O-(α-Phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’: synthesis and resolution of 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids

Article abstract of DOI:10.1016/j.tetasy.2017.10.027

An approach to the synthesis and resolution of five- and six-membered lactams (i.e., 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids) is described. The method relies on the one-pot Michael reaction—cyclization of itaconic acid or diethyl homoitaconate and enantiopure O-(α-phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’. It is shown that this chiral auxiliary can be used for the separation of diastereomeric lactam products and then easily removed by catalytic hydrogenolysis.

Full text of DOI:10.1016/j.tetasy.2017.10.027

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
O-(
a-Phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’:
synthesis and resolution of 5-oxopyrrolidine- and 6-oxopiperidine-3-
carboxylic acids
Ihor Kleban a,b, Andriy V. Tymtsunik b,c, Yuliya V. Rassukana c,d, Oleksandr O. Grygorenko a,b,
⇑
a National Taras Shevchenko University of Kyiv, Volodymyrska Street, 60, Kyiv 01601, Ukraine
b Enamine Ltd, Chervonotkatska 78, Kyiv 02094, Ukrainey
c National Technical University of Ukraine ‘Igor Sikorsky Kyiv Polytechnic Institute’, Prospect Peremogy 37, Kyiv 03056, Ukraine
d Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach to the synthesis and resolution of five- and six-membered lactams (i.e., 5-oxopyrrolidine-
and 6-oxopiperidine-3-carboxylic acids) is described. The method relies on the one-pot Michael
reaction—cyclization of itaconic acid or diethyl homoitaconate and enantiopure O-(a-phenylethyl)
hydroxylamine as a ‘chiral ammonia equivalent’. It is shown that this chiral auxiliary can be used for
the separation of diastereomeric lactam products and then easily removed by catalytic hydrogenolysis.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 13 October 2017
Accepted 26 October 2017
Available online xxxx
1. Introduction
effectively only after reduction of the lactam moiety9—an experi-
mental result which has been confirmed in our hands. In the sec-
Functionalized five-1 and six-membered2 ring lactams (i.e.,
c
-
ond case, the method was more effective (48% overall yield)5 but
required two additional steps for installation and removal of the
oxazolidone moiety, was very atom-inefficient, and finally, the pro-
cedures were described in a patent without detailed compound
characterization.
and d-lactams) are present in a large number of natural and non-
natural biologically active compounds and are therefore of high
interest in drug discovery. For example, derivatives of 5-oxopyrro-
lidine-3-carboxylic acid 1 and 6-oxopiperidine-3-carboxylic acid 2
were evaluated as inhibitors of tank-binding kinase 1 (TBK1),3
autotaxin,4 sodium-glucose linked transporter 1 (SGLT1),5 or b-sec-
Enzymatic resolution of esters 6 was also studied.14 In the case
of N-unsubstituted compound 6a, only two-fold enantioselectivity
was observed (E = 2), although the method was efficient for
N-benzyl derivative 6b (E = 200). Alternatively, enantiomers of 6b
were resolved using crystallization of its diastereomeric salts.15
Nevertheless, removal of the benzyl protective group from the
lactam moiety in the products obtained was not described; by
analogy with 4 and according to other literature data,16,17 it might
be problematic.
Other methods for the synthesis of enantiopure derivatives of 1
included cyclization of the Cbz derivative 7 (prepared in six steps
from common reagents) upon esterification with diazomethane
and nitrogen deprotection,7 as well as enantioselective hydrogena-
tion of the lactam-based b-aminoacrylate 8 using a chiral rhodium
(I) complex as a catalyst.18
retase 1 (BACE-1)6 (Fig. 1). Since C-substituted
c- and d-lactams are
chiral compounds, their synthesis should preferably provide
possibility to obtain pure enantiomers of the target products. In
particular, there are several asymmetric or resolution-based
approaches to the preparation of 1 or its derivatives reported in
the literature. Most of them rely on the Michael reaction of itaconic
acid or its derivatives 3 with an N-nucleophile (i.e., ammonia or its
synthetic equivalent), which is accompanied/followed by the lac-
tam ring formation (Scheme 1). To achieve enantiomer resolution,
N-(a
-phenylethyl)amine7–12 and Evans oxazolidone5,13 were used
as the chiral auxiliaries, so that separation of diastereomeric
derivatives 4 and 5 was performed at the corresponding steps of
the synthesis. In the first case, the target product (S)-1 (methyl
ester) was obtained in 1.4% overall yield, mainly due to problems
with removal of the chiral auxiliary.7 The latter could be removed
Surprisingly, synthesis of enantiopure 6-oxopiperidine-3-car-
boxylic acid 2 has not been reported to date, although N-benzyl
derivative 9 was prepared using the methods similar to those
described above for 6b.18,19
The main idea of this work was inspired by our previous synthe-
sis of the racemic methyl ester 6a, which commenced from itaconic
⇑
Corresponding author. Tel.: +38 044 239 33 15; fax: +38 044 502 48 32.
E-mail address: gregor@univ.kiev.ua (O.O. Grygorenko).
www.enamine.net.
y
https://doi.org/10.1016/j.tetasy.2017.10.027
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
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2
I. Kleban et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
N
N
N
N
O
OBn
HN
O
F
F
HO
S
N
NH
N
O
H
Cl
Autotaxin inhibitor, IC50 = 37 nM
N
H
O
N
O
N
O
H
F
CN
HN
O
OH
O
N
1
NH
H
N
N
N
O
*
O
N
n
N
N
R
HO
O
O
NH
Ph
N
O
SGLT1 inhibitors
n = 1, R = t-Bu: IC50 = 1.8 nM
n = 2, R = n-Pr: IC50 = 6.9 nM
H
O
O
2
TBK1 inhibitor, IC50 = 28 nM
BACE-1 inhibitor, IC50 = 45 nM
Figure 1. 5-Oxopyrrolidine-3-carboxylic acid 1, 6-oxopiperidine-3-carboxylic acid 2 and some biologically active derivatives thereof.
O
O
O
Cl-
NH3
O
*
O
py
R1O
Ph
O
O
+
HO
HO
R2NH2
+
OH
N
OR1
90%
OH
BnO
R1O
10.
O
3a
HCl
O
MeOH
N
O
O
N
3, R1 = H, Me, Et
83%
O
strong
R2
H
cationite
: R1 = H
O
1, R or S
3a
O
O
N
O
O
O
H2 (50 atm), Pd-C
O
*
R1O
O
HN
N
MeOH, 50 o
100%
C
OMe
OMe
*
*
O
BnO
O
6a
O
N
*
O
N
N
Bn
Scheme 2.
O
R2
Ph
O
4, R1 = H, Me, Et
6, R2 = H, Alkyl, Bn
5
6a: R2 = H; 6b: R2 = Bn
MeO2C
THF
−78 oC
OTBDMS
HOOC
CbzHN
OTBDMS
Ph
N
CO2Me
*
+
HO2C
O
Ph
N
O
R
Li
CO2Me
N
N
Bn
R
CO2H
R = Me, C7H15, Aryl
12
Bn
29−46%
7
8
9
dr 75:25 to 95:5
Scheme 1.
Scheme 3.
acid 3a and used O-benzylhydroxylamine 10 as N-nucleophile (and
ammonia synthetic equivalent) for the lactam formation
(Scheme 2).20 This method appeared to be so efficient that the tar-
get compound could be obtained on up to 100 g scale. We won-
dered if enantiopure five- and six-membered ring lactams could
GF
*
GF
*
O
NH2
O
*
GF
O
+
N
O
OR1
n
O
N
H
Ph
11
Ph
*
, R or S
be obtained by a similar strategy using (R)- or (S)-O-(a-pheny-
lethyl)hydroxylamine 11 as a ‘chiral ammonia equivalent’ for the
Michael addition—cyclization step (Scheme 3). Notably, hydroxy-
lamines 11 were used previously in diastereoselective addition of
organometallic reagents to C@N double bonds.21,22 Another related
literature example includes stereoselective addition of lithium N-
n = 1, 2; R1 = H, Alkyl; FG = electron-withdrawing group e. g. CO2R1
Scheme 4.
O
tert-butyldimethylsilyloxy-N-(a-methylbenzyl)amide (12) to a,b-
HO
unsaturated esters (Scheme 3).23 In this work, we report imple-
mentation of similar strategy shown in the Scheme 4 for the syn-
thesis of enantiopure 1 and 2.
N
+
NH3
Cl-
O
*
OH
O
O
*
1. N2H4.xH2O
2. HCl
N
O
*
O
DIAD, Ph3P
11a.
2. Results and discussion
HCl (R), 80%
11b.HCl (S), 86%
Our synthesis of enantiopure 1 and 2 started with preparation
of the chiral auxiliaries 11a,b (Scheme 5). They were obtained
using the known method, namely, Mitsunobu reaction of optically
active (R)- or (S)-1-phenylethanols with N-hydroxysuccinimide,
followed by removal of the phthalimide moiety by hydrazinolysis
(80–86% overall yield).21 The products 11a,b were isolated as
hydrochlorides.
Reaction of 11aꢀHCl with itaconic acid 3 using conditions
described previously for 10ꢀHCl (pyridine, reflux) proceeded
smoothly and gave the product 13 as ca. 1:1 mixture of diastere-
omers (Scheme 6). It should be noted that the crystalline product
(for 2 steps)
Scheme 5.
13 was isolated in excellent yield (97%) simply by evaporation of
the solvent, addition of 2 M aq HCl and filtration. Unfortunately,
all the attempts to separate the diastereomers of 13 were not suc-
cessful. We have found, however, that chromatographic separation
is possible for the corresponding methyl ester 14. Therefore, 13
was esterified with methanol, and the product 14 thus obtained
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I. Kleban et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
O
O
O
O
O
O
HO
+
H2
H2
1. NaOH
NH3
N
N
HN
HN
O
Cl-
OH
O 2. H+
OH
Ph
O
Pd-C
98%
O
Pd-C
99%
HO
O
O
O
O
Ph
O
91%
O
14a, 32%, dr >95:5
15a
15b
(S)-6a
(R)-6a
1a
1b
11a.
1. MeOH, H+
2. Separation
HCl
py, 97%
+
O
N
O
O
O
O
O
HO
O
H2
H2
1. NaOH
Ph
N
N
HN
HN
OH
3a
+
Ph
O
Pd-C
96%
O
Pd-C
100%
O
OH
2. H
O
O
O
O
13, dr ~1:1
94%
14b, 32%, dr 88:12
Scheme 6.
O
O
O
O
H2
1. NaOH
2. H+
O
O
Cl-
NH3
N
OEt
HN
OEt
OEt
HN
HN
OH
O
Pd-C
82%
+
Ph
1.
96%
O
O
Ph
19a
2a
18a, 26%, dr >95:5
EtO2C
CO2Et
11a.HCl
n-Bu3P
+
CO2Et
O
O
DIPEA (5 eq)
EtOH, 11 d
2. Separation
86%
17
H2
1. NaOH
2. H+
92%
O
O
N
OEt
HN
OH
Pd-C
77%
Ph
O
O
18b
19b
2b
, 23%, dr 90:10
Scheme 7.
Table 1
Optimization of the reaction conditions between 17 and 11a
Table 2
Specific rotation values and chiral stationary phase HPLC analysis of the products 1a,b
and 2a,b
#
Solvent
Base
Time, d
Yield of 18 (%)d
Compound
[
a
]
Columna
Rt, min
Er
D
a
1
2
3
4
5
6
7
8
9
10
Pyridine
Toluene
MeOH
EtOH
—
—
—
—
4
4
9
4
4
4
4
10
9
11
0
0
0
0
0
0
0
52
55
57
b
1a
1b
2a
2b
ꢁ26.7
+20.1
ꢁ21.0
+18.4
Chirobiotic RÒ
Chirobiotic RÒ
Chirobiotic TÒ
Chirobiotic TÒ
6.9
6.4
16.7
15.4
96:4
86:14
96:4
92:8
b
b
c
—
—
MeOH
MeCN
MeOH
MeOH
EtOH
Cs2CO3 (5 mol)a
Cs2CO3 (5 mol)a
DIPEA (2.5 mol)a
DIPEA (5 mol)a
DIPEA (5 mol)a
a
Eluent: MeOH–NH4OH–AcOH (100:0.1:0.05), injection volume: 2.0
L; eluent flow: 1 mL/min.
l
L or 5.0
l
Rauhut–Currier reaction of ethyl acrylate (86% yield, Scheme 7).24
Unfortunately, the product 17 did not give the target piperidone
derivative 18 upon reaction with 11aꢀHCl under the conditions
described above (pyridine, reflux). Therefore, we performed
screening of the reaction conditions for this transformation, and
it was found that the best yield of the product 18 (57% by 1H
NMR, ca. 1:1 dr) is obtained when 17 and 11aꢀHCl were refluxed
in the presence of DIPEA (5 equiv) in EtOH for 11 d (Table 1). The
crude product after reaction was subjected to preparative chro-
matography to give the target compounds 18a (26% yield, >95:5
dr) and 18b (23% yield, 90:10 dr). Hydrogenolysis of 18a,b gave
esters 19a,b (77–82% yield), which were transformed into the tar-
get carboxylic acids 2a,b (92–96% yield) by alkaline hydrolysis.
Absolute configurations of the products 1a and 1b were estab-
lished by comparison of specific rotation values with the literature
data.5 In the case of 2a and 2b, transformation to the known com-
pound 20 was used to assign the configuration (Scheme 8). To
check enantiomeric excess of the final products obtained, they
were analyzed using chiral stationary phase HPLC (Table 2).
a
b
c
17 (1 mol), 11aꢀHCl (1 mol), reflux.
17 (1 mol), 11a (1 mol), reflux.
17 (1 mol), 11a (1 mol), no solvent, 120 °C.
Yield by 1H NMR.
d
O
BH3.Me2S
HN
OH
HN
OEt
64%
O
19a
20
Scheme 8.
was subjected to preparative chromatography (hexanes–t-BuOMe
(3:2) as eluent) to give diastereomers 14a (32% yield, >95:5 dr)
and 14b (32% yield, 88:12 dr).
Removal of the chiral auxiliary in the products 14a,b (H2, Pd–C,
50 atm, 50 °C) started with cleavage of the CAO bond, so that inter-
mediate hydroxamic acids 15a,b could be isolated (96–98% yield).
Further hydrogenolysis of 15a,b gave the target enantiopure esters
6a (96–97% yield from 14a,b), which were subjected to alkaline
hydrolysis (NaOH, MeOH–H2O). The final products 1a and 1b were
isolated in 91–94% yield after ion-exchange chromatography.
Synthesis of enantiopure carboxylic acids 2a,b started with
preparation of diethyl homoitaconate 17 using the known
3. Conclusions
The Michael reaction—cyclization of appropriate
a,b-unsatu-
rated carboxylic acids or their derivatives with O-( -phenylethyl)
a
hydroxylamine can be used for the synthesis of enantiopure lac-
tams, which is demonstrated for 5-oxopyrrolidine- and 6-oxopi-
peridine-3-carboxylic acids. Although the reaction itself does not
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I. Kleban et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
20
provide diastereoselectivity, separation of diastereomers followed
by removal of the chiral auxiliary can be used to obtain both enan-
(86%). White crystals. Mp 125–127 °C. [
a
]
D
ꢁ125.0 (c 0.25, MeOH).
Other physico-chemical and spectral data were identical to those
tiomers of the target products. Therefore, O-(
a
-phenylethyl)hy-
of enantiomer 11aꢀHCl.
droxylamine can be considered as a ‘chiral ammonia equivalent’
in reactions with electrophilic substrates such as Michael addition,
and in our opinion, this method can be extended to other synthetic
sequences.
4.4. 5-Oxo-1[(1R)-1-phenylethoxy]pyrrolidine-3-carboxylic acid
13
To a suspension of itaconic acid (3a) (38.0 g, 0.293 mol) in pyr-
idine (210 mL), 11aꢀHCl (51.0 g, 293 mol) was added. The resulting
mixture was refluxed until the reaction was completed (monitored
by 1H NMR, ca. 16 h). After cooling to rt, the mixture was evapo-
rated in vacuo. The residue was triturated with 2 M aq HCl (150
mL), the precipitate obtained was filtered and dried in vacuo to
give 13 (70.8 g) as a brownish solid which was used in the next
step without characterization.
4. Experimental
4.1. General
The solvents were purified according to the standard proce-
dures.25 All the starting materials were purchased from Acros, Mer-
ck, Fluka, and Enamine Ltd. Melting points were measured on
MPA100 OptiMelt automated melting point system. Analytical
TLC was performed using Polychrom SI F254 plates. Column chro-
matography was performed using Kieselgel Merck 60 (230–400
mesh) as the stationary phase. 1H and 13C NMR spectra were
recorded on a Bruker 170 Avance 500 spectrometer (at 499.9
MHz for Protons and 124.9 MHz for Carbon-13) and Varian Unity
Plus 400 spectrometer (at 400.4 MHz for protons and 100.7 MHz
for Carbon-13). Chemical shifts are reported in ppm downfield
from TMS as an internal standard. Elemental analyses were per-
formed at the Laboratory of Organic Analysis, Department of
Chemistry, National Taras Shevchenko University of Kyiv. Mass
spectra were recorded on an Agilent 1100 LCMSD SL instrument
(chemical ionization (APCI), electrospray ionization (ESI)) and Agi-
lent 5890 Series II 5972 GCMS instrument (electron impact ioniza-
tion (EI)). Preparative flash chromatography was performed using
Combiflash Companion chromatograph with 12 g or 40 g RediSep
column.
4.5. Methyl (3R)-5-oxo-1[(1S)-1-phenylethoxy]pyrrolidine-3-
carboxylate 14a and methyl (3S)-5-oxo-1[(1S)-1-phenylethoxy]
pyrrolidine-3-carboxylate 14b
Strong cationite (KU-2) (17.8 g) was added to a stirred solution
of acid 13 from the previous step (35.4 g, 0.142 mol) in absolute
MeOH (180 mL). The mixture was refluxed for 1 d, filtered through
silica gel (50 g), which was washed thoroughly with MeOH (100
mL). The filtrate was evaporated in vacuo to give a mixture of
14a and 14b (29.3 g). The diastereomers were separated by prepar-
ative flash chromatography (hexanes–t-BuOMe (3:2) as eluent).
14a: yield 9.25 g (32%). Brownish oil. [a]
20 = +16.3 (c 0.25,
D
MeOH). Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32.
Found: C, 63.5; H, 6.50; N, 5.68. MS (CI): 264 (MH+). 1H NMR
(500 MHz, DMSO-d6) d 7.51–7.18 (m, 5H), 5.17 (q, J = 6.4 Hz, 1H),
3.67 (s, 3H), 3.49 (t, J = 7.9 Hz, 1H), 3.10 (t, J = 8.6 Hz, 1H), 2.97–
2.87 (m, 1H), 2.55 (t, J = 7.9 Hz, 2H), 1.59 (d, J = 6.5 Hz, 3H). 13C
NMR (126 MHz, CDCl3) d 172.2, 169.7, 140.7, 128.7, 128.5, 127.2,
82.9, 52.5, 49.3, 33.6, 30.9, 20.5.
4.2.
(R)-O-(
a
-Phenylethyl)hydroxylamine
hydrochloride
11aꢀHCl
14b: yield 9.49 g (32%). Brownish oil. [
a]
20 = ꢁ144.3 (c 0.25,
D
MeOH). Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32.
Found: C, 63.98; H, 6.74; N, 5.15. MS (CI): 264 (MH+). 1H NMR
(500 MHz, DMSO-d6) d 7.52–7.35 (m, 5H), 5.17 (q, J = 6.5 Hz, 1H),
3.61 (s, 3H), 3.50 (t, J = 8.8 Hz, 1H), 3.15 (dd, J = 8.9, 4.9 Hz, 1H),
3.05–2.97 (m, 1H), 2.64 (dd, J = 17.2, 5.6 Hz, 1H), 2.48 (dd, J =
17.3, 9.8 Hz, 1H), 1.59 (d, J = 6.5 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 172.3, 169.4, 140.5, 128.6, 128.4, 127.3, 82.6, 52.4, 49.4, 33.5,
30.6, 20.4.
To a solution of (S)-1-phenylethanol (170 g, 1.39 mol) in THF
(2.5 L), triphenylphosphine (438 g, 1.67 mol) was added at rt, fol-
lowed by N-hydroxyphthalimide (272 g, 1.67 mol). To the resulting
mixture, diisopropyl azodicarboxylate (338 g, 1.67 mol) was added
at 0 °C. The mixture was stirred at rt overnight and evaporated in
vacuo. The residue was dissolved in CHCl3 (2.5 L) and MeOH
(250 mL). Hydrazine hydrate (206 mL, 1.41 mol) was added. The
mixture was stirred at rt overnight. The suspension was filtered,
and the filtrate was evaporated in vacuo. The residue was dissolved
in 2 M aq HCl (2 L), washed with CH2Cl2 (2 ꢂ 500 mL), neutralized
to pH = 9 by addition of K2CO3 and extracted with CH2Cl2 (2 ꢂ 500
mL). The combined extracts were dried over Na2SO4 and evapo-
rated in vacuo to give the product 11a as a colorless liquid. To
obtain the hydrochloride of 11a, it was dissolved in THF (1 L). Sat-
urated HCl in dioxane (1 L) was added, and the mixture was stirred
at rt for 2 h. The suspension was filtered, and the precipitate was
dried in vacuo to give the product 11aꢀHCl as white crystals. Yield
4.6. Methyl (3R)-1-hydroxy-5-oxopyrrolidine-3-carboxylate 15a
An autoclave was charged with 14a (9.39 g, 36.7 mmol), 10%
Pd–C (1.00 g) and THF (50 mL). The mixture was stirred vigorously
at 50 atm of hydrogen and 50 °C for 24 h. The suspension was fil-
tered, and the slurry of catalyst was washed with MeOH (2 ꢂ 25
mL). The filtrate was evaporated to dryness in vacuo to give the
product 15a. Yield 5.56 g (98%). Colorless oil. Anal. Calcd for
C6H9NO4: C, 45.28; H, 5.70; N, 8.80. Found: C, 45.26; H, 5.45; N,
8.66. MS (CI): 160 (MH+). 1H NMR (500 MHz, CDCl3) d 10.17 (s,
1H), 3.83 (s, J = 7.9 Hz, 2H), 3.73 (s, 3H), 3.29–3.20 (m, 1H), 2.71
(dd, J = 17.2, 7.0 Hz, 1H), 2.62 (dd, J = 17.2, 10.0 Hz, 1H). 13C NMR
(126 MHz, CDCl3) d 172.3, 168.6, 52.6, 50.5, 33.3, 31.1.
155 g (80%). White crystals. Mp 128–130 °C. [a]
20 = +123.0 (c 0.25,
D
MeOH). Anal. Calcd for C8H12ClNO: C, 55.34; H, 6.97; N, 8.07; Cl,
20.42. Found: C, 55.31; H, 7.24; N, 7.88; Cl, 20.09. MS (CI): 138
(MH+). 1H NMR (400 MHz, DMSO-d6) d 11.04 (s, 3H), 7.41 (br s,
5H), 5.29 (q, J = 6.2 Hz, 1H), 1.51 (d, J = 6.2 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) d 139.5, 129.4, 129.2, 127.4, 82.0, 21.2.
4.7. Methyl (3S)-1-hydroxy-5-oxopyrrolidine-3-carboxylate 15b
4.3.
11bꢀHCl
(S)-O-(
a
-Phenylethyl)hydroxylamine
hydrochloride
The product 15b was obtained from 14b using the procedure
described above for 15a. Yield 4.37 g (96%). Colorless oil. Other
physico-chemical and spectral data were identical to those of
enantiomer 15a.
The product 11bꢀHCl was obtained from (R)-1-phenylethanol
using the procedure described above for 11aꢀHCl. Yield 167 g
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I. Kleban et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
4.8. Methyl (3S)-5-oxopyrrolidine-3-carboxylate (S)-6a
added at rt, followed by N,N-diisopropylethylamine (26.9 mL,
0.154 mmol). The resulting mixture was refluxed for 10 d and
evaporated in vacuo. The residue was dissolved in t-BuOMe (100
mL), and the solution was washed with 2 M aq HCl (50 mL) to
pH = 4. The organic phase was dried over Na2SO4 and evaporated
in vacuo to give a mixture of 18a and 18b. The diastereomers were
separated by preparative flash chromatography hexanes–t-BuOMe
(3:2) as eluent).
An autoclave was charged with 14a (9.39 g, 36.7 mmol), 10%
Pd–C (1.00 g) and THF (50 mL). The mixture was stirred vigorously
at 50 atm of hydrogen and 50 °C until the reaction was completed
(monitored by 1H NMR, ca. 96 h). The suspension was filtered, and
the slurry of catalyst was washed with MeOH (2 ꢂ 25 mL). The fil-
trate was evaporated to dryness in vacuo to give the product 6a.
Yield 5.10 g (97%). Colorless oil. [
a
]
20 = ꢁ9.6 (c 0.25, MeOH) (lit.14
18a: yield 1.19 g (26%). Colorless oil. [
a
]
D
20 = ꢁ141.4 (c 0.25,
D
ꢁ7.3 (c 0.7, CH3OH), ee 76%). Anal. Calcd for C6H9NO3: C, 50.35;
H, 6.34; N, 9.79. Found: C, 50.52; H, 6.42; N, 9.70. MS (CI): 144
(MH+). 1H NMR (500 MHz, DMSO-d6) d 6.80 (s, 1H), 3.74 (s, 3H),
3.67–3.61 (m, 2H), 3.40–3.29 (m, 1H), 2.67 (dd, J = 17.2, 7.7 Hz,
1H), 2.57 (dd, J = 17.2, 9.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) d
176.6, 173.1, 52.4, 44.4, 38.7, 33.1.
MeOH). Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.82; H, 7.15; N, 4.52. MS (CI): 292 (MH+). 1H NMR
(400 MHz, CDCl3) d 7.45–7.24 (m, 5H), 5.20 (q, J = 6.4 Hz, 1H),
4.20–3.91 (m, 2H), 3.56 (dd, J = 11.4, 5.4 Hz, 1H), 3.24 (dd, J =
11.3, 8.7 Hz, 1H), 2.78–2.61 (m, 1H), 2.52 (dt, J = 17.3, 5.5 Hz,
1H), 2.42–2.28 (m, 1H), 2.00–1.89 (m, 1H), 1.80–1.65 (m, 1H),
1.54 (d, J = 6.5 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (126
MHz, CDCl3) d 171.3, 166.9, 140.8, 128.5, 128.4, 127.3, 81.4, 61.1,
52.3, 39.7, 31.2, 23.3, 20.4, 14.0.
4.9. Methyl (3R)-5-oxopyrrolidine-3-carboxylate (R)-6a
The product (R)-6a was obtained from 15b using the procedure
described above for (S)-6a. Yield 4.03 g (96%). Colorless oil. [
+6.9 (c 0.25, MeOH). Other physico-chemical and spectral data
were identical to those of enantiomer (S)-6a.
18b: yield 1.04 g (23%). Colorless oil. [
a
]
D
20 = ꢁ153.2 (c 0.25,
20
a
]
=
MeOH). Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.95; H, 7; N, 4.54. MS (CI): 292 (MH+). 1H NMR (400
MHz, CDCl3) d 7.45–7.27 (m, 5H), 5.21 (q, J = 6.5 Hz, 1H), 4.17–
3.93 (m, 2H), 3.64–3.51 (m, 1H), 3.14 (dd, J = 11.2, 5.1 Hz, 1H),
2.58–2.28 (m, 3H), 2.00–1.89 (m, 1H), 1.89–1.75 (m, 1H), 1.56 (d,
J = 6.6 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 171.4, 167.0, 140.7, 128.6, 128.6, 127.4, 81.4, 61.1, 52.3, 39.8,
31.3, 23.6, 20.0, 14.0.
D
4.10. (3S)-5-Oxopyrrolidine-3-carboxylic acid 1a
Ester 6a (5.10 g, 35.6 mmol) was dissolved in THF (30 mL) and
H2O (15 mL). Sodium hydroxide (1.42 g, 35.6 mmol) was added.
The resulting mixture was stirred at rt for 1 h and evaporated in
vacuo, filtered through strong cationite (KU-2, 35 g) and washed
4.14. Ethyl (3R)-6-oxopiperidine-3-carboxylate 19a
thoroughly with H2O (20 mL). The filtrates were evaporated to dry-
20
ness to give 1a. Yield 4.20 g (91%). White solid. Mp 166–167 °C. [
a]
An autoclave was charged with 18a (1.10 g, 3.77 mmol), 10%
Pd–C (0.110 g) and THF (20 mL). The mixture was stirred vigor-
ously at 50 atm of hydrogen and 50 °C until the reaction was com-
pleted (monitored by 1H NMR, ca. 96 h). The suspension was
filtered, and the slurry of catalyst was washed with MeOH (2 ꢂ
D
= ꢁ26.8 (c 0.25), er 96:4. Anal. Calcd for C5H7NO3: C, 46.51; H, 5.46;
N, 10.85. Found: C, 46.48; H, 5.39; N, 10.67. MS (CI): 130 (MH+).
1H NMR (500 MHz, DMSO-d6) d 12.56 (br s, 1H), 7.63 (s, 1H), 3.45
(t, J = 9.2 Hz, 1H), 3.37–3.30 (m, 1H), 3.29–3.17 (m, 1H), 2.41–2.23
(m, 2H). 13C NMR (126 MHz, CDCl3) d 175.6, 175.1, 44.2, 38.7, 33.5.
10 mL). The filtrate was evaporated to dryness in vacuo to give
20
the product 19a. Yield 0.523 g (82%). Colorless oil. [
a
]
ꢁ27.5 (c
D
4.11. (3R)-5-Oxopyrrolidine-3-carboxylic acid 1b
0.25, MeOH). Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18.
Found: C, 56.12; H, 7.56; N, 8.46. MS (CI): 172 (MH+). 1H NMR
(400 MHz, CDCl3) d 6.93 (s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.47 (d, J
= 6.9 Hz, 2H), 2.80–2.65 (m, 1H), 2.50–2.27 (m, 2H), 2.16–2.05
(m, 1H), 2.03–1.89 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (126
MHz, CDCl3) d 172.3, 171.8, 61.0, 43.2, 38.4, 29.8, 23.5, 14.1.
The product 1b was obtained from (R)-6a using the procedure
described above for 1a. Yield 3.51 g (94%). White crystals. Mp
149–153 °C (lit.14 147–149 °C). [ 20 = +20.1 (c 0.25, MeOH), er
a]
D
86:14 (lit.14 +10.2 (c 0.1, MeOH), ee 34%). Other physico-chemical
and spectral data were identical to those of enantiomer 1a.
4.15. Ethyl (3S)-6-oxopiperidine-3-carboxylate 19b
4.12. Diethyl 2-methylenepentanedioate 1724
The product 19b was obtained from 18b using the procedure
20
To ethyl acrylate 17 (100 g, 0.998 mol), tri-n-butylphosphine
(20.2 g, 0.998 mmol) was added slowly under an argon atmosphere
without external cooling (the addition rate was controlled so that
the temperature was kept below 80 °C). After cooling to rt, the
reaction mixture was distilled in vacuo. Yield 86.0 g (86%). Color-
less liquid. Bp 95–96 °C/3 Torr (lit.26 92–94 °C/3 Torr). Anal. Calcd
for C10H16O4: C, 59.98; H, 8.05. Found: C, 60.27; H, 8.02. MS (EI):
200 (M+). 1H NMR (500 MHz, CDCl3) d 6.19 (s, 1H), 5.59 (s, 1H),
4.22 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 2.65 (t, J = 7.4 Hz,
2H), 2.52 (t, J = 7.4 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1
Hz, 3H). 13C NMR (126 MHz, CDCl3) d 172.7, 166.7, 139.2, 125.5,
60.7, 60.4, 33.2, 27.3, 14.2, 14.2.
described above for 19a. Yield 0.499 g (77%). Colorless oil. [
a
]
=
D
+23.8 (c 0.25, MeOH). Other physico-chemical and spectral data
were identical to those of enantiomer 19a.
4.16. (3R)-6-Oxopiperidine-3-carboxylic acid 2a
Ester 19a (0.291 g, 1.69 mmol) was dissolved in THF (10 mL)
and H2O (5 mL). Sodium hydroxide (0.700 g, 1.69 mmol) was
added. The resulting mixture was stirred at rt for 1 h and filtered
through strong cationite (KU-2, 5 g) and washed thoroughly
with H2O (10 mL). The filtrates were evaporated to dryness to
give 2a.
20
Yield 0.230 g (96%). Colorless solid. Mp 181–182 °C. [
a]
=
D
4.13. Ethyl (3R)-6-oxo-1-[(1R)-1-phenylethoxy]piperidine-3-
carboxylate 18a and ethyl (3S)-6-oxo-1-[(1R)-1-phenylethoxy]
piperidine-3-carboxylate 18b
ꢁ21.0 (c 1.0, MeOH). Anal. Calcd for C6H9NO3: C, 50.35; H, 6.34;
N, 9.79. Found: C, 50.53; H, 6.11; N, 9.6. MS (CI): 144 (MH+). 1H
NMR (400 MHz, DMSO-d6) d 7.43 (s, 1H), 3.32–3.16 (m, 2H),
2.73–2.58 (m, 1H), 2.21–2.09 (m, 2H), 2.01–1.88 (m, 1H), 1.86–
1.72 (m, 1H), COOH is exchanged with HDO. 13C NMR (126 MHz,
DMSO-d6) d 174.7, 170.2, 43.1, 38.3, 30.3, 23.8.
To a solution of diethyl 2-methylenepentanedioate 17 (6.19 g,
30.9 mmol) in EtOH (60 mL), 11aꢀHCl (12.7 g, 92.7 mmol) was
Please cite this article in press as: Kleban, I.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.027

6
I. Kleban et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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5. Miura, T., Ogoshi, Y., Ueyama, K., Motoda, D., Iwayama, T., Suzawa, K.,
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Whitlock, G. A. Bioorg. Med. Chem. Lett. 2009, 19, 2829–2834.
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The product 2b was obtained from 19b using the procedure
described above for 19a. Yield 0.222 g (92%). White crystals. Mp
184–185 °C. [a]
20 = +18.4 (c 0.25, MeOH). Other physico-chemical
D
and spectral data were identical to those of enantiomer 2a.
4.18. (3S)-Piperidin-3-ylmethanol 20
To a solution of ester 19a (0.200 g, 1.16 mmol) in THF (5 mL),
BH3ꢀTHF (0.3 mL, 2.92 mmol, 1 M in THF) was added at rt. The
resulting mixture was refluxed for 2 d and then evaporated in
vacuo. The residue was dissolved in MeOH (5 mL) and 4 M HCl in
dioxane (5 mL). The mixture was refluxed overnight and evapo-
rated in vacuo. The residue was dissolved in MeOH (10 mL),
neutralized by addition of K2CO3 and evaporated in vacuo. The resi-
due was dissolved in CHCl3 (10 mL). The precipitate was filtered
off, and the filtrate was evaporated in vacuo to give 20. Yield
85.7 mg (64%). Yellowish oil. [
a
]
20 = ꢁ7.4 (c 0.25, MeOH) (lit.27
D
ꢁ8.4 (c 0.25, MeOH)). Other physico-chemical and spectral data
were identical to those reported in the literature.28
Acknowledgements
The authors thank Prof. Andrey A. Tolmachev for his encourage-
ment and support, Mrs. Kseniya Krasnopolska for chiral stationary
phase HPLC measurements, and UOSLab (www.en.uoslab.com) for
providing high pressure reactors.
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25. Armarego, W. L. F.; Chai, C. Purification of Laboratory Chemicals, 5th ed.;
Elsevier: Oxford, 2003.
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Girijavallabhan, V. M., Santhanam, B., Pinto, P. A., Vibulbhan, B., Keertikar, K.
M., Alvarez, C. S., Baldwin, J. J., Li, G., Huang, C.-Y., James, R. A., Bishop, W. R.,
Wang, J. J.-S., Desai, J. A., US 2003/229099 2003.
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Please cite this article in press as: Kleban, I.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.027