An enantiodivergent synthesis of Cα-methyl nipecotic acid analogues from δ-lactam derivatives obtained through a highly stereoselective cyclization strategy

Article abstract of DOI:10.1016/j.tetasy.2015.09.014

A stereoselective and enantiodivergent strategy for the construction of δ-lactams is described. The strategy utilizes chiral malonic esters prepared from enantiomerically enriched mono esters of disubstituted malonic acid. A cyclization occurs with the selective displacement of a substituted benzyl alcohol as the leaving group. The resulting δ-lactams are then converted into nipecotic acid analogues using straightforward transformations. The resulting nipecotic acid analogues proved capable organocatalysts in Mannich reactions.

Full text of DOI:10.1016/j.tetasy.2015.09.014

Tetrahedron: Asymmetry 26 (2015) 1292–1299
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
a
An enantiodivergent synthesis of C -methyl nipecotic acid analogues
from d-lactam derivatives obtained through a highly stereoselective
cyclization strategy
⇑
Souvik Banerjee, Emily R. Vogel, Daniel Hinton, Michael Sterling, Douglas S. Masterson
The University of Southern Mississippi, Department of Chemistry and Biochemistry, 118 College Drive #5043, Hattiesburg, MS 39406, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective and enantiodivergent strategy for the construction of d-lactams is described. The strat-
egy utilizes chiral malonic esters prepared from enantiomerically enriched mono esters of disubstituted
malonic acid. A cyclization occurs with the selective displacement of a substituted benzyl alcohol as the
leaving group. The resulting d-lactams are then converted into nipecotic acid analogues using straightfor-
ward transformations. The resulting nipecotic acid analogues proved capable organocatalysts in Mannich
reactions.
Received 21 September 2015
Accepted 28 September 2015
Available online 21 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
lase catalyzed ring expansion of aziridines,17 and the use of
organophosphorus reagents as organocatalysts.18 Unlike d-lactams,
d-Lactams constitute an important class of compounds in syn-
thetic chemistry and biology. They are often found in important
building blocks of a variety of biologically intriguing natural prod-
ucts and as key intermediates in many potent bioactive com-
pounds.1–4 In addition, d-lactams are useful precursors to
piperidine analogues that are essential pharmacophores in a num-
ber of medicinal compounds currently on the market or in
advanced clinical studies.3,5–8 One of the most important classes
of the piperidine family is the piperidine-3-carboxylic acids, other-
wise known as derivatives of nipecotic acid. These nipecotic acid
analogues are important structural motifs in several natural and
synthetic bioactive molecules.1,6–10 Hence, it is important to have
a concise and efficient synthetic strategy to prepare d-lactams in
order to construct a variety of nipecotic acid analogues.
there are few reports detailing the asymmetric synthesis of nipeco-
tic acid analogues; many of these strategies rely on functional
group modifications of preformed nicotinic acids or nipecotic acid
derivatives.9,10,19,20 However, the asymmetric synthesis of piperi-
dine derivatives utilizing a stereoselective cyclization approach is
surprisingly rare. To the best of our knowledge, Shintani et al. is
the first to report the synthesis of diastereomerically enriched
nipecotic acid analogues through a palladium catalyzed decar-
boxylative cyclization.9 Therefore, there is a need for additional
straightforward methods capable of preparing enantiomerically
enriched nipecotic acid derivatives.
We have recently demonstrated that
c-lactams can be readily
prepared by a stereoselective cyclization strategy.21 These corre-
sponding c-lactams were then readily converted into highly opti-
Recently a number of synthetic strategies have been established
to prepare d-lactams. Some of these strategies include N-hetero-
cyclic catalyzed intramolecular amidations,11 palladium catalyzed
cally enriched b-proline derivatives.21 Hence, we wanted to
employ this cyclization strategy to prepare d-lactams in a stereos-
elective manner.
intramolecular
intramolecular
amidations,12
lactone–amine
aza-Diels–Alder
reactions,13
catalyzed
coupling,4
gold
2. Results and discussion
intramolecular C–C couplings of b-ketoamide to unactivated alke-
nes,14 and palladium catalyzed intramolecular hydroamidations of
alkynes.15 There have also been several methods detailing the
enantioselective synthesis of d-lactams through ring closing
metathesis reactions of enantiomerically pure precursors,16 nitri-
Recently, we have reported a Pig Liver Esterase (PLE) catalyzed
asymmetric hydrolysis of the prochiral malonic ester 1.22 This bio-
catalytic hydrolysis of 1 resulted in chiral malonic acid-ester 2 with
high enantiomeric purity (97% ee), and good yields (71%) as shown
in the Scheme 1. The enantiomerically enriched malonic acid-ester
2 was determined to be predominantly the (R)-enantiomer by syn-
thetic means. The acid ester 2 was then converted into benzyl ester
⇑
Corresponding author. Tel.: +1 601 266 4714; fax: +1 601 266 6075.
E-mail address: douglas.masterson@usm.edu (D.S. Masterson).
http://dx.doi.org/10.1016/j.tetasy.2015.09.014
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
1293
O
O
O
O
O
O
O
O
N
O
O
N
O
OH
N
PLE
p-NO2-BnBr
NO2
pH = 7.4
K2CO3
O
O
O
O
O
O
1
3
(S)
2
(R)
97 % ee
71%
87%
N2H4.H2O
K2CO3
O
O
O
O
HN
O
O
NH
+
NO2
4a
4b
60
1
81% combined yield
Scheme 1. Synthesis of d-lactams.
3. In our previous study, we witnessed that the para-NO2-benzyl
ester readily undergoes stereoselective cyclization upon removal
of the phthalimide protecting group. Upon treatment of 3 with
hydrazine hydrate, a cyclization took place resulting in d-lactams
4a, and 4b as shown in Scheme 1. The ratio of 4a:4b was 60:1 as
determined by 1H NMR. Therefore, the results show a high propen-
sity toward cyclization along with a high selectivity to form d-lac-
tam 4a.
The strategy illustrated in Scheme 1 shows a straightforward
approach whereby the manipulation of this type of ester allows
for a high level of cyclization control. This demonstrates a simple
strategy that can be very useful in the construction of d-lactams
and their derivatives.
We decided to further explore this cyclization strategy to obtain
4b as the major product. The ability to construct 4b as the major
product would provide access to a useful enantiodivergent strategy
to prepare d-lactams. However, in our previous study a Hammet
study demonstrated the difficulties in acquiring 4b as the major
product simply by exploiting the electronic factors through substi-
tuted benzyl esters. In order to address this issue, we synthesized
diester 5 from 2 to introduce steric congestion as shown in
Scheme 2.
From a steric congestion standpoint, the ethyl ester in 5 should
be more accessible toward nucleophilic attack by the free amine.
Upon treatment with hydrazine, 6a was obtained as the only pro-
duct and there was no indication of the formation of 6b as indi-
cated by 1H NMR. 6a is a derivative of 4b with the same absolute
stereochemistry as 4b. Therefore, introduction of steric hindrance
gives rise to a highly stereoselective, and potentially stereospecific,
cyclization strategy to prepare (S)-d-lactams. To the best of our
knowledge, this is the first time an enantiodivergent strategy has
been optimized to prepare such d-lactams.
a
Over the last few years, C -methyl-nipecotic acid has served as
an important structural entity in a number of synthetic and natural
therapeutic lead compounds. For example, a group of scientists
from Merck have discovered a potent NK1 receptor antagonist,
a
where (R)-C -methyl-nipecotic acid is used as an essential building
block.7 Nisho et al. have come up with dipeptidyl peptidase IV inhi-
a
bitors consisting of (R)-C -Methyl-nipecotic acid derivative serving
as pharmacophore.5,6 Despite a number of practical applications,
a
asymmetric synthesis of C -methyl-nipecotic acid has been rarely
reported in recent years. We wanted to demonstrate the potential
impact of this cyclization strategy by utilizing the d-lactams to
construct enantiomerically pure nipecotic acid analogues. Upon
O
O
O
O
O
O
O
O
O
O
N
O
OH
N
HN
O
O
NH
N2H4
isobutylene
H+
+
K2CO3
O
O
O
O
6a
6b
nd
100
75%
5
2
(R)
(S)
97 % ee
71%
87%
Scheme 2. Selective cyclization proving access to (S)-d-lactam.

1294
S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
O
O
O
O
O
S
O
NH
Lawesson's
O
NBn
BnBr
NaH
O
NBn
4a
8
7
80%
81%
Raney-Ni/H2
O
O
O
LiOH
Pd-C/H2
O
NBn
HO
NH
HO
NBn
9
11
10
88%
78%
93%
a
Scheme 3. Synthesis of (R)-C -methyl-nipecotic acid analogue.
O
O
O
O
O
O
1. TFA
NaH, BnBr
HN
O
BnN
O
BnN
O
2. K2CO3, CH3I
12
80%
6a
13
(S)-δ-Lactam
89%
Lawesson's
S
O
O
O
Raney-Ni/H2
KOH
BnN
O
BnN
OH
BnN
O
16
14
15
80%
78%
75%
Pd-C/H2
O
HN
OH
17
92%
(S)-nipecotic acid analogue
a
Scheme 4. Synthesis of (S)-C -methyl-nipecotic acid analogue.
close inspection of 4a and 6a, it was conceived that the corre-
sponding nipecotic acid analogues could be prepared by the selec-
tive reduction of the d-lactam to a piperidine ring. This would
analogue 10 in good yield (88%) requiring no further purification.
Finally, 10 was fully deprotected by hydrogenolysis of the benzyl
group resulting in pure C -methyl-nipecotic acid 11 without fur-
ther purification and in good yield (93%). Therefore, the (R)-nipeco-
tic acid analogue was achieved in five overall steps requiring little
purification and in very good overall yield (41%).
At this point, we wanted to use the (S)-d-lactam 6a as the key
intermediate in the preparation of (S)-nipecotic acid analogue 17
as shown in the Scheme 4. Lactam 6a was converted into N-benzyl
protected lactam 12 in very good yield (80%). In the next step we
discovered that the tert-butyl ester was not tolerated under the
conditions utilized to prepare the thiolactam. To circumvent this
problem, the tert-butyl ester was cleaved and reprotected as
methyl ester 13 in one pot (89%). Lactam 13 was then converted
into thiolactam 14 utilizing Lawesson’s reagent in good yield
a
a
allow us to prepare both enantiomers of C -methyl-nipecotic acid
analogues and establish it as a useful enantiodivergent strategy in
the preparation of such analogues.
a
To accomplish the asymmetric synthesis of (R)-C -methyl-nipe-
cotic acid 11, we started with the enantiomerically enriched d-lac-
tam 4a as shown in Scheme 3. First, d-lactam 4a was benzyl
protected to give 7 in good yield (81%). Then the N-benzylated lac-
tam 7 was converted into thiolactam 8 employing Lawesson’s
reagent in good yield (80%). Thiolactam 8 was selectively reduced
to the piperidine derivative 9 utilizing the Raney-Ni desulphuriza-
tion technique in good yield (78%) without further purification. The
saponification of 9 resulted in the N-benzylated-nipecotic acid

S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
1295
O
O
O
HO
NH
O
O
HN
O
HN
+
O
30 mol%
H
CO2Et
H
CO2Et
N
DMSO, RT
12 hrs
+
H
EtO2C
H
(2R,3S) (anti-minor)
(2S,3R) (anti-major)
a
Scheme 5. C -Methyl-nipecotic acid catalyzed Mannich reaction.
(78%). Thiolactam 14 was subject to Raney-Ni desulfurization
resulting in (S)-piperidine-3-carboxylate 15 in good yield (80%).
Saponification of 15 resulted in (S)-N-benzylated nipecotic acid
derivative 16 in 75% yield. Compound 16 was subjected to hydro-
genation to achieve (S)-nipecotic acid analogue 17 in very good
yield (92%). The specific rotation confirms 17 as the enantiomer
of 11. This success provides access to the (S)-nipecotic acid ana-
logue 17 with a limited number of steps and a respectable overall
yield of 31%.
additional methyl group in 11 would play a role in the selectivity
of the resulting Mannich product. We performed the same Man-
nich reaction tested by Zhang et al. as shown in Scheme 5 employ-
ing 30 mol % of 11 as an organocatalyst.23 The reaction was
complete within 12 h and the Mannich product was obtained upon
purification in reasonable yield (78%). Chiral HPLC (Fig. 1) and 1H
NMR established the product as moderately anti-selective (anti/
syn = 72.5:27.5), and with slightly diminished ee of anti-enan-
tiomers (anti = 26% ee) compared to the literature.
a
With the nipecotic acids in hand, we wanted to explore the
It is evident from the experimental data that C -methyl
a
organocatalytic efficiency of (R)-C -methyl-nipecotic acid 11 in
nipecotic acid 11 provides the Mannich product with approxi-
mately the same anti/syn-selectivity as nipecotic acid, but with
slightly diminished enantiomeric excess for the anti-Mannich
product. Based on the obtained result, we propose that
Mannich type reactions. To the best of our knowledge, Zhang
et al. are the first to test (R)-nipecotic acid as a catalyst in Mannich
reactions.23 They observed (R)-nipecotic acid to produce the Man-
nich product with moderate anti-selectivity (anti/syn = 78:22) and
enantioselectivity (anti = 36% ee, syn = 12% ee).23 In this context,
we wanted to envisage if the enhanced rigidity employed by an
a
C -methyl-nipecotic acid 11 prefers the (S)-cis-enamine and has
a slight preference to react with the imine at the si-face as shown
in Figure 2.
a
Figure 1. Chiral HPLC (Daicel Chairalcel AS-H, hexanes/i-PrOH = 99:1, 1.0 mL/min) of (R)-C -methylnipecotic acid 11 catalyzed Mannich product.

1296
S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
to be 97% by chiral HPLC (Diacel Chiralpak OJ-H, 4% iPrOH/hexanes,
O
O
flow rate = 1 mL/min, k = 305 nm) Rt(S) = 54.9 min (area = 130.13),
Rt(R) = 58.8 min (area = 7770.41). Rf = 0.22 (40% EtOAc/hexanes). IR
O
(cmÀ1) = 2983, 2937, 1773, 1747, 1697. [ 24 = +5.8 (c 2, MeOH).
a]
D
NH
O
H
N
PMP
1H NMR (CDCl3, 400 MHz): d 7.85 (m, 2H), 7.73 (m, 2H), 4.21 (q,
2H, J = 7 Hz), 3.71 (t, 2H, J = 7 Hz), 1.93 (m, 2H), 1.71 (m, 2H),
1.45 (s, 3H), 1.26 (t, 3H, J = 7 Hz). 13C NMR (CDCl3, 100 MHz): d
176.0, 172.0, 168.0, 134.0, 132.0, 123.0, 62.0, 53.0, 38.0, 33.0,
24.0, 20.0, 14.0. HRMS [C17H19NO6Na+] calcd = 356.3256,
found = 356.3253.
EtO2C
H
N
H
CO2Et
(2S,3R) (anti-major)
TS (S)-cis-si
O
O
4.3. Synthesis of (S)-1-ethyl 3-(4-nitrobenzyl) 2-[3-(1,3-dioxoiso-
indolin-2-yl)propyl]-2-methylmalonate 3
N
O
NH
O
H
MeO2C
EtO2C
H
A 250 mL round-bottomed flask was charged with 6.41 g of 2
(19 mmol), 2.62 g of K2CO3 (19 mmol), 75 mL of anhydrous DMF,
and a stir bar. A solution of the 4-nitrobenzyl bromide (17.1 mmol)
in 20 mL of anhydrous DMF was slowly added over 15 min. The
reaction was allowed to stir approximately 12 h under a nitrogen
atmosphere. The reaction mixture was then diluted with 100 mL
of water, and the resulting mixture was washed with Et2O
(3 Â 150 mL). The combined ether layer was washed with water
(8 Â 150 mL) and brine (2 Â 100 mL), dried over MgSO4, filtered,
and the solvent was removed under reduced pressure. The product
was isolated by flash chromatography (30% EtOAc/hexanes), giving
8.10 g (17.4 mmol, 87%) pure 3 as a white solid. Rf = 0.1 (30%
N
H
PMP
(2R,3S) (anti-minor)
TS (S)-trans-re
a
Figure 2. Proposed transition state of C -methyl-nipecotic acid catalyzed Mannich
reaction.
3. Conclusions
We have optimized a highly enantioselective and enantiodiver-
gent cyclization strategy for the preparation of d-lactams starting
with the enantiomerically enriched common intermediate 2. This
is the first reported strategy in which d-lactams are prepared in a
highly stereoselective manner simply by regulating steric and elec-
tronic factors. We believe that this straightforward approach will
provide access to a wide variety of enantiomerically enriched d-
lactams. We have demonstrated that both the (R)- and (S)-d-lac-
tams can be readily converted into their respective nipecotic acid
analogues. This success provides access to a concise and enantiodi-
vergent approach to potentially achieve a number of highly
demanding enantiomerically enriched nipecotic acid analogues.
EtOAc/hexanes). [a] )
23 = -33.0 (c 1, CH2Cl2). Mp = 66 °C. IR (cmÀ1
D
= 2982, 1775, 1710. 1H NMR (CDCl3, 400 MHz): d 8.19 (d, 2H,
J = 8.32 Hz), 7.81 (m, 2H), 7.72 (m, 2H), 7.46 (d, 2H, J = 8.32 Hz),
5.22 (m, 2H), 4.15 (q, 2H, J = 7 Hz), 3.68 (t, 2H, J = 7 Hz), 1.95 (m,
2H), 1.65 (m, 2H), 1.44 (s, 3H), 1.18 (t, 3H, J = 7 Hz). 13C NMR
(CDCl3, 100 MHz): d 171.5, 168.2, 148.7, 134.0, 132.0, 128.2,
124.0, 123.3, 65.2, 61.4, 58.5, 53.0, 37.8, 33.0, 24.0, 20.0, 18.2,
13.6. HRMS [C24H24N2O8Na+] calcd = 491.1425, found = 491.1422.
4.4. Synthesis of (R)-ethyl 3-methyl-2-oxopiperidine-3-car-
boxylate 4a
a
We have explored C -methyl-nipecotic acid as a catalyst in the
Mannich reaction. Our initial results show that C -methyl-nipeco-
a
A volume of 1.8 mL (20 mmol) 35% hydrazine in water was
added to a solution of 5.10 g (11 mmol) of 3 in 50 mL of MeOH.
The mixture was heated at reflux overnight. A white precipitate
was observed within 1 h of reflux. The reaction mixture was
allowed to cool to room temperature, and the resulting mixture
was filtered through a polypropylene 0.2 mm pore size syringe
filter. An amount of 1.36 g (9.9 mmol) of K2CO3 was added to the
filtrate. The solution was allowed to reflux for 6 h, after which
the solvent was evaporated under reduced pressure. The resulting
residue was taken up in CH2Cl2 and washed with water. The
organic layer was dried over MgSO4, evaporated under reduced
pressure, and purified by column chromatography using 60% Hex-
anes/EtOAc giving 1.5 g (8.3 mmol, 75%) of 4 as a white solid.
tic acid provides a similar diastereomeric excess as nipecotic acid
but with diminished % ee (36% ee to 26% ee) for the anti-diastere-
omers. We suspect that the increased rigidity of the piperidine ring
introduced by an additional methyl group is responsible for the
reduced % ee.
4. Experimental
4.1. Synthesis of diethyl-2-[3-(1,3-dioxoisoindolin-2-yl)-2-
methylmalonate 1
Diester 1 was obtained from the reaction between 10 g of
diethyl-2-methylmalonate (57.4 mmol), 15.40 g (57.4 mmol) of
N-(bromopropyl)-phthalimide and 2.74 g (68.9 mmol) of NaH fol-
lowing a literature procedure. An amount of 12.8 g (35.4 mmol,
62%) pure 1 was obtained as a colorless liquid upon purification
by column chromatography (30:70 EtOAc/hexanes). Characteriza-
tion data of 1 matched literature values.22
Rf = 0.35 (30% EtOAc/hexanes).
[a]
24 = +29.2 (c 1, CH2Cl2).
D
Mp = 65 °C. IR (cmÀ1) = 3219.6, 2940.4, 2871.9, 1726.5, 1655.5. 1H
NMR (CDCl3, 400 MHz): d 6.25 (br s, 1H), 4.2 (m, 2H), 3.36 (m,
2H), 2.26 (m, 1H), 1.84 (m, 2H), 1.73 (m, 1H), 1.50 (s, 3H), 1.27
(t, 3H, J = 7 Hz). 13C NMR (CDCl3, 100 MHz): d 173.6, 172.0, 61.2,
50.3, 42.3, 33.0, 22.4, 90.4, 14.0. HRMS [C9H15NO3Na+]
calcd = 208.0944, found = 208.0944.
4.2. Synthesis of (R)-5-(1,3-dioxoisoindolin-2-yl)-2-(ethoxy-
carbonyl)-2-methylpentanoic acid 2
4.5. Synthesis of (S)-1-tert-butyl 3-ethyl 2-methyl-2-(3-(1,3-
dioxoisoindolin-2-yl)propyl)malonate 5
Compound 2 was prepared from 10 g of 1 (28 mmol) employing
pig liver esterase (PLE) catalyzed desymmetrization following a lit-
erature procedure.22 The resulting half-ester was purified by flash
chromatography (40:60 EtOAc/hexanes) to give 6.60 g of the pro-
duct as a colorless liquid (20 mmol, 68%). The% ee was determined
A volume of 600 lL concd H2SO4 was added to a solution of 2 g
of 2 (6 mmol) in 30 mL of CH2Cl2 in a 100 mL sealed tube. The solu-
tion was cooled to À7 °C. A volume of 6 mL of condensed isobuty-
lene was added to the solution. The tube was sealed tightly and

S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
1297
allowed to stir overnight at rt. The tube was uncapped and allowed
to stir for 2 h at ambient pressure to allow excess isobutylene to
evaporate. The solution was diluted with 30 mL of CH2Cl2 and
gently washed three times with 1 M NaOH (50 mL). The CH2Cl2
layer was dried over MgSO4, evaporated under reduced pressure,
and chromatographed (40% EtOAc/hexanes), giving 2 g (5.1 mmol,
under an N2 atmosphere. The reaction mixture was heated to 95 °C
and stirred for over 12 h. The reaction completion was verified by
TLC (20% EtOAc/hexanes). The toluene layer was evaporated under
reduced pressure, and the residue was chromatographed (20%
EtOAc/hexanes) giving 0.97 g (3.3 mmol, 80%) of 8 as a colorless
oil. The conversion of lactam 7 to the corresponding thiolactam 8
was confirmed by comparing the 13C NMR chemical shift of the lac-
tam 7 carbonyl carbon (173.6 ppm) to thiolactam 8 carbonyl car-
87%) of
5 as a white solid. Rf = 0.53 (40% EtOAc/hexanes).
[
a]
D
23 = À5.2 (c 1, MeOH). Mp = 77 °C. IR (cmÀ1): 2976.2, 2936.4,
1771.3, 1712.5. 1H NMR (CDCl3, 400 MHz): 7.84 (m, 2H), 7.71 (m,
2H), 4.18 (m, 2H), 3.74 (m, 2H), 1.91 (m, 2H), 1.61 (m, 2H), 1.48
(s, 9H), 1.39 (s, 3H), 1.28 (t, 3H, J = 7 Hz). 13C NMR (CDCl3,
100 MHz) 172.3, 171.03, 168.3, 134.0, 132.1, 123.2, 81.5, 61.1,
54.0, 38.1, 34.7, 28.0, 25.3, 20.0, 14.0. HRMS [C21H27NO6Na+]:
calcd = 412.1730, found = 412.1730.
bon (202.5 ppm). Rf = 0.3 (20% EtOAc/hexanes). [a]
22 = +75.2 (c 1,
D
CH2Cl2). IR (cmÀ1) = 2936.7, 1731.3, 1506.9. 1H NMR (CDCl3,
400 MHz): d 7.31 (m, 5H), 5.69 (d, 1H, J = 14.37 Hz), 5.04 (d, 1H,
J = 14.37 Hz), 4.23 (m, 2H), 3.43 (m, 2H), 2.28 (m, 1H), 2.01 (m,
1H), 1.83 (m, 2H), 1.75 (s, 3H), 1.30 (t, 3H, J = 7 Hz). 13C NMR
(CDCl3, 100 MHz): d 202.5, 173.6, 135.0, 129.0, 127.7, 127.5, 61.5,
57.7, 55.5, 50.4, 32.1, 27.8, 19.4, 14.0. HRMS [C16H21NO2SNa+]
calcd = 314.1185, found = 314.1184.
4.6. Synthesis of (S)-tert-butyl 3-methyl-2-oxopiperidine-3-
carboxylate 6a
4.9. Synthesis of (R)-ethyl 1-benzyl-3-methylpiperidine-3-
A volume of 398
lL (4.4 mmol) 35% hydrazine in water was added
carboxylate 9
to a solution of 1.50 g (4 mmol) of 5 in 25 mL of MeOH. The mixture
was heated at reflux overnight. A white precipitate was observed
within an hour of reflux. The reaction mixture was allowed to cool
to rt and the solution was filtered. An amount of 0.55 g of K2CO3
(4 mmol) was added to the filtrate, and the solution was allowed to
reflux for another 6 h. The solvent was evaporated under reduced
pressure and the residue taken up in CH2Cl2. The resulting mixture
was washed with water and the organic layer was dried over MgSO4,
evaporated under reduced pressure, and chromatographed using 30%
hexanes/EtOAc giving 0.62 g (3 mmol, 75%) of 6a as a white solid.
Rf (6a) = 0.27 (30% hexanes/EtOAc). Mp = 130 °C. IR (cmÀ1): 3218.5,
A 0.80 g portion of 8 (2.7 mmol) was dissolved in 20 mL of 4:1
THF/EtOH. A 0.16 g portion of Raney-Ni slurry in water (20% by
weight) was added to the solution. The solution was stirred vigor-
ously under a H2 atmosphere for 6 h, at which point the reaction
was found to be half-complete by TLC (10% hexanes/CH2Cl2). The
mixture was continued to stir under an H2 atmosphere another
6 h. The reaction was found to be completed via TLC to give
0.54 g (2 mmol, 78%) of 9 as a colorless liquid. Rf = 0.35 (20% hex-
anes/CH2Cl2).
[a]
21 = +11.8 (c 1, CH2Cl2). IR (cmÀ1) = 2939.4,
D
2795.4, 1725.9. 1H NMR (CDCl3, 400 MHz): 7.29 (m, 5H), 4.43 (m,
2H), 3.52 (d, 1H, J = 13.54 Hz), 3.40 (d, 1H, J = 13.59 Hz), 2.97 (br
m, 1H), 2.58 (br m, 1H), 2.02 (m, 3H), 1.73 (m, 1H), 1.59 (m, 1H),
1.21 (t, 3H, J = 7 Hz), 1.16 (br s, 1H), 1.13 (s, 3H). 13C NMR (CDCl3,
100 MHz): 176.5, 138.2, 128.8, 127.0, 63.1, 62.0, 60.2, 54.0, 43.1,
33.2, 24.0, 23.0, 14.0. HRMS [C16H23NO2Na+] calcd = 284.1621,
found = 284.1621.
2975.6, 2938.5, 2870.8, 1726.7, 1660.3. [a D
]
23 = À16.2 (c 1, CH2Cl2).
1H NMR (CDCl3, 400 MHz): 6.28 (br s, 1H), 3.61 (m, 2H), 2.2 (m,
1H), 1.8 (m, 2H), 1.61 (m, 1H), 1.42 (s, 12H). 13C NMR (CDCl3,
100 MHz): 174.2, 173.9, 83.0, 51.0, 43.0, 34.0, 28.0, 20.0, 14.0. HRMS
[C11H19NO3Na+]: calcd = 236.1257, found = 236.1258.
4.7. Synthesis of (R)-ethyl 1-benzyl-3-methyl-2-oxopiperidine-
3-carboxylate 7
4.10. Synthesis of (R)-1-benzyl-3-methylpiperidine-3-carboxylic
acid 10
A solution of 0.30 g (1.6 mmol) of 4a in 10 mL of anhydrous THF
was added slowly to a suspension of 0.046 g NaH (1.92 mmol) in
10 mL of THF at 0 °C under an N2 atmosphere. The reaction mixture
A 0.125 g portion of crushed LiOH powder (5.2 mmol) was
added to a solution of 0.46 g (1.7 mmol) of 9 in 20 mL of 3:2
H2O/EtOH. The reaction was stirred at rt overnight. The reaction
was determined to be complete by TLC (5% MeOH/CH2Cl2). The
mixture was acidified to pH 3 (10% HCl), and the water layer was
evaporated under reduced pressure giving a colorless gummy resi-
due. The gummy residue was triturated with 10% MeOH/CH2Cl2
(20 mL Â 20), and the MeOH fractions were dried over MgSO4.
The solvent was removed under reduced pressure giving 0.36 g
(1.56 mmol, 88%) of 10 as a white solid as verified by TLC and
staining with bromocresol green. Rf = 0.15 (5% MeOH/CH2Cl2).
was allowed to stir for 5 min. A volume of 210 lL (1.76 mmol) of
BnBr was added dropwise to the reaction mixture at 0 °C. The reac-
tion mixture was allowed to stir for 10 min at 0 °C and then
allowed to warm to rt. The reaction was continued for 1 h at rt. A
volume of 6 mL of dry DMF was added to the reaction mixture,
which continued to stir for 2 h. The reaction mixture was poured
into 15 mL of H2O. The water layer was extracted with Et2O
(3 Â 25 mL). The combined ether layer was washed with water
(3 Â 10 mL), dried over MgSO4, evaporated under reduced pres-
sure, and chromatographed (gradient, 15–20% EtOAc/hexanes) giv-
ing 0.36 g (1.3 mmol, 81%) of pure 7 as a colorless oil. Rf = 0.3 (20%
[a]
22 = +19.0 (c 1, MeOH). IR (cmÀ1) = 3367.5, 2961.4, 1706.1. 1H
D
NMR (CD3OD, 400 MHz):
d
7.52 (m, 5H), 4.50 (d, 1H,
EtOAc/hexanes). [
a
]
24 = +62.6 (c 2, CH2Cl2). IR (cmÀ1) = 3219.6,
J = 13.61 Hz), 4.17 (d, 1H, J = 13.59 Hz), 3.60 (d, 1H, J = 13.3 Hz),
3.40 (d, 1H, J = 13.3 Hz), 3.10 (m, 1H), 2.80 (d, 1H, J = 13.40 Hz),
2.20 (d, 1H, J = 13.40 Hz), 1.98 (m, 1H), 1.80 (m, 1H), 1.54 (m,
1H), 1.2 (s, 3H). 13C NMR (CD3OD, 100 MHz): d 178.1, 132.0,
131.2, 130.4, 130.3, 62.1, 57.7, 55.0, 43.4, 33.0, 24.1, 22.1. HRMS
[C14H19NO2Na+] calcd = 256.1308, found = 256.1309.
D
2940.4, 2871.9, 1726.5, 1655.5. 1H NMR (CDCl3, 400 MHz): 7.29
(m, 5H), 5.0 (d, 1H, J = 14.24 Hz), 4.2 (m, 3H), 3.24 (m, 2H), 2.23
(m, 1H), 1.79 (m, 3H), 1.54 (s, 3H), 1.29 (t, 3H, J = 7 Hz). 13C NMR
(CDCl3, 100 MHz): d 173.6, 169.3, 137.2, 128.5, 127.8, 127.3, 61.4,
50.7, 50.4, 47.3, 33.4, 22.7, 19.4, 14.2. HRMS [C16H21NO3Na+]
calcd = 298.1413, found = 298.1411.
4.11. Synthesis of (R)-3-methylpiperidine-3-carboxylic acid 11
4.8. Synthesis of (S)-ethyl 1-benzyl-3-methyl-2-thioxo-
piperidine-3-carboxylate 8
A 0.30 g (1.3 mmol) portion of 10 was dissolved in 15 mL of
MeOH and added to 0.06 g Pd/C (20% by weight). The solution
was allowed to stir overnight under a H2 atmosphere at rt. The
resulting mixture was filtered through Celite, and the filtrate was
A 1.70 g (4.2 mmol) portion of Lawesson’s reagent was added to
a solution of 1.30 g (4.7 mmol) of 7 in 20 mL of anhydrous toluene

1298
S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
evaporated under reduced pressure giving 0.185 g (1.29 mmol,
93%) of 11 as a white solid. Mp = 90 °C, [
24 = +1.2 (c 1, MeOH),
under a N2 atmosphere. The reaction mixture was heated to 95 °C
and stirred over 12 h. The reaction completion was verified by TLC
(20% EtOAc/hexanes). The toluene layer was evaporated under
reduced pressure, and the residue was chromatographed (20%
EtOAc/hexanes) giving 0.58 g (2.1 mmol, 78%) of 14 as colorless
oil. The conversion of lactam 13 to the corresponding thiolactam
14 was confirmed by comparing the 13C NMR chemical shift of
the lactam 13 carbonyl carbon (173.6 ppm) to the thiolactam 14
carbonyl carbon (202.3 ppm). Rf = 0.33 (20% EtOAc/hexanes).
a
]
D
Rf = 0.08 (5% MeOH/CH2Cl2). IR (cmÀ1) = 3374.7, 2959.4, 1706.1.
1H NMR (CD3OD, 400 MHz): d 3.53 (d, 1H, J = 12.56 Hz), 3.28 (m,
1H), 2.97 (m, 1H), 2.83 (d, 1H, J = 12.56 Hz), 2.19 (d, 1H,
J = 12.56 Hz), 1.88 (m, 1H), 1.69 (m, 1H), 1.58 (m, 1H), 1.27 (s,
3H). 13C NMR (CD3OD, 100 MHz): d 178.5, 50.10, 44.3, 41.4, 33.5,
23.5, 21.0. ESI-MS [C7H13NO2H+] calcd = 143.1, found = 144.1. We
could not perform HRMS analysis due to the molecular weight
being lower than the detection limit of the instrument.
[a]
22 = À15.7 (c 1, CHCl3). 1H NMR (CDCl3, 400 MHz): d 7.33 (m,
D
5H), 5.35 (m, 2H), 3.76 (s, 3H), 3.42 (m, 2H), 2.30 (m, 1H), 1.92
(m, 3H), 1.75 (s, 3H). 13C NMR (CDCl3, 100 MHz): 202.3, 174.1,
135.3, 128.8, 127.7, 127.5, 58.0, 56.1, 52.7, 50.4, 32.4, 27.7, 19.3.
HRMS [C15H19NO2SNa+] calcd = 300.1028, found = 300.1029.
4.12. Synthesis of (S)-tert-butyl 1-benzyl-3-methyl-2-oxo-
piperidine-3-carboxylate 12
A solution of 1.0 g (4.7 mmol) of 6a in 20 mL of anhydrous THF
was added slowly to a suspension of 0.14 g NaH (5.6 mmol) in
10 mL of THF at 0 °C under an N2 atmosphere. The reaction mixture
4.15. Synthesis of (S)-methyl 1-benzyl-3-methylpiperidine-3-
carboxylate 15
was allowed to stir for 5 min. A volume of 0.63 lL (5.2 mmol) of
BnBr was added dropwise to the reaction mixture at 0 °C. The reac-
tion mixture was allowed to stir for 10 min at 0 °C and then
allowed to warm to rt. The reaction was continued for 1 h at rt. A
volume of 20 mL of dry DMF was added to the reaction mixture,
which continued to stir for 2 h. The reaction mixture was poured
into 15 mL of H2O. The water layer was extracted with Et2O
(3 Â 25 mL). The combined ether layer was washed with water
(3 Â 10 mL), dried over MgSO4, evaporated under reduced pres-
sure, and chromatographed (gradient, 15–20% EtOAc/hexanes) giv-
ing 1.20 g (3.8 mmol, 80%) of pure 12 as a white solid. Rf = 0.32
A 0.40 g portion of 14 (1.4 mmol) was dissolved in 20 mL of 4:1
THF/EtOH. A 0.08 g portion of Raney-Ni slurry in water (20% by
weight) was added to the solution. The solution was stirred vigor-
ously under a H2 atmosphere for 6 h at which point the reaction
was found to be half-complete by TLC (10% hexanes/CH2Cl2). The
mixture was continued to stir under H2 atmosphere for another
6 h. The reaction was found to be completed via TLC to give
0.27 g (1.12 mmol, 80%) of 15 as a colorless liquid. Rf = 0.33 (20%
hexanes/CH2Cl2). [
a]
23 = À5.0 (c 0.8, CHCl3). IR (cmÀ1) = 2954.8,
D
2794.6, 1729.6. 1H NMR (CDCl3, 400 MHz): 7.26 (m, 5H), 3.66 (s,
3H), 3.53 (d, 1H, J = 13.01 Hz), 3.40 (d, 1H, J = 13.01 Hz), 2.94 (m,
1H), 2.59 (m, 1H), 2.09 (m, 2H), 1.92 (m, 1H), 1.73 (m, 1H), 1.60
(m, 1H), 1.14 (m, 4H). 13C NMR (CDCl3, 100 MHz): 176.9, 138.6,
128.7, 127.9, 126.8, 62.9, 61.7, 54.0, 51.4, 43.3, 33.3, 23.9, 22.9.
HRMS [C15H21NO2Na+] calcd = 270.1464, found = 270.1466.
(20% EtOAc/hexanes). [
a]
D
24 = À64.2 (c 1, CHCl3). Mp = 108 °C IR
(cmÀ1) = 2977.8, 2933.4, 1727.5, 1625.9. 1H NMR (CDCl3,
400 MHz): 7.28 (m, 5H), 5.04 (d, 1H, J = 14.54 Hz), 4.16 (d, 1H,
J = 14.54 Hz), 3.22 (m, 2H), 2.21 (m, 1H), 1.76 (m, 3H), 1.47 (m,
12H). 13C NMR (CDCl3, 100 MHz): d 173.0, 170.2, 137.4, 128.5,
128.0, 127.3, 81.4, 51.3, 50.5, 47.4, 33.5, 28.0, 22.3, 20.0. HRMS
[C18H25NO3Na+] calcd = 326.1726, found = 326.1728.
4.16. Synthesis of (S)-1-benzyl-3-methylpiperidine-3-carboxylic
acid 16
4.13. Synthesis of (S)-methyl 1-benzyl-3-methyl-2-oxo-
piperidine-3-carboxylate 13
A 0.89 g portion of crushed KOH powder (16 mmol) was added
to a solution of 0.20 g (0.8 mmol) of 15 in 20 mL of EtOH. The reac-
tion was allowed to reflux overnight. The reaction was determined
to be complete by TLC (5% MeOH/CH2Cl2). The mixture was acidi-
fied to pH 3 (10% HCl), and the water layer was evaporated under
reduced pressure giving a colorless gummy residue. The gummy
residue was triturated with 10% MeOH/CH2Cl2 (20 mL Â 20), and
the MeOH fractions were dried over MgSO4. The solvent was
removed under reduced pressure giving 0.14 g (0.6 mmol, 75%) of
A volume of 3 mL TFA was added to a solution of 1 g 12
(3.2 mmol) in 25 mL CH2Cl2. The reaction was continued to stir
over 2 h at ambient temperature. At which point the reaction
was found to be completed as evident by TLC and ESI-MS. The
methylene chloride layer was evaporated and the residue was dis-
solved in 20 mL of DMF. An amount of 0.50 g (3.6 mmol) K2CO3
was added to the solution, followed by, an amount of 0.91 g
(6.4 mmol) of CH3I. The reaction was continued to stir under N2
atmosphere over 3 h at which point the reaction was found to be
completed by TLC. The reaction mixture was poured into 50 mL
of H2O. The water layer was extracted with Et2O (3 Â 50 mL). The
combined ether layer was extracted with water, washed with
brine, dried over MgSO4, and evaporated out to dryness giving
16 as a white wax. [
a]
D
22 = À9.5 (c 1, MeOH). Characterization data
of 16 matched that of 10.
4.17. Synthesis of (S)-3-methylpiperidine-3-carboxylic acid 17
A 0.30 g (1.3 mmol) portion of 10 was dissolved in 15 mL of
MeOH and added to 0.06 g Pd/C (20% by weight). The solution
was allowed to stir overnight under a H2 atmosphere at rt. The
resulting mixture was filtered through Celite, and the filtrate was
evaporated under reduced pressure giving 0.185 g (1.29 mmol,
0.74 g (2.85 mmol, 89%) of pure 13 as
a
colorless oil.
[
a
]
22 = À40.0 (c 0.7, CHCl3). Rf = 0.29 (20% EtOAc/hexanes). IR
D
(cmÀ1) = 2948.6, 1730.8, 1634.6. 1H NMR (CDCl3, 400 MHz) 7.30
(m, 5H), 4.81 (d, 1H, J = 14.27 Hz), 4.41 (d, 1H, J = 14.27 Hz), 3.74
(s, 3H), 3.24 (m, 2H), 2.25 (m, 1H), 1.77 (m, 3H), 1.54 (s, 3H). 13C
NMR (CDCl3, 100 MHz) d 174.4, 169.8, 137.2, 128.6, 127.8, 127.3,
52.3, 50.7, 50.5, 47.3, 33.4, 22.9, 19.7. HRMS [C15H19NO3Na+]
calcd = 284.1257, found = 284.1258.
93%) of 17 as an oil. [
of 17 matched that of 11.
a
]
24 = À1.5 (c 1, MeOH). Characterization data
D
Acknowledgements
4.14. Synthesis of (R)-methyl 1-benzyl-3-methyl-2-thioxo-
piperidine-3-carboxylate 14
D.S.M. would like thank the National Science Foundation for a
CAREER award (MCB-0844478). E.R.V. is grateful to the National
Science Foundation for a GK-12 fellowship (NSF-GK12 0947944).
We are thankful to the National Science Foundation for instrument
grants providing mass spectrometry and NMR facilities used in this
A 1.03 g (2.5 mmol) portion of Lawesson’s reagent was added to
a solution of 0.70 g (2.7 mmol) of 13 in 20 mL of anhydrous toluene

S. Banerjee et al. / Tetrahedron: Asymmetry 26 (2015) 1292–1299
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