Enantioselective synthesis of gabapentin analogues via organocatalytic asymmetric Michael addition of α-branched aldehydes to β-nitroacrylates

Article abstract of DOI:10.1039/c2ob25413a

Michael addition reaction of α-branched aldehydes to β-nitroacrylates was successfully carried out by using a mixed catalyst consisting of a primary amino acid, l-phenylalanine, and its lithium salt to give β-formyl-β′-nitroesters having a quaternary carbon centre in good yields (up to 85%) with high enantioselectivity (up to 98% ee). By using benzyl β-nitroacrylates as Michael acceptors, the obtained β-formyl-β′-nitroesters were converted into various 4,4-disubstituted pyrrolidine-3-carboxylic acids including analogues of gabapentin (Neurotin) in one step from the Michael adducts in high yields. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob25413a

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PAPER
Enantioselective synthesis of gabapentin analogues via organocatalytic
asymmetric Michael addition of α-branched aldehydes to β-nitroacrylates†‡
Masanori Yoshida,*a,b Erika Masaki,c Hiroto Ikeharab and Shoji Haraa,b
Received 25th February 2012, Accepted 16th May 2012
DOI: 10.1039/c2ob25413a
Michael addition reaction of α-branched aldehydes to β-nitroacrylates was successfully carried out by
using a mixed catalyst consisting of a primary amino acid, L-phenylalanine, and its lithium salt to give
β-formyl-β′-nitroesters having a quaternary carbon centre in good yields (up to 85%) with high
enantioselectivity (up to 98% ee). By using benzyl β-nitroacrylates as Michael acceptors, the obtained
β-formyl-β′-nitroesters were converted into various 4,4-disubstituted pyrrolidine-3-carboxylic acids
including analogues of gabapentin (Neurotin®) in one step from the Michael adducts in high yields.
for the synthesis of various γ-nitroaldehydes having a quaternary
Introduction
carbon centre.6 For obtaining more functionalized organic mole-
Michael addition of aldehydes to nitroalkenes is an effective
method to create a new carbon–carbon bond for obtaining syn-
thetically useful γ-nitroaldehydes. An asymmetric version of this
reaction has been achieved by various catalytic reactions,1 and
most of them are organocatalyses that proceed via formation of
an imine–enamine intermediate from an aldehyde and an amine
catalyst.1a,2 For this type of organocatalysis, secondary amines
are often employed as catalysts, since an enamine, which is a
real Michael donor in the reaction, is generated readily by reac-
tion of a secondary amine with an aldehyde.3 In the case of
using sterically hindered substrates such as α-branched
aldehydes, however, primary amines generally afford better results
than secondary amines as catalysts, since a secondary amine
catalyst needs to form a sterically hindered imine–enamine inter-
mediate to promote the Michael addition reaction.4,5 We recently
reported that a primary amino acid salt was an effective catalyst
for the Michael addition of α-branched aldehydes to nitroalkenes
cules, β-nitroacrylates are attractive substrates for the Michael
addition reaction of aldehydes, since Michael adducts having
three synthetically useful functionalities such as formyl, nitro
and alkoxycarbonyl groups, namely β-formyl-β′-nitroesters, can
be synthesized.7 Although Bonne,7a Hayashi7b and Ma7c indivi-
dually reported that asymmetric Michael addition of aldehydes
to β-nitroacrylates was successfully carried out in the presence of
a secondary amine catalyst, O-TMS diphenylprolinol, there was
only one example employing an α-branched aldehyde.7c To
show the usefulness of the Michael adducts, Ma and co-workers
examined the transformation of a β-formyl-β′-nitroester into a
pyrrolidine-3-carboxylic acid by multistep reactions.7c
On the other hand, Bryans and co-workers reported that a 4,4-
disubstituted pyrrolidine-3-carboxylic acid, 1a-R, has a biologi-
cal activity similar to that of gabapentin (Neurotin®), which is an
anticonvulsant drug (Fig. 1).8a,b Various analogues of gabapentin
have also been synthesized and their biological activities have
been evaluated.8c–f
In this context, we planned to use a primary amino acid salt as
a catalyst for the Michael addition of α-branched aldehydes to
β-nitroacrylates, and we succeeded in synthesizing β-formyl-β′-
nitroesters having a quaternary carbon centre in good yields
with high enantioselectivity. Furthermore, by using benzyl
β-nitroacrylates as Michael acceptors, the obtained β-formyl-β′-
nitroesters were readily converted into 4,4-disubstituted
pyrrolidine-3-carboxylic acids including gabapentin analogues in
aDivision of Chemical Process Engineering, Faculty of Engineering,
Hokkaido University, Kita 13-jo Nishi 8, Kita-ku, Sapporo, Hokkaido
060-8628, Japan. E-mail: myoshida@eng.hokudai.ac.jp;
Fax: +81 11 706 6557; Tel: +81 11 706 6557
bMolecular Chemistry and Engineering Course, Graduate School of
Chemical Sciences and Engineering, Hokkaido University, Kita 13-jo
Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
cDepartment of Applied Science and Engineering, School of
Engineering, Hokkaido University, Kita 13-jo Nishi 8, Kita-ku, Sapporo,
Hokkaido 060-8628, Japan
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡Electronic supplementary information (ESI) available: Synthesis of
cycloheptanecarboxaldehyde 2d and β-nitroacrylates 3, HPLC data of 4,
6 and 7, 1H and 13C NMR spectra of 1, 4–7 and N-nosyl 1b, X-ray struc-
ture report for N-nosyl 1b, nOe analysis of 1c. CCDC 881970. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25413a
Fig. 1 Gabapentin and its analogue.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5289–5297 | 5289

Table 1 Solvent screen for the Michael addition of 2a to 3aa
one step from the Michael adducts. In this paper, we disclose the
details of the Michael addition reaction and the transformation of
the Michael adducts to 4,4-disubstituted pyrrolidine-3-carboxylic
acids.
Results and discussion
Michael addition reaction of aldehydes (2) to β-nitroacrylate (3)
Entry
Solvent
Yieldb (%)
eec (%)
Initially, we examined the Michael addition of isobutyraldehyde
(2a) to benzyl (E)-β-nitroacrylate (3a) to optimise the reaction
conditions. As shown in Table 1, a solvent screen was carried
out in the presence of L-phenylalanine lithium salt (Phe-OLi) as
a catalyst. The results indicated that the Michael addition reac-
tion cleanly proceeded in haloalkanes or in aromatic solvents to
provide a Michael adduct, β-formyl-β′-nitroester 4a, in a good
yield with high enantioselectivity. Compared to these solvents,
relatively high-polarity solvents gave the Michael adduct in
lower yields, since generation of high-polar impurities was also
detected by TLC analysis. Thus, we chose dichloromethane as
the solvent for further investigations by considering the balance
between the yield and enantioselectivity of 4a.
1
2
3
4
5
6
7
8
DMSO
CH3CN
AcOEt
THF
Et2O
11
38
62
40
68
74
78
81
76
78
60
35
84
83
82
81
88
87
86
88
87
80
CHCl3
CH2Cl2
(CH2Cl)2
Toluene
Benzene
Cyclohexane
9
10
11
a The reaction was carried out with 2a (1 mmol), 3a (0.5 mmol) and
Phe-OLi (0.1 mmol) in solvent (1 mL) at 25 °C for 19 h. b Isolated yield
of 4a based on 3a. c Determined by chiral HPLC analysis. The absolute
configuration was determined to be (S), since amino acid 1b was
obtained from 4a as shown in Scheme 1.
We then carried out a catalyst screen for the Michael addition
reaction of 2a to 3a (Table 2). Various primary amino acid
lithium salts gave the Michael adduct 4a in good yields with
high enantioselectivity; however, a secondary amino acid salt,
L-proline lithium salt (Pro-OLi), was ineffective as a catalyst for
the reaction (Table 2, entries 1–7). Since Phe-OLi afforded the
Michael adduct 4a in a good yield with relatively higher enantio-
selectivity, L-phenylalanine (Phe-OH) was chosen as a basic
amino acid for investigation of the effects of the counter cation
of amino acid salt. As was observed in our previous work,
Phe-OH did not show catalytic activity for the Michael addition
reaction (Table 2, entry 8).6b,c Although an alkali metal salt of
Phe-OH other than lithium salt gave the Michael adduct 4a with
over 90% ee, the chemical yield was lower than that of the reac-
tion using Phe-OLi due to the low catalytic activity (Table 2,
entries 9–12). Fortunately, we found that the addition of a cataly-
tic amount of benzoic acid to the Michael addition reaction
using Phe-OLi was effective for improvement of the enantio-
selectivity and enhancement of the reaction rate (Table 2,
entry 13). Since Phe-OLi is a base, we assumed that the addition
of an acid to Phe-OLi immediately generated the corresponding
amino acid, Phe-OH, in situ by an acid–base equilibrium reac-
tion and that both Phe-OLi and Phe-OH were necessary to
achieve a high yield and high enantioselectivity.9 Indeed, the
Michael addition reaction using a mixed catalyst consisting of
Phe-OLi and -OH gave better results than did the reaction using
Phe-OLi or Phe-OH as a sole catalyst (Table 2, entries 14–16).
After detailed screening of a mixed catalyst consisting of
Phe-OH and its alkali metal salt, a 1 : 4 mixture of Phe-OLi
and Phe-OH was chosen as the catalyst for the Michael addition
reaction (Table 2, entry 16).
Table 2 Catalyst screen for the Michael addition of 2a to 3aa
Entry
Catalystb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
Phe-OLi
Met-OLi
Leu-OLi
Ile-OLi
Tle-OLi
Trp-OLi
Pro-OLi
78e
80e
68e
74e
68e
71e
9e
87
75
77
83
78
80
—
—
92
94
94
95
92
90
92
92
92
92
92
95
95
94
8
9
Phe-OH
Phe-ONa
Trace
50
10
11
12
13
14
15
16
17
18
19
20
21
22
Phe-OK
Phe-ORb
Phe-OCs
Phe-OLi
Phe-OLi/-OH (1 : 1)
Phe-OLi/-OH (1 : 2)
Phe-OLi/-OH (1 : 4)
Phe-ONa/-OH (1 : 1)
Phe-ONa/-OH (1 : 2)
Phe-ONa/-OH (1 : 4)
Phe-OK/-OH (1 : 4)
Phe-ORb/-OH (1 : 4)
Phe-OCs/-OH (1 : 4)
24
19
24
60f
75
75
80
66
65
60
47
32
18
a Unless otherwise mentioned, the reaction was carried out with 2a
(1 mmol), 3a (0.5 mmol) and catalyst (0.1 mmol) in dichloromethane
(1 mL) at 25 °C for 24 h. b Phe: L-phenylalanine; Met: L-methionine;
Leu: L-leucine; Ile: L-isoleucine; Tle: L-t-leucine; Trp: L-tryptophane;
Pro: L-proline. c Isolated yield of 4a based on 3a. d Determined by chiral
HPLC analysis. e The reaction was carried out for 19 h. f The reaction
was carried out for 5 h using benzoic acid (0.1 mmol) as an additive.
Under the reaction conditions, we investigated the substrate
scope with various aldehydes (2) and β-nitroacrylates (3)
(Table 3). Study of the steric effect of the alkoxycarbonyl group
of 3 indicated that the yield and enantioselectivity of the Michael
adduct 4 did not greatly depend on the bulkiness of the alkoxy-
carbonyl group (Table 3, entries 1–4). On the other hand, the
Michael addition of sterically hindered aldehydes such as cyclo-
hexane- (2c) and cycloheptanecarboxaldehyde (2d) was slower
than that of less hindered substrates, and increased catalyst
5290 | Org. Biomol. Chem., 2012, 10, 5289–5297
This journal is © The Royal Society of Chemistry 2012

Table 3 Substrate scope in the Michael addition reaction of 2 to 3a
Entry
2
3
4
t/h
Yieldb(%)
eec(%)
drd
1
2
2a
2a
3a
4a
24
24
80
71
92 (S)
—
—
93 (S)e
3
4
5
2a
2a
24
24
9
76
74
68
92 (S)e
89 (S)e
88
—
—
—
3a
3a
6
7
72f
72f
72
70
87 (S)g
—
—
3a
95
8
3a
3a
3b
48
48
38
75h
85
95
4 : 1
9
97 (2S,3R)i
98 (2S,3R)k
>20 : 1j
>20 : 1j
10
2f
84
11
12
2c
96f
72f
84
92
>20 : 1j
2c
No reaction
—
—
a Unless otherwise mentioned, the reaction was carried out with 2 (1 mmol), 3 (0.5 mmol) and a mixed catalyst, Phe-OLi/-OH (1 : 4, 0.1 mmol), in
dichloromethane (1 mL) at 25 °C. b Isolated yield of 4 based on 3. c Determined by chiral HPLC analysis. The absolute configuration of the major
1
enantiomer of 4 is shown in parentheses. d Determined by H NMR analysis of the crude product. e The absolute configuration was determined to be
(S), since the NMR spectra and specific rotation of carboxylic acids obtained by deprotection of the alkoxycarbonyl group of 4a–d are in good
agreement. f The reaction was carried out with 30 mol% of the catalyst (0.15 mmol). g The absolute configuration was determined to be (S), since
i
amino acid 1a-S was obtained from 4f as shown in Table 4. h Yield of a mixture of diastereomers. The absolute configuration was determined to be
(2S,3R), since the NMR spectra and specific rotation of carboxylic acids obtained by deprotection of the alkoxycarbonyl group of 4i and 4j are in
good agreement. j syn/anti. k The absolute configuration was determined by comparison of the specific rotation with that of the literature.7c
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5289–5297 | 5291

loading was required to complete the Michael addition reaction
within a reasonable reaction time (Table 3, entries 6 and 7).
Asymmetric α-branched aldehydes such as 2-methylvaler-
aldehyde (2e) and 2-phenylpropionaldehyde (2f) were also
subjected to the Michael addition reaction, and the correspond-
ing Michael adducts 4h–j were synthesized in good yields
with high enantioselectivity (Table 3, entries 8–10). Since
the absolute configuration of a major enantiomer of 4j was deter-
mined to be (2S,3R) by comparison of the specific rotation with
that of the previous report,7c it was found that the Michael
addition reaction proceeded syn selectively. Study of the substitu-
ent effect of β-nitroacrylates using benzyl (E)-3-nitropent-2-
enoate (3e) and methyl (E)-2-methyl-3-nitroprop-2-enoate (3f)
indicated that a substituent on the β-position did not disturb the
Michael addition reaction to give the corresponding Michael
adduct 4k,10 while a substituent on the α-position inhibited the
attack of a nucleophile upon the nitroacrylate (Table 3, entries 11
and 12).
Fig. 2 ORTEP of N-nosyl 1b.
The reaction mechanism would be similar to that of the
Michael addition reaction of aldehydes to nitroalkenes catalyzed
by a primary amino acid salt,6b,c and the addition of an acid
would accelerate the formation of an imine–enamine intermedi-
ate from an aldehyde and the catalyst.9 Seebach and Hayashi
recently proposed an interesting reaction mechanism of O-TMS
diphenylprolinol-catalyzed Michael addition of aldehydes to
nitroalkenes involving a cyclobutane intermediate consisting of
an enamine and a nitroalkene; however, no generation of such a
species was observed in our case by monitoring the reaction of
2a to 3a with NMR.11
obtained in 92% yield (Scheme 1). Probably, removal of the
benzyl group, reduction of the nitro group to an amino group,
and intramolecular imine formation and its reduction would suc-
cessively occur to complete the transformation. Stereochemistry
of 1b was determined to be (S) by carrying out X-ray analysis of
N-nosyl 1b (Fig. 2). A linear β-amino acid 5 was also syn-
thesized by hydrogenolysis after protecting the formyl group of
4a. By measuring the enantiomeric excess of protected amino
acids 6 and 7 obtained from 1b and 5, respectively, it was
confirmed that no racemization occurred during the syntheses of
1b and 5 from 4a. Encouraged by these results, we then carried
out the hydrogenolysis of Michael adducts 4 to synthesize
various 4,4-disubstituted pyrrolidine-3-carboxylic acids 1. The
spiro-type gabapentin analogue 1a was synthesized in a high
yield by hydrogenolysis of 4f and subsequent treatment with aq.
HCl (Table 4, entry 1). The absolute configuration of the major
enantiomer was determined to be (S) by comparison of
the specific rotation with that of the literature.8a The opposite
enantiomer 1a-R could be obtained as a major enantiomer from
Michael adduct 4f-R, which was synthesized by using D-phenyl-
alanine and its lithium salt as a mixed catalyst (Table 4, entry 2).
A spiro-type gabapentin analogue 1c having a substituent on the
pyrrolidine ring was also synthesized from 4k in a high yield
(Table 4, entry 3). Similarly, spiro amino acids having a five- or
seven-membered ring, 1d and 1e, and other 4,4-disubstituted
pyrrolidine-3-carboxylic acids such as 1f and 1g were
synthesized in high yields by the present method (Table 4,
entries 4–7).
Synthesis of gabapentin analogues
We then attempted a transformation of β-formyl-β′-nitroesters 4
into amino acids. By subjecting 4a to a common condition of
hydrogenolysis using H2–Pd/C, a cyclic amino acid, 4,4-
dimethylpyrrolidine-3-carboxylic acid (1b), was successfully
Conclusions
We found that a mixture of L-phenylalanine and its lithium salt
was an effective catalyst for the Michael addition of α-branched
aldehydes to β-nitroacrylates to give β-formyl-β′-nitroesters
having a quaternary carbon centre in good yields with high
enantioselectivity. Michael adducts obtained from benzyl
β-nitroacrylates were readily converted into 4,4-disubstituted
pyrrolidine-3-carboxylic acids including gabapentin analogues in
Scheme 1 Transformation of 4a to a cyclic γ-amino acid 1b and a
linear β-amino acid 5.
5292 | Org. Biomol. Chem., 2012, 10, 5289–5297
This journal is © The Royal Society of Chemistry 2012

Table 4 Transformation of 4 to 1a
General procedure for the Michael addition of aldehydes (2) to
β-nitroacrylates (3)
In a 7 mL vial, benzyl β-nitroacrylate (3a) (103.5 mg, 0.5 mmol)
and isobutyraldehyde (2a) (72 mg, 1 mmol) were successively
added to a slurry of a mixed catalyst Phe-OLi/-OH (1 : 4,
16.6 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 25 °C. After stirring
for 24 h at 25 °C, the reaction mixture was filtered through a
small plug of silica gel, eluted with Et2O (2 mL × 3) and con-
centrated under reduced pressure. Benzyl (S)-3,3-dimethyl-2-
nitromethyl-4-oxobutyrate (4a) was isolated by column
chromatography (silica gel, hexane–Et2O) in 80% yield as clear
oil. The enantioselectivity was determined by chiral HPLC
analysis (92% ee). [α]1D9.2 −13.7 (c = 1.0, CHCl3, 92% ee).
HPLC [Daicel CHIRALPAK AD-H, hexane–isopropanol (93 : 7,
v/v), 0.8 mL min−1, 215 nm; tr(major enantiomer) = 17.2 min,
tr(minor enantiomer) = 15.7 min]. δH(CDCl3) 1.08 (3H, s), 1.13
(3H, s), 3.60 (1H, dd, J 3.3, 10.8 Hz), 4.46 (1H, dd, J 3.3,
14.9 Hz), 4.80 (1H, dd, J 10.8, 14.9 Hz), 5.15–5.22 (2H, m),
7.32–7.41 (5H, m), 9.43 (1H, s); δC(CDCl3) 19.2, 20.2, 46.7,
47.1, 67.8, 72.5, 128.5, 128.7, 128.8, 134.9, 170.5, 201.7;
γ(neat)/cm−1 1732 [C(vO)H, C(vO)OBn], 1557 (NO2);
[HR ESI-MS: Calc. for C14H17NO5 + Na (M + Na): 302.0999.
Found: M+ + Na, 302.1000].
Entry
1
4
1
Yieldb (%)
97
4f
2
3
4f-R
4k
1a-Rc
97
93
4
5
4e
4g
94
94
Methyl (S)-3,3-dimethyl-2-nitromethyl-4-oxobutyrate (4b)
Oil. [α]2D1.9 −21.5 (c = 1.0, CHCl3, 93% ee). HPLC [Daicel
CHIRALPAK AD-H, hexane–isopropanol (93 : 7, v/v),
0.8 mL min−1, 215 nm; tr(major enantiomer) = 18.0 min,
tr(minor enantiomer) = 14.9 min]. δH(CDCl3) 1.14 (3H, s), 1.17
(3H, s), 3.57 (1H, dd, J 3.3, 10.5 Hz), 3.77 (3H, s), 4.47 (1H,
dd, J 3.3, 14.3 Hz), 4.80 (1H, dd, J 10.5, 14.3 Hz), 9.47 (1H, s);
δC(CDCl3) 19.1, 20.0, 46.4, 46.9, 52.5, 72.3, 170.9, 201.5;
γ(neat)/cm−1 1732 [C(vO)H, C(vO)OMe], 1558 (NO2);
[HR ESI-MS: Calc. for C8H13NO5 + Na (M + Na): 226.0686.
Found: M+ + Na, 226.0689].
6
7
4h
4i
99
90
a The reaction was carried out with 4 (0.5 mmol), Pd/C and H2 (rubber
balloon) in methanol (1 mL) at rt for 48 h. b Isolated yield of 1 based on
4. c After reduction of 4f or 4f-R, the obtained amino acid was treated
with aq. HCl.
Ethyl (S)-3,3-dimethyl-2-nitromethyl-4-oxobutyrate (4c)
Oil. [α]2D2.3 −17.5 (c = 1.0, CHCl3, 92% ee). HPLC [Daicel
CHIRALPAK AD-H, hexane–isopropanol (98 : 2, v/v), 0.8 mL
min−1, 215 nm; tr(major enantiomer) = 23.1 min, tr(minor
enantiomer) = 21.8 min]. δH(CDCl3) 1.14 (3H, s), 1.16 (3H, s),
1.28 (3H, t, J 7.4 Hz), 3.55 (1H, dd, J 3.3, 10.6 Hz), 4.22 (2H,
q, J 7.4 Hz), 4.46 (1H, dd, J 3.3, 14.9 Hz), 4.80 (1H, dd, J 10.6,
14.9 Hz), 9.48 (1H, s); δC(CDCl3) 13.9, 19.1, 19.8, 46.4, 47.0,
61.8, 72.3, 170.2, 201.5; γ(neat)/cm−1 1732 [C(vO)H,C(vO)-
OEt], 1559 (NO2); [HR ESI-MS: Calc. for C9H15NO5 + Na
(M + Na): 240.0842. Found: M+ + Na, 240.0846].
almost quantitative yield by a common hydrogenolysis using
H2–Pd/C in high yields.
Experimental
General
Aldehydes 2a–c,e,f were purchased and used after distillation.
Synthesis of cycloheptanecarboxaldehyde 2d and β-nitro-
acrylates 3 are described in the ESI.‡ Amino acid salts12 and
a mixture of an amino acid and its alkali metal salts9 were
prepared according to the literature.
tert-Butyl (S)-3,3-dimethyl-2-nitromethyl-4-oxobutyrate (4d)
Oil. [α]2D2.3 −17.0 (c = 1.0, CHCl3, 89% ee). HPLC [Daicel
CHIRALPAK AD-H, hexane–isopropanol (99 : 1, v/v),
0.7 mL min−1, 208 nm; tr(major enantiomer) = 21.8 min,
tr(minor enantiomer) = 23.0 min]. δH(CDCl3) 1.13 (3H, s), 1.14
(3H, s), 1.45 (9H, s), 3.47 (1H, dd, J 3.5, 10.8 Hz), 4.41
1H NMR (400 MHz) 13C NMR (100 MHz) spectra were
recorded on a FT NMR. Chemical shifts, δ are referred to TMS
(CDCl3 and CD3OD) or 3-(trimethylsilyl)propionic-2,2,3,3-d4
acid sodium salt (D2O).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5289–5297 | 5293

(1H, dd, J 3.5, 14.5 Hz), 4.76 (1H, dd, J 10.8, 14.5 Hz), 9.50
(1H, s); δC(CDCl3) 19.2, 19.5, 27.7, 46.4, 47.8, 72.2, 83.2,
169.1, 201.5; γ(neat)/cm−1 1732 [C(vO)H, C(vO)Ot-Bu],
1559 (NO2); [HR ESI-MS: Calc. for C11H19NO5 + Na
(M + Na): 268.1155. Found: M+ + Na, 268.1159].
0.8 mL min−1, 215 nm; tr(major enantiomer) = 22.9 min,
tr(minor enantiomer) = 24.8 min]. δH(CDCl3) 0.77 (3H, t,
J 7.0 Hz), 1.11 (3H, s), 1.35–1.48 (4H, m), 3.61 (1H, dd, J 3.1,
11.4 Hz), 4.45 (1H, dd, J 3.1, 14.3 Hz), 4.78 (1H, dd, J 11.4,
14.3 Hz), 5.14–5.27 (2H, m), 7.34–7.39 (5H, m), 9.34 (1H, s);
δC(CDCl3) 14.1, 16.5, 16.9, 37.3, 45.1, 49.9, 67.5, 72.9, 128.5,
128.6, 134.8, 170.5, 202.2; γ(neat)/cm−1 1731 [C(vO)H,
C(vO)OBn], 1557 (NO2); [HR ESI-MS: Calc. for C16H21NO5
+ Na (M + Na): 330.1312. Found: M+ + Na, 330.1316].
Benzyl 2-(1-formylcyclopentyl)-3-nitropropionate (4e)
Oil. [α]2D1.8 −12.0 (c = 1.0, CHCl3, 88% ee). HPLC [Daicel
CHIRALCEL AS-H, hexane–isopropanol (97 : 3, v/v),
0.7 mL min−1, 215 nm; tr(major enantiomer) = 54.3 min,
Benzyl (2S,3R)-3-methyl-3-phenyl-2-nitromethyl-4-oxobutyrate (4i)
tr(minor enantiomer)
= 58.5 min]. δH(CDCl3) 1.49–1.74
Oil. [α]2D1.5 −128.7 (c = 1.0, CHCl3, 97% ee). HPLC
[Daicel CHIRALPAK AD-H, hexane–isopropanol (90 : 10, v/v),
0.6 mL min−1, 215 nm; tr(major enantiomer) = 21.3 min,
tr(minor enantiomer) = 19.8 min]. δH(CDCl3) 1.63 (3H, s), 3.98
(1H, dd, J 2.7, 11.2 Hz), 4.56–4.65 (2H, m), 4.80–4.90 (2H, m),
6.93–7.38 (10H, m), 9.31 (1H, s); δC(CDCl3) 14.4, 47.6, 54.0,
67.1, 73.1, 127.2, 128.1, 128.2, 128.48, 128.52, 129.1, 134.4,
135.2, 170.7, 197.8; γ(neat)/cm−1 1720 [C(vO)H, C(vO)-
OBn], 1559 (NO2); [HR ESI-MS: Calc. for C19H19NO5 + Na
(M + Na): 364.1155. Found: M+ + Na, 364.1159].
(5H, m), 1.79–1.86 (1H, m), 1.94–2.00 (2H, m), 3.58 (1H, dd,
J 3.1, 10.7 Hz), 4.44 (1H, dd, J 3.1, 14.8 Hz), 4.83 (1H, dd,
J 10.7, 14.8 Hz), 5.15–5.21 (2H, m), 7.33–7.41 (5H, m), 9.40
(1H, s); δC(CDCl3) 25.2, 25.6, 30.9, 31.7, 43.4, 47.1, 57.3, 67.8,
73.4, 128.6, 128.7, 134.8, 170.6, 201.1; γ(neat)/cm−1 1731
[C(vO)H, C(vO)OBn], 1557 (NO2); [HR ESI-MS: Calc. for
C16H19NO5 + Na (M + Na): 328.1155. Found: M+ + Na,
328.1153].
Benzyl (S)-2-(1-formylcyclohexyl)-3-nitropropionate (4f)
Oil. [α]2D1.2 −15.0 (c
= 1.0, CHCl3, 87% ee). HPLC
Methyl (2S,3R)-3-methyl-3-phenyl-2-nitromethyl-4-oxobutyrate (4j)
[Daicel CHIRALCEL AS-H, hexane–isopropanol–ethanol
(98.5 : 1.0 : 0.5 v/v/v), 0.8 mL min−1, 229 nm; tr(major enantio-
mer) = 45.5 min, tr(minor enantiomer) = 48.1 min]. δH(CDCl3)
1.14–1.36 (4H, m), 1.48–1.70 (4H, m), 1.89–1.92 (1H, m),
1.99–2.01 (1H, m), 3.33 (1H, dd, J 2.9, 11.4 Hz), 4.47 (1H, dd,
J 2.9, 14.5 Hz), 4.76 (1H, dd, J 11.4, 14.5 Hz), 5.16–5.23
(2H, m), 7.34–7.41 (5H, m), 9.53 (1H, s); δC(CDCl3) 22.1, 22.2,
24.8, 29.2, 29.9, 48.8, 49.6, 67.6, 72.4, 128.51, 128.54, 128.6,
134.6, 170.0, 204.0; γ(neat)/cm−1 1735 [C(vO)H, C(vO)
OBn], 1560 (NO2); [HR ESI-MS: Calc. for C17H21NO5 + Na
(M + Na): 342.1312. Found: M+ + Na, 342.1314].
Oil. [α]1D9.8 −158.0 (c = 1.0, CHCl3, 98% ee). HPLC [Daicel
CHIRALPAK AD-H, hexane–isopropanol (93 : 7, v/v), 0.8 mL
min−1, 215 nm; tr(major enantiomer) = 16.4 min, tr(minor enan-
tiomer) = 14.5 min]. δH(CDCl3) 1.64 (3H, s), 3.29 (3H, s), 3.92
(1H, dd, J 2.5, 11.2 Hz), 4.60 (1H, dd, J 2.5, 14.3 Hz), 4.81
(1H, dd, J 11.2, 14.3 Hz), 7.17–7.44 (5H, m), 9.36 (1H, s);
δC(CDCl3) 14.6, 47.7, 52.0, 54.1, 73.1, 127.1, 128.5, 129.1,
135.5, 171.3, 198.0; γ(neat)/cm−1 1731 [C(vO)H, C(vO)-
OMe], 1559 (NO2).
Spectroscopic data are in agreement with the published data.7c
Benzyl (R)-2-(1-formylcyclohexyl)-3-nitropropionate (4f-R)
[α]2D1.5 +16.0 (c = 1.0, CHCl3, 87% ee).
Benzyl 2-(1-formylcyclohexyl)-3-nitropentanoate (4k)
Oil. [α]2D0.3 −4.0 (c
= 1.0, CHCl3, 92% ee). HPLC
[Daicel CHIRALCEL AS-H, hexane–isopropanol (95 : 5 v/v),
1.0 mL min−1, 229 nm; tr(major enantiomer) = 10.7 min,
tr(minor enantiomer) = 15.9 min]. δH(CDCl3) 0.83 (3H, t, J 7.6
Hz), 1.06–1.16 (3H, m), 1.28–1.37 (1H, m), 1.47–1.68 (5H, m),
1.71–1.83 (1H, m), 1.97–2.00 (2H, m), 3.33 (1H, d, J 8.4 Hz),
4.70–4.76 (1H, m), 5.13–5.19 (2H, m), 7.33–7.40 (5H, m), 9.56
(1H, s); δC(CDCl3) 6.4, 10.1, 22.3, 24.9, 25.8, 29.1, 30.2, 49.8,
56.0, 67.5, 86.5, 128.7, 128.8, 134.5, 169.5, 204.4; γ(neat)/cm−1
1731 [C(vO)H, C(vO)OBn], 1555 (NO2); [HR ESI-MS: Calc.
for C19H25NO5 + Na (M + Na): 370.1625. Found: M+ + Na,
370.1628].
Benzyl 2-(1-formylcycloheptyl)-3-nitropropionate (4g)
Oil. [α]2D0.5 −26.5 (c
= 1.0, CHCl3, 95% ee). HPLC
[Daicel CHIRALPAK AD-H, hexane–isopropanol–ethanol
(97.5 : 2.0 : 0.5 v/v/v), 1.0 mL min−1, 229 nm; tr(major enantio-
mer) = 31.5 min, tr(minor enantiomer) = 33.6 min]. δH(CDCl3)
1.33–1.74 (10H, m), 1.83–1.95 (2H, m), 3.47 (1H, dd, J 2.9,
11.0 Hz), 4.42 (1H, dd, J 2.9, 14.8 Hz), 4.80 (1H, dd, J 11.0,
14.8 Hz), 5.12–5.23 (2H, m), 7.33–7.41 (5H, m), 9.47 (1H, s);
δC(CDCl3) 23.1, 23.3, 30.3, 30.4, 30.5, 31.2, 48.5, 52.9, 67.9,
72.8, 128.66, 128.68, 134.7, 170.6, 202.1; γ(neat)/cm−1 1732
[C(vO)H, C(vO)OBn], 1559 (NO2); [HR ESI-MS: Calc. for
C18H23NO5 + Na (M + Na): 356.1468. Found: M+ + Na,
356.1470].
General procedure for hydrogenolysis of 4: synthesis of (S)-4,4-
dimethylpyrrolidine-3-carboxylic acid (1b)7c
In a round bottom flask, 10% Pd/C (200 mg) was placed, and
the flask was flushed with N2. Then a methanol solution
(10 mL) of benzyl (S)-3,3-dimethyl-2-nitromethyl-4-oxobutyrate
(4a) (139.5 mg, 0.5 mmol) was poured into the flask. A balloon
Benzyl 3-formyl-3-methyl-2-nitromethylhexanoate (4h)
Oil. [α]2D1.5 −11.0 (c = 1.0, CHCl3, dr = 4 : 1, 95% ee). HPLC
[Daicel CHIRALCEL AS-H, hexane–isopropanol (97 : 3, v/v),
5294 | Org. Biomol. Chem., 2012, 10, 5289–5297
This journal is © The Royal Society of Chemistry 2012

charged with H2 was attached to the flask, and the atmosphere in
the flask was replaced with H2. After the reaction mixture
was stirred for 48 h at room temperature, Pd/C was filtered off
with Celite. The obtained organic layer was concentrated
under reduced pressure to give (S)-4,4-dimethylpyrrolidine-3-
carboxylic acid (1b) in 92% yield (65.8 mg, 0.46 mmol) as
white solid. M.p. 165.0–166.0 °C. [α]1D8.3 −5.0 (c = 1.0,
CH3OH). δH(D2O) 1.07 (3H, s), 1.25 (3H, s), 2.74–2.78 (1H,
m), 3.09–3.24 (2H, m), 3.52–3.62 (2H, m), δC(D2O) 24.3, 28.5,
43.8, 50.4, 58.0, 59.6, 180.8; γ(KBr)/cm−1 1574 [C(vO)O−];
[HR ESI-MS: Calc. for C7H12NO2 (M – H): 142.0874. Found:
M+ − H, 142.0870].
The enantiomeric excess (92% ee) was confirmed after protec-
tion of the amino acid moiety: benzyl N-benzyloxycarbonyl
(S)-4,4-dimethylpyrrolidine-3-carboxylate (6). Oil. [α]1D9.3 −4.0
(c = 1.0, CHCl3, 92% ee). HPLC [Daicel CHIRALPAK AS-H,
hexane–isopropanol (90 : 10, v/v), 0.7 mL min−1, 210 nm;
tr(major enantiomer) = 24.9 min, tr(minor enantiomer) =
32.4 min]. δH(CDCl3) 0.96 (3H, s), 1.19–1.21 (3H, s × 2,
rotamer), 2.75–2.83 (1H, m), 3.17–3.22 (1H, m), 3.33–3.41 (1H,
m), 3.65–3.84 (2H, m), 5.09–5.18 (4H, m), 7.31–7.36 (10H, m);
δC(CDCl3) 22.05–22.10 (rotamer), 26.3–26.4 (rotamer),
40.6–41.5 (rotamer), 46.9–47.4 (rotamer), 52.0–52.8 (rotamer),
58.9–59.3 (rotamer), 66.49–66.54 (rotamer), 66.78–66.80
(rotamer), 127.80, 127.82, 127.9, 128.38, 128.42, 128.6, 135.5,
136.7, 154.7–154.8 (rotamer), 171.25–171.34 (rotamer); γ(neat)/
cm−1 1731 [C(vO)OBn], 1703 [NC(vO)OBn]; [HR ESI-MS:
Calc. for C22H25NO4 + Na (M + Na): 390.1676. Found:
M+ + Na, 390.1675].
(I > 2σ(I)). The final wR(F2) values were 0.1186 (I > 2σ(I)). The
final R1 values were 0.0468 (all data). The final wR(F2) values
were 0.1235 (all data). The goodness of fit on F2 was 1.090.
Flack parameter = 0.02(8). CCDC number 881970.
Synthesis of (S)-2-aminomethyl-3-[1,3]dioxolan-2-yl-3-
methylbutyric acid (5)
In a round bottomed flask equipped with a Dean–Stark trap,
ethylene glycol (1 mL) and p-toluenesulfonic acid mono hydrate
(5.7 mg, 0.03 mmol) were successively added to a toluene
solution (15 mL) of benzyl (S)-3,3-dimethyl-2-nitromethyl-4-
oxobutyrate (4a) (2.5 mmol) at room temperature. The reaction
mixture was refluxed for 16 h, and then cooled to room tempera-
ture. The reaction mixture was neutralized with saturated
aqueous NaHCO3 and extracted with Et2O. The combined
organic phase was dried over MgSO4, filtered and concentrated
under reduced pressure. Benzyl (S)-3-[1,3]dioxolan-2-yl-2-nitro-
methyl-3-methylbutyrate was isolated by column chromato-
graphy (silica gel, hexane–Et2O) in 83% yield (888 mg,
2.08 mmol) as yellow oil. In a round bottom flask, 10% Pd/C
(250 mg) was placed, and the flask was flushed with N2. A
methanol solution (40 mL) of benzyl (S)-3-[1,3]dioxolan-2-yl-2-
nitromethyl-3-methylbutyrate (239 mg, 0.56 mmol) was poured
into the flask. A balloon charged with H2 was attached to the
flask, and the atmosphere in the flask was replaced with H2.
After the reaction mixture was stirred for 24 h at room tempera-
ture, Pd/C was filtered off with Celite. The obtained organic
layer was concentrated under reduced pressure to give (S)-2-amino-
methyl-3-[1,3]dioxolan-2-yl-3-methylbutyric acid (5) in 94%
yield (108 mg, 0.53 mmol) as a white solid. M.p. 270 °C
(decomp.). [α]1D8.8 −2.0 (c = 0.5, H2O). δH(D2O) 1.01 (3H, s),
1.02 (3H, s), 2.64–2.71 (1H, m), 3.25–3.34 (2H, m), 3.90–4.02
(4H, m), 4.76 (1H, s); δC(D2O) 21.4, 21.5, 39.7, 40.2, 50.1,
66.36, 66.38, 109.3, 177.1; γ(KBr)/cm−1 1627 [C(vO)O−];
[HR ESI-MS: Calc. for C9H18NO4 (M + H): 204.1230. Found:
M+ + H, 204.1230].
The enantiomeric excess (92% ee) was confirmed after protec-
tion of the amino acid moiety: benzyl N-benzyloxycarbonyl
(S)-2-aminomethyl-3-[1,3]dioxolan-2-yl-3-methylbutyrate (7).
Oil. [α]1D9.6 +18.3 (c = 1.0, CHCl3, 92% ee). HPLC [Daicel
CHIRALPAK AD-H, hexane–isopropanol (80 : 20, v/v),
0.8 mL min−1, 209 nm; tr(major enantiomer) = 16.9 min,
tr(minor enantiomer) = 13.4 min]. δH(CDCl3) 0.98 (3H, s), 1.05
(3H, s), 2.88 (1H, dd, J 4.1, 11.0 Hz), 3.33–3.41 (1H, m),
3.70–3.96 (5H, m), 4.61 (1H, s), 4.82–4.86 (1H, m), 5.02–5.14
(4H, m), 7.28–7.36 (10H, m); δC(CDCl3) 20.4, 20.6, 39.4, 39.8,
50.9, 65.1, 65.2, 66.3, 66.6, 108.4, 127.99, 128.03, 128.1,
128.2, 128.4, 128.5, 135.8, 136.5, 156.1, 173.6; γ(neat)/cm−1
1731 [C(vO)OBn, NC(vO)OBn]; [HR ESI-MS: Calc. for
C24H29NO6 + Na (M + Na): 450.1887. Found: M+ + Na,
450.1884].
Synthesis of (S)-N-(2-nitrophenylsulfonyl)-4,4-
dimethylpyrrolidine-3-carboxylic acid (N-nosyl 1b)
In a 7 mL vial, a solution of 2-nitrobenzenesulfonyl chloride
(40 mg, 0.180 mmol) in Et2O (1 mL) was added to a solution of
1b (25 mg, 0.175 mmol) in 1 N NaOH (0.5 mL) at room temp-
erature. After stirring for 1 h at room temperature, Et2O was
removed under reduced pressure. The resulting solution was
acidified to pH 3 by adding 1 N HCl, and extracted with EtOAc
(2 mL × 3). The combined organic phase was dried with
MgSO4, filtered and concentrated under reduced pressure.
Recrystallization from 2-propanol–hexane gave (S)-N-(2-nitro-
phenylsulfonyl)-4,4-dimethylpyrrolidine-3-carboxylic
acid
(N-nosyl 1b) (28.3 mg, 0.073 mmol) as colourless crystals.
M.p. 157–158 °C. [α]2D0.6 −7.2 (c = 1.0, CH3OH). δH(CD3OD)
0.96 (3H, s), 1.21 (3H, s), 2.83 (1H, t, J 7.9 Hz), 3.22 (1H, d,
J 9.7 Hz), 3.37 (1H, d, J 9.8 Hz), 3.65–3.77 (2H, m), 7.73–7.83
(3H, m), 8.04–8.07 (1H, m); δC(CD3OD) 21.9, 26.1, 42.3, 49.9,
53.8, 61.5, 125.2, 131.6, 132.2, 132.8, 135.2, 149.7, 174.2;
γ(KBr)/cm−1 1695 [C(vO)OH], 1538 (NO2); [HR ESI-MS:
Calc. for C13H16N2O6S + Na (M + Na): 351.0621. Found:
M+ + Na, 351.0620].
Crystal data for N-nosyl 1b: C13H16N2O6S, M = 328.34, tricli-
nic, a = 7.5722(4) Å, b = 9.8018(4) Å, c = 10.6602(5) Å, α =
75.7440(10)°, β = 72.7350(10)°, γ = 80.7840(10)°, V = 729.04
(6) Å3, T = 123(2) K, space group P1, Z = 2, μ(MoKα) =
0.254 mm−1, 7153 reflections measured, 5411 independent
reflections (Rint = 0.0156). The final R1 values were 0.0440
Synthesis of (S)-aza-spiro[4,5]decane-4-carboxylic acid
hydrochloride (1a-S)
In a round bottomed flask, 10% Pd/C (200 mg) was placed, and
the flask was flushed with N2. A methanol solution (10 mL) of
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5289–5297 | 5295

benzyl (S)-2-(1-formylcyclohexyl)-3-nitropropionate (4f) (159.5 mg,
0.5 mmol) was poured into the flask. A balloon charged
with H2 was attached to the flask, and the atmosphere in the
flask was replaced with H2. After the reaction mixture was
stirred for 48 h at room temperature, Pd/C was filtered off with
Celite. The obtained organic layer was concentrated under
reduced pressure, and aqueous 3 N HCl (2 mL) was added to the
residue. After the mixture was stirred for 2 h, the resulting
aqueous solution was washed with Et2O (2 mL × 3). The
obtained aqueous layer was concentrated under reduced pressure
to give (S)-aza-spiro[4,5]decane-4-carboxylic acid hydrochloride
(1a-S) in 97% yield (106.5 mg, 0.49 mmol). white solid. M.
p. 109–110 °C. [α]2D3.0 −30.0 (c = 1.0, CH3OH). δH(D2O)
1.30–1.70 (10H, m), 3.03–3.06 (1H, m), 3.29–3.37 (2H, m),
3.56–3.67 (2H, m); δC(D2O) 25.4, 25.5, 27.8, 33.5, 37.7,
48.9, 49.1, 54.8, 55.5, 178.1; γ(KBr)/cm−1 1724 [C(vO)OH];
[HR ESI-MS: Calc. for C10H17NO2 + H (M + H): 184.1332.
Found: M+ + H, 184.1335]. The absolute configuration was
determined by comparison of the specific rotation with that of
the literature.8a
2.73–2.82 (1H, m), 3.18 (2H, s), 3.47–3.60 (2H, m); δC(D2O)
18.8, 20.3, 21.9, 44.1, 47.1, 50.1, 56.9, 58.1, 180.9; γ(KBr)/
cm−1 1583 [C(vO)O−]; [HR ESI-MS: Calc. for C9H17NO2
+ Na (M + Na): 194.1152. Found: M+ + Na, 194.1153].
(3S,4R)-4-Methyl-4-phenylpyrrolidine-3-carboxylic acid (1g)
White solid. M.p. 157 °C (decomp.). [α]2D2.2 −34.5 (c = 1.0,
CH3OH). δH(D2O) 1.47 (3H, s), 2.92–3.68 (4H, m), 3.78–3.85
(1H, m), 7.32–7.58 (5H, m); δC(D2O) 24.8, 50.4, 51.2, 58.1,
58.8, 128.7, 130.2, 131.8, 146.1, 180.4. γ(KBr)/cm−1 1585
[C(vO)O−]; [HR ESI-MS: Calc. for C12H15NO2
(M + Na): 228.0995. Found: M+ + Na, 228.0996].
+ Na
Acknowledgements
The authors thank Dr Yasunori Yamamoto (Hokkaido Univer-
sity) for his assistance in X-ray analysis of N-nosyl 1b. This
work was partly supported by Grant-in-Aid for Regional R&D
Proposal-Based Program from Northern Advancement Center
for Science & Technology of Hokkaido Japan and by the Global
COE Program (Project No. B01: Catalysis as the Basis for Inno-
vation in Materials Science) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
(R)-Aza-spiro[4,5]decane-4-carboxylic acid hydrochloride (1a-R)
[α]2D2.4 +29.5 (c = 1.0, CH3OH).
Aza-spiro[4,5]decane-3-ethyl-4-carboxylic acid (1c)
Notes and references
Very pure 1c was obtained after the product synthesized by the
general procedure for hydrogenolysis was washed with acetone.
White solid. M.p. 215 °C (decomp.). [α]2D2.6 −4.0 (c = 1.0,
CH3OH). δH(D2O) 1.00 (3H, t, J 7.5 Hz), 1.14–1.36 (4H, m),
1.55–1.81 (8H, m), 2.41 (1H, d, J 10.6 Hz), 3.19–3.41 (2H, m),
3.73–3.80 (1H, m); δC(D2O) 9.5, 13.1, 24.9, 26.2, 27.9, 34.2,
39.2, 47.6, 55.2, 65.5, 66.0, 179.8; γ(KBr)/cm−1 1560 [C(vO)-
O−]; [HR ESI-MS: Calc. for C12H21NO2 + H (M + H):
212.1645. Found: M+ + H, 212.1646].
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Aza-spiro[4,4]nonane-4-carboxylic acid (1d)
White solid. M.p. 201 °C (decomp.). [α]2D2.6 −16.5 (c = 1.0,
CH3OH). δH(D2O) 1.53–1.80 (8H, m), 2.81–2.84 (1H, m),
3.16–3.35 (2H, m), 3.45–3.58 (2H, m); δC(D2O) 26.5, 26.7,
34.9, 39.8, 51.0, 55.2, 56.4, 57.7, 181.8; γ(KBr)/cm−1 1572
[C(vO)O−]; [HR ESI-MS: Calc. for C9H15NO2 + Na (M + Na):
192.0995. Found: M+ + Na, 192.0997].
Aza-spiro[4,6]undecane-4-carboxylic acid (1e)
White solid. M.p. 162 °C (decomp.). [α]2D2.6 −12.5 (c = 1.0,
CH3OH). δH(D2O) 1.38–1.86 (12H, m), 2.75–2.78 (1H, m),
3.13–3.31 (2H, m), 3.45–3.56 (2H, m); δC(D2O) 25.9, 26.0,
32.1, 32.2, 36.1, 41.1, 50.5, 51.4, 58.4, 58.6, 181.3; γ(KBr)/
cm−1 1579 [C(vO)O−]; [HR ESI-MS: Calc. for C11H19NO2 + H
(M + H): 198.1489. Found: M+ + H, 198.1489].
4-Methyl-4-propylpyrrolidine-3-carboxylic acid (1f)
White solid. M.p. 151–152 °C. [α]2D2.3 −16.1 (c = 0.9, CH3OH).
δH(D2O) 0.92 (3H, t, J 7.4 Hz), 1.05 (3H, s), 1.19–1.48 (4H, m),
5296 | Org. Biomol. Chem., 2012, 10, 5289–5297
This journal is © The Royal Society of Chemistry 2012

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