Transition-Metal-Free Total Synthesis and Revision of the Absolute Configuration of Pipermethystine

Article abstract of DOI:10.1021/acs.joc.9b03218

Starting from 3-hydroxy piperidines, a novel transition-metal-free strategy to 5-hydroxy-5,6-dihydro-2(1H)pyridones is reported. This unprecedented approach, which provides a practical, economical, and ecofriendly alternative to either the classical ring-closing metathesis of N-homoallyl-unsaturated amides or the dehydrogenation of amides, occurs by means of a triple C-H functionalization of three unreactive piperidine sp³ carbons. The completion of the total synthesis revealed that the natural levo-isomer possesses the R absolute configuration, not S.

Full text of DOI:10.1021/acs.joc.9b03218

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Note
Transition-Metal-Free Total Synthesis and Revision
of the Absolute Configuration of Pipermethystine
Laura Y Vázquez-Amaya, Leticia Quintero, Braulio Rodríguez-Molina, and Fernando Sartillo-Piscil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03218 • Publication Date (Web): 29 Jan 2020
Downloaded from pubs.acs.org on February 2, 2020
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Page 1 of 6
The Journal of Organic Chemistry
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Transition-Metal-Free Total Synthesis and Revision of the Absolute
Configuration of Pipermethystine
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2
Laura Y. Vázquez-Amaya, Leticia Quintero, Braulio Rodríguez-Molina, and Fernando Sartillo-
Piscil. *
1
1Centro 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.
2Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Ciudad de
México 04510, México.
Supporting Information Placeholder
on
lizati
Triple
(R)
functiona
(R)
(R) OH
OAc
OH
C-H
TEMPO
Transiti
O
N
O
N
N
NaClO , NaOCl
from 0°C to 145 °C
2
on-metal
free
PMB
PMB
Ph
O
5
1%
(
R)-Pipermethystine
20
[
] D = -164.2 (c = 1.0, Me2CO)
Current synthesis:
20
Natutal source: [] = -176.4 (c = 0.49, Me2CO)
D
Previous synthesis: []
D
= +191 (c = 0.8, CH2Cl2)
ABSTRACT: Starting from 3-hydroxy piperidines, a novel transition-metal free strategy to 5-hydroxy-5,6-dihydro-2(1H)pyridones
is reported. This unprecedented approach, which provides a practical, economical and ecofriendly alternative to either the classical
ring-closing metathesis of N-allyl-unsaturated amides or the dehydrogenation of amides, occurs by means of a triple C−H
3
functionalization of three unreactive piperidine sp carbons. The completion of the total synthesis revealed that the natural levo-
isomer possesses R absolute configuration, not S.
3
The selective C−H activation of sp carbon atoms can be
understood as the conversion of a specific unreactive carbon
center into a functionalized carbon group. In order to achieve
this, the use of precious or transition metal catalyst and
benzylpiperidines, and the application to the total synthesis
and revision of the absolute configuration of naturally
occurring pipermethystine.
4
1
directing groups is required. Although the transition-metal
Despite the biological importance of pipermethystine (-)-1,
catalyzed process has revolutionized the organic chemistry
industry, it is not recommendable to use highly active metals
in the late-step of the synthesis pathway because traces of
a secondary metabolite alkaloid contained in the leaves of
5
Piper methysticum, there is only one single report of its total
6
synthesis. The reason, as Liebeskind stated in his
2
these metal residues could contaminate the final product.
enantiodivergent synthesis of both enantiomers of
pipermethystine 1, is due to the few existing methodologies
for preparing nonracemic 5-oxygenated 5,6-dihydro-2(1H)-
Therefore, eliminating the use of transition or precious metals
would contribute to the development of a greener and more
sustainable synthesis, which is desirable for the
pharmaceutical production processes. In this regard, our
research group has developed efficient, accessible, economic
6
pyridones (A, Scheme 1). His approach is based on the
construction of the piperidone ring by classical ring closing
metathesis (RCM) reaction of N-allyl-3-butenamide 2 to ,-
unsaturated piperidone 3, and the optical purity upon an
enzymatic enantioselective transesterification of racemic
alcohol 1 to pipermethystine (-)-1 (eq 1, Scheme 1).
and
environmentally
friendly
protocols
for
the
functionalization of simple N-heterocycle substrates into
3
relevant bioactive alkaloids.
Continuing with this research approach, the present work
reports a novel transition-metal free protocol to 5-hydroxy-
5,6-dihydro-2(1H)-pyridinones from simple 3-hydroxy
Scheme 1. Liebeskind’s approach to pipermethystine (eq 1).
Proposed transition-metal free approach to pipermethystine
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The Journal of Organic Chemistry
With this novel synthetic approach to 5-hydroxy-5,6-
Page 2 of 6
HO
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dihydro-2-pyridone from 3-hydroxypiperidines in hands, we
turned attention to synthesize pipermethystine (S)-1 from (R)-
hydroxypiperidine 9 according to the synthesis route depicted
in Scheme 3. Precursor 9 was prepared in four steps from the
N
H
A
O
HO
Three steps
AcO
transesterification
*
(eq. 1)
Enzymatic
10,3a
3
chiral pool,
Application of the triple C(sp )−H
RCM
N
O
N
O
functionalization protocol to (R)-9, now under tandem fashion,
gave the (R)-piperidone derivative (R)-10 with similar
chemical yield as for the “one-pot” fashion applied to 4.
Mitsunobu reaction applied to (R)-10 provided the required
acetylated stereoisomer (S)-11, which was deprotected with
ceric ammonium nitrate (CAN) to (S)-12, and after acylation
with the respective cinnamoyl chloride derivative allowed us
to accomplish the synthesis of (S)-pipermethystine [(S)-1] in
four steps from (R)-9 (Scheme 3).
N
O
N
H
O
H
O
Ph
O
Ph
2
3
rac-1
(-)-1
1
1
AcO
*
HO
Triple
C-H functionalization?
HO
*
*
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
O
(eq. 2)
N
N
R
5
O
O
Ph
R
4
(
-)-1
Scheme 3. Triple C−H functionalization of hydroxypiperidine
(R)-9 to (S) and (R)-pipermethystine
In contrast, we envisioned a novel and simple transition-
metal-free triple C(sp )−H functionalization protocol that
3
OAc
OH
OH
AcOH, DIAD, Ph3P
(67%)
would directly transform a chiral 3-hydroxypiperidine (e.g., 4)
into 5-hydroxy 5,6-dihydro-2(1H)-pyridone (e.g., 5) (eq 2,
Scheme 1). To this end, we planned to achieve the third C−H
functionalization of 3-hydroxypiperidine 4 to the required
unsaturated product 5 by incorporating an additional step to
the dual C(sp )−H oxidation of piperidines to 3-
alkoxyaminopiperidones,
oxoammonium ion derived from TEMPO (2,2,6,6-tetramethyl-
1-piperidinyloxy) radical. This additional step would be a
thermal homolytic C−O bond cleavage of transient
intermediate 6 to stable radical B plus TEMPO radical, which
after a hydrogen atom transfer process from B to TEMPO, the
-hydroxy-5,6-dihydro-2(1H)-pyridone 5 would be prepared
eq 3, Scheme 2). To execute this plan, racemic N-benzyl-3-
hydroxypiperidine (4: R = Bn), which was prepared from
TEMPO
NaClO2, NaOCl
°C to 145 °C
O
N
R
N
O
N
0
PMB
(R)-9
PMB
R = PMB; (S)-11
CAN
70%)
(R)-10 (51%)
(
R = H; (S)-12
(
AcO)2, NEt3
3
Ph(CH2)2COCl
nBuLi
(96%)
7
OAc
Ph(CH2)2COCl
which
is
mediated
by
OAc
OAc
nBuLi
O
N
8
O
N
R
O
N
O
9
Ph
O
Ph
R = PMB; (R)-11
CAN
(68%)
(
R)-1 (70%)
(
S)-1 (72%)
R = H; (R)-12
[] 2D 0 = +158.2 (c = 0.2, Me CO)
20
D
2
[] = -166.1 (c = 1.0, Me2CO)
20
5
(
Lit.4c []20= -176.4 (c = 0.49, Me CO)
Lit.5 []
D
= -191 (c = 0.7, CH2Cl2)
D
2
(Natural source)
(Previous synthesis)
3
c
carbonyl reduction of N-Benzyl-3-hydroxy-2-piperidone 7,
was subjected to dual C−H oxidation affording diastereomeric
intermediates 8, which without any purification process, was
placed into a sealed tube and refluxed in t-BuOH at 145° C for
12 h to give 5-hydroxy-5,6-dihydro-2(1H)-pyridone 5 in 54%
yield (eq 4, Scheme 2).
Surprisingly, although NMR data of (S)-1 were identical to
6
those reported by Liebeskind, the sign of optical rotation was
opposite. According to them, the S enantiomer is levorotary,
meanwhile current synthesis indicated that it is dextrorotary
(
Scheme 3). Assuming the possibility that the Mitsunobu
1
2
reaction did not occur with inversion of configuration, we
prepared the enantiomer (R)-1 from (R)-10. First, O-
acetylation of (R)-10 under base conditions to (R)-11 followed
by oxidative debenzylation to (R)-12 and subsequent N-
acylation with the respective cinnamoyl chloride derivative
gave (R)-1 with a negative and close optical rotation value
Scheme 2. Proposed triple C−H functionalization of 4-
hydroxypiperidine 4 to 5-hydroxy-5,6-dihydro-2(1H)-pyridone 5
(eq 1). Execution of the triple C−H oxidation proposal (eq 2)
OH
HO
Dual C-H oxidation
O
O
HO
N
heat
4c
compared to the natural occurring pipermethystine (Scheme
(eq. 3)
N
Ref. 7
N
R
6
N
R
5
O
3
).
R
4
In the light of this controversy, we decided to prepare a
derivative compound from (R)-10 suitable for X-ray
diffraction studies. Fortunately, compound (R,S)-13,13 which
H
O
N
was prepared by coupling known (S)-phenyl-propionyl acid
N
R
O
(S)-14 with (R)-10 under Steglich conditions, followed by
B
double bond reduction and debenzylation with CAN, provided
crystalline material suitable for single-crystal X-ray diffraction
(see Scheme 4 and Supporting Information). Crystal structure
of (R,S)-13 showed that the natural (-)-pipermethystine
possesses absolute R configuration.
OH
O
OH
HO
OTEMP
144 °C
12 h
O
OH
LiAlH4
90%
TEMPO
(eq. 4)
NaClO2, NaOCl
N
N
N
O
N
R
Bn
7
R
Bn
8 (cis/trans ~ 2/1)
4 (R = Bn)
5 (R = Bn)
5% from 4
5
Finally, the current total synthesis and revision of the
absolute configuration of (-)-pipermethystine validates the
biosynthetic hypothesis of the formation of Piper alkaloid (-)-
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The Journal of Organic Chemistry
α,4α-epoxy-5β-pipermethystine (3R,4R,5S)-14 from (-)-
pipermethystine (R)-1. The absolute misassignment of (-)-
pipermethystine did not support this proposal (Scheme 5).
3
(J). Splitting patterns are designated as follow: s, singlet; d,
doublet; t, triplet; q, quartet; qu, quintet; m, multiple; and br,
broad. Commercially available reagents were used without
further purification. Unless otherwise stated, chemical
reactions were carried out under an inert argon atmosphere and
anhydrous solvents. 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 apparatus and were not
corrected. Optical rotations were measured in digital Perkin-
Elmer-241 polarimeter using the sodium D-line (589 nm) and
are reported as degrees at 20 °C. Concentrations are given as
g/100 mL. 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.
4
,14
1
2
3
4
5
6
7
8
9
Scheme 4. Preparation of compound (R,S)-13 from (R)-10 for X-
ray diffraction study and molecular structure of (R,S)-13 obtained
by SXRD analysis. Ellipsoids are drawn at the 50% probability
level
HO
(
S) Ph
O
O
(
S) Ph Pd(OH)2
(S) Ph
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
(R)
(R)
(
R)-10
O
O
DCC, DMAP
82%)
O
N
(85%)
O
N
H
(
R
(R,S)-13
X-ray (CCDC: 1950270)
R = PMB; (R,S)-14
CAN
(71%)
R = H; (R,S)-15
1
-Benzylpiperidin-3-ol (4). To a suspension of LiAlH
g, 0.73 mmol) in dried THF (5 mL) was added a solution of 7
0.05 g, 0.24 mmol) in THF (5 mL) at 0 °C. Then, the reaction
4
(0.29
(
mixture was stirred at room temperature for 12 h. The reaction
was cooled to 0 °C and quenched by the addition of 3 mL of
H
2
O. The resulting solution was filtered through sintered
funnel and rinsed with EtOAc (3 × 15 mL). The combined
organic phases were dried over Na SO and concentrated
under reduced pressure. The residue was purified by column
chromatography with SiO and eluted with Hexane/AcOEt
1:1) to give 41 mg of 4 (90%) as a yellow oil.
2
4
2
(
1
5
1
-Benzyl-5-hydroxy-5,6-dihydropyridin-2(1H)-one (5). To
PO (54 mg, 0.45
(32 mg, 0.36 mmol) and TEMPO (28 mg,
.18 mmol) in t-butyl alcohol (3 mL) at 0 °C was added
Scheme 5. Confirmation of the biosynthetic proposal of (-)-
pipermethystine to (-)-3α,4α-epoxy-5β-pipermethystine. (Note
that the stereochemical descriptor at C-5 changes but not its
stereochemistry integrity).
a solution of 4 (0.035 g, 0.18 mmol), NaH
mmol), NaClO
0
2
4
2
dropwise an aqueous solution of NaOCl (0.68 mL, 3%). The
reaction mixture was stirred for 1 hour and before to
transferred it into a tube which was sealed and immersed in an
oil bath at 145 °C for 12 h. The reaction was quenched by
adding a saturated aqueous solution of NaOH (1 ml).
Whereupon, the mixture reaction was extracted with AcOEt (3
O
R)
(R)
(S)
OAc
anti-bioepoxydation
OAc
(
(R)
O
N
O
N
O
Ph
O
Ph
×
5 mL); the combined organic phases were dried over
SO and concentrated under reduced pressure. The residue
and eluted
with Hexane/AcOEt (1:1) to give 20 mg of 5 (55%) as a
(
-)-(R)-1
(-)-(3R,4R,5S)-14
Na
2
4
was purified by column chromatography with SiO
2
CONCLUSIONS
We have developed, under transition-metal free conditions
and using environmentally friendly reagents, a new synthetic
protocol that permits the direct access to 5-hydroxy-5,6-
dihydro-2(1H)pyridones from 3-hydroxypiperidines. By
applying this novel methodology to the total synthesis of
naturally occurring (-)-pipermethysthine, we were able to
revise, not only its absolute configuration but validate the
biosynthetic proposal, which suggests that (-)-pipermethystine
is the bio precursor of Piper alkaloid (-)-3α,4α-epoxy-5β-
pipermethystine. Further scope and synthetic application of
this novel methodology are under investigation in our
laboratory.
1
yellow oil. H NMR (500 MHz, CDCl
3
) δ: 7.35-7.26 (m, 5H),
6
4
1
.62 (ddd, J = 10.0, 5.0, 1.0 Hz, 1H), 6.06 (d, J = 9.5 Hz, 1H),
.72 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 14.5 Hz, 1H), 4.30 (br,
H), 3.49 (dd, J = 13.5, 5.0 Hz, 1H), 3.39 (ddd, J = 13.5, 5.0,
13
1.0 Hz, 1H). C{H} NMR (125 MHz, CDCl
3
) δ: 163.3, 140.0,
136.8, 128.9, 128.6, 128.3, 127.8, 126.7, 62.4, 52.3, 50.1.
R)-1-(4-methoxybenzyl) piperidin-3-ol [(R)-9]. (R)-9 was
(
10,3a
obtained from L-proline following the reported procedure.
20
1
Mp = 77-79 °C. []
D
= + 15.1 (c = 3.0, CHCl
) δ: 7.19 (apparent d, J = 8.5 Hz, 2H), 6.84
apparent d, J = 8.5 Hz, 2H), 3.79 (apparent s, 4H), 3.44 (d, J
13.5 Hz, 1H), 3.43 (d, J = 13.5 Hz, 1H), 2.24 (br, 1H), 2.45
3
). H NMR
(
(
=
500 MHz, CDCl
3
1
3
(
(
br, 3H), 1.74-1.82 (m, 1H), 1.47-1.64 (m, 3H). C{H} NMR
125 MHz, CDCl ) δ: 158.8, 130.4, 130.2, 113.7, 66.4, 62.5,
EXPERIMENTAL SECTION
Unless otherwise stated, 1H NMR and 13C{H} NMR spectra
were obtained in a 500 MHz and 125 MHz spectrometer,
3
+
60.2, 55.4, 53.5, 31.9, 21.7. HRMS (ESI-TOF) m/z: [M + H]
calcd for C H NO 222.1494, found 222.1490.
1
3
20
2
respectively. Samples were analyzed in CDCl
internal reference using a relative scale in parts per million
ppm) for the chemical shift () and Hz for coupling constants
3
with TMS as
(R)-5-Hydroxy-1-(4-methoxybenzyl)-5,6-dihydropyridin-
2(1H)-one [(R)-10]. To a sealed tube, which contains a
solution of 9 (100 mg, 0.43 mmol), NaH PO (136 mg, 1.13
(
2
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 6
mmol), NaClO
2
(82 mg, 0.90 mmol), TEMPO (70 mg, 0.45
mmol). The reaction mixture was stirred for 20 minutes, then a
solution of freshly prepared hydrocinnamoyl chloride (11.5
L) in dried THF (2.0 mL) was added through a cannula. The
reaction mixture was allowed to react for 2 h, followed by the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol) and an aqueous solution of NaOCl (1.68 mL, 3%) in t-
butyl alcohol at 0 °C was stirred for 30 min before to heat the
reaction mixture at 145 °C for 12 h in an oil bath. The reaction
was quenched by adding a saturated aqueous solution of
NaOH (3 mL). Whereupon, the mixture reaction was extracted
with AcOEt (5 × 5 mL); the combined organic phases were
addition of H O (1.0 mL). The aqueous phase was extracted
2
with AcOEt (4×10 mL). The combined organic lawyers were
dried over Na SO and concentrated under reduced pressure.
2
4
dried over Na
2
SO
4
and concentrated under reduced pressure to
The residue was purified by column chromatography (SiO2,
obtain 53.6 mg of 10 (51% of yield) as a crystalline solid. Mp
hexane/AcOEt, 9:1) to obtain 5.3 mg of (S)-1 (72%) as a
2
0
1
20
4c
20
=
68-70 °C. []
D
= - 89.7 (c = 0.5, CHCl
3
). H NMR (500
colorless oil. []D = + 158.2, (c = 0.2, Me CO); Lit. [] =
2
1
MHz, CDCl
3
) δ: 7.19 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz,
2 3
- 176.4 (c = 0.49, Me CO). H NMR (500 MHz, CDCl ) δ:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
H), 6.59 (dd, J = 9.5, 4.5 Hz, 1H), 5.96 (d, J = 9.5 Hz, 1H),
.73 (d, J = 14.5 Hz, 1H), 4.35 (d, J = 14.5 Hz, 1H), 4.27 (q, J
7.30–7.24 (m, 4H), 7.20 (m, 1H), 6.86 (ddd, J = 9.5, 4.5, 1.0
Hz, 1H), 6.13 (dd, J = 9.5, 1.0 Hz, 1H), 5.39 (q, J = 4.5, Hz,
1H), 4.35 (ddd, J = 14.0, 4.5, 1.0 Hz, 1H), 3.83 (dd, J = 14.0,
4.0 Hz, 1H), 3.37-3.24 (m, 2H), 3.0 (m, 2H), 2.06 (s, 3H).
= 5.0 Hz, 1H), 3.77 (s, 3H), 3.42 (dd, J = 13.5, 5.0 Hz, 1H),
1
3
3.35 (dd, J = 13.5, 5.0 Hz, 1H). C{H} NMR (125 MHz,
CDCl ) δ: 163.5, 159.1, 140.6, 129.6, 128.7, 126.0, 114.1,
2.0, 55.3, 52.1, 49.5. HRMS (ESI-TOF) m/z: [M + H] calcd
234.1130, found 234.1130.
S)-1-(4-Methoxybenzyl)-6-oxo-1,2,3,6-tetrahydropyridin-
1
3
3
3
C{H} NMR (125 MHz, CDCl ) δ: 175.6, 170.1, 163.9,
+
6
141.0, 140.3, 129.0, 128.7, 128.6, 126.2, 63.4, 45.1, 41.0,
31.0, 20.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C H NO 288.1236, found 288.1230.
for C13H16NO
3
(
1
6
18
4
3
-yl acetate [(S)-11]. To a solution of 10 (35.0 mg, 0.15
(70.0 mg, 0.27 mmol) in dried THF (3 mL)
(R)-1-(4-Methoxybenzyl)-6-oxo-1,2,3,6-tetrahydropyridin-
3-yl acetate [(R)-11]. To a solution of (R)-10 (10 mg, 0.04
mmol) and DMAP (15.7 mg, 0.13 mmol) in dried MeCN (2
mL) was added dropwise a solution of triethylamine (7.4 L,
0.06 mmol) in dried MeCN (1 mL) followed by the addition of
a solution of acetic anhydride (6.1 L, 0.06 mmol) in dried
MeCN (1 mL). The reaction mixture was stirred for 2 h at
mmol) and P(Ph)
3
was added dropwise 17 L of acetic acid (0.3 mmol). The
reaction mixture was cooled to 0 °C, and then, DIAD (53 L,
0
.27 mmol) was added dropwise. The reaction mixture was
stirred for 15 h at room temperature. The reaction mixture was
quenched by the addition of a saturated solution of NaHCO
3
(0.5 mL) and washed with brine (2 × 3 mL). The aqueous
layer was extracted with AcOEt (4 × 5 mL). The combined
room temperature. Upon completion, NaHCO was added until
3
reach neutral pH. The liquid phase was filtered, dried over
Na SO , concentrated under reduced pressure and purified by
2 4
organic layers were dried over Na
reduced pressure. The residue was purified by column
chromatography (SiO , Hexane/AcOEt, 1:1) to afford 27.4 mg
of (S)-11 (61% of yield) as a yellow oil. []
2
SO
4
and concentrated under
column chromatography (SiO , hexane/AcOEt, 3: 1, v/v) to
2
give 11.3 mg of (R)-11 (96%) as a yellow oil. []D20 = - 153.9,
2
2
0
D
= + 160.0 (c =
) δ: 7.20 (d, J = 8.5
(c = 0.88, CHCl ). NMR data is identical to (S)-11. HRMS
3
1
+
0
.35, CHCl
3
). H NMR (500 MHz, CDCl
3
(ESI-TOF) m/z: [M + H] calcd for C H NO 276.1236,
1
5
18
4
Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.55 (ddd, J = 9.5, 5.0, 1.0
Hz, 1H), 6.19 (d, J = 9.5 Hz, 1H), 5.26 (q, J = 4.5 Hz, 1H),
found 276.1223.
(R)-6-Oxo-1,2,3,6-tetrahydropiridin-3-yl acetate [(R)-12].
Employing the same procedure as for (S)-12, 50 mg of lactam
(R)-11 was used to obtain 19 mg of (R)-12 (68% of yield) as a
4
3
.78 (d, J = 14.5 Hz, 1H), 4.40 (d, J = 14.5 Hz, 1H), 3.80 (s,
H), 3.56 (dd, J = 14.0, 5.0 Hz, 1H), 3.38 (ddd, J = 14.0, 4.0,
1
3
20
1.0 Hz, 1H), 1.97 (s, 3H). C{H} NMR (125 MHz, CDCl3) δ:
170.3, 162.7, 159.2, 135.1, 129.6, 129.3, 128.6, 114.1, 63.7,
55.4, 49.1, 48.7, 21.0. HRMS (ESI-TOF) m/z: [M + H] calcd
white crystalline solid. Mp = 105-107 °C. []D = - 188.6 (c =
0.88 CHCl ). NMR data is identical to reported for (S)-12.
3
+
+
HRMS (ESI-TOF) m/z: [M + H] calcd for C H NO
7
10
3
for C15
H
18NO
4
276.1236, found 276.1226.
156.0661, found 156.0648.
(R)-Pipermethystine [(R)-1]. Following the same procedure
as for (S)-1, 16 mg (0.1 mmol) of (R)-1 was obtained from
(S)-6-Oxo-1,2,3,6-tetrahydropyridin-3-yl acetate [(S)-12].
To a solution of (S)-11 (13 mg, 0.05 mmol) in MeCN (1 mL)
at 0 °C was added a solution of ceric ammonium nitrate (103
mg, 0.19 mmol) in water (0.3 mL). The reaction mixture was
20
(
0
R)-12 in 70% of yield as a colorless oil. [
D
= -166.0 (c =
2
CO). NMR
20
4c
.55, Me
2
CO); Lit [] = - 176.4, (c = 0.49, Me
data is identical to reported for (S)-1. HRMS (ESI-TOF) m/z:
stirred for 4 h before adding 0.5 mL of H
mixture was extracted with AcOEt (4 × 5 mL); the combined
organic layers were dried over Na SO and the solvent was
removed under reduced pressure. The crude was purified by
column chromatography (SiO , AcOEt) to obtain 4.9 mg of
(S)-12 (70%) as a crystalline solid. Mp = 105-107°C. []
2
O. The resulting
+
[M + H] calcd for C16
4
H18NO 288.1236, found 288.1238.
2
4
1
-(4-Methoxybenzyl)-(R)-2-oxo-5,6-dihydropyridin-5-yl-
(S)-2-phenylpropanoate [(R,S)-14]. To a suspension of DCC
2
(44 mg, 0.21 mmol), DMAP (2.4 mg, 0.019 mmol) and 10 (45
2
0
D
=
mg, 0.19 mmol) in CH
solution of (S)-phenylpropionic acid (34.7 mg, 0.23 mmol) in
CH Cl (1 mL). The reaction mixture was stirred for 15 min at
2
Cl (3 mL) at 0 °C was added a
2
1
+ 183 (c = 0.4, CHCl
3
). H NMR (500 MHz, CDCl3) δ: 6.82
(br, 1H), 6.67 (dd, J = 10.0, 4.5 Hz, 1H), 6.09 (d, J = 10.0 Hz,
2
2
1
3
H), 5.35 (q, J = 4.5 Hz, 1H), 3.70 (dd, J = 14.0, 4.5 Hz, 1H),
.55 (apparent d, J = 14.0 Hz, 1H), 2.09 (s, 3H). C NMR
) δ: 170.4, 165.0, 137.7, 128.1, 63.4, 44.2,
0 ºC, then at room temperature for 3 h. After completion of the
reaction, the solids were filtered over celite and washed with
1
3
(125 MHz, CDCl
3
CH
pressure. The residue was purified by column chromatography
SiO , hexano/EtOAc 4:1) to give 57.7 mg of (R,S)-14 as a
colorless oil (82% of yield). []
2 2
Cl . The organic solvent was evaporated under reduced
+
2
1
1.0. HRMS (ESI-TOF) m/z: [M + H] calcd for C
56.0661, found 156.0652.
7 3
H10NO
(
2
(
0
S)-Pipermethystine [(S)-1]. To a solution of (S)-12 (4.0 mg,
.03 mmol) in dried THF (1.0 mL) at -78 °C was added
dropwise a solution of n-BuLi in THF (1.6 M, 20.9 L, 0.03
20
D
= - 185.8 (c = 1.14,
3
). H NMR (500 MHz, CDCl3) δ: 7.32–7.23 (m, 3H),
1
CHCl
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Page 5 of 6
The Journal of Organic Chemistry
7
.21–7.17 (m, 4H), 6.87–6.85 (m, 2H), 6.43 (ddd, J = 10.0,
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
9
5.0, 1.0 Hz, 1H), 6.13 (d, J = 10.0 Hz, 1H), 5.24 (q, J = 4.5
Hz, 1H), 4.82 (d, J = 14.5 Hz, 1H), 4.29 (d, J = 14.5 Hz, 1H),
3.80 (s, 3H), 3.57 (q, J = 7.5 Hz, 1H), 3.55 (dd, J = 14.0, 1.0
Hz, 1H), 3.37 (ddd, J = 14.0, 5.0, 1.0 Hz, 1H), 1.38 (d, J = 7.5
Hz, 3H). C{H} NMR (125 MHz, CDCl3) δ: 173.8, 162.7,
1
6
Financial support was provided by the CONACyT (project
number: 255891) and the Marcos Moshinsky Foundation. L. Y. V.
A. acknowledges CONACyT for graduate scholarship. Partial
support by the BUAP-VIEP is gratefully acknowledged. Authors
also thank Dr. Rubén A. Toscano for X-ray diffraction studies.
1
3
59.3, 139.9, 134.9, 129.7, 129.2, 128.8, 128.7, 127.5, 114.2,
3.9, 55.4, 49.0, 48.6, 45.5, 18.4. HRMS (ESI-TOF) m/z: [M
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1
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5
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7
8
9
0
procedure, lactam (R,S)-15 was obtained from (R,S)-14 in 71%
as a colorless oil. []
(500 MHz, CDCl ) δ: 7.34–7.25 (m, 5H), 6.52 (ddd, J = 10.0,
4.5, 1.0 Hz, 1H), 6.02 (ddd, J = 10.0, 2.0, 1.0 Hz, 1H), 5.78
(br, 1H), 5.36 (apparent q, J = 5.0 Hz, 1H), 3.74 (q, J = 7.0 Hz,
20
1
D
3
= - 159.9 (c = 0.66, CHCl ). H NMR
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011, 40, 1885-1898. (d) Godula, K.; Sames, D. C–H Bond
Functionalization in Complex Organic Synthesis. Science 2006, 312,
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1
H), 3.69 (ddd, J = 13.5, 5.5, 2.5 Hz, 1H), 3.51 (dddd, J =
1
3
3.5, 5.0, 3.0, 0.5 Hz, 1H), 1.51 (d, J = 7.0 Hz, 1H). C{H}
) δ: 174.0, 164.4, 139.8, 137.6, 128.9,
27.9, 127.5 (2C), 63.8, 45.5, 44.3, 18.5. HRMS (ESI-TOF)
2. (a) Neubacher, S.; Peralta, D. The Benefits of Transition-Metal
Free Reactions. DOI: 10.1002/chemv.201400092. (b) Ghosh, R.;
Lindstedt, E.; Jalalian, N.; Olofsson, B. Room Temperature, Metal-
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3. (a) Romero-Ibañez, J.; Cruz-Gregorio, S.; Sandoval-Lira, J.;
Hernández-Pérez, J. M.; Sartillo-Piscil. F. Transition-Metal-Free
Deconstructive Lactamization of Piperidines. Angew. Chem. Int. Ed.
NMR (125 MHz, CDCl
1
3
+
m/z: [M + H] calcd for C14
46.1139.
R)-6-Oxopiperidin-3-yl (2S)-2-phenylpropanoate [(R,S)-
3]. A mixture of (R,S)-15 (10.0 mg, 0.04 mmol) and
palladium hydroxide on carbon (10 wt. %; 1.0 mg) in EtOH (2
mL) was stirred under H atmosphere (100 psi) for 12 h at
3
H16NO 246.1130, found
2
(
1
2
019, 58, 8867-8871. (b) Chamorro-Arenas, D.; Osorio-Nieto, U.;
Quintero, L.; Hernández-García, L.; Sartillo-Piscil, F. Selective,
3
2
Catalytic, and Dual C(sp )–H Oxidation of Piperazines and
room temperature. Then, the solution was passed through a
pad of silica gel using EtOH as the mobile phase. The solvent
was removed under reduced pressure to yield 8.5 mg of 13 as
a colorless crystalline solid in 85% yield. Mp = 103-105 °C.
Morpholines under Transition-Metal-Free Conditions. J. Org. Chem.
2018, 83, 15333-15346. (c) Romero-Ibáñez, J.; Cruz-Gregorio, S.;
Quintero, L.; Sartillo-Piscil, F. Concise and Environmentally Friendly
Asymmetric Total Synthesis of the Putative Structure of
a
Biologically Active 3-Hydroxy-2-piperidone Alkaloid. Synthesis
2018, 50, 2878-2886. (d) Romero-Ibañez, J.; Xochicale-Santana, L.;
Quintero, L.; Fuentes, L.; Sartillo-Piscil, F. Synthesis of the
Enantiomers of Tedanalactam and the First Total Synthesis and
Configurational Assignment of (+)-Piplaroxide J. Nat. Prod. 2016,
79, 1174-1178.
4. (a) Smith, R. Pipermethystine, a Novel Pyridone Alkaloid from
Piper Methysticum. Tetrahedron 1979, 35, 437-439. (b) Smith, R.
Kava Lactones in Piper Methysticum from Fiji. Phytochemistry 1983,
2
0
1
[
]
δ: 7.34–7.25 (m, 5H), 5.69 (br, 1H), 5.15 (m, 1H), 3.73 (q, J =
.0 Hz, 1H), 3.53 (ddd, J = 13.0, 3.5, 1.0 Hz, 1H), 3.39 (dtd, J
13.0, 3.0, 1.5 Hz, 1H), 2.29–2.16 (m, 2H), 1.95–1.84 (m,
D
3 3
= +30.5 (c = 0.38, CHCl ). H NMR (500 MHz, CDCl )
7
=
13
2
H), 1.51 (d, J = 7.5 Hz, 3H). C{H} NMR (125 MHz,
CDCl ) δ: 174.0, 171.0, 140.2, 128.9, 127.6, 127.5, 65.5, 46.3,
45.7, 26.9, 24.9, 18.2. HRMS (ESI-TOF) m/z: [M + H] calcd
248.1287, found 248.1293.
3
+
for C14H18NO
3
2
2, 1055-1056. (c) Dragull, K.; Yoshida, W. Y.; Tang, C.-S.
Piperidine Alkaloids from Piper Methysticum. Phytochemistry 2003,
3, 193-198. (d) Naumov, P.; Dragull, K.; Yoshioka, M.; Tang, C.-S.;
Ng, S. W. Structural Characterization of Genuine (-)-Pipermethystine,
-)-Epoxypipermethystine, (+)-Dihydromethysticin and Yangonin
from the Kava Plant (Piper methysticum). Nat. Prod. Res. 2008, 3,
33-1336.
. Roots and stems of Piper methysticum (Kava) have been
ASSOCIATED CONTENT
Supporting Information
6
(
The Supporting Information is available free of charge on the
ACS Publications website.
1
5
Copy of NMR spectra (PDF), and CIF for (R,S)-13.
Accession code
employed for preparing ceremonial and social drinks, which induces
relaxation. See: Singh, Y. N., and Singh, N. N. Therapeutic potential
of kava in the treatment of anxiety disorders. CNS Drugs, 2002, 16,
7
31-743.
Arrayas, R. G.; Alcudia, A.; Liebeskind, L. S. Facile
CCD: 1950270.
6
.
This data can be obtained free of charge at
www.ccdc.cam.ac.uk/data_request/cif
Enantiodivergent Approach to 5-Hydroxy-5,6-Dihydro-2(1H)-
pyridones. First Total Synthesis of Both Enantiomers of
Pipermethystine. Org. Lett. 2001, 3, 3381-3383.
7
. (a) Osorio-Nieto, U.; Chamorro-Arenas, D.; Quintero, L.; Höpfl,
AUTHOR INFORMATION
Corresponding Author
3
H.; Sartillo-Piscil, F. Transition Metal-Free Selective Double sp C–H
Oxidation of Cyclic Amines to 3-Alkoxyamine Lactams. J. Org.
Chem. 2016, 81, 8625-8632.
Email: fernando.sartillo@correo.buap.mx.
ORCID
Fernando Sartillo-Piscil: 0000-0002-4322-7534
8
. (a) Merbouh, N.; Bobbitt, J. M.; Brückner, C. Preparation of
Tetramethylpiperidine-1-oxoammonium Salts and Their Use as
Oxidants in Organic Chemistry. A Review. Organic Preparations and
Procedures. 2004, 36, 1-31. (b) Iwabuchi, Y. Recent progress in
oxidative organic transformations employing nitroxyl radicals. J. Syn.
Org. Chem. JPN. 2019, 77, 424-432.
Notes
Authors declare no competing financial interest.
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Page 6 of 6
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. (a) Studer, A. Tin-Free Radical Cyclization Reactions Using the
Persistent Radical Effect. Angew. Chem. Int. Ed. 2000, 39, 1108-
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Kang, Y.-B. J. Org. Chem. 2019, 84, 8267-8274.
0. Métro, T.-X.; Gómez-Pardo, D.; Cossy, J. Highly
13. CCDC: 1950270
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2
2
2
2
2
2
2
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4
4
4
4
4
4
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5
5
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5
5
5
6
14. Osorio-Nieto, U.; Vázquez-Amaya, L. Y.; Höpfl, H.; Quintero,
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Synthesis of 3,4-Epoxy-2-Piperidones. Application to the Total
Synthesis and Absolute Configurational Assignment of 3,4-Epoxy-
5-Pipermethystine. Org. Biomol. Chem. 2018, 16, 77-88.
15 Herdeis, C.; Waibel, D. Synthese Homochiraler 2-Piperidone
aus D-Ribonolacton. Arch. Pharm. 1991, 324, 269-274.
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Enantioselective Synthesis of β-Amino Alcohols:ꢀ
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A Catalytic
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2. Ahn, C.; Correia, R.; DeShong, P. Mechanistic Study of the
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