 mm,
eluent: acetonitrile/buffer (0.05 M decanesulfonic acid,
pH 3) 40/60, reaction time: 90 min) water (550 mL) was
added over 10 min at 20–25°C. The reaction mixture
was concentrated at 40°C/60 mbar to a volume of 600
mL and toluene (1.8 L) was added. The phases were
separated and the organic phase was washed twice with
an aqueous solution of potassium carbonate and once
with an aqueous solution of ammonium chloride. The
organic phase was then concentrated at 60°C/60 mbar
Note 1: Recovery of (R)-(+)-4-benzyl-2-oxazolidinone:
2 L of organic phase (contains 49.3 g (R)-(+)-4-benzyl-
2-oxazolidinone 7, 278 mmol) was concentrated at
50°C/40 mbar as completely as possible. The resulting
residue was dissolved in isopropyl acetate (73 mL) at
20–25°C and n-heptane (124 mL) was added over 25
min to the solution. The resulting suspension was
cooled to between 0 and 5°C and stirred at that temper-
ature for 1 h. The product was isolated by filtration,
washed with n-heptane (10 mL) and dried at 40–45°C
to give 23 g (46%); HPLC-assay: 98.8% versus satd,
99.6% by area; enantiomeric purity (HPLC): >99.5% of
(R)-(+)-4-benzyl-2-oxazolidinone.
5.4. Synthesis of (3R)-[2-(methylamino)-2-oxoethyl]-2-
oxo-[1,4%-bipiperidine]-1%-carboxylic acid, 1,1-dimethyl-
ethyl ester 14
A mixture of 13 (1000 g, 2.94 mol) in dry THF (3.5 L)
and triethylamine (500 mL, 3.6 mol) was heated to
45°C to dissolve and then cooled to between −40 and
−60°C. Ethyl chloroformate (320 mL, 3.3 mol) was then
added keeping the temperature below −35°C. The solu-
tion was stirred for 30 min whereupon methylamine

G. A. Reichard et al. / Tetrahedron: Asymmetry 13 (2002) 939–943
943
(2 M in THF, 2.2 L, 4.4 mol) was added, keeping the
temperature under −20°C. Water (1.0 L) was added and
the THF was removed by distillation at 40°C under
vacuum. The oil remaining was then extracted into
ethyl acetate (1×2 L, 1×1 L). The combined ethyl
acetate layers were washed with saturated sodium
bicarbonate (1×200 mL) and allowed to separate
overnight. The ethyl acetate was separated and then the
solution was concentrated under vacuum at 40°C to
give an oil. Methyl t-butyl ether (MTBE, 2.5 L) was
then added and the solution was heated to 55°C,
seeded, and cooled to 0–5°C for 1 h. The crystalline
product was filtered, washed with MTBE (1×500 mL)
and dried under vacuum overnight at 40°C to yield a
colorless crystalline solid (950 g, 2.69 mol, 91.4%, e.e.
>98%), mp 120–122°C. [h]2D3 +30.0 (c 0.5, methanol). 1H
NMR (500 MHz, CDCl3): l 1.43 (s, 9H), 1.48–1.58 (m,
5H), 1.80–1.86 (m, 1H), 1.95–2.02 (m, 1H), 2.69 (m,
1H), 2.37 (dd, J=4.9, 14.3 Hz, 1H), 2.57–2.73 (m, 4H),
2.75 (d, J=5.1 Hz, 3H), 3.10–3.21 (m, 2H), 4.17 (brs,
2H), 4.43–4.61 (m, 1H), 6.62 (br s, 1H). 13C NMR (125
MHz, CDCl3): l 22.7, 26.6, 27.3, 28.8, 29.0, 39.3, 39.7,
42.1, 51.3, 80.0, 154.9, 172.6, 172.9. HRMS calcd for
C18H32N3O4 (M+H)+ 354.2393; found 354.2398.
0.1% TFA, 0.15% water; flow: 2.0 mL/min; tempera-
ture: 30°C; detection: 210 nm; tR (R)-14, 19.9 min; tR
(S)-14, 18.1 min]. [h]2D3 +32.6 (c 0.2, methanol, oxalate
1
salt) H NMR (500 MHz, CDCl3): l 1.55 and 2.00 (m,
2H), 1.62 (m, 2H, H), 1.75 and 1.84 (m, 2H), 2.39 and
2.61 (m, 2H), 2.69 (m, 1H), 2.73 and 3.16 (m, 2H), 2.77
(3H), 3.21 (m, 2H), 4.54 (m, 1H), 6.6 (br s, 1H). 13C
NMR (125 MHz, CDCl3): l 22.4 (C), 26.2, 27.1, 29.6,
39.2, 39.4, 41.7, 45.9, 51.0, 172.2, 172.7. HRMS calcd
for C13H24N3O2 (M+H)+ 254.1869; found 254.1868.
Acknowledgements
The authors thank Dr. Neng-Yang Shih, Dr. John
Piwinski and Dr. David Andrews for helpful discus-
sions. Additionally, the authors thank Dr. Corey
Strickland and Mr. Cheng Wang for their help in
preparing the manuscript.
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5.5. Synthesis of (3R)-N-methyl-2-oxo-[1,4%-bipiperid-
ine]-3-acetamide 1
A suspension containing 14 (650 g, 1.84 mol) in toluene
(1.4 L) was heated at 55–60°C until all the solids were
dissolved. This warm solution was then added to a
mixture containing trifluoroacetic acid (1.43 L, 18.6
mol) and toluene (1.2 L), preheated to 55–60°C. During
the addition, the temperature was maintained at 55–
60°C, and instant gas evolution was observed. After
complete addition, the reaction mixture was stirred for
another 15 min. HPLC analysis [YMC Pack ODS-A
(250×4.6 mm); 0.025% TFA in water/acetonitrile 65/35;
flow: 1.0 mL/min; detection: 215 nm; tR 14 11.9 min; tR
1, 3.5 min] showed that the reaction was complete
(>99%). After cooling the reaction mixture to about
20°C, the mixture was concentrated under reduced
pressure. The internal temperature was kept below
60°C. The concentrate was diluted with THF (1.2 L),
and added to a suspension of KHCO3 (1.43 kg, 14.3
mol) in THF (1.2 L) while maintaining the internal
temperature at about 25°C (the neutralization was
endothermic). The suspension was filtered, and the
collected inorganic salt was washed with THF (300
mL). A solution assay showed that the THF solution
contained 415 g (1.64 mol, 89%) of (3R)-N-methyl-2-
oxo-[1,4%-bipiperidine]-3-acetamide 1. Chiral HPLC
assay showed this material to be >99% e.e. [CHIRAL-
CEL® OD (250×4.6 mm); 92% hexane, 8% ethanol,
4. Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.;
Cherry, D.; Kato, Y. J. Org. Chem. 1991, 56, 5750.
5. Dugan, M. E. US Patent 5 281 585, 1994.
6. The stereointegrity of 10 was confirmed to be >99.5:0.5
d.r. by removal of the auxiliary via cyclization to the
unsubstituted lactam followed by HPLC analysis of the
enantiomeric d-lactams (CHIRALPAK® AD; hexane/IPA
90:1 with 0.1% diethylamine; tR R isomer: 11.3 min, tR
S
isomer 10.5 min).