Asymmetric synthesis of β-substituted γ-lactams employing the samp-/ramp-hydrazone methodology. Application to the synthesis of (R-(-)-baclofen

Article abstract of DOI:10.3987/COM-05-S(K)41

A short and efficient asymmetric synthesis of β-substituted γ-lactams is described. Key steps are the α-alkylation of aldehyde SAMP-hydrazones with alkyl bromoacetates, their MMPP mediated conversion to the corresponding nitriles and a reductive cyclization with Raney Ni or Ni boride to the title pyrrolidin-2-ones. The β-substituted γ-lactams are obtained in three steps, good overall yields (27-78%) and excellent enantiomeric excesses (ee=93-99%). The applicability of this procedure for the asymmetric synthesis of GABAs (γ-aminobutyric acids) is demonstrated for (R-(-)-baclofen hydrochloride, which is obtained in 4 steps 55% yield and 94% ee.

Full text of DOI:10.3987/COM-05-S(K)41

HETEROCYCLES, Vol. 66, 2005
385
HETEROCYCLES, Vol. 66, 2005, pp. 385 – 403. © The Japan Institute of Heterocyclic Chemistry
Received, 30th August, 2005, Accepted, 20th October, 2005, Published online, 21st October, 2005. COM-05-S(K)41
ASYMMETRIC SYNTHESIS OF β-SUBSTITUTED γ-LACTAMS
EMPLOYING THE SAMP-/RAMP-HYDRAZONE METHODOLOGY.
APPLICATION TO THE SYNTHESIS OF (R)-(−)-BACLOFEN
Dieter Enders* and Oliver Niemeier
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany; Fax: +49(241)8092127, E-mail: enders@rwth-aachen.de
Abstract – A short and efficient asymmetric synthesis of β-substituted γ-lactams
is described. Key steps are the α-alkylation of aldehyde SAMP-hydrazones with
alkyl bromoacetates, their MMPP mediated conversion to the corresponding
nitriles and a reductive cyclization with Raney Ni or Ni boride to the title
pyrrolidin-2-ones. The β-substituted γ-lactams are obtained in three steps, good
overall yields (27-78%) and excellent enantiomeric excesses (ee = 93-99%). The
applicability of this procedure for the asymmetric synthesis of GABAs
(γ-aminobutyric acids) is demonstrated for (R)-(−)-baclofen hydrochloride, which
is obtained in 4 steps, 55% yield and 94% ee.
INTRODUCTION
The lactam group is a characteristic structural feature of many natural products and biologically active
compounds. For example, β-lactams are of enormous importance as antibiotics.1 The extensive use of
classical β-lactam antibiotics in medicine led to an increasing number of resistant strains of bacteria
through mutation and β-lactamase gene transfer. Therefore, the homologeous γ-lactams2 are popular
targets as analogues of β-lactam antibiotics.3 The pyrrolidin-2-one moiety is also often found in bioactive
compounds.4 Among the drugs bearing a γ-lactam ring, for instance (±)-rolipram,5 which has been
originally developed as an antidepressant by the Schering AG, is aselective inhibitor of phosphodiesterase
(PDE) type IV.6 The (R)-enantiomer of rolipram is primarily responsible for the pharmacological effects.7
The amide bond of lactams can be easily hydrolysed to the corresponding acyclic amino acids. GABAs
(γ-aminobutyric acids) are the acyclic forms of γ-lactams and play important roles in various nervous
Dedicated to the memory of Professor Kenji Koga

386
HETEROCYCLES, Vol. 66, 2005
system functions.8 They are used in the regulation of neurological disorders such as Parkinson´s disease
and epilepsy.9 The strongly lipophilic β-substituted GABA derivative baclofen [γ-amino-β-(4-
chlorophenyl)butyric acid] is the only available selective agonist of the GABAB receptor10 and is used as a
muscle relaxant in the treatment of spasticy caused by diseases at the spinal cord (Figure 1).
Cl
Cl
O
MeO
CO2H
O
N
H2N
O
H
N
H
(R)-Rolipram
(R)-Baclofen
Figure 1
Baclofen is commercially available in its racemic form (Lioresal® and Baclon®), but the biological activity
is known to residue in the (R)-enantiomer.11 Some syntheses of (±)-baclofen and its enantiomers have been
reported in the literature12 as well as some stereoselective syntheses of β-alkyl- or β-aryl-substituted
γ-lactams.13 In contrast, protocols for astereoselective entry with abroad substitution pattern are rather rare.
Intrigued by the manifold properties of γ-lactams and their derivatives and our own efforts in the synthesis
of lactams,14 we wish to report ashort and efficient asymmetric synthesis of β-substituted 2-pyrrolidinones
as well as its application to the synthesis of (R)-(−)-baclofen employing the SAMP/RAMP-hydrazone
methodology.15
RESULTS AND DISCUSSION
The synthetic three step strategy leading to the β-substituted γ-lactams is outlined in Scheme 1. Starting
from the aldehyde SAMP-hydrazones (1a-e, g), α-alkylation with methyl or tert-butyl bromoacetate16 and
subsequent oxidative removal of the auxiliary with magnesium monoperoxyphthalate (MMPP) gave the
corresponding nitriles (3a-g).17 Reduction of the nitriles to the corresponding amines and in situ cyclization
afforded the target lactams in moderate to good yields (27-78%) and high enantiomeric excesses
(ee = 93-99%) .
The α-alkylation of the aldehyde-SAMP-hydrazones (1a-e, g) with methyl or tert-butyl 2-bromoacetate
proceeded smoothly either in Et2O or THF. After deprotonation with lithium diisopropylamide the resulting
azaenolates were trapped with the bromoacetate at −100 °C. Aqueous work up and purification by flash
chromatography gave the alkylated hydrazones (2a-g) in acceptable to good yields and excellent
diastereomeric excesses (de ≥ 96%) (Table 1).

HETEROCYCLES, Vol. 66, 2005
387
O
N
NH
3 steps
27-78%
R1 = Me, Et, i-Pr,
t-Bu, Bn, p-Cl-C6H4
R2 = Me, t-Bu
N
OCH3
R1
R1
4a-e, g
H
ee = 93-99%
1a-e, g
H3CO
NH2
1. 1.2 eq. LDA, THF
or Et2O, 0 °C
2. 1.2 eq. BrCH2CO2R2,
−100 °C
O
R1
36-84%
A) Raney Ni/H2 (20 bar),
MeOH, 70 °C
B) R = p-Cl-C6H4:
2 eq. NiCl2 6H2O,
80-97%
(R2 =Me)
11 eq. NaBH4, MeOH,
−25 °C, 0 °C
N
2 eq. MMPP 6 H2O,
N
MeOH/pH7-Puffer (1:1), rt
OCH3
R2O
CN
R1
R2O
H
R1 = Me, Et, i-Pr, t-Bu: 95-99%
R1 = Bn, p-Cl-C6H4: 76-96% (2 steps)
O
O
R1
2a-g
de ≥ 96%
3a-g
ee = 93-98%
Scheme 1
Table 1
2
R1
Me
R2
Me
Me
Me
Me
Me
t-Bu
Me
Yield [%]
36
de [%]a
Config.
S, S
a
b
c
d
e
f
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
Et
49 (73)b,c
83
S, S (R, R)c
S, R
i-Pr
t-Bu
Bn
76 (93)b,c
70
S, R (R, S)c
S, S
Bn
78
S, S
g
p-Cl-C6H4
97b (84)c
S, R (R, S)c
a) Determined by 1H and 13C NMR spectroscopy.
b) Conversion determined by GC.
c) Utilizing the corresponding RAMP-hydrazone.

388
HETEROCYCLES, Vol. 66, 2005
The configuration of the newly formed stereogenic center was assigned as R (2a, b, e, f) or S (2c, d, g)
starting from the corresponding SAMP-hydrazones and opposite utilizing the RAMP-auxiliary,
respectively. Two different electrophiles (methyl and tert-butyl 2-bromoacetates) were employed in the
α-alkylation step of the 3-phenylpropionaldehyde SAMP-hydrazone (1e) to the alkylated hydrazones (2e)
and (2f). They could serve as model substrates in the chemoselective reduction of the nitrile to the amine
functionality and subsequent cyclization to the desired γ-lactam.
Oxidative conversion of the α-substituted aldehyde hydrazones (2a-g) to the corresponding nitriles (3a-g)
was achieved with magnesium monoperoxyphthalate hexahydrate (MMPP) without racemization.17,18
Attempts for a direct reductive transformation of the aldehyde hydrazone (2f) to the corresponding amine
with BH3⋅THF in refluxing THF produced a complex reaction mixture.19 The hydrazones were added to a
rapidly stirred suspension of MMPP in a methanol/pH 7 phosphate buffer at 0 °C and the reaction mixture
was stirred until complete conversion (TLC control). After work up and flash chromatography the nitriles
(3a-g) were obtained with high yields and enantiomeric excesses (Table 2).
Table 2
3
a
b
c
d
e
f
R1
Me
R2
Me
Me
Me
Me
Me
t-Bu
Me
Yield [%]
95
eea [%]
93
Config.
S
S (R)c
R
Et
99 (46)b,c
97
98 (98)c
98
i-Pr
t-Bu
Bn
98 (71)b,c
66b
97 (97)c
96
R (S)c
S
Bn
75b
95
S
g
p-Cl-C6H4
92b (98)b,c
95 (93)c
R (S)c
a) Determined by GC with a chiral stationary phase.
b) Yield over 2 steps starting from the corresponding hydrazone (1).
c) Utilizing the corresponding RAMP-hydrazone.
The nitriles (3e) and (3f) were used in initial experiments to find sufficient reaction conditions for a one
pot reduction / cyclization process to the desired γ-lactams (4a-e, g). Hydrogenation of the tert-butyl ester
(3f) with Raney Ni in methanol at 70 °C led to a mixture of the amine and lactam (4e). Addition of 10%
of aqueous NH4OH-solution (30%) to favor the cyclization under more basic condition resulted in slighty
higher amounts of the cyclized product (Table 3).

HETEROCYCLES, Vol. 66, 2005
389
Table 3
R2
Conditions
Amine : Lactama Yield [%]
t-Bu
t-Bu
Raney Ni (W2), H2 (20 bar), MeOH, 70 °C, 6 h
50 : 50
-
-
Raney Ni (W2), H2 (20 bar), MeOH/NH4OH, 70 °C, 6 h
40 : 60b
1. Raney Ni (W2), H2 (20 bar), MeOH, 70 °C, 16 h
t-Bu
0 : 100
0 : 100
66
89
2. Na2CO3, MeOH, Δ, 24 h
Me
Raney Ni (W2), H2 (20 bar), MeOH, 70 °C, 16 h
a) Conversion determined by GC.
b) Utilizing of a 30% aqueous NH4OH-solution/MeOH (1:10).
To increase the amount of the lactam the obtained reaction mixture was refluxed for 24 h in methanol
basified with sodium carbonate leading to the cyclic product in moderate yield. This two step procedure
could be optimized by employing the methyl ester which directly cyclized after reduction to the amine.
Using the optimized conditions the methyl ester substituted nitriles (3a-e) were converted to the
corresponding γ-lactams (4) in high yields and without racemization (Table 4).
Table 4
4
a
b
c
R1
Me
Et
Yield [%]
80
eea [%]
93
Config.
S
S (R)c
R
95 (46)b,c
97
97 (97)c
97
i-Pr
t-Bu
Bn
d
e
90 (71)b,c
89b
99 (97)c
95
R (S)c
S
a) Determined by HPLC with a chiral stationary phase.
b) Yield over 2 steps starting from the corresponding hydrazone (1).
c) Utilizing the corresponding RAMP-hydrazone.
Unfortunately, the more reactive α-p-Cl-C6H4-substituted nitrile (4g) decomposed under these reaction
conditions. Investigations for amilder reduction with Raney Ni at room temperature resulted in alow yield
of the desired product. Efforts for a reduction using catalytic amounts of PtO2 also afforded a complex
mixture of products. A two step procedure using 10% Pd/C and subsequent cyclization of the amine led to
the corresponding dechlorinated γ-lactam in high yields. Rh on Al2O3 seemed also not to be a suitable

390
HETEROCYCLES, Vol. 66, 2005
catalyst for the reduction, because the desired lactam was obtained as a racemate but with a high yield
(99%). A mild method for the reduction of nitriles to primary amines is the reaction with Co or Ni boride
using NaBH4.20 With Co boride in a THF/H2O-mixture at room temperature the desired product was
formed, but a significant racemization occurred (ee = 58%). Using the same reaction conditions with the
more reactive Ni boride led to decomposition of the nitrile even if methanol as solvent was used as reported
in the literature.21 Perfoming the reaction at −25 °C and addition of the NaBH4 in small portions over a
period of 30 min finally led to the γ-lactam (4f) in good yield (80%) and still high enantiomeric excess
(94%) (Table 5).
Table 5
Conditions
Yield of 4g [%]
complex mixture
50
eea [%]
Raney Ni (W2), H2 (20 bar), MeOH, 70 °C, 15 h
Raney Ni (W2), H2 (20 bar), MeOH, rt, 15 h
PtO2, H2 (3.5 bar), EtOH, HCl, rt, 3 h
-
-
-
complex mixture
1. 10% Pd/C, H2 (3.5 bar), MeOH, rt, 5h
2. 3 N NaOH, MeOH, rt , 1h
97b
-
5% Rh/Al2O3, H2 (1 bar), EtOH, NH3, rt , 22h
CoCl2⋅6H2O, NaBH4, THF/H2O, 0 °C to rt, 24 h
NiCl2⋅6H2O, NaBH4, THF/H2O, rt, 1 h
99
96c
0
58
-
complex mixture
complex mixture
80
-
NiCl2⋅6H2O, NaBH4, MeOH, rt, 1 h
94
NiCl2⋅6H2O, NaBH4, MeOH, −25 to 0 °C, 1 h
a) Determined by HPLC with a chiral stationary phase with the corresponding N-Boc-protected
γ-lactam.
b) Yield of the corresponding dechlorinated γ-lactam.
c) Conversion determined by GC.
The β-substituted γ-lactams serve as precursors for the synthesis of GABA derivatives. To show the
applicability of our method the p-chlorophenyl-substituted γ-lactam (4g) was hydrolysed with 6 N HCl to
the pharmaceuticaly active (R)-baclofen hydrochloride (5) in good yield (75%). By this method
(R)-baclofen was synthesized in only 4 steps with an excellent overall yield of 55% and 94%
enantiomeric excess.

HETEROCYCLES, Vol. 66, 2005
391
O
HO2C
NH
6
N
HCl, Δ, 8 h
NH2 HCl
75%
Cl
Cl
(R)-4g
(R)-5
Scheme 2
CONCLUSION
In conclusion, we have developed an efficient and short asymmetric synthesis of β-aryl- and β-alkyl-
substituted γ-lactams employing the SAMP-/RAMP-hydrazone methodology. The title γ-lactams were
obtained in moderate to good overall yields and excellent enantiomeric excesses. The application of this
procedure as an entry to GABAs could be demonstrated for the asymmetric synthesis of (R)-baclofen
hydrochloride.
EXPERIMENTAL
The enantiopure aldehyde SAMP- or RAMP-hydrazones (1a-e, g) were synthesized by direct condensation
of equimolar amounts of the corresponding commercially available aldehydes and (S or R)-1-amino-
2-methoxymethylpyrrolidine (SAMP or RAMP). The reactions were performed neat at 0 °C and stirred at
room temperature until complete conversion (TLC control). After purification by column chromatography
on silica gel (ether / n-pentane) the aldehyde hydrazones were obtained in virtually quantitative yields as
colorless liquids. 4-Chlorobenzaldehyde was prepared from the corresponding alcohol by Dess-Martin
oxidation.22 Swern or Collins23 oxidation did not give acceptable yields.
(S)-N-(3,3-Dimethylbutylidene)-2-methoxymethylpyrrolidin-1-amine (1d):
[
α
24 = −93.2 (c = 1.06,
]
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ = 0.95 (s, 9H, C(CH3)3), 1.80-2.00 (m, 4H, NCH2CH2, NCHCH2),
2.11 (d, 2H, J = 5.9 Hz, (CH3)3CCH2), 2.75 (dd, 1H, J = 16.6/8.2 Hz, NCHHCH2), 3.34-3.46 (m, 3H,
CH3OCHH, NCHCH2, NCHHCH2), 3.38 (s, 3H, CH3O), 3.54-3.60 (m, 1H, CH3OCHH), 6.72 (t, 1H, J =
6.2 Hz, NCH) ppm; 13C NMR (75 MHz, CDCl3) δ= 22.19, 26.59 (CH2), 29.46 (CH3), 31.05 (CH3C), 46.77
~
(CH2), 50.76 (NCH2), 59.20 (CH3), 63.53 (CH), 74.92 (OCH2), 137.64 (NCH) ppm; IR (film) υ = 2954
(vs), 2876 (vs), 2828 (s), 1602 (w), 1466 (s), 1365 (m), 1342 (m), 1283 (vw), 1242 (vw), 1197 (m), 1120
(vs), 973 (w), 911 (w) cm−1; MS (EI, 70 eV) m/z (%) = 212 (9) [M+•], 168 (10), 167 (100), 70 (14). Anal.
Calcd for C12H24N2O: C, 67.88; H, 11.39; N, 13.19. Found: C, 68.04; H, 11.67; N, 13.28.

392
HETEROCYCLES, Vol. 66, 2005
(S)-N-(2-(4-Chlorophenyl)ethylidene)-2-methoxymethylpyrrolidin-1-amine (1g):
[
α
23 = −98.5 (c =
]
D
1.25, CHCl3); 1H NMR (300 MHz, CDCl3) δ = 1.75-2.01 (m, 4H, NCH2CH2, NCHCH2), 2.76 (dt, 1H, J =
8.4/8.4 Hz, NCHHCH2), 3.30-3.37 (m, 1H, NCHHCH2), 3.40 (s, 3H, CH3O), 3.42-3.49 (m, 2H,
CH3OCHH, NCHCH2), 3.53 (d, 2H, J = 5.7 Hz, NCHCH2), 3.58 (dd, 1H, J = 7.9/2.7 Hz, CH3OCHH),
6.63 (t, 1H, J = 5.7 Hz, NCH), 7.14-7.28 (m, 4H, arom CH) ppm; 13C NMR (75 MHz, CDCl3) δ = 22.19,
26.63, 38.95 (CH2), 50.16 (NCH2), 59.24 (CH3), 63.36 (CH), 74.80 (OCH2), 128.56, 130.14 (arom CH),
~
132.05 (arom CCl), 135.38 (NCH), 137.47 (arom C) ppm; IR (film) υ = 2972 (vs), 2881 (vs), 2826 (vs),
1597 (m), 1490 (vs), 1458 (s), 1408 (w), 1343 (m), 1304 (w), 1284 (w), 1197 (vs), 1118 (vs), 1015 (m),
973 (w), 924 (w), 902 (vw), 871 (vw), 825 (s), 717 (w), 692 (w), 649 (w), 549 (w), 490 (w) cm−1; MS (EI,
70 eV) m/z (%) = 266 (11) [M+•], 223 (31), 222 (15), 221 (100), 125 (22). Anal. Calcd for C14H19N2OCl:
C, 63.03; H, 7.18; N, 10.50. Found: C, 63.22; H, 6.97; N, 10.53.
General procedure 1 (GP1) for α-alkylation of aldehyde SAMP-hydrazones with alkyl bromoacetates
(2a-g):
To a solution of diisopropylamine (1.2 mmol/mmol hydrazone) in Et2O or THF (5 mL/mmol) was added
dropwise n-buthyllithium (2.5 M in hexane) (1.2 mmol/mmol hydrazone) at 0 °C. The solution was stirred
for 15 min and the aldehyde hydrazone (1a-f) was added dropwise. The reaction mixture was stirred for
an additional 1 h and then cooled to −100 °C. Methyl or tert-butyl 2-bromoacetate (1.2 mmol/mmol
hydrazone) in Et2O or THF (1 mL/mmol) was added slowly over a period of 30 min and the reaction
mixture was left over night while allowing to warm to rt. It was quenched with saturated aqueous NH4Cl
solution and extracted three times with Et2O. The organic layer was then washed with H2O and brine and
the aqueous layers were reextracted with Et2O. The combined organic layers were dried over MgSO4 and
evaporated under reduced pressure. The crude product was purified by column chromatography.
(S)-Methyl 4-((S)-2-methoxymethylpyrrolidin-1-ylimino)-3-methylbutanoate (2a): According to GP1
hydrazone (1a) (1.70 g, 10 mmol) and methyl 2-bromoacetate (1.84 g, 12 mmol) were added to a solution
of lithium diisopropylamide (12 mmol) in Et2O (45 mL). Purification by column chromatography (ether /
n-pentane 1:3, 3% triethylamine) afforded 2a (869 mg, 36%) as a colorless liquid. de ≥ 96% (determined
by 1H NMR and 13C NMR spectrum).
[
α
23 = −121.5 (c = 1.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ =
]
D
1.11 (dd, 3H, J = 6.9/1.4 Hz,CH3), 1.74-1.98 (m, 4H, NCHCH2, NCH2CH2), 2.30 (ddd, 1H, J =
15.1/7.2/1.4 Hz, NCHCHCHH), 2.58 (ddd, 1H, J = 15.4/7.1/1.4 Hz, NCHCHCHH), 2.69 (dt, 1H, J =
8.5/8.5 Hz, NCHHCH2), 2.81-2.90 (m, 1H, NCHCH), 3.29-3.37 (m, 1H, NCHHCH2), 3.37 (d, 3H, J = 1.4
Hz, CH3O), 3.40-3.45 (m, 2H, CH3OCHH, NCHCH2), 3.54-3.58 (m, 1H, CH3OCHH), 3.67 (d, 3H, J =
13
1.6 Hz, CH3OCO), 6.55 (d, 1H, J = 4.7 Hz, NCH) ppm; C NMR (100 MHz, CDCl3) δ = 18.75 (CH3),

HETEROCYCLES, Vol. 66, 2005
393
21.98, 26.49 (CH2), 33.65 (CH), 39.31 (CH2), 49.77 (NCH2), 51.28 (CH3OCO), 59.11 (CH3O), 63.31
~
(CH), 74.46 (OCH2), 139.95 (NCH), 172.90 (CO) ppm; IR (film) υ = 2963 (vs), 2879 (vs), 1739 (vs),
1603 (w), 1456 (s), 1364 (w), 1343 (w), 1280 (m), 1196 (s), 1172 (s), 1121 (m), 1047 (vw), 1008 (m),
972 (vw), 900 (w) cm−1; MS (EI, 70 eV) m/z (%) = 242 (13) [M+•], 198 (10), 197 (100), 96 (18), 70 (27),
59 (5). Anal. Calcd for C12H22N2O3: C, 59.48; H, 9.15; N, 11.56. Found: C, 59.50; H, 8.87; N, 11.55.
(S)-Methyl 3-(((S)-2-methoxymethylpyrrolidin-1-ylimino)methyl)pentanoate (2b): According to GP1
hydrazone (1b) (1.84 g, 10 mmol) and methyl 2-bromoacetate (1.84 g, 12.0 mmol) were added to a
solution of lithium diisopropylamide (12 mmol) in Et2O (45 mL). Purification by column chromatography
(ether / n-pentane 1:4, 3% triethylamine) afforded 2b (1.257 g, 49%) as a colorless liquid. de ≥ 96%
(determined by 1H NMR and 13C NMR spectrum).
[
α
23 = −97.3 (c = 1.05, CHCl3); 1H NMR (300 MHz,
]
D
CDCl3) δ = 0.93 (t, 3H, J = 7.4 Hz, CH3CH2), 1.51 (dq, 2H, J = 7.2/7.2 Hz, CH3CH2), 1.73-2.00 (m, 4H,
NCHCH2, NCH2CH2), 2.39 (dd, 1H, J = 15.1/6.1 Hz, NCHCHCHH), 2.54 (dd, 1H, J = 15.1/8.2 Hz,
NCHCHCHH), 2.64-2.75 (m, 2H, NCHHCH2), NCHCH), 3.30-3.40 (m, 2H, NCHCH2, NCHHCH2), 3.38
(d, 3H, J = 0.5 Hz, CH3O), 3.43 (dd, 1H, J = 9.2/7.2 Hz, CH3OCHH), 3.56 (dd, 1H, J = 8.7/3.2 Hz,
CH3OCHH), 3.67 (s, 3H, CH3OCO), 6.56 (d, 1H, J = 5.0 Hz, NCH) ppm; 13C NMR (75 MHz, CDCl3) δ
= 11.26 (CH3), 22.00, 26.35, 26.52, 37.35 (CH2), 40,28 (CH), 49.96 (NCH2), 51.36 (CH3OCO), 59.20
~
(CH3O), 63.42 (CH), 74.60 (OCH2), 129.43 (NCH), 173.33 (CO) ppm; IR (film) υ = 2961 (vs), 2877
(vs), 1739 (vs), 1602 (w), 1458 (s), 1340 (m), 1251 (s), 1194 (s), 1170 (vs), 1122 (vs), 1013 (w), 972 (w),
902 (w) cm−1; MS (EI, 70 eV) m/z (%) = 256 (12) [M+•], 212 (13), 211 (100), 110 (21), 82 (6), 70 (28).
Anal. Calcd for C13H24N2O3: C, 60.91; H, 9.44; N, 10.93. Found: C, 60.53; H, 9.87; N, 11.05.
(S)-Methyl
3-(((R)-2-methoxymethylpyrrolidin-1-ylimino)methyl)-4-methylpentanoate
(2c):
According to GP1 hydrazone (1c) (1.983 g, 10 mmol) and methyl 2-bromoacetate (1.84 g, 12 mmol)
were added to a solution of lithium diisopropylamide (12 mmol) in Et2O (45 mL). Purification by column
chromatography (ether / n-pentane 1:4, 3% triethylamine) afforded 2c (2.248 g, 83%) as a colorless liquid.
24
D
1
13
1
de ≥ 96% (determined by H NMR and C NMR spectrum).
[
α
]
= −83.2 (c = 1.20, CHCl3); H NMR
(400 MHz, CDCl3) δ = 0.91 (d, 3H, J = 6.0 Hz, CH3CHCH3), 0.93 (d, 3H, J = 6.0 Hz, CH3CHCH3),
1.74-1.98 (m, 5H, NCHCH2, NCH2CH2, CH), 2.38 (dd, 1H, J = 15.1/5.0 Hz, NCHCHCHH), 2.56 (dd, 1H,
J = 14.8/9.3 Hz, NCHCHCHH), 2.63-2.73 (m, 2H, NCHHCH2, NCHCH), 3.29-3.36 (m, 2H, NCHCH2,
NCHHCH2), 3.36 (s, 3H, CH3O), 3.40 (dd, 1H, J = 9.1/6.6 Hz, CH3OCHH), 3.55 (dd, 1H, J = 9.1/3.6 Hz,
CH3OCHH), 3.65 (s, 3H, CH3OCO), 6.57 (d, 1H, J = 5.2 Hz, NCH) ppm; 13C NMR (100 MHz, CDCl3) δ
= 19.29, 19.82 (CH3), 21.93, 26.46 (CH2), 30.78 (CH), 34.67 (CH2), 44.61 (CH), 49.92 (NCH2), 51.27
~
(CH3OCO), 59.11 (CH3O), 63.36 (CH), 74.49 (OCH2), 138.18 (NCH), 173.41 (CO) ppm; IR (film) υ =

394
HETEROCYCLES, Vol. 66, 2005
2958 (vs), 2877 (vs), 1740 (vs), 1601 (w), 1461 (s), 1439 (m), 1370 (w), 1340 (m), 1291 (w), 1258 (s),
1194 (s), 1168 (vs), 1119 (s), 998 (w), 973 (w), 892 (w) cm−1; MS (EI, 70 eV) m/z (%) = 270 (9) [M+•],
226 (14), 225 (100), 124 (18), 96 (5), 70 (36), 69 (7). High Resol. MS Calcd for C14H26N2O3: 270.1943.
Found: 270.1943.
(S)-Methyl 3-(((R)-2-methoxymethylpyrrolidin-1-ylimino)methyl)-4,4-dimethylpentanoate (2d):
According to GP1 hydrazone (1d) (2.123 g, 10 mmol) and methyl 2-bromoacetate (1.84 g, 12 mmol)
were added to a solution of lithium diisopropylamide (12 mmol) in Et2O (45 mL). Purification by column
chromatography (ether / n-pentane 1:4) afforded 2d (2.163 g, 76%) as a colorless liquid. de ≥ 96%
(determined by 1H NMR and 13C NMR spectrum).
[
α
24 = −56.1 (c = 1.00, CHCl3); 1H NMR (300 MHz,
]
D
CDCl3) δ = 0.93 (s, 9H, (CH3)3C), 1.75-1.99 (m, 4H, NCHCH2, NCH2CH2), 2.40-262 (m, 3H, NCHCH,
NCHCHCH2), 2.69 (dt, 1H, J = 8.4/8.4 Hz, NCHHCH2), 3.29-3.49 (m, 3H, CH3OCHH, NCHCH2,
NCHHCH2), 3.36 (s, 3H, CH3O), 3.55 (dd, 1H, J = 8.9/3.2 Hz, CH3OCHH), 3.63 (s, 3H, CH3OCO), 6.60
13
(d, 1H, J = 4.5 Hz, NCH) ppm; C NMR (75 MHz, CDCl3) δ = 21.97, 26.49 (CH2), 27.67 (CH3), 33.29
(CH2, (CH3)C), 48.73 (CH), 50.09 (NCH2), 51.37 (CH3OCO), 59.20 (CH3O), 63.53 (CH), 74.65 (OCH2),
~
138.00 (NCH), 173.96 (CO) ppm; IR (film) υ = 2959 (vs), 2875 (vs), 1741 (vs), 1600 (w), 1464 (m),
1438 (m), 1368 (m), 1292 (w), 1252 (w), 1197 (s), 1159 (s), 1120 (s) cm−1; MS (EI, 70 eV) m/z (%) = 284
(11) [M+•], 240 (15), 239 (100), 227 (9), 138 (7), 70 (18). Anal. Calcd for C15H28N2O3: C, 63.35; H, 9.92;
N, 9.85. Found: C, 63.51; H, 10.22; N, 10.17.
(S)-Methyl 4-((S)-2-methoxymethylpyrrolidin-1-ylimino)-3-benzylbutanoate (2e): According to GP1
hydrazone (1e) (493 mg, 2.0 mmol) and methyl 2-bromoacetate (367 mg, 2.4 mmol) were added to a
solution of lithium diisopropylamide (2.4 mmol) in Et2O (9 mL). Purification by column chromatography
(ether / n-pentane 1:4, 3% triethylamine) afforded 2e (443 mg, 70%) as a colorless liquid. de ≥ 96%
(determined by 1H NMR and 13C NMR spectrum).
[
α
24 = −102.5 (c = 1.04, CHCl3); 1H NMR (300 MHz,
]
D
CDCl3) δ = 1.72-1.99 (m, 4H, NCHCH2, NCH2CH2), 2.38 (dd, 1H, J = 15.6/5.7 Hz, NCHCHCHH), 2.56
(dd, 1H, J =15.6/8.2 Hz, NCHCHCHH), 2.59-2.66 (m, 1H, NCHHCH2), 2.71 (dd, 1H, J = 13.6/7.9 Hz,
arom CCHH), 2.87 (dd, 1H, J = 13.6/6.9 Hz, arom CCHH), 3.03-3.15 (m, 1H, NCHCH), 3.22-3.30 (m,
1H, NCHHCH2), 3.30-3.41 (m, 2H, CH3OCHH, NCHCH2), 3.36 (s, 3H, CH3O), 3.46-3.56 (m, 1H,
CH3OCHH), 3.62 (s, 3H, CH3OCO), 6.56 (d, 1H, J = 4.5 Hz, NCH), 7.16-7.32 (m, 5H, arom CH) ppm;
13C NMR (75 MHz, CDCl3) δ = 21.97, 26.56, 36.80, 39.82 (CH2), 40.30 (CH), 49.73 (NCH2), 51.33
(CH3OCO), 59.20 (CH3O), 63.28 (CH), 74.50 (OCH2), 126.17 (p-arom CH), 128.31, 129.33 (arom CH),
~
138.04 (NCH), 139.45 (arom C), 173.17 (CO) ppm; IR (CHCl3) υ = 3061 (w), 3025 (s), 2949 (vs),
1737 (vs), 1602 (m), 1495 (m), 1453 (s), 1339 (s), 1257 (s), 1200 (vs), 1152 (vs), 1120 (vs), 1018 (m),

HETEROCYCLES, Vol. 66, 2005
395
973 (w), 880 (w), 754 (vs), 702 (s), 667 (w), 544 (w) cm−1; MS (EI, 70 eV) m/z (%) = 318 (7) [M+•], 274
(18), 273 (100), 172 (7), 144 (7), 117 (6), 91 (9), 70 (25). Anal. Calcd for C18H26N2O3: C, 67.90; H, 8.23;
N, 8.80. Found: C, 67.70; H, 8.58; N, 9.04.
(S)-tert-Butyl 4-((S)-2-methoxymethylpyrrolidin-1-ylimino)-3-benzylbutanoate (2f): According to
GP1 hydrazone (1e) (2.46 g, 10 mmol) and tert-butyl 2-bromoacetate (2.34 g, 12 mmol) were added to a
solution of lithium diisopropylamide (12 mmol) in Et2O (45 mL). Purification by column chromatography
(ether / n-pentane 1:4, 3% triethylamine) afforded 2f (2.805 g, 78%) as a colorless liquid. de ≥ 96%
(determined by 1H NMR and 13C NMR spectrum).
[
α
23 = −83.3 (c = 1.00, CHCl3); 1H NMR (400 MHz,
]
D
CDCl3) δ = 1.42 (s, 9H, ((CH3)3C), 1.72-1.96 (m, 4H, NCHCH2, NCH2CH2), 2.29 (dd, 1H, J = 15.4/6.0
Hz, NCHCHCHH), 2.43 (dd, 1H, J = 15.4/8.3 Hz, NCHCHCHH), 2.65-2.75 (m, 1H, NCHHCH2), 2.72
(dd, 1H, J = 13.6/7.7 Hz, arom CCHH), 2.84 (dd, 1H, J = 13.7/7.1 Hz, arom CCHH), 2.97-3.05 (m, 1H,
NCHCH), 3.27 (ddd, 1H, J = 9.9/7.4/3.3 Hz, NCHHCH2), 3.32-3.39 (m, 2H, CH3OCHH, NCHCH2), 3.35
(s, 3H, CH3O), 3.50-3.55 (m, 1H, CH3OCHH), 6.54 (d, 1H, J = 5.2 Hz, NCH), 7.16-7.29 (m, 5H, arom
13
CH) ppm; C NMR (100 MHz, CDCl3) δ = 22.01, 26.59 (CH2), 28.12 ((CH3)3C), 38.38, 39.58 (CH2),
40.49 (CH), 49.91 (NCH2), 59.09 (CH3O), 63.21 (CH), 74.55 (OCH2), 79.98 ((CH3)3C), 125.87 (p-arom
~
CH), 128.06, 129.19 (arom CH), 138.44 (NCH), 139.42 (arom C), 171.67 (CO) ppm; IR (film) υ =
3061 (w), 3025 (m), 2974 (vs), 2927 (vs), 1728 (vs), 1602 (w), 1455 (s), 1414 (w), 1367 (vs), 1340 (s),
1255 (s), 1146 (vs), 1032 (w), 958 (m), 905 (w), 845 (w), 749 (m), 702 (s), 544 (vw) cm−1; MS (EI, 70
eV) m/z (%) = 360 (17) [M+•], 316 (23), 315 (100), 287 (12), 260 (10), 259 (62), 190 (6), 123 (6), 62 (91),
70 (24), 57 (9). Anal. Calcd for C21H32N2O3: C, 69.97; H, 8.95; N, 7.77. Found: C, 69.59; H, 9.12; N,
7.86.
(S)-Methyl
3-(4-chlorophenyl)-4-((R)-2-methoxymethylpyrrolidin-1-ylimino)butanoate
(2g):
According to GP1 hydrazone (1f) (450 mg,
1.7 mmol) and methyl 2-bromoacetate (310 mg, 2 mmol)
were added to a solution of lithium diisopropylamide (2 mmol) in THF (7.6 mL). Purification by column
chromatography (ether / n-pentane 1:4) afforded 2g (483 mg, 84%) as a colorless liquid. de ≥ 96%
(determined by 1H NMR and 13C NMR).
[
α
23 = −156.5 (c = 1.10, CHCl3); 1H NMR (300 MHz, CDCl3)
]
D
δ = 1.75-2.00 (m, 4H, NCHCH2, NCH2CH2), 2.59 (dd, 1H, J = 15.8/7.2 Hz, NCHCHCHH), 2.72 (dt, 1H,
J = 8.2/8.2 Hz, NCHHCH2), 3.05 (dd, 1H, J = 15.8/7.9 Hz, NCHCHCHH), 3.24-3.32 (m, 1H,
NCHHCH2), 3.37 (s, 3H, CH3O), 3.40-3.49 (m, 2H, CH3OCHH, NCHCH2), 3.51-3.57 (m, 1H,
CH3OCHH), 3.63 (s, 3H, CH3OCO), 4.04 (dt, 1H, J = 7.4/4.0 Hz, NCHCH), 6.61 (d, 1H, J = 4.0 Hz,
13
NCH), 7.16-7.29 (m, 4H, arom CH) ppm; C NMR (75 MHz, CDCl3) δ = 21.96, 26.58, 38.64 (CH2),
44.21 (CH), 49.52 (NCH2), 51.49 (CH3OCO), 59.22 (CH3O), 63.26 (CH), 74.49 (OCH2), 128.75, 129.39

396
HETEROCYCLES, Vol. 66, 2005
~
(arom CH), 132.59 (arom CCl), 136.00 (NCH), 140.54 (arom C), 172.52 (CO) ppm; IR (film) υ = 2950
(s), 2881 (s), 1739 (vs), 1596 (vw), 1490 (s), 1483 (m), 1412 (w), 1362 (w), 1304 (vw), 1249 (m), 1198
(m), 1164 (m), 1119 (w), 1093 (w), 1016 (m), 971 (w), 912 (vw), 831 (m), 726 (vw), 563 (vw) cm−1; MS
(EI, 70 eV) m/z (%) = 340 (6) [M+•+2], 339 (7) [M+•+1], 338 (16) [M+•], 296 (6), 295 (34), 294 (18), 293
(100), 166 (12), 164 (36), 157 (8), 155 (25), 116 (8), 70 (18), 59 (6), 45 (6). Anal. Calcd for
C17H23N2O3Cl: C, 60.26; H, 6.84; N, 8.27. Found: C, 60.49; H, 6.78; N, 8.27.
General procedure 2 (GP2) for the MMPP-mediated hydrazone nitrile conversion of aldehyde hydrazones
(2a-g):
MMPP⋅6H2O (2.0 mmol/mmol hydrazone) was suspended in a rapidly stirred mixture of MeOH and pH 7
phosphate buffer (1:1, 5 mL/mmol MMPP each) at 0 °C. The corresponding hydrazone was dissolved in
MeOH (4 mL/mmol hydrazone) and added dropwise. The mixture was stirred at 0 °C until the reaction
was complete (TLC control). The suspension was diluted with Et2O and washed with saturated aqueous
NaHCO3 solution. The organic layer was separated and the aqueous phase extracted three times with Et2O.
The combined organic phases were washed with H2O and brine and dried over MgSO4. Evapuration and
purification by column chromatography affords the pure nitrile as a colorless liquid.
(S)-Methyl 3-cyanobutanoate (3a): According to GP2 asolution of hydrazone (2a) (300 mg, 1.24 mmol)
in MeOH (5 mL) was added to a solution of magnesium monoperoxyphthalate hexahydrate (1.225 g, 2.48
mmol) in MeOH (12.5 mL) and pH7-buffer (12.5 mL). Purification by column chromatography (diethyl
ether / n-pentane 1:4) afforded 3a (150 mg, 95%) as a colorless liquid. ee = 93% (determined by GC on a
23
D
1
chiral stationary phase (Lipodex E)).
[
α
]
= +35.3 (c = 1.05, MeOH); H NMR (400 MHz, CDCl3) δ =
1.39 (d, 3H, J = 7.1 Hz, CH3), 2.55 (dd, 1H, J = 16.8/7.1 Hz, CHH), 2.73 (dd, 1H, J = 16.5/7.1 Hz, CHH),
3.10 (ddq, 1H, J = 7.1/7.1/7.1 Hz, CH), 3.75 (s, 3H, CH3O) ppm; 13C NMR (100 MHz, CDCl3) δ = 17.69
~
(CH3), 21.73 (CH), 37.89 (CH2), 52.17 (CH3O), 121.62 (NC), 169.83 (CO) ppm; IR (film) υ = 3640
(vw), 2989 (m), 2955 (m), 2888 (w), 2852 (vw), 2244 (w), 1741 (vs), 1441 (s), 1367 (s), 1280 (s), 1202
(vs), 1125 (vw), 1077 (w), 1004 (s), 944 (vw), 888 (w), 709 (vw), 603 (vw) cm−1; MS (EI, 70 eV) m/z (%)
= 128 (1) [M+•+1], 112 (11), 97 (6), 96 (100), 95 (6), 74 (94), 69 (7), 68 (83), 67 (6), 59 (25), 54 (6), 52
(6). Anal. Calcd for C6 H9NO2: C, 56.68; H, 7.13; N, 11.02. Found: C, 56.55; H, 7.05; N, 10.84.
(S)-Methyl 3-cyanopentanoate (3b): According to GP2 a solution of hydrazone (2b) (550 mg, 2.15
mmol) in MeOH (9 mL) was added to a solution of magnesium monoperoxyphthalate hexahydrate (2.12
g, 4.29 mmol) in MeOH (21 mL) and pH7-buffer (21 mL). Purification by short way flash
chromatography (ether / n-pentane 1:4) afforded 3b (300 mg, 99%) as a colorless liquid. ee = 98%

HETEROCYCLES, Vol. 66, 2005
397
(determined by GC on a chiral stationary phase (Lipodex G)).
[
α
]
24 = +11.8 (c = 1.00, MeOH); 1H NMR
D
(300 MHz, CDCl3) δ = 1.12 (t, 3H, J = 7.4 Hz, CH3), 1.62-1.77 (m, 2H, CH3CH2), 2.62 (dd, 1H, J =
16.8/6.9 Hz, CHH), 2.73 (dd, 1H, J = 16.6/7.7 Hz, CHH), 2.94-3.04 (m, 1H, CH), 3.76 (s, 3H, CH3O)
ppm; 13C NMR (75 MHz, CDCl3) δ = 11.37 (CH3), 25.20 (CH2), 29.16 (CH), 36.21 (CH2), 52.27 (CH3O),
~
120.94 (NC), 170.30 (CO) ppm; IR (film) υ = 3639 (vw), 3552 (vw), 2970 (s), 2881 (m), 2243 (w),
1741 (vs), 1440 (s), 1368 (s), 1253 (s), 1180 (vs), 1100 (vw), 1018 (w), 977 (w), 918 (vw), 706 (vw)
cm−1; MS (EI, 70 eV) m/z (%) = 142 (3) [M+•+1], 126 (5), 113 (13), 110 (65), 101 (18), 82 (54), 81 (10),
80 (7), 74 (100), 68 (27), 59 (17), 55 (38), 54 (68), 53 (9), 52 (5). Anal. Calcd for C7H11NO2: C, 59.56; H,
7.85; N, 9.92. Found: C, 59.50; H, 7.67; N, 10.22.
(R)-Methyl 3-cyano-4-methylpentanoate (3c): According to GP2 a solution of hydrazone (2c) (1.85 g,
6.84 mmol) in MeOH (28 mL) was added to a solution of magnesium monoperoxyphthalate hexahydrate
(6.77 g, 13.7 mmol) in MeOH (68 mL) and pH7-buffer (68 mL). Purification by short way flash
chromatography (ether / n-pentane 1:4) afforded 3c (1.034 g, 97%) as a colorless liquid. ee = 98%
(determined by GC on a chiral stationary phase (Lipodex E)).
[
α
]
23 = +27.7 (c = 1.05, MeOH); 1H NMR
D
(400 MHz, CDCl3) δ = 1.07 (d, 3H, J = 6.9 Hz, CH3CHCH3), 1.10 (d, 3H, J = 6.7 Hz, CH3CHCH3),
1.86-1.97 (m, 1H, CH3CH), 2.57 (dd, 1H, J = 16.8/6.3 Hz, CHH), 2.71 (dd, 1H, J = 16.5/8.5 Hz, CHH),
2.96-3.01 (m, 1H, CH), 3.75 (m, 3H, CH3O) ppm; 13C NMR (100 MHz, CDCl3) δ = 18.24, 20.80 (CH3),
~
29.72 (CH), 34.65 (CH2), 34.71 (CH), 52.20 (CH3O), 119.78 (NC), 170.26 (CO) ppm; IR (film) υ =
2966 (s), 2879 (w), 2241 (w), 1742 (vs), 1465 (m), 1439 (m), 1370 (m), 1255 (s), 1177 (s), 994 (w), 896
(vw), 734(vw) cm−1; MS (EI, 70 eV) m/z (%) = 156 (17) [M+•], 140 (5), 124 (28), 115 (18), 114 (6), 113
(100), 108 (8), 96 (23), 82 (29), 81 (16), 80 (14), 74 (19), 71 (12), 69 (8). Anal. Calcd for C8H14NO2: C,
61.91; H, 8.44; N, 9.03. Found: C, 62.18; H, 8.82; N, 9.05.
(R)-Methyl 3-cyano-4,4-dimethylpentanoate (3d): According to GP2 a solution of hydrazone (2d) (1.90
g, 6.66 mmol) in MeOH (27 mL) was added to a solution of magnesium monoperoxyphthalate
hexahydrate (6.59 g, 13.3 mmol) in MeOH (67 mL) and pH7-buffer (67 mL). Purification by short way
flash chromatography (ether / n-pentane 1:4) afforded 3d (1.109 g, 98%) as a colorless liquid. ee = 97%
23
D
1
(determined by GC on chiral stationary phase (Lipodex E)).
[
α
]
= +59.8 (c = 1.10, MeOH); H NMR
(300 MHz, CDCl3) δ = 1.09 (s, 9H, CH3), 2.61 (dd, 2H, J = 8.2/6.7 Hz, CH2), 2.89 (dd, 1H, J = 8.4/6.7 Hz,
CH), 3.76 (s, 3H, CH3O) ppm; 13C NMR (75 MHz, CDCl3) δ = 27.14 (CH3), 32.82 (CH2), 32.89
~
((CH3)3C), 39.45 (CH), 52.36 (CH3O), 120.45 (NC), 171.02 (CO) ppm; IR (film) υ = 2966 (vs), 2877
(m), 2241 (w), 1743 (vs), 1471 (m), 1439 (s), 1372 (s), 1323 (vw), 1287 (s), 1265 (m), 1207 (vs), 1163 (s),
987 (m), 881 (vw), 694 (vw) cm−1; MS (EI, 70 eV) m/z (%) = 170 (3) [M+•+1], 154 (12), 138 (14), 122

398
HETEROCYCLES, Vol. 66, 2005
(13), 113 (9), 94 (28), 57 (100), 54 (11), 53 (5). Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28.
Found: C, 64.37; H, 8.66; N, 8.56.
(S)-Methyl 3-cyano-4-phenylbutanoate (3e): According to GP2 a solution of crude hydrazone (2e) (3.0
g, 9.42 mmol) in MeOH (40 mL) was added to a solution of magnesium monoperoxyphthalate
hexahydrate (9.40 g, 19 mmol) in MeOH (100 mL) and pH7-buffer (100 mL). Purification by column
chromatography (ether / n-pentane 1:4) afforded 3e (1.109 g, 58% over 2 steps, 76% per step) as a
colorless liquid. ee = 96% (determined by GC on a chiral stationary phase (Lipodex E)).
[
α
24 = −2.2 (c =
]
D
1.25, MeOH); 1H NMR (400 MHz, CDCl3) δ = 2.58 (dd, 1H, J = 16.8/6.6 Hz, arom CCHH), 2.67 (dd, 1H,
J = 17.0/7.7 Hz, aromC CHH), 2.93 (dd, 1H, J = 13.7/6.9 Hz, CHH), 2.97 (dd, 1H, J = 13.7/7.4 Hz,
CHH), 3.23-3.30 (m, 1H, CH), 3.72 (s, 3H, CH3), 7.22-7.37 (m, 5H, arom CH) ppm; 13C NMR (100 MHz,
CDCl3) δ = 29.37 (CH), 35.58 (arom CCH2), 37.51 (CH2), 52.20 (CH3), 120.47 (NC), 127.36 (p-arom
~
CH), 128.67, 128.95 (arom CH), 135.77 (arom C), 169.87 (CO) ppm; IR (film) υ = 3062 (vw), 3029
(w), 2953 (w), 2244 (w), 1739 (vs), 1603 (vw), 1497 (w), 1440 (m), 1368 (m), 1262 (m), 1208 (s), 1080
(vw), 996 (w), 983 (vw), 749 (m), 703 (s), 484 (vw) cm−1; MS (EI, 70 eV) m/z (%) = 203 (27) [M+•], 176
(18), 172 (12), 131 (9), 130 (90), 129 (15), 117 (9), 92 (7), 91 (100), 74 (39), 65 (12). Anal. Calcd for
C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.02; H, 6.42; N, 7.07.
(S)-tert-Butyl 3-cyano-4-phenylbutanoate (3f): According to GP2 a solution of crude hydrazone (2f)
(3.82 g, 10.5 mmol) in MeOH (40 mL) was added to a solution of magnesium monoperoxyphthalate
hexahydrate (9.91 g, 20 mmol) in MeOH (100 mL) and pH7-buffer (100 mL). Purification by column
chromatography (ether / n-pentane 1:8) afforded 3f (1.84 g, 75% over 2 steps, 87% per step) as a colorless
liquid. ee = 95% (determined by GC on a chiral stationary phase (Lipodex E)).
[
α
]
24 = +1.2 (c = 1.05,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ = 1.48 (s, 9H, (CH3)3C), 2.48 (dd, 1H, J = 16.5/6.9 Hz, arom
CCHH), 2.57 (dd, 1H, J = 16.8/7.4 Hz, aromC CHH), 2.94 (d, 2H, J = 7.1 Hz, CH2), 3.20 (pent, 1H, J =
7.1 Hz, CH), 7.23-7.37 (m, 5H, arom CH) ppm; 13C NMR (100 MHz, CDCl3) δ = 27.99 ((CH3)3C), 29.56
(CH), 36.93 (arom CCH2), 37.54 (CH2), 81.99 ((CH3)3C), 120.62 (NC), 127.29 (p-arom CH), 128.64,
~
128.96 (arom CH), 135.96 (arom C), 168.55 (CO) ppm; IR (film) υ = 3063 (vw), 3030 (w), 2979 (s),
2932 (m), 2243 (vw), 1730 (vs), 1603 (vw), 1496 (w), 1455 (m), 1369 (s), 1257 (m), 1152 (vs), 1082
(vw), 1033 (vw), 951 (vw), 847 (w), 771 (m), 702 (m), 617 (vw) cm−1; MS (EI, 70 eV) m/z (%) = 245
(25) [M+•], 189 (14), 173 (8), 172 (68), 163 (9), 162 (92), 145 (10), 144 (6), 130 (15), 129 (13), 117 (15),
91 (39), 65 (8), 59 (5), 57 (100). Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.83;
H, 7.79; N, 5.98.

HETEROCYCLES, Vol. 66, 2005
399
(R)-Methyl 3-(4-chlorophenyl)-3-cyanopropanoate (3g): According to GP2 a solution of crude
hydrazone (2g) (2.06 g, 6.08 mmol) in MeOH (27 mL) was added to a solution of magnesium
monoperoxyphthalate hexahydrate (6.63 g, 13.4 mmol) in MeOH (67 mL) and pH7-buffer (67 mL).
Purification by column chromatography (ether / n-pentane 1:2) afforded 3g (1.246 g, 92% over 2 steps,
96% per step) as a colorless liquid. ee = 95% (determined by GC on a chiral stationary phase
23
D
1
(Chirasil-dex)).
[α
]
= +8.7 (c = 1.11, MeOH); H NMR (300 MHz, CDCl3) δ = 2.83 (dd, 1H, J
=16.6/6.9 Hz, CHH), 3.02 (dd, 1H, J = 16.8/7.9 Hz, CHH), 3.72 (s, 3H, CH3), 4.29 (t, 1H, J = 7.4 Hz,
CH), 7.30-7.39 (m, 4H, arom CH) ppm; 13C NMR (75 MHz, CDCl3) δ = 32.58 (CH), 39.62 (CH2), 52.43
(CH3), 119.48 (NC), 128.79, 129.51 (arom CH), 132.91 (arom CCl), 134.71 (arom C), 169.38 (CO) ppm;
~
IR (film) υ = 3876 (vw), 2992 (vw), 2950 (m), 2248 (w), 1914 (vw), 1736 (vs), 1594 (vw), 1494 (m),
1440 (m), 1411 (m), 1366 (m), 1256 (m), 1204 (vs), 1092 (m), 998 (m), 911 (w), 829 (vs), 711 (w), 671
(vw), 626 (w), 550 (w), 505 (m) cm−1; MS (EI, 70 eV) m/z (%) = 225 (18) [M+•+2], 224 (8) [M+•+1], 223
(58) [M+•], 194 (11), 192 (5), 180 (6), 166 (7), 165 (35), 164 (20), 163 (100), 152 (14), 150 (41), 139 (9).
Anal. Calcd for C11H10NO2Cl: C, 59.07; H, 4.51; N, 6.26. Found: C, 59.23; H, 4.52; N, 6.22.
General procedure 3 (GP3) for the Raney Ni catalysed reduction of nitriles (3a-e) to β-substituted
γ-lactams (4a-e):
Strongly basic W2 Raney Ni catalyst was freshly prepared according to a known literature procedure.24 A
steel autoclave with a glass inlet was charged with Raney Ni (500 mg/mmol nitrile) and MeOH (10 mL/g
Raney Ni). The nitrile was added and the mixture was hydrogenated at 20 bar H2 pressure and 70 °C for
16 h. The reaction mixture was cooled to rt and filtered over celite. Evapuration of the solvent and
purification by column chromatography affords the pure product.
(R)-4-Isopropylpyrrolidin-2-one (4c): According to GP3 nitrile (3c) (230 mg, 1.47 mmol) was added to
a mixture of Raney Ni (740 mg) in MeOH (8 mL) and was hydrogenated. Purification by short way flash
chromatography (ethyl acetate) afforded 4c (182 mg, 97%) as a colorless solid; mp = 91 °C. ee = 97%
23
D
1
(determined by HPLC on chiral stationary phase (Chiralpak AS)).
[
α
]
= +16.9 (c = 1.05, MeOH); H
NMR (300 MHz, CDCl3) δ = 0.91 (d, 3H, J = 6.4 Hz, CH3CHCH3), 0.93 (d, 3H, J = 6.7 Hz, CH3CHCH3),
1.52-1.72 (m, 1H, CH3CHCH3), 2.06 (dd, 1H, J = 16.1/9.4 Hz, NHCHH), 2.13-2.27 (m, 1H, CH), 2.37
(dd, 1H, J = 15.8/8.2 Hz, NHCHH), 3.07 (dd, 1H, J = 9.7/7.9 Hz, COCHH), 3.42-3.49 (m, 1H, COCHH),
6.51 (1H, br s, 1H, NH) ppm; 13C NMR (75 MHz, CDCl3) δ = 20.07, 20.63 (CH3), 32.54 (CH3CH), 35.15
~
(CH2), 42.29 (CH), 46.62 (CH2), 78.69 (CO) ppm; IR (KBr) υ = 3967 (vw), 3655 (vw), 3439 (m), 3206
(s), 3101 (m), 2957 (s), 2871 (s), 1685 (vs), 1490 (w), 1466 (w), 1422 (vw), 1384 (m), 1365 (m), 1313
(m), 1267 (m), 1169 (w), 1080 (vw), 1047 (vw), 1028 (vw), 974 (vw), 886 (vw), 800 (m), 692 (m), 528

400
HETEROCYCLES, Vol. 66, 2005
(m) cm−1; MS (EI, 70 eV) m/z (%) = 128 (11) [M+•+1], 127 (100) [M+•], 112 (5), 110 (16), 97 (20), 85 (7),
84 (33), 83 (5), 71 (6), 70 (42), 69 (22), 68 (6). Anal. Calcd for C7H13NO: C, 66.10; H, 10.30; N, 11.01.
Found: C, 65.68; H, 10.76; N, 10.69.
(R)-4-tert-Butylpyrrolidin-2-one (4d): According to GP3 nitrile (3d) (600 mg, 3.47 mmol) was added to
a mixture of Raney Ni (1.80 g) in MeOH (20 mL) and was hydrogenated. Purification by column
chromatography (ethyl acetate) afforded 4d (487 mg, 90%) as a colorless solid; mp = 112 °C. ee = 99%
(determined by HPLC on a chiral stationary phase (S,S-Whelk O1)).
1H NMR (300 MHz, CDCl3) δ = 0.90 (s, 9H, CH3), 2.16 (dd, 1H, J = 16.8/10.4 Hz, NHCHH), 2.25 (dd,
[
α
23 = −14.1 (c = 1.03, MeOH);
]
D
1H, J = 17.1/8.9 Hz, NHCHH), 2.29-2.41 (m, 1H, CH), 3.17 (dd, 1H, J = 9.7/7.9 Hz, COCHH), 3.34 (dd,
13
1H, J = 9.7/8.2 Hz, COCHH), 6.61 (s, br, 1H , NH) ppm; C NMR (75 MHz, CDCl3) δ = 26.87 (CH3),
~
31.63 ((CH3)3C), 32.12, 43.78 (CH2), 45.38 (CH), 178.60 (CO) ppm; IR (KBr) υ = 3183 (s), 3102 (s),
2957 (s), 2905 (s), 2870 (s), 1697 (vs), 1494 (w), 470 (w), 1366 (m), 1284 (m), 1257 (w), 1194 (vw),
1068 (vw), 802 (m), 695 (w), 533 (w) cm−1; MS (EI, 70 eV) m/z (%) = 142 (23) [M+•+1], 141 (100) [M+•],
126 (22), 111 (14), 85 (75), 84 (85), 70 (10), 69 (43), 57 (68), 56 (6), 55 (19). Anal. Calcd for C8H15NO:
C, 68.04; H, 10.71; N, 9.92. Found: C, 68.15; H, 10.49; N, 9.54.
(S)-4-Benzylpyrrolidin-2-one (4e): According to GP3 nitrile (3e) (1.0 g, 4.92 mmol) was added to a
mixture of Raney-Ni (2.50 g) in MeOH (25 mL) and was hydrogenated. Purification by column
chromatography (ethyl acetate) afforded 4e (768 mg, 89%) as a colorless solid; mp = 98 °C. ee = 95%
24
D
1
(determined by HPLC on a chiral stationary phase (Chiralpak AD)).
[
α
]
= +5.4 (c = 1.00, MeOH); H
NMR (400 MHz, CDCl3) δ = 2.07-2.16 (m, 1H, NHCHH), 2.38-2.45 (m, 1H, NHCHH), 2.70-2.83 (m, 3H,
CH, arom CCH2), 2.98 (dd, 1H, J = 9.6/7.1 Hz, COCHH), 3.09-3.13 (m, 1H, COCHH), 6.58 (br s, 1H,
13
NH), 7.14-7.32 (m, 5H, arom CH) ppm; C NMR (100 MHz, CDCl3) δ = 36.28 (CH), 36.48, 40.35,
47.41 (CH2), 126.28 (p-arom CH), 128.40, 128.52 (arom CH), 139.06 (arom C), 177.94 (CO) ppm; IR
~
(KBr) υ = 3231 (vs), 3119 (m), 3063 (w), 3027 (w), 2996 (vw), 2901 (w), 1657 (vs), 1495 (w), 1451
(m), 1373 (vw), 1304 (w), 1283 (w), 1251 (w), 1065 (w), 789 (m), 757 (w), 738 (m), 701 (m), 624 (w),
550 (vw), 501 (w) cm−1; MS (EI, 70 eV) m/z (%) = 176 (16) [M+•+1], 175 (89) [M+•], 132 (5), 118 (7),
117 (25), 115 (9), 93 (6), 92 (77), 91 (91), 84 (100), 83 (17), 65 (13). Anal. Calcd for C11H13NO: C,
75.40; H, 7.48; N, 7.99. Found: C, 75.26; H, 7.70; N, 7.78.
(R)-4-(4-Chlorophenyl)pyrrolidin-2-one (4g):
A solution of NiCl2⋅6H2O (106 mg, 0.45 mmol) in MeOH (2.25 mL) under argon was cooled to −25 °C.
The nitrile (3g) (50 mg, 0.22 mmol) was added and the green solution was stirred for 15 min at this
temperature. 91 mg (2.4 mmol) of NaBH4 was added in small portions over a period of 30 min and the

HETEROCYCLES, Vol. 66, 2005
401
black reaction mixture was stirred for additional 30 min at −25 °C and for 45 min at 0 °C. After
completion of the reaction (TCL control) the solvent was evaporated and the residue was dissolved in a
mixture of DCM and H2O (1:1). After separation of the phases the aqueous phase was extracted four
times with DCM. The combined organic phases were dried over Na2SO4 and the solvent was evaporated.
Purification by column chromatography (ethyl acetate) afforded 35 mg (80%) of the pure product; mp =
111 °C [lit.,25 112 °C].
26 = −32.7 (c = 1.00, EtOH), lit.,25
ee = 94% (determined by HPLC on a chiral stationary phase (Chiralcel OJ)).
23 = −39 (c = 1.00, EtOH); 1H NMR (400 MHz, CDCl3) δ = 2.45
[
α
]
[ ]
α
D
D
(dd, 1H, J = 17.0/8.8 Hz, NHCHH), 2.73 (dd, 1H, J = 17.0/9.1 Hz, NHCHH), 3.38 (dd, 1H, J = 9.6/7.1 Hz,
COCHH), 3.67 (pent, 1H, J = 8.2 Hz, CH), 3.76-3.81 (m, 1H, COCHH), 6.89 (br s, 1H , NH), 7.17-7.21
13
(m, 2H, arom CH), 7.28-7.33 (m, 2H, arom CH) ppm; C NMR (100 MHz, CDCl3) δ = 37.91 (CH2),
39.60 (CH), 49.39 (CH2), 127.94, 128.79 (arom CH), 132.68 (arom CCl), 140.42 (arom C), 177.37 (CO)
ppm; The spectroscopic data were in accordance with those reported in the literature.25
Synthesis of (R)-4-Amino-3-(4-chlorophenyl)butanoic acid hydrochloride [(R)-baclofen
hydrochloride] (5):
The γ-lactam (4f) (100 mg, 0.51 mmol) was heatet in 6 N HCl (3 mL) at 100 °C for 10 h. The excess of
water in the reaction mixture was removed under reduced pressure to obtain a solid redidue, which was
trituated in isopropanol affording 95 mg (75%) of (R)-(−)-baclofen hydrochloride as a colorless solid; mp
= 194 °C [lit.,26 195 °C].
[
α
]
23 = −1.7 (c = 0.60, H2O), lit.,26
[
α
20 = −2.0 (c = 0.60, H2O); 1H NMR (300 MHz, CDCl3) δ = 0.90 (s,
]
D
D
9H, CH3), 2.16 (dd, 1H, J = 16.8/10.4 Hz, NHCHH), 2.25 (dd, 1H, J = 17.1/8.9 Hz, NHCHH), 2.29-2.41
(m, 1H, CH), 3.17 (dd, 1H, J = 9.7/7.9 Hz, COCHH), 3.34 (dd, 1H, J = 9.7/8.2 Hz, COCHH), 6.61 (br s,
1H , NH) ppm; 13C NMR (75 MHz, CDCl3) δ = 26.87 (CH3), 31.63 ((CH3)3C), 32.12 (CH2), 43.78 (CH2),
45.38 (CH), 178.60 (CO) ppm; The spectroscopic data were in accordance with those reported in the
literature.26
ACKNOWLEDGEMENT
We thank the Fonds der Chemischen Industrie for financial support and the companies Degussa AG,
BASF AG and BAYER AG for the donation of chemicals.
REFERENCES
1. ´The Organic Chemistry of β-Lactams,´ed. by G. I. Georg, VCH, New York, 1993; N. de Kimpe,
´Comprehensive Heterocyclic Chemistry II,´ Vol. 1B, ed. by A. R. Katritzky, C. W. Rees and J.
Scriven, Pergamon, Oxford, 1996, pp. 536-575; G. N. Rolinson, J. Antimicrob. Chemother., 1998,

402
HETEROCYCLES, Vol. 66, 2005
41, 589; S. France, A. Weatherwax, A. E. Taggi and T. Lectka, Acc. Chem. Res., 2004, 37, 592.
2. M. B. Smith, ´Science of Synthesis,´Vol. 21, ed. by S. M. Weinreb, Thieme, Stuttgard, 2005, pp.
647-711.
3. J. Marchard-Brynaert and L. Ghosez, ´Recent Progress in the Chemical Synthesis of Antibiotics,´ ed.
by M. Ohno and G. Lukacs, Springer, Berlin, 1990, pp. 729-794; J. Aszodi, D. A. Rowlands, P.
Mauvais, P. Collette, A. Bonnefoy and M. Lampilas, Bioorg. Med. Chem. Lett., 2004, 14, 2489, and
ref. 4 cited therein.
4. A. L. Vergnon, R. S. Pottorf, M. P. Winters and M. R. Player, J. Comb. Chem., 2004, 6, 903.
5. For a review of syntheses of rolipram see: J. Mulzer, J. Prakt. Chem., 1994, 336, 287.
6. H. Wachtel, J. Pharm. Pharmacol., 1983, 35, 440; H. H. Schneider, R. Schmiechen, M. Brezinski
and J. Seidler, Eur. J. Pharmacol., 1986, 127, 105.
7. P. W. Baures, D. S. Egglestone, K. F. Erhard, L. B. Cieslinski, T. J. Trophy and S. B. Christensen, J.
Med. Chem., 1993, 36, 3274.
8. P. L. McGeer and E. G. McGeer, ´Basic Neurochemisrtry: Molecular, Cellular and Medical
Aspects,´ ed. by G. J. Siegel, B. W. Arganoff, R. W. Albers and P. B. Molinoff, 4th ed., Raven Press,
New York, 1989; A. Mann, T. Boulanger, B. Brandau, F. Durant, G. Evrard, M. Heaulme, E.
Desaulles and C.-G. Wermuth, J. Med. Chem., 1991, 34, 1307; R. Karla, B. Ebert, C. Thorkildsen, C.
Herdeis, T. N. Johansen, B. Nielsen and P. Krogsgaard-Larsen, J. Med. Chem., 1999, 42, 2053.
9. P. Krogsgaard-Larsen, ´Comprehensive Medicinal Chemistry,´Vol. 3, ed. by P. G. Sammes and J. B.
Taylor, Pergamon Press, Oxford, 1990, pp. 493-537.
10. N. G. Bowery, D. R. Hill, A. L. Hudson, A. Doble, D. N. Middlemiss, J. Shaw and M. Turnbull,
Nature, 1980, 283, 92; P. Berthelot, C. Vaccher, N. Floquet, M. Debaert, M. Luyckx and C. Brunet,
J. Med. Chem., 1991, 34, 2557.
11. H.-R. Olpe, H. Demiéville, V. Baltzer, W. L. Bencze, W. P. Koella, P. Wolf and H. L. Haas, Eur. J.
Pharmacol., 1978, 52, 133.
12. M.-Y. Chang, P.-P. Sun, S.-T. Chen and N.-C. Chang, Tetrahedron Lett., 2003, 44, 5271 and ref. 11
cited therein; P. Champs, D. Muñoz and L. Sánchez, Tetrahedron: Asymmetry, 2004, 15, 2039; F.
Felluga, V. Gombac, G. Pitacco and E. Valentin, Tetrahedron: Asymmetry, 2005, 16, 1341.
13. A. I. Meyers and L. Snyder, J. Org. Chem., 1993, 58, 36; N. Langlois, N. Dahuron and H.-S. Wang,
Tetrahedron, 1996, 52, 15117; A. G. H. Wee, B. Liu and D. D. McLeod, J. Org. Chem., 1998, 63,
4218; M. Anada and S.-I. Hashimoto, Tetrahedron Lett., 1998, 39, 79; D. M. Barnes, J. Ji, M. G.
Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw, S. J.
Wittenberger and J. Zhang, J. Am. Chem. Soc., 2002, 124, 13097; Y. Omata, A. Kakehi, M. Shirai
and A. Kamimura, Tetrahedron Lett., 2002, 43, 6911; A. Kamimura, Y. Omata, K. Tanaka and M.

HETEROCYCLES, Vol. 66, 2005
403
Shirai, Tetrahedron, 2003, 59, 6291; J. L. O. Domingos, E. C. Lima, A. G. Dias and P. R. R. Costa,
Tetrahedron: Asymmetry, 2004, 15, 2313; V. Rodríguez, M. Sánchez, L. Quintero and F.
Sartillo-Piscil, Tetrahedron, 2004, 60, 10809.
14. D. Enders, P. Teschner, G. Raabe and J. Runsink, Eur. J. Org. Chem., 2001, 4463; S. Schunk and D.
Enders, Org. Lett., 2000, 2, 907; D. Enders and D. Bartzen, Liebigs. Ann./Recueil, 1997, 1115; D.
Enders, R. Gröbner, G. Raabe and J. Runsink, Synthesis, 1996, 941; D. Enders, S. Brauer-Scheib and
P. Fey, Synthesis, 1985, 393.
15. For a review see: A. Job, C. F. Janeck, W. Bettray, R. Peters and D. Enders, Tetrahedron, 2002, 58,
2253.
16. For the tert-butyl bromoacetate alkylation of SAMP-hydrazones, see: D. Enders, U. Baus, P. Müller,
K. C. Nicolaou and B. Jandeleit, Molecules Online, 1998, 2, 15.
17. D. Enders, D. Backhaus and J. Runsink, Angew. Chem., 1994, 106, 2167; Angew. Chem., Int. Ed.,
1994, 33, 2098; D. Enders, A. Plant, D. Backhaus and U. Reinhold, Tetrahedron, 1995, 51, 10699.
18. R. Fernández, C. Gasch, J.-M. Lassaletta, J.-M. Llera and J. Vázquez, Tetrahedron Lett., 1993, 34,
141; D. Enders and A. Plant, Synlett, 1994, 1054.
19. D. Enders, R. Lochtman, M. Meiers, S. Müller and R. Lazny, Synlett, 1998, 1182.
20. J. O. Osby, S. W. Heinzman and B. Ganem, J. Am. Chem. Soc., 1986, 108, 67; P. A. Reddy, B. C. H.
Hsiang, T. N. Latifi, M. W. Hill, K. E. Woodward, S. M. Rothman, J. A. Ferrendelli and D. F. Covey,
J. Med. Chem., 1996, 39, 1898; J. M. Khurana and G. Kukreja, Synth. Commun., 2002, 32, 1265.
21. V. V. Thakur, M. D. Nikalje and A. Sudalai, Tetrahedron: Asymmetry, 2003, 14, 581.
22. D. A. Evans, J. R. Gage and J. L. Leighton, J. Am. Chem. Soc., 1992, 114, 9434.
23. M. Li and M. E. Johnson, Synth. Commun., 1995, 25, 533.
24. R. Mozingo, ´Org. Synth.,´ Coll. Vol. III, ed. by E. C. Horning, Wiley, New York, 1955, pp.
181-183.
25. A. Schoenfelder, A. Mann and S. Le Coz, Synlett, 1993, 63.
26. P. Resende, W. P. Almeida and F. Coelho, Tetrahedron: Asymmetry, 1999, 10, 2113.