Concise and Environmentally Friendly Asymmetric Total Synthesis of the Putative Structure of a Biologically Active 3-Hydroxy-2-piperidone Alkaloid

Article abstract of DOI:10.1055/s-0037-1610089

An asymmetric total synthesis of stereoisomers of a putative structure of 3-hydroxy-2-piperidone alkaloid derivative is described. This route is not only concise and efficient but also is achieved under an environmentally friendly approach. To this end, a direct and double C-H oxidation reaction of simple benzylated piperidine and Baker's yeast reduction of a carbonyl group allowed the rapid access to the optically enriched (S)-1-benzyl-3-hydroxy-2-piperidone in only three steps. The NMR data agreed with those obtained in the first total synthesis (and in discrepancy with the natural product), however, optical rotation did not match with both neither the natural and synthetic material.

Full text of DOI:10.1055/s-0037-1610089

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
feature
A
en
J. Romero-Ibañez et al.
Feature
Synthesis
Concise and Environmentally Friendly Asymmetric Total Synthesis
of the Putative Structure of a Biologically Active 3-Hydroxy-2-
piperidone Alkaloid
Julio Romero-Ibañez
Oxidative deamination &
Baker's yeast carbonyl reduction
This work, 2018
Silvano Cruz-Gregorio
O
OH
Leticia Quintero
2 steps
Ph
(S)
(R)
Fernando Sartillo-Piscil*
0
0
0
0
0-
0
0
2
4-
3
2
2
7-
5
3
4
Dual C–H
tandem oxidation
O
N
O
N
(R,S)-1a
N
O
Asymmetric, economical,
fast and green
H
<98% ee
76% ee
PMB
PMB
Centro de Investigación de la Facultad de Ciencias Químicas,
Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur
Esq. San Claudio, Col. San Manuel, 72570 Puebla, México
fernando.sartillo@correo.buap.mx
(3 steps)
Krishna et al., 2013
O
O
Ph
(S) Ph
(S)
(R)
(R)
CO2EtO
O
O
1 step
N3
N
1a
OH
H
11 steps
Received: 10.03.2018
Accepted after revision: 11.05.2018
Published online: 26.06.2018
Although the 3-hydroxy-2-piperidone possesses a some-
what simple chemical structure, starting from 4-penten-1-
ol, 13 steps were required to synthesize them. Evidently,
the construction of the 3-hydroxy-2-piperidone ring is the
most complicated challenge for the synthesis.3 Indeed, 12
steps were required for the elaboration of the simple 3-hy-
droxy-2-piperidone skeleton.2 The incorporation of the chi-
ral acid fragment was achieved under Steglich conditions4
(Scheme 1). Even though the optical rotation value of 1a
gave a similar value with the natural product, NMR data of
both diastereomers 1a and 1b showed strong discrepancies
with the natural product.
DOI: 10.1055/s-0037-1610089; Art ID: ss-2018-z0169-fa
Abstract An asymmetric total synthesis of stereoisomers of a putative
structure of 3-hydroxy-2-piperidone alkaloid derivative is described.
This route is not only concise and efficient but also is achieved under an
environmentally friendly approach. To this end, a direct and double C–H
oxidation reaction of simple benzylated piperidine and Baker’s yeast re-
duction of a carbonyl group allowed the rapid access to the optically en-
riched (S)-1-benzyl-3-hydroxy-2-piperidone in only three steps. The
NMR data agreed with those obtained in the first total synthesis (and in
discrepancy with the natural product), however, optical rotation did not
match with both neither the natural and synthetic material.
Key words alkaloids, 3-hydroxypiperidin-2-ones, total synthesis, envi-
ronmentally friendly, TEMPO, C–H oxidation, sodium chlorite
HO
(S)
Ph
O
(S)
Ph
O
(R)
O
Steglich
conditions
O
N
H
In 2011, the group of Zhang, Liu, and co-workers report-
ed the isolation and cytotoxicity evaluation (among other
known secondary metabolites) of a new chemical constitu-
ent 1 from endophytic fungus Fusarium oxysporum.1 Mo-
lecular structure was determined by HR-TOF-MS, NMR, and
CD, which appeared to be consistent with a new 3-hydroxy-
2-piperidone derivative 1 (Figure 1).
1a
OH
O
12 steps
(R)
OH
N
4-penten-1-ol
H
3-hydroxy-2-
piperdidone
Steglich
conditions
O
O
(R) Ph
(R)
O
N
H
HO
(R)
Ph
unresolved
1b
O
O
8
Ph
(R)
Scheme 1 Synthesis of 3-hydroxy-2-piperidone derivative alkaloid 1a
and 1b by Krishna et al.
O
O
N
H
1
In the light of this apparent molecular structure dis-
crepancy, an asymmetric total synthesis of the four possible
stereoisomers of alkaloid 1 was envisioned. Although one
might consider that the enantiomeric synthesis of each dia-
stereoisomer of 1a and 1b (ent-1a and ent-1b) is unneces-
sary, because both compounds would provide the same
spectroscopic information and the same optical rotation
Figure 1 Proposed molecular structure of (R)-2-phenylpropionyl-2-
piperidone-3-yl ester (1)
Given the fact that the absolute configuration at C-8 of 1
was unresolved, two years later, the group of Krishna re-
ported the total synthesis of two diastereomers 1a and 1b.2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
J. Romero-Ibañez et al.
Feature
Synthesis
value (but with opposite sign), we presumed that their syn-
thesis from different ways would provide validity regarding
the molecular structure of the target compounds 1a and 1b
(Scheme 2). Moreover, the main premises of this total syn-
thesis are the development of a more concise total synthe-
sis of the target products and the use of cheap and environ-
mentally friendly reactants, thus providing an economic
and ecological asymmetric total synthesis of a relevant nat-
ural product.
Since the major challenge of the synthesis of this alka-
loid is the asymmetric elaboration of the 3-hydroxy-2-
piperidone framework, this novel approach is based upon
the adaptation of the recent dual sp3 C–H oxidation reaction
of cyclic amines to 3-hydroxylactams into an asymmetric
version.5 Consequently, it was envisioned to prepare opti-
Biographical Sketches
Julio Romero Ibañez was
born in 1992 in Puebla, México.
He obtained his B.S. and Mas-
ter’s degree (with honors in
both 2015 and 2017, respec-
tively) at the Benemérita Uni-
versidad Autónoma de Puebla
developing the first total syn-
thesis of a bioactive naturally
occurring alkaloid [(+)-Piplarox-
ide]. He is presently doing grad-
uate studies with Prof. Fernando
Sartillo Piscil developing new
ways of rapid functionalization
of cyclic amines to bioactive al-
kaloids with an economic and
environmental approach.
Silvano Cruz Gregorio stud-
ied chemistry (B.S. and Ph.D. in
2002 and 2008, respectively) at
the Benemérita Universidad
Autónoma de Puebla, México.
His doctoral thesis focused on
the conformational and config-
urational analysis of six-mem-
bered-ring phosphates under
the supervision of Dr. Fernando
Sartillo-Piscil and Dra. Leticia
Quintero. After obtaining his
Ph.D. degree, he moved to the
Universidad del Mar (Oaxaca,
México, 2009) and UPIIG-IPN
(Guanajuato México, 2010) as
an organic chemistry lecturer.
He returned to the Benemérita
Universidad
Autónoma
de
Puebla in 2011 as an associate
professor in the Sartillo-Piscil’s
group. His current research in-
terests lie on the total synthesis
of natural products and the syn-
thesis and conformational study
of HepDirect prodrug ana-
logues.
Leticia Quintero was born in
Puebla, México. She received
her B.S. in pharmacobiological
chemistry from the Benemérita
mans, in 1983. After a postdoc-
toral stay with Prof. David Crich
at the University College Lon-
don, she returned to Puebla to
create the Unidad de Investi-
gación en Síntesis Orgánica
(UISO), the first Center of Inves-
tigation in Organic Synthesis in
the province of México, in 1988.
Although she maintains her ma-
jor research interest in organic
synthesis, she is considered as a
‘Master Educator’, because she
teaches undergraduate classes
with enrollments up to or more
than 100 students.
Universidad
Autónoma
de
Puebla, and her degree of Doc-
teur ès Sciences in Gif sur Yvette
working with Dr. R. Beugel-
Fernando Sartillo-Piscil was
born in Tlaxcala, México. He re-
ceived his B.S. in chemistry in
1996 from the Universidad
Autónoma de Tlaxcala. After a
predoctoral stay in 2000 with
Prof. David Crich at the Universi-
ty of Illinois at Chicago, he ob-
tained his doctoral degree in
2003 working with Dra. Leticia
Quintero at the Benemérita Uni-
versidad Autónoma de Puebla.
In the same year, Sartillo-Piscil
started his independent investi-
gations at the same university
focusing on the development of
novel synthetic methodologies
involving free radicals, and on
the conformational and config-
urational study of six-mem-
bered-ring phosphates. His
current research interest has
been extended to the studies of
reaction mechanism, the total
synthesis of biologically active
compounds using the Chiron
Approach, and the rapid func-
tionalization of simple cyclic
amines to bioactive alkaloids
under
transition-metal-free
conditions.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
J. Romero-Ibañez et al.
Feature
Synthesis
HO
(S)
Ph
O
O
O
O
(S)
(S)
Ph
Ph
or
(R)
O
(S)
O
O
1. Steglich
2. CAN
N
N
H
H
1a
ent-1b
OH
*
Hβ
1. Double C–Hα,β tandem oxidation
2. Reductive Zn elimination
N
O
N
Hα
3. Hydroxyl group oxidation
4. Enzymatic reduction
OMe
OMe
3
2
1. Mitsunobu
2. CAN
O
O
O
(R)
Ph
(R)
Ph
(S)
(R)
O
or
O
O
N
H
N
HO
H
(R)
Ph
ent-1a
O
1b
Scheme 2 Asymmetric synthesis of the four stereoisomers of 1 from N-p-methoxybenzylpiperidine (3)
cally enriched N-p-methoxy-benzylated 3-hydroxy-2-
NaClO2, NaOCl
OY
O
OH
Zn (40 equiv)
piperidone 2 in only four simple steps from N-p-methoxy-
N
O
TEMPO, MeCN
(74%)
THF/H2O/AcOH
(82%)
N
N
benzylpiperidine (3) by following the four sequential chem-
ical transformations depicted in Scheme 2. Thereafter, by
coupling 2 with optically pure (R)- and (S)-2-phenylpropi-
onic acid under Steglich4 and Mitsunobu6 conditions fol-
lowed by oxidative removal of the p-methoxybenzyl group,
the four stereoisomers of 1 will be prepared (Scheme 2).
Execution of the synthesis plan started when N-p-me-
thoxybenzylpiperidine (3) (which can be quantitatively
prepared from simple benzylation of piperidine and p-me-
thoxybenzyl chloride) was treated with two equivalents of
NaClO2 and 2.2 equivalents of both NaOCl and 2,2,6,6-te-
tramethyl-1-piperidinyloxy (TEMPO) to give 3-alkoxyami-
no-2-piperidone 4 in good yield. The treatment of 4 with 40
equivalents of Zn provided racemic 3-hydroxy-2-piperi-
done (rac-2) in also good yield. Because one of the prime
premises of this asymmetric total synthesis was the envi-
ronmentally friendly approach, then, oxidation protocols
involving transition metals or Swern and related reactions
which produce toxic and unpleasant-smelling by-products
were excluded.7 Thus, Dess–Martin reagent8 was tested giv-
ing very poor yield of keto amide 5. Aqueous oxidation with
NaOCl catalyzed with TEMPO9 gave the same poor yield. In-
terestingly, by using 2-iodoxybenzoic acid (IBX) as oxidiz-
ing reagent10 in acetonitrile, the complete conversion of
rac-2 to 5 was achieved. Without further purification pro-
cess, enzymatic reduction of 5 with Baker’s yeast and D-glu-
cose11 produced the enantio-enriched 3-hydroxy-2-piperi-
done (S)-2 in 65% yield and 76% of enantiomeric excess12
(Scheme 3).
OMe
rac-2
OMe
4
3
OMe
IBX
MeCN
OTBS
OH
O
O
Baker's yeast
TBSCl
N
N
O
Y =
D-glucose
N
O
N
Imidazole
CH2Cl2
(90%)
65%, 76% ee
from rac-2
OMe
OMe
OMe
(S)-6
5
(S)-2
20–20 (c = 1.0 CHCl3)
[α]
[α]
D
20–34 (c = 1.1 CHCl3)
Lit.13
D
Scheme 3 Enzymatic asymmetric enantio-enriched synthesis of
3-hydroxy-2-piperidone (S)-2
id.13 NMR data and optical rotation of (S)-6 was consistent
with the reported values in the literature.
Although the (R)- and (S)-2-phenylpropionic acids [(R)-
and (S)-7] are commercially available, it was very compli-
cated for us to get them from chemical companies. Conse-
quently, an efficient enantiopure route to prepare them was
adapted.14 Chiral resolution of racemic 2-phenylpropionic
acid (rac-7) with a non-covalent resolving agent, such as
the (S)- and (R)-α-methylbenzylamine [(S)-8 and (R)-8] was
employed (Scheme 4).
Starting from benzyl bromide, rac-7 was prepared in
three steps. First, nucleophilic displacement of bromine
atom of benzyl bromide by cyanide ion with trimethylsilyl
cyanide (TMSCN), then α-alkylation of benzonitrile with
MeI in the presence of lithium diisopropylamide (LDA), and
finally, base-mediated hydrolysis of nitrile group to carbox-
ylic acid with NaOH gave racemic 2-phenylpropionic acid
Determination of absolute configuration at C-3 was
achieved by chemical correlation with the known O-silylat-
ed compound (S)-6, which was previously prepared by
Huang et al. using the chiron approach from L-glutamic ac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
J. Romero-Ibañez et al.
Feature
Synthesis
[(R,R)-1b] (Table 1). Additionally, detailed COSY and HSQC
experiments of (R,S)-1a revealed that C-6 resonates at 42.2
ppm, and not at 45.4 ppm,15 as stated in the literature.2
However, the most disturbing discrepancy was the optical
rotation values for both 2-piperidones (R,S)-1a and (R,R)-
1b. While our synthetic 2-piperidone (R,S)-1a gave a value
1. LDA, MeI
TMSCN
BnCN
BnBr
Ph
CO2H
rac-7
2. aq NaOH (5 N) then concd
HCl
(90% over 2 steps)
K2CO3
(88%)
+
enriched (S)-7
(R)-8
(S)
Ph
(S)-8
NH2
H3N (S)
Ph
25
[α]D20 +50.0 (c 0.4, MeOH), the literature value was [α]D
(0.5 equiv)
(0.5 equiv)
(R)
Ph
CO2
rac-7
toluene
[(R)-7·(S)-8]
(R)
H3N
–96.4 (c 0.3, MeOH). On the other hand, our 2-piperidone
Ph
(S)
Ph
CO2
20
(R,R)-1b showed an even more marked discrepancy: [α]D
[(S)-7·(R)-8]
HCl
–7.0 (c 1.2, MeOH), and the literature value was [α]D25 +23.5
(c 0.3, MeOH) (Scheme 5).
HCl
(R)
Ph
CO2H
(S)
Ph
CO2H
(R)-7
(22% from rac-7)
O
(S)-7
(25% from rac-7)
20
O
O
Ph
+
Ph
20
[α]
–72 (c 2.0 CHCl3)
–72 (c 1.6 CHCl3)
D
O
O
N
R
O
20
(Aldrich company) [α]
[α]
N
R
+72 (c 2.0 CHCl3)
D
D
(R,S)-9
CAN
65%
(S,S)-9 (minor)
OH
O
R = H;
(R,S)-1a
Scheme 4 Enantiopure preparation of carboxylic acids (R)- and (S)-7
20
D
[α]
[α]
+50.0 (c 0.4, MeOH); <98% ee
–96.4 (c 0.3, MeOH)
25
D
N
R
DEAD, Ph3P
Lit.2
(A)
(rac-7). Resolution of rac-7 was achieved by dissolving it
with 0.5 equivalent of (S)-methylbenzylamine [(S)-8] in tol-
uene to afford precipitation of the diastereomeric salt [(R)-
7·(S)-8], which after the treatment with aqueous HCl gave
the optically pure (R)-phenylpropionic acid [(R)-7]. The en-
antiomerically enriched carboxylic acid (S)-7 remaining in
the toluene solution was treated with 0.5 equivalent of (R)-
8 thus to obtain the respective diastereomeric salt [(S)-
7·(R)-8], which afforded the corresponding optically pure
carboxylic acid (S)-7 after treatment with HCl (Scheme 4).
The synthesis of 1a and 1b (Krishna’s alkaloids2), in
which the absolute configuration at the C-3 position is R,
was projected via inversion of the configuration of (S)-2 un-
der Mitsunobu reaction conditions with (S)-7 and (R)-7, fol-
lowed by oxidative debenzylation. Under classical Mitsuno-
bu reaction conditions [diethyl azodicarboxylate (DEAD),
Ph3P in THF], (S)-2 and (S)-7 gave N-p-methoxybenzyl-2-
piperidones (R,S)-9 and (S,S)-9 in good combined yield with
an 8:1 ratio, respectively (Scheme 5). The minor product
(S,S)-9 comes from the R-enantiomer (not shown) generat-
ed from the enzymatic reduction of keto-2-piperidone 5,
whereby its contribution in the diastereomeric ratio is con-
sistent with the obtained 76% of enantiomeric excess (see
Scheme 3). After treatment of (R,S)-9 with ceric ammonium
nitrate (CAN), the target piperidone 1a [(R,S)-1a] was ob-
tained in 65% yield and <98% of enantiomeric excess.12 Fol-
lowing the same two-step procedure, starting from (S)-2
and (R)-7, diastereomers (R,R)-9 and (S,R)-9 were obtained
in 75% yield in the same 8:1 ratio, respectively. The major
diastereoisomer (R,R)-9 was transformed to piperidone
(R,R)-1b via oxidative debenzylation with cerium ammoni-
um nitrate (65% yield and <98% of enantiomeric excess12).
NMR data analysis of both (R,S)-1a and (R,R)-1b with those
synthesized by Krishna showed good close matching, espe-
cially between (R,S)-1a with that labelled by Krishna as 1b
(S)-2
76% ee
O
O
O
Ph
Ph
+
O
R = 4-methoxybenzyl
O
N
R
O
N
R
(R,R)-9
CAN
65%
(S,R)-9 (minor)
R = H;
(R,R)-1b
20
[α]
–7.0 (c 1.2, MeOH); <98% ee
+23.5 (c 0.3, MeOH)
D
25
D
Lit.2
[α]
O
O
Ph
+
Ph
O
O
N
R
O
N
O
R
(S,S)-9
CAN
67%
(R,S)-9 (minor)
OH
R = H;
(S,S)-1b
20
D
[α]
+6.7 (c 0.4, MeOH); 96% ee
DCC, DMAP
(B)
N
R
O
O
O
Ph
(S)-2
76% ee
Ph
+
O
O
N
R
O
N
R
O
R = 4-methoxybenzyl
CAN
63%
(S,R)-9
(R,R)-9 (minor)
R = H; (S,R)-1a
20
[α]
–46.2 (c 0.5, MeOH); 95% ee
D
Scheme 5 Asymmetric synthesis of (R,S)-1a and (R,R)-1b via Mitsuno-
bu reaction (A), and enantiopure synthesis (S,R)-1a and (S,S)-1b via
Steglich reaction (B)
By coupling hydroxyactam (S)-2 with both carboxylic
acids (S)-7 and (R)-7 under Steglich condition, in which the
absolute configuration at C-3 of (S)-2 is retained, afforded
(S,S)-9 and (S,R)-9 in high yield, high enantiomeric excess,12
and with similar diastereomeric ratio. After oxidative de-
benzylation of (S,R)-9 and (S,S)-9 with CAN, the respective
enantiomers of 1a and 1b were obtained. As expected, both
NMR data and optical rotation values (but with opposite
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
J. Romero-Ibañez et al.
Feature
Synthesis
Table 1 NMR Data of Alkaloids Synthesized by Krishna and this Worka
15
10
4
O
O
O
O
O
O
O
8
3
O
O
7
5
6
11
12
9
2
O
O
O
O
O
N
N
N
O
N
14
N
H
H
H
H
13
H1
Position Krishna 1a
Krishna 1b
This work 1a via Mitsunobu This work 1b via Mitsunobu Proposed structure Zhang
δ 13
C
δ 1H (J)
δ 13
C
–
δ 1
H
δ 13
C
δ 1H (J)
δ 13
C
δ 1H (J)
δ 13
C
δ 1H (J)
1
2
3
4
–
5.73
–
6.06
–
–
6.27
–
–
5.83
–
–
–
–
168.7
168.9
168.7
168.6
173.2
69.1 5.16 (dd, 9.0, 6.5 Hz) 68.7 5.24 (dd, 8.9, 6.5 Hz) 68.8 5.25 (dd, 9.5, 6.0 Hz) 69.1 5.17 (dd, 9.5, 6.0 Hz) 60.2 4.56 (dd, 8.0, 3.3 Hz)
26.8 1.87–1.97 (m);
2.06–2.15 (m)
26.7 1.88–1.96 (m);
2.05–2.14 (m)
26.8 1.66–1.74 (m);
1.99–2.04 (m)
26.9 1.89–1.97 (m);
2.09–2.15 (m)
27.6 1.90–1.93 (m);
2.23–2.29 (m)
5
20.5 1.74–1.86 (m);
1.98–2.05 (m)
19.9 1.74–1.83 (m);
1.98–2.04 (m)
20.1 1.76–1.84 (m)
20.5 1.8–1.97 (m)
24.7 1.82–1.85 (m);
1.98–2.02 (m)
6
45.4 3.25–3.31 (m)
45.2 3.24–3.32 (m)
42.2 3.27–3.31 (m)
42.1 3.27–3.37 (m)
47.5 3.18–3.22 (m);
3.62–3.64 (m)
7
8
9
173.6
42.1 3.82 (q, 7.0 Hz)
140.1
–
173.7
42.1 3.82 (q, 6.9 Hz)
140.5
–
173.7
45.5 3.84 (q, 7.0 Hz)
140.5
–
173.6
45.5 3.84 (q, 7.0 Hz)
140.1
–
175.5
45.1 3.82 (q, 7.0 Hz)
140.3
–
–
–
–
–
–
10,14 128.5 7.3–7.35 (m)
11,13 127.6 7.22–7.27 (m)
128.6 7.3–7.36 (m)
127.4 7.22–7.27 (m)
127.1 7.22–7.27 (m)
18.5 1.52 (d, 6.9 Hz)
127.4 7.30–7.34 (m)
128.6 7.30–7.34 (m)
127.1 7.24–7.29 (m)
18.6 1.53 (d, 7.0 Hz)
127.6 7.31–7.37 (m)
128.5 7.31–7.37 (m)
127.1 7.24–7.27 (m)
18.6 1.56 (d, 7.5 Hz)
129.0 7.32–7.35 (m)
127.5 7.26–7.29 (m)
127.2 7.26–7.29 (m)
20.1 1.48 (d, 7.0 Hz)
12
15
127.1 7.22–7.27 (m)
18.6 1.54 (d, 7.0 Hz)
a NMR spectra were recorded on a 500 MHz equipment (CDCl3). Chemical shifts (δ) in ppm and J in Hz. 13C NMR referenced at 77.0 ppm.
sign) of ent-1a and ent-1b were fully consistent with their
respective enantiomers, confirming thus the success of the
total synthesis of the targeted alkaloids 1a and 1b.
the use of bases to promote an unprecedent reductive elim-
ination of tetramethylpiperidine 12 and thus to afford the
required 3-keto-2-piperidone 5. The foundation of this re-
action was based on the intrinsic acidic nature of H-3
caused by the carbonyl group of 4 (Table 2, eq 2). Alkoxy-
We do not wish to adumbrate the origin of the optical
rotation value problem; however, observing the closer NMR
similarities between our 1a (R,S) with those from Krishna’s
group 1b (R,R), the possibility should be considered that the
authors involuntarily exchanged the carboxylic acids in
their Steglich esterification. Thus, the value of +50 of 1a is
closer to that authors’ value of +23.5 for 1b. And the –96.4
for their 1a could be in fact –9.64, so, it would be closer to
the –7.0 value of 1b.
Having completed this concise and asymmetric total
synthesis of 1a and 1b, we realized that this current ap-
proach could be more environmentally friendly if we were
able to develop an efficient protocol to directly transform 3-
alkoxyaminolactam 4 into 3-ketopiperidone 5. Thus, the
oxidative deamination mediated by oxidizing reagents [O]
such as m-chloroperbenzoic acid (mCPBA) was explored;16
however, this chemical transformation did not provide the
expected compound (Table 2, eq 1). By assuming that this
oxidative deamination reaction goes through the oxidation
of the nitrogen atom of 4 to N-oxide intermediate 10 fol-
lowed by an intramolecular hydrogen abstraction that pro-
motes the elimination of the hydroxylamine 11 and forma-
tion of keto piperidone 5,17,18 it was envisioned to explore
aminolactam
4
was unreactive with 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) even at reflux temperature of
THF (Table 2, entry 1). While stronger base like n-BuLi de-
graded the starting material at 0 °C (entry 2), lithium diiso-
propylamide (LDA) was also unreactive at –78 °C (entry 3)
and very reactive at 0 °C (entry 4). Potassium bis(trimethyl-
silyl)amide (KHMDS) did not react with the starting materi-
al neither at –78 °C (entry 5) nor at 0 °C (entry 6). Further-
more, the use of t-BuOK afforded traces of 5 when THF was
used as solvent (entry 7), and high yield when t-BuOH was
employed as solvent (entry 8). Consequently, having
achieved the direct transformation of alkoxyaminolactam 4
into ketolactam 5 in high yield, the global steps of the
asymmetric total synthesis of all stereoisomers of 1 can be
counted as only five steps from benzylated piperidine 2, or
six from simple piperidine.
Starting from a simple non-functionalized piperidine
and using cheap and environmentally friendly reagents, the
asymmetric total synthesis of the four stereoisomers of a
putative biologically active alkaloid was obtained in only
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
J. Romero-Ibañez et al.
Feature
Synthesis
Table 2 Direct Synthesis of 3-Keto-2-piperidone 5 from 3-Hydroxy-
amino-2-piperidone 4
apparatus and are not corrected. Optical rotations were measured in a
digital PerkinElmer-241 polarimeter using the sodium D-line (589
nm) and are reported as degrees at 20 °C. Concentrations are given as
g/100 mL. NMR spectra were recorded on Bruker-500 (500 MHz) and
Varian (300 MHz) spectrometers using TMS as internal reference for
1H (0.0 ppm) and CDCl3 for 13C (77.16 ppm); chemical shifts (δ) are
stated in parts per million (ppm) and Hz for the coupling constants
(J). Standard abbreviations were used to explain the multiplicities.
High-resolution mass spectra-electron impact mode (HRMS-EI) and
high-resolution mass spectra in fast atom bombardment mode
(HRMS-FAB) were used to record mass spectra. FT-IR spectra of com-
pounds were recorded on solid sample in KBr pellets with a DIGILAB
Scimitar Series FT-IR spectrophotometer with a scanning range from
O
O
[O]
N
+
N
N
R
O
N
R
O
OH
5
11
(not observed)
4
O
H
N
O
N
R
O
10
400 to 4000 cm–1
.
B
4-Methoxybenzylpiperidine (3)21
H3
O
O
O
O
base
solvent, temp
N
To a stirred suspension of NaH (37.6 mmol) in anhyd THF (69 mL) at
r.t. was added piperidine (2.8 g, 33.18 mmol). The reaction mixture
was stirred for 15 min before adding 4-methoxybenzyl chloride (3
mL, 22.12 mmol), and then was refluxed for 6 h. The mixture was
cooled to 0 °C, quenched with sat. aq NH4Cl (10 mL), and then the
aqueous phase was extracted with EtOAc (4 × 10 mL). The combined
organic phases were dried (Na2SO4), and the solvent was removed un-
der reduced pressure. The residue was purified by column chroma-
tography [SiO2, hexanes/EtOAc 3:1; Rf = 0.13 (hexanes/EtOAc 3:2 with
0.2% Et3N)] to give 4.45 g (98%) of 3 as a yellow oil.
+
N
N
R
N
R
H
12
4
5
Entry
Conditions
Yield of 5
a
1
2
3
4
5
6
7
8
DBU in THF, 0 °C to reflux
n-BuLi in THF, 0 °C
–
b
–
a
LDA in THF, –78 °C
LDA in THF, 0 °C
–
b
IR (KBr): 2933, 2852, 2833, 2792, 2754, 1612, 1514, 1251, 1039, 821,
–
588, 553, 518 cm–1
.
a
KHMDS in THF, –78 °C
KHMDS in THF, 0 °C
t-BuOK in THF, 0 °C
t-BuOK in t-BuOH, 32 °C
–
1H NMR (500 MHz, CDCl3): δ = 1.42 (br, 2 H, CH2CH2CH2), 1.56 (quint,
J = 5.5 Hz, 4 H, CH2CH2CH2), 2.35 (br, 4 H, CH2NCH2), 3.41 (s, 2 H,
ArCH2N), 3.80 (s, 3 H, OCH3), 6.85 (d, J = 8.5 Hz, 2 H, Ar), 7.22 (d, J = 8.5
Hz, 2 H, Ar).
a
–
traces
80%
13C NMR (125 MHz, CDCl3): δ = 24.5 (CH2CH2CH2), 26.1 (CH2CH2CH2),
54.5 (CH2NCH2), 55.4 (ArCH2N), 63.4 (OCH3), 113.6 (Ar), 130.6 (Ar),
130.6 (Ar), 158.7 (Ar).
a Remaining starting material.
b Degradation of starting material.
five steps. Although the NMR data for the target products is
consistent with that products reported in the first total syn-
thesis, which did not match with the natural product, the
optical rotation did not match, neither in value nor in sign.
Evidently, further synthetic studies are needed for stablish-
ing the correct molecular structure of the natural product.
Moreover, this asymmetric approach represents not only a
convenient venue for the synthesis of many alkaloids bear-
ing the 3-hydroxy-2-piperidine moiety,19 but also a highly
affordable alternative for sterocontrolled synthesis of func-
tionalized alkaloids from simple piperidines or pyrroli-
dines. In other words, the current work represents a conve-
nient alternative for the long, tedious, and expensive proto-
cols that involve the intramolecular cyclization strategy.20
1-(4-Methoxybenzyl)-3-[(2,2,6,6-tetramethylpiperidin-1-
yl)oxy]piperidin-2-one (4)
To a mixture of 3 (0.75 g, 3.65 mmol), TEMPO (0.855 g, 5.475 mmol),
and NaH2PO4·H2O (5.04 g, 36.5 mmol) in MeCN (61 mL) at 0 °C were
added NaClO2 (0.66 g, 7.3 mmol) and aq 3% NaClO (18 mL, 8.0 mmol).
The reaction mixture was stirred at the same temperature for 1.5 h
before the dropwise addition of aq 5 N NaOH (8 mL) to quench the
reaction until the red-wine color was turned into orange. The solids
were filtered and washed with EtOAc, and the liquid phase was sepa-
rated, and the organic phase was washed with sat. aq NH4Cl (30 mL).
The combined organic phases were dried (Na2SO4), and the solvent
was removed under reduced pressure. The residue was purified by
column chromatography (SiO2, hexanes/EtOAc 5:1; Rf = 0.13) to give
1.01 g of 4 as an orange oil (74%).
IR (KBr): 2933, 2870, 1654, 1512, 1460, 1361, 1246, 1174, 1132, 1035
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.12 (br s, 3 H, CCH3), 1.20 (br s, 6 H, 2
× CCH3), 1.28 (br s, 3 H, CCH3), 1.32 (br, 1 H, CCH2CHH), 1.47–1.54 (m,
5 H, CCH2CHHCH2C), 1.61–1.69 (m, 1 H, NCH2CHH), 1.91–2.01 (m, 2 H,
CHHCHHCH), 2.03–2.08 (m, 1 H, CHHCH), 3.11 (dt, J = 12.0, 6.0 Hz, 1
H, NCHH), 3.26 (ddd, J = 12.5, 7.0, 5.5 Hz, 1 H, NCHH), 3.80 (s, 3 H,
OCH3), 4.31 (d, J = 14.5 Hz, 1 H, ArCHH), 4.37 (dd, J = 6.2, 4.2 Hz, 1 H,
O=CCH), 4.71 (d, J = 14.0 Hz, 1 H, ArCHH), 6.84 (d, J = 8.5 Hz, 2 H, Ar),
7.21 (d, J = 8.5 Hz, 2 H, Ar).
Commercially available reagents were used without further purifica-
tion. All reactions were carried out under an inert argon atmosphere
with anhydrous solvents under anhydrous conditions, unless other-
wise noted. Solvents were used as technical grade, and freshly dis-
tilled prior to use. Column chromatography (CC) was performed using
silica gel (230–400 mesh) with solvents indicated in the text. Melting
points were carried out on a Fisher-Scientific 12-144 melting point
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
J. Romero-Ibañez et al.
Feature
Synthesis
13C NMR (125 MHz, CDCl3): δ = 17.2 (CCH2CH2), 18.9 (NCH2CH2), 20.4
(CCH3), 20.6 (CCH3), 27.4 (CH2CH), 33.2 (CCH3), 34.3(CCH3), 40.3 (2 ×
CCH2), 45.9 (NCH2), 49.5 (ArCH2), 55.3 (OCH3), 59.9 (CCH3), 60.8
(CCH3), 80.7 (O=CCH), 113.9 (Ar), 129.3 (Ar), 129.8 (Ar), 158.9 (Ar),
169.5 (C=O).
IR (KBr): 2927, 2852, 1734, 1664, 1610, 1514, 1442, 1354, 1246, 1176,
1031, 815 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.14 (quint, J = 6.3 Hz, 2 H, NCH2CH2),
2.75 (t, J = 6.8 Hz, 2 H, CH2C=O), 3.46 (t, J = 5.8 Hz, 2 H, NCH2), 3.81 (s,
3 H, OCH3), 4.65 (s, 2 H, ArCH2), 6.88 (app d, J = 8.5 Hz, 2 H, Ar), 7.25
(app d, J = 8.5 Hz, 2 H, Ar).
HRMS-EI: m/z calcd for C22H34N2O3: 374.2569; found: 374.2562.
13C NMR (125 MHz, CDCl3): δ = 21.8 (NCH2CH2), 38.8 (CH2C=O), 46.7
(NCH2), 50.6 (ArCH2), 55.4 (OCH3), 114.2 (Ar), 127.8 (Ar), 130.1 (Ar),
157.8 (Ar), 159.4 (NC=O), 191.9 (CH2C=O).
1-(4-Methoxybenzyl)-3-hydroxypiperidin-2-one (rac-2)
To a solution of 4 (0.9 g, 2.4 mmol) in a mixture of AcOH/H2O/THF
(3:1:1, 84 mL) was added Zn dust (6.28 g, 96 mmol). The suspension
was refluxed for 1 h. Upon completion, the mixture was cooled to 0 °C
and an aq saturated solution NaOH was added until pH 12. After ex-
traction with EtOAc (3 x 50 mL), the resulting phases were separated,
the combined organic phases were dried (Na2SO4), and the solvent
was removed under reduced pressure. The residue was purified by
column chromatography (SiO2, hexanes/EtOAc 1:1; Rf = 0.14) to give
463 mg of rac-2 as a cream solid (82%); mp 84–85 °C.
(S)-3-[(tert-Butyldimethylsilyl)oxy]-1-(4-methoxybenzyl)piperi-
din-2-one [(S)-6]
A solution of (S)-2 (45 mg, 0.191 mmol), TBSCl (43 mg, 0.287 mmol),
and imidazole (26 mg, 0.382 mmol) in anhyd CH2Cl2 was stirred at r.t.
for 6 h. After completion of the reaction, H2O (2 mL) was added, and
the resulting phases were separated. The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The residue was
purified by column chromatography (SiO2, hexanes/EtOAc 9:1; Rf =
0.19) to give 60 mg of (S)-6 as a colorless oil (90%); [α]D20 –20.0 (c 1.0,
CHCl3) {Lit.13 [α]D20 –34.0 (c 1.1, CHCl3)}.
IR (KBr): 3241, 2937, 2872, 2835, 1637, 1512, 1440, 1355, 1303, 1246,
1174, 1132, 1035 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.71 (qd, J = 12.0, 4.0 Hz, 1 H, CHHCH),
1.77–1.86 (m, 1 H, NCH2CHH), 1.87–1.93 (m, 1 H, NCH2CHH), 2.25–
2.30 (m, 1 H, CHHCH), 3.21 (dd, J = 8.5, 4.5 Hz, 2 H, NCH2), 3.80 (s, 3 H,
OCH3), 4.02 (br, 1 H, OH), 4.09 (dd, J = 11.0, 6.0 Hz, 1 H, O=CCH), 4.47
(d, J = 14.5 Hz, 1 H, ArCHH), 4.57 (d, J = 14.5 Hz, 1 H, ArCHH), 6.86 (d,
J = 9.0 Hz, 2 H, Ar), 7.19 (d, J = 8.5 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): δ = 20.0 (NCH2CH2), 28.3 (CH2CH), 46.9
(NCH2), 49.8 (ArCH2), 55.3 (OCH3), 68.2 (O=CCH), 114.0 (Ar), 128.5
(Ar), 129.6 (Ar), 159.1 (Ar), 172.4 (C=O).
IR (KBr): 2951, 2927, 2854, 1735, 1718, 1654, 1610, 1514, 1490, 1460,
1246, 1172, 1147, 1109, 1039, 989, 835, 779 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.17 (s, 3 H, SiCH3), 0.19 (s, 3 H, SiCH3),
0.92 [s, 9 H, SiC(CH3)3], 1.64–1.72 (m, 1 H, NCH2CHH), 1.82–1.89 (m, 1
H, NCH2CHH), 1.92–2.01 (m, 2 H, CH2CH), 3.09–3.20 (m, 2 H, NCH2),
3.79 (s, 3 H, OCH3), 4.16 (dd, J = 7.0, 4.5 Hz, 1 H, CH), 4.46 (d, J = 14.5
Hz, 1 H, ArCHH), 4.53 (d, J = 14.5 Hz, 1 H, ArCHH), 6.84 (d, J = 9.0 Hz, 2
H, Ar), 7.18 (d, J = 8.5 Hz, 2 H, Ar).
HRMS-EI: m/z calcd for C13H17NO3: 235.1208; found: 235.1214.
13C NMR (125 MHz, CDCl3): δ = –5.3 (SiCH3), –4.3 (SiCH3), 18.5
[SiC(CH3)3], 19.2 (NCH2CH2), 25.9 [SiC(CH3)3], 31.0 (CH2CH), 46.9
(NCH2), 49.5 (ArCH2), 55.4 (OCH3), 69.7 (CH), 114.0 (Ar), 129.4 (Ar),
129.6 (Ar), 159.0 (Ar), 170.2 (C=O).
(S)-3-Hydroxy-1-(4-methoxybenzyl)piperidin-2-one [(S)-2)]
A mixture of rac-2 (0.247 g, 1.05 mmol) and IBX (0.88 g, 3.15 mmol)
in anhyd MeCN (7 mL) was stirred at 55 °C for 1 h. The reaction mix-
ture was cooled to 0 °C, and the solids formed were filtered and
washed with cold CH2Cl2. The solvent was removed under reduced
pressure to give 0.328 g of ketolactam 5 as a green oil. Without fur-
ther purification process, 5 (0.328 g), D-glucose (0.66 g, 3.67 mmol),
and baker’s yeast (TradiPan®, 6.3 g) were suspended in distilled H2O
(16.8 mL). The suspension was stirred at r.t. for 12 h before the addi-
tion of EtOAc (20 mL). The organic phase was separated and an addi-
tional amount of EtOAc (20 mL) was added to the aqueous phase and
stirred for 20 min. This procedure was repeated three more times.
The combined organic phases were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by column chroma-
tography (SiO2, hexanes/EtOAc 1:1) to give 161 mg of (S)-2 as a white
solid (65%); mp 84–85 °C; [α]D20 –12 (c 3.4, CHCl3).
(R)-1-(4-Methoxybenzyl)-2-oxopiperidin-3-yl (S)-2-Phenylpropa-
noate [(R,S)-9] and (S)-1-(4-Methoxybenzyl)-2-oxopiperidin-3-yl
(S)-2-Phenylpropanoate [(S,S)-9]
Via Mitsunobu Reaction
To a mixture of (S)-2 (66 mg, 0.278 mmol) and PPh3 (73 mg, 0.278
mmol) in anhyd THF (3 mL) at 0 °C was added a solution of (S)-phen-
ylpropionic acid (41.7 mg, 0.278 mmol) in THF (3 mL), followed by the
dropwise addition of DEAD (0.066 mL, 0.334 mmol). After 15 min, the
reaction mixture was stirred at r.t. for 1 h. Upon completion, H2O (1
mL) was added and extracted with EtOAc (3 × 5 mL). The combined
organic phases were dried (Na2SO4) and evaporated under reduce
pressure. The residue was purified by column chromatography (SiO2,
hexanes/EtOAc 4:1) to give 0.084 g (82%) of a diastereomeric mixture
(R,S)-9 and (S,S)-9 in an 8:1 ratio. Further column chromatography
was performed (SiO2, CH2Cl2/toluene/Et2O, 82:14:4) to perfectly sepa-
rate each diastereoisomer.
The enantiomeric excess of (S)-2 was determined by HPLC with a
CHIRALPAK IA [250 mm × 4.6 mm, eluting with hexane/EtOH (85:15),
1.0 mL/min; detection at 261 nm].
1-(4-Methoxybenzyl)piperidine-2,3-dione (5) from 4
Via Steglich Esterification
To a solution of 4 (57 mg, 0.15 mmol) in anhyd t-BuOH (3 mL) was
added t-BuOK (0.3 mL, 1 M in THF). The reaction mixture was stirred
3 h at 32 °C. After quenching with sat. aq NH4Cl (3 mL), the product
was extracted with EtOAc (2 × 5 mL). The combined organic layers
were washed with a dilute solution of NaH2PO4, dried (Na2SO4), and
concentrated in vacuum. The residue was purified by silica gel col-
umn chromatography [SiO2, hexanes/EtOAc, 1:2; Rf = 0.12 (hex-
anes/EtOAc 1:1)] to afford 28.4 mg of 5 (80%) as a white solid; mp
108–110 °C.
To a suspension of DCC (42 mg, 0.2 mmol), DMAP (2 mg, 0.017 mmol),
and (S)-2 (40 mg, 0.17 mmol) in anhyd CH2Cl2 (0.5 mL) at 0 °C was
added a solution of (S)-phenylpropionic acid (28 mg, 0.187 mmol) in
anhyd CH2Cl2 (0.4 mL). The reaction mixture was stirred for 15 min
and then for 3 h at r.t. After completion of the reaction, the solids
were filtered over Celite and washed with CH2Cl2. The organic solvent
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
J. Romero-Ibañez et al.
Feature
Synthesis
was evaporated under reduced pressure. The residue was purified by
column chromatography (SiO2, CH2Cl2/toluene/Et2O, 82:14:4) to give
6 mg of (R,S)-9 and 41.5 mg of (S,S)-9; both as colorless oils.
(R)-2-Oxopiperidin-3-yl (S)-2-Phenylpropanoate [(R,S)-1a]
To a solution of (R,S)-9 (0.09 g, 0.245 mmol) in MeCN (4.9 mL) at 0 °C
was added a cold solution of CAN (0.4 g, 0.735 mmol) in H2O (1.3 mL).
The reaction mixture was stirred for 3 h at 0 °C and then warmed to
r.t., and H2O (3 mL) was added. The resulting phases were separated,
and the aqueous phase was extracted with EtOAc (3 × 5 mL). The
combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy (SiO2, hexanes/EtOAc/Et2O, 1:3:1.2; Rf = 0.14) to give 39.4 mg of
(R,S)-1a as a colorless oil (65%, <98% ee); [α]D20 +50.0 (c 0.4, MeOH).
(R,S)-9
Rf = 0.16 (CH2Cl2/toluene/Et2O 82:14:4); [α]D20 +22.0 (c 1.5, CHCl3).
IR (KBr): 3061, 3028, 2935, 2870, 2837, 1737, 1654, 1610, 1512, 1490,
1452, 1359, 1340, 1301, 1246, 1199, 1163, 1101, 1070, 1031, 815,
763, 733, 700, 513 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.55 (d, J = 7.0 Hz, 3 H, CHCH3), 1.66–
1.78 (m, 3 H, CH2CHHCH), 1.93–2.01 (m, 1 H, CHHCH), 3.15 (app t, J =
5.5 Hz, 2 H, NCH2), 3.80 (s, 3 H, OCH3), 3.86 (q, J = 7.0 Hz, 1 H, CHCH3),
4.41 (d, J = 14.5 Hz, 1 H, ArCHH), 4.61 (d, J = 14.5 Hz, 1 H, ArCHH), 5.32
(dd, J = 8.8, 5.8 Hz, 1 H, CH2CH), 6.86 (app d, J = 8.8 Hz, 2 H, Ar), 7.19
(app d, J = 8.8 Hz, 2 H, Ar), 7.23–7.28 (m, 1 H, Ar), 7.30–7.34 (m, 4 H,
Ar).
The enantiomeric excess of (R,S)-1a was determined by HPLC with a
CHIRALCEL OD [250 mm × 4.6 mm, eluting with hexane/EtOH
(90:10), 1.0 mL/min; detection at 212 nm].
IR (KBr): 3251, 3064, 3028, 2935, 2873, 1737, 1681, 1494, 1452, 1377,
1361, 1334, 1307, 1201, 1163, 1101, 1070, 933, 765, 736, 700 cm–1
.
HRMS-EI: m/z calcd for C14H17NO3: 247.1208; found: 247.1203.
13C NMR (125 MHz, CDCl3): δ = 18.8 (CHCH3), 19.8 (NCH2CH2), 26.9
(CH2CH), 45.4 (CHCH3), 46.6 (NCH2), 49.7 (ArCH2), 55.4 (OCH3), 69.4
(CH2CH), 114.0 (Ar), 127.1 (Ar), 127.6 (Ar), 128.7 (Ar), 128.7 (Ar), 129.7
(Ar), 140.7 (Ar), 159.0 (Ar), 166.9 (NC=O), 173.9 (OC=O).
(S)-2-Oxopiperidin-3-yl (S)-2-Phenylpropanoate [(S,S)-1b]
Following the same procedure as for (R,S)-9, 40.6 mg of (S,S)-1b (67%,
96% ee) as a colorless oil was obtained from (S,S)-9; Rf = 0.14 (hex-
anes/EtOAc/Et2O, 1:3:1.2); [α]D20 +6.7 (c 0.4, MeOH).
HRMS-FAB: m/z [M + H]+ calcd for C22H26NO4: 368.1862; found:
368.1863.
The enantiomeric excess of (S,S)-1b was determined by HPLC with a
CHIRALCEL OD [250 mm × 4.6 mm, eluting with hexane/EtOH
(90:10), 1.0 mL/min; detection at 215.6 nm].
(S,S)-9
Rf = 0.13 (CH2Cl2/toluene/Et2O 82:14:4); [α]D20 +3.14 (c 2.37, CHCl3).
IR (KBr): 3246, 3062, 3030, 2935, 2873, 1735, 1679, 1492, 1452, 1384,
1355, 1336, 1307, 1199, 1163, 1099, 1076, 931, 763, 744, 700 cm–1
.
IR (KBr): 3062, 3030, 2935, 2873, 2837, 1737, 1654, 1610, 1512, 1490,
1452, 1359, 1338, 1301, 1246, 1199, 1163, 1103, 1070, 1031, 819,
HRMS-FAB: m/z [M + H]+ calcd for C14H18NO3: 248.1287; found:
248.1283.
759, 732, 700, 513 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.57 (d, J = 7.5 Hz, 3 H, CHCH3), 1.71–
1.80 (m, 1 H, NCH2CHH), 1.83–1.97 (m, 2 H, CHHCHHCH), 2.04–2.10
(m, 1 H, CHHCH), 3.13–3.22 (m, 2 H, NCH2), 3.80 (s, 3 H, OCH3), 3.85
(q, J = 7.5 Hz, 1 H, CHCH3), 4.39 (d, J = 14.5 Hz, 1 H, ArCHH), 4.60 (d, J =
14.5 Hz, 1 H, ArCHH), 5.23 (dd, J = 9.5, 6.0 Hz, 1 H, CH2CH), 6.84 (d, J =
8.5 Hz, 2 H, Ar), 7.17 (d, J = 8.5 Hz, 2 H, Ar), 7.24–7.28 (m, 1 H, Ar),
7.32–7.38 (m, 4 H, Ar).
13C NMR (125 MHz, CDCl3): δ = 18.8 (CHCH3), 20.1 (NCH2CH2), 27.1
(CH2CH), 45.6 (CHCH3), 46.5 (NCH2), 49.5 (ArCH2), 55.3 (OCH3), 69.7
(CH2CH), 114.0 (Ar), 127.1 (Ar), 127.7 (Ar), 128.6 (Ar), 128.8 (Ar), 129.6
(Ar), 140.3 (Ar), 159.0 (Ar), 166.7 (NC=O), 173.8 (OC=O).
(S)-2-Oxopiperidin-3-yl (R)-2-Phenylpropanoate [(S,R)-1a]
Following the same procedure as for (R,S)-9, 38.2 mg of (S,R)-1a (63%,
20
95% ee) as a colorless oil was obtained from (S,R)-9; [α]D –46.2 (c
0.5, MeOH).
The enantiomeric excess of (S,R)-1a was determined by HPLC with a
CHIRALCEL OD [250 mm × 4.6 mm, eluting with hexane/EtOH
(90:10), 1.0 mL/min; detection at 209.7 nm].
(R)-2-Oxopiperidin-3-yl (R)-2-Phenylpropanoate [(R,R)-1b]
Following the same procedure as for (R,S)-9, 39.4 mg of (R,R)-1b (65%,
HRMS-FAB: m/z [M + H]+ calcd for C22H26NO4: 368.1862; found:
368.1860.
20
<98% ee) as a colorless oil was obtained from (R,R)-9; [α]D –7.0 (c
1.2, MeOH).
The enantiomeric excess of (R,R)-1b was determined by HPLC with a
CHIRALCEL OD [250 mm × 4.6 mm, eluting with hexane/EtOH
(90:10), 1.0 mL/min; detection at 205 nm].
(S)-1-(4-Methoxybenzyl)-2-oxopiperidin-3-yl (R)-2-Phenylpropa-
noate [(S,R)-9] and (R)-1-(4-Methoxybenzyl)-2-oxopiperidin-3-yl
(R)-2-Phenylpropanoate [(R,R)-9]
Following the same procedure as for (R,S)-9 and (S,S)-9, 43.7 mg of
(S,R)-9 and 6.3 mg of (R,R)-9 (80% combined yield in a 7:1 ratio) were
prepared from (S)-2 and (R)-phenylpropionic acid under Steglich con-
ditions.
Benzyl Cyanide
To a mixture of BnBr (6 mL, 50.45 mmol) and K2CO3 (8.36 g, 60.54
mmol) in MeCN (93 mL) was added TMSCN (9.47 mL, 75.67 mmol).
The reaction mixture was refluxed for 24 h, then cooled to r.t. and di-
luted with aq 2 N NaOH (100 mL). The layers were separated, and the
aqueous layer was extracted with toluene (3 × 100 mL). The combined
organic phases were washed with aq 1 N NaOH (50 mL) and brine (80
mL), dried (Na2SO4), and the solvent was removed under reduced
pressure. The residue was purified by column chromatography (SiO2,
hexanes/EtOAc 9:1; Rf = 0.33) to give 5.19 g of benzyl cyanide as a yel-
low oil (88%).
(S,R)-9; [α]D20 –22.3 (c 2.8, CHCl3).
Following the same Mitsunobu procedure as for (R,S)-9 and (S,S)-9,
76.6 mg of a diastereomeric mixture of (S,R)-9 and (R,R)-9 (75% com-
bined yield in a 1:8 ratio) were prepared from (S)-2 and (R)-phenyl-
propionic acid.
(R,R)-9; [α]D20 –2.9 (c 3.9, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 3.74 (s, 2 H, CH2), 7.30–7.41 (m, 5 H,
Ar).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
J. Romero-Ibañez et al.
Feature
Synthesis
13C NMR (75 MHz, CDCl3): δ = 23.5 (CH2), 117.8 (CN), 127.8 (Ar), 128.0
(Ar), 129.1 (Ar), 129.9 (Ar).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610089.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(±)-2-Phenylpropionic Acid (rac-7)
To a solution of BnCN (1.73 g, 14.76 mmol) in THF (150 mL) at –78 °C
was added LDA (16.5 mL, 1 M in THF). After 5 min, MeI (1.1 mL, 17.72
mmol) was added. Upon completion, sat. aq NH4Cl (25 mL) was add-
ed, the organic solvent was evaporated under reduced pressure, and
the residue was extracted with EtOAc (3 × 20 mL). The combined or-
ganic phases were dried (Na2SO4) and evaporated under reduced
pressure. The crude material was dissolved in aq 5 N NaOH (34 mL)
and the mixture was refluxed for 4 h. After completion of the reac-
tion, the mixture was cooled to 0 °C and acidified to pH 2 with concd
HCl. The product was extracted with EtOAc (4 × 25 mL), the combined
organic phases were dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by column chromatography (SiO2,
hexanes/EtOAc 9:1; Rf = 0.14) to give 1.99 g of rac-7 as a colorless oil
(90%).
References
(1) Wang, Q.-X.; Li, S.-F.; Zhao, F.; Dai, H.-Q.; Bao, L.; Ding, R.; Gao,
H.; Zhang, L. X.; Wen, H.-A.; Liu, H.-W. Fitoterapia 2011, 82, 777.
(2) Krishna, P. R.; Kumar, P. V. A.; Mallula, V. S.; Ramakrishna, K. V.
S. Tetrahedron 2013, 69, 2319.
(3) For instance, optically pure 3-hydroxy-2-piperidones are
obtained in six steps from δ-valerolactone under harsh condi-
tions; see: Kamal, A.; Ramana, K. V.; Ramana, A. V.; Babu, A. H.
Tetrahedron: Asymmetry 2003, 14, 2587.
(4) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(5) Osorio-Nieto, U.; Chamorro-Arenas, D.; Quintero, L.; Höpfl, H.;
Sartillo-Piscil, F. J. Org. Chem. 2016, 81, 8625.
1H NMR (500 MHz, CDCl3): δ = 1.51 (d, J = 7.5 Hz, 3 H, CH3), 3.74 (q, J =
7.5 Hz, 1 H, CH), 7.25–7.29 (m, 1 H, Ar), 7.31–7.35 (m, 4 H, Ar), 11.53
(s, 1 H, OH).
(6) Mitsunobu, O. Synthesis 1981, 1.
(7) Tojo, G.; Fernández, M. Oxidation of Alcohols to Aldehydes and
Ketones; Springer: New York, 2010.
(8) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(9) Okada, T.; Asawa, T.; Sugiyama, Y.; Kirihara, M.; Iwai, T.;
Kimura, Y. Synlett 2014, 596.
13C NMR (125 MHz, CDCl3): δ = 18.1 (CH3), 45.3 (CH), 127.4 (Ar), 127.6
(Ar), 128.7 (Ar), 139.7 (Ar), 180.5 (C=O).
(10) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(11) Dutton, F. E.; Lee, B. H.; Johnson, S. S.; Coscarelli, E. M.; Lee, P. H.
J. Med. Chem. 2003, 46, 2057.
(12) Enantiomeric excess was determined by HPLC.
(13) Feng, C-G.; Chen, J.; Ye, J. L.; Ruan, Y. P.; Zheng, X.; Huang, P.-Q.
Tetrahedron 2006, 62, 7459.
(14) Fogassy, K.; Harmat, V.; Böcskei, Z.; Tárkányi, G.; Tóke, L.; Faigl,
F. Tetrahedron: Asymmetry 2000, 11, 4771.
(15) See Supporting Information.
(16) Hartmann, M.; Li, Y.; Studer, A. J. Am. Chem. Soc. 2012, 134,
16516.
(17) Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B. J. Org. Chem. 2007, 72,
4504.
(18) Tebben, L.; Studer, A. Angew. Chem. Int. Ed. 2011, 50, 5034.
(19) Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem.
2010, 2831.
(20) Dragutan, I.; Dragutan, V.; Mitan, C.; Vosloo, H. C. M.; Deluade,
L.; Demonceau, A. Beilstein J. Org. Chem. 2011, 7, 699.
(21) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc.
2010, 132, 1770.
Resolution of (±)-2-Phenylpropionic Acid (rac-7)
To a solution of rac-7 (0.88 g, 5.86 mmol) in toluene (30 mL) was add-
ed (S)-phenylethylamine (0.35 g, 2.93 mmol). The reaction mixture
was refluxed for 5 min, and then cooled to r.t. The formed solids were
filtered and recrystallized from toluene (90 mL), then they were acid-
ified with aq 2 N HCl (1 mL), and extracted with EtOAc (3 × 10mL).
The combined organic layers were dried (Na2SO4) and evaporated un-
der reduced pressure. The residue was purified by column chroma-
20
tography (SiO2, hexanes/EtOAc 9:1) to give 194 mg of (R)-7, [α]D
–72.0 (c 2.0, CHCl3); commercial sample from Aldrich: [α]D20 –72.0 (c
1.6, CHCl3). The residual toluene was evaporated under reduced pres-
sure, acidified and extracted with EtOAc (3 × 20 mL) to give of 0.68 g
of optically enriched 2-phenylpropionic acid. The crude material was
treated with (R)-phenylethylamine (0.274 g, 2.26 mmol) in of toluene
(34 mL). Recrystallization from toluene, acidification, extraction, and
purification provided 220 mg of (S)-7; [α]D20 +72 (c 2.0, CHCl3); com-
mercial sample from Aldrich: [α]D20 +72 (c 1.6, CHCl3).
Funding Information
Financial support was provided by CONACyT (project number:
255891) and the Marcos Moshinsky Foundation and BUAP-VIEP.
C
o
nsoe
j
N
a
ocin
a
l
de
Ceinaci
y
Te
c
n
o
lga
í
2(
5
5
8
9
1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I