A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione

Article abstract of DOI:10.1007/s13738-018-1404-1

Abstract: We present a novel asymmetric synthesis route for synthesis of (S)-ketamine?using a chiral reagent according to the strategy (Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional group of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-N-tert-butanesulfinyl ketamine (3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-018-1404-1

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1404-1
ORIGINAL PAPER
A novel strategy for the asymmetric synthesis of (S)-ketamine using
(S)-tert-butanesulfinamide and 1,2-cyclohexanedione
Mohammad Javad Taghizadeh1 · Seyed Jamal Addin Gohari1 · Abdollah Javidan1,2,3 · Abolghasem Moghimi1 ·
Maryam Iman4
Received: 28 February 2018 / Accepted: 13 May 2018
© Iranian Chemical Society 2018
Abstract
We present a novel asymmetric synthesis route for synthesis of (S)-ketamine using a chiral reagent according to the strategy
(Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts
as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the
first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional
group of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-
tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-N-tert-butanesulfinyl ketamine
(3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated
chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the
sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities
of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield.
Graphical abstract
Keywords (S)-Ketamine · Asymmetric synthesis · (S)-tert-Butanesulfinamide · 1,2-Cyclohexanedione · Monoketal ·
Enantioselective construction
Introduction
Ketamine is used in medicine as an anesthetic; however, due
to the hallucinations it may cause, it is not typically used as
* Mohammad Javad Taghizadeh
a primary anesthetic, in combination with other drugs [1–7].
mohammadjavadtaghizadeh31@yahoo.com
Ketamine has been classified as an NMDA receptor antago-
1
nist but its mechanism was not well understood as of 2017
[8]. The S(+) and R(−) ketamine bind with different affini-
ties: Ki=3200 and 1100 nM, respectively [9–15]. There are
some reports on the synthesis of α-phenyl cycloalkanones
in the literature [16]. Such ketones have been the targets
to some studies followed by Calvin L. Stevens et al. using
aryl–alkyl migration, ring contraction, ring expansion and
Department of Chemistry, Faculty of Science, Imam Hossein
University, Tehran, Iran
2
Department of Medicine Chemistry, Faculty of Science
Pharmaceutical Sciences Branch, Islamic Azad University,
Tehran, Iran
3
4
University of Eyvanekey, Eyvanki, Iran
Department of Chemistry, Faculty of Science, Baghyatollah
Medical Sciences University, Tehran, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
rearrangement of phenyl α-aminoketones [17–29]. Enan-
tioselective construction of nitrogen-substituted quater-
nary carbon centers adjacent to the carbonyl group in the
cyclohexane ring was performed with respect to the asym-
metric synthesis of (S)-ketamine anesthetic. A few report for
asymmetric synthesis of (S)-ketamine were recorded in the
literature. Recently, Kiyooka et al. presented two procedures
for this propose [30]. At first procedure, the phenyllithium
was reacted to chiral α-ketoketal bearing chiral auxiliary on
a ketone group with 83% yield and 82% de. However, the
reaction of 2-chlorophenyllithium did not perform in which
this procedure was unavailable for the (S)-ketamine. At sec-
ond procedure, a different strategy was designed, which the
chiral carbon of ketamine with a reduction step by S-BINAL
catalyst was obtained (>99% ee). Beside, Biermann et al.
were presented a new method, the chirality induction pre-
pared using Sharpless Dihydroxylation and followed with
Ritter reaction. Finally, the obtained alcohol amine was
converted to (S)-norketamine by Jones oxidation (=99%
ee) [31].
ketimines have been reacted with organometallic reagents
with good yields and high diastereoselectivity to provide
the tertiary carbinamines [42–47]. Because the general and
efficient methods for the asymmetric synthesis of this class
of amines are not accessible now [42–44, 48]. We report
here on the preparation of quaternary carbon by the addition
of Grignard reagent to N-sulfinyl imine derived from ket-
aled cyclohexanone. In this new procedure, the (S)-ketamine
was prepared after nucleophilic addition of N-sulfinyl cyclic
imine where both conditions of ring and the sulfinyl group
have the potential to control of diastereoselectivity reac-
tion. As far as we know, this is the first time that the three
new intermediates (2–4) were synthesized and identified in
the present study in which are differed from the previously
reported compound (Scheme 1).
Results and discussion
Synthesis of the target (S)-ketamine started with the prepa-
ration of cyclic monoketal from the 1,2-cyclohexandione
(Scheme 2) [30, 46, 49–51]. The monoketal 1 is obtained
with moderate yield due to the high reactivity of monoketal
and conversion to diketal.
On the other hand, the synthesis of chiral amines is
important to both academic and pharmaceutical research.
During the past few years, one of main research lines has
focused on the use of N-(tert-butylsulfinyl) imines in asym-
metric synthesis [32–41]. We were willing to find a practi-
cal method for synthesis of this kind chiral imine in high
yield and purity. Direct nucleophilic addition of the chiral
tert-butanesulfinyl group to the imine and reduction depro-
tonation competition at the α-carbon. The tert-butanesulfinyl
Ketalization of 1,2-cyclohexanedione with ethylene gly-
col in a Dean–Stark device afforded a 1:3 mixture of diketal
and monoketal after reflux. Although the azeotropic removal
of H2O should, in principle, shift the equilibrium towards
the undesired diketal byproduct and the reaction could not
O
Scheme 1 Asymmetric synthe-
O
O
O
O
sis of S-ketamine
S
O
N
NH2
O
S
HO
OH
O
O
PTSA
Ti(OEt)4
2
1
75%
90%
Cl
THF , -78C
MgBr
Cl
O
O
S
O
O
S
NH
O
MeI
HCl
MeOH
N
O
K2CO3
HN
O
Cl
Cl
5
3
4
82%
85%
90%
O
Scheme 2 Preparation of
O
O
monoketal
O
Ethylene glycol, PTSA, Benzene
18h, reflux, Deanstark
O
O
O
+
O
O
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Journal of the Iranian Chemical Society
Table 1 Ketalization of 1,2-cyclohexandione with ethylene glycol
Table 2 Condensations of TBSA with 1 mediated by Ti(IV) compounds
and PTSA
O
O
O
HO
OH
O
O
PTSA
1
Yielda (%)
Entry
Lewis acida
Solvent
Time (h)
Yieldb (%)
Entry
PTSA (%mol)
Solvent
Time (h)
1
2
3
4
5
6
7
8
9
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
THF
THF
THF
THF
Toluene
THF
THF
THF
THF
3
6
12
24
6
3
6
12
24
6
80
90
75
70
79
73
80
65
62
65
1
2
3
4
5
6
0.2
0.2
0.4
0.2
0.2
0.4
Benzene
Benzene
Benzene
Benzene
Toluene
Toluene
8
18
18
24
18
18
30
75
45
50
45
30
Ti(OEt)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
The reaction could not be driven to completion and starting materials
remain
aYield determined by 1H NMR analysis
10
Toluene
aMol ratio of Lewis acid to monoketal, 2–1
bYield determined by NMR analysis
be driven to completion, probably because of the competing
polymerization of ethylene glycol which delivered H2O to
the medium. After extensive experimentation, we found that
the best reaction conditions involved performing P-toluene-
sulfonic acid (PTSA)-mediated ketalization in benzene after
18 h. (entry 2 Table 1). In the presence of PTSA catalyst,
under acidic condition, the carbonyl group of 1,2-cyclohex-
andione is protonated, which activates it towards nucleo-
philic attack of ethylene glycol.
of TBSA with ketone. Due to their Lewis acidity and excel-
lent water-absorbing ability, Ti(IV) salts such as Ti(OEt)4
and Ti(O-i-Pr)4 have been used and Ti(OEt)4 gave the better
yields.
The several factors contribute to the efficiency of cur-
rent precedure: (1) (S)-tert-butanesulfinamide is available
commercially in a pure state, also it is easily synthesized
in two steps from inexpensive raw material; (2) (S)-N-tert-
butanesulfinyl imines was formed from condensation of
(S)-tert-butanesulfinamide and ketones in high yield; (3) the
(S)-N-tert-butanesulfinyl imine actives for the nucleophilic
addition of Grignard and (S)-tert-butanesulfinyl group acts
as a powerful chiral inductive group; (4) the (S)-tert-butane-
sulfinyl group that acts as a Boc-surrogate is stable under
basic conditions but may be easily cleaved with acid. In next
step, addition reaction of Grignard reagent to N-sulfinylim-
ine derived from 2-ketaled cyclohexanone (Scheme 3) was
evaluated. Optimizing the reaction conditions was then car-
ried out to improve both the yields and the diastereoselectiv-
ity of the reaction.
The reaction was performed in a Dean–Stark device and
monoketal was separated by chromatography from the mix-
ture and subjected to hydrolysis. In this way, the preparation
of monoketal can be achieved in 75% yield. The key step in
this approach is the hydrolysis of diketal, by acidic treatment
(PTSA), in which afforded monoketal. Beside, condensa-
tion of (S)-tert-butanesulfinamide with ketale cyclohexanone
employing Ti(IV) salts at reflux temperature provided imine
2 in about 60–90% yields (Table 2). The carbonyl group of
compound 1 is coordinated with Ti(IV) as a catalyst, which
activates it towards nucleophilic attack of (S)-tert-butane-
sulfinamide. The imine was slowly hydrolysed on silica gel,
so the column length of 8–10 cm was used with a flow rate
such that the imine was eluted for 15 min. The imines were
stored by placing a vial of the product into a container of
drierite within a −20 °C freezer. In this step, this transfor-
mation could complete in 6 h (entry 2), and extending reac-
tion time resulted in a decrease in yield (entries 3, 4, 8, 9).
The investigation of various solvents was shown in Table 2
and THF was found to be the best choice. Titanium(IV) salts
were next investigated, primarily to effect the condensation
In addition, temperature was proved to be important for
this reaction. An obvious increase in the yields was observed
when the reaction temperature increased (up to 90%), but
caused dramatic decrease in diastereoselectivity (entries 3,
4). It can be reasonably expected that equatorial attack were
to occur on the lowest energy chair conformation, which has
the ketal group located C2.
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Journal of the Iranian Chemical Society
Scheme 3 Intermediates
of nucleophilic addition to
N-sulfinylimine
Table 3 Optimization of addition of Grignard reagent to N-tert-
(5) in 82% yield [30, 46, 49–51]. The enantiomeric excess
was determined to be > 80% by HPLC analysis (DAICEL
CHIRALCEL OD-H column).
butanesulfinylimine 2
Cl
O
O
O
O
S
N
NH
O
O
MgBr
Experimental
S
Solvent
General
2
3
Cl
All the chemicals were used as purchased (Merck) for the
reactions without further purification. All the organic sol-
vents were purchased from commercial suppliers and were
purified according to standard procedures. In addition,
Lewis acids were obtained from commercial suppliers. All
reactions were carried out in oven-dried glassware under
nitrogen atmosphere. Infrared spectra were recorded using a
Perkin-Elmer Spectrum-100 FT-IR spectrometer. IR spectra
of liquids were recorded as thin films on NaCl plates. The
1HNMR and 13CNMR spectra were determined using TMS
as an internal reference with an Avance FT NMR spectrom-
eter operating at 250 and 60 MHz. The 13CNMR spectra
were determined using TMS as an internal reference with an
Avance FT NMR spectrometer operating at 60 MHz. Mass
spectra analyses were recorded on an Agilent Technolo-
gies, Model: 5975C VL MSD by EI mass spectrometry on
a Q-TOF instrument. Preparative normal-phase HPLC was
performed on a Waters HPLC prep 4000 system equipped
with a 4000-controller pump using column DAICEL CHI-
RALCEL OD-H; detection: UV 254 nm, mobile phases
were 5% 2-propanol/n-hexane, flow: 0.5 mL/min. Flash
chromatography was performed using silica gel 60 (200–300
mesh). Thin-layer chromatography was carried out on sil-
ica gel 60 F-254 TLC plates of 20 cm × 20 cm. Column
chromatography was performed using Merck Silica gel 60
(0.063–0.200 mm). Elemental analysis on C, H and N was
performed using a Perkin-Elmer 2400 Elemental Analyser.
Entry
Solvent
T (°C)
Time (h)
Yielda (%)
drb S:R
1
2
3
4
5
6
7
8
THF
THF
THF
THF
CH2Cl2
Toluene
Toluene
Toluene
−78
−50
0
4
4
4
4
4
4
8
4
85
90
95
97
55
65
64
80
90:10
85:15
78:22
65:35
94:6
88:12
85:25
70:30
25
−78
−78
−78
−50
aIsolated yield of material after chromatography
bDiastereomeric ratio was determined by chiral HPLC assay
As shown in Scheme 3, a six-membered cyclic transition
state with Mg coordinated to the oxygen of the sulfinyl group
is consistent with the sense of induction. In addition, the
proposed cyclic transition state is consistent with the reac-
tion proceeding with highest selectivities in noncoordinating
solvents. Notably, the best diastereoselectivity (94: 6 dr) was
obtained with CH2Cl2 as noncoordinating solvent, but along
with low yield (55%, entry 5). The selectivity observed for
Grignard reagent is also noteworthy, considering that trans-
formation is performed in the coordinating solvent THF.
Therefore, the best condition for Grignard addition was
obtained in THF as solvent (entry 1, Table 3). In this model,
Grignard reagent preferably added to the imine from the
less hindered face to afford (Ss, S) as major diastereomer
(Scheme 3).
The N-tert-butylsulfinyl group can act as not only an
chiral auxiliary, but also an amine-protecting group. Then,
using methyl iodide to provide easily the monomethylation
and obtained desired product (4) with 70% yield [52–55].
Finally, the sulfinyl and ketale groups were removed from
the compound (4) by brief treatment with stoichiometric
quantities of HCl in a protic solvent to produce the ketamine
Synthesis of intermediates
Preparation of 1,4‑dioxaspiro[4.5]decan‑6‑one (1)
A mixture containing of 1,2-cyclohexanedione (0.56 g,
5 mmol) in benzene (10 mL), ethylene glycol (0.31 g,
5 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol) was
1 3

Journal of the Iranian Chemical Society
refluxed using a Dean–Stark apparatus for 18 h. Then, ether
(20 mL) was added to the reaction mixture and diketone
was extracted twice with 1 N NaOH solution (15 mL). The
combined organic layer dried over anhydrous MgSO4 and
concentrated under reduced pressure to afford the yellow
oily product (yield 0.59 g, 75%). The crude product was
used in the next reaction without further purification. IR
(KBr): 3446 (OH), 2947, 2870, 1732, 1358, 1265, 1192,
1102, 1023, 952, 892, 804, 568 cm−1; 1H NMR (250 MHz,
CDCl3, TMS) δ: 1.44–2.48 ppm (m, 8 H), 3.91 ppm (m, 4 H)
ppm. 13C NMR (62.5 MHz, CDCl3): δC=22.6, 26.1, 36.8,
39.5, 65.1, 106.7, 205.3 ppm. Mass spectrum (EI, 70 eV),
m/z (Irel, %): [М+1] + 157 (13), [М] + 156 (27), 128 (35),
100 (31), 99 (100), 97 (32); elemental analysis for C8H12O3:
calculated C 61.52, H 7.74, found C 61.53, H 7.69%.
warmed to room temperature for 4 h. The reaction mixture
was quenched by the addition of saturated aqueous NH4Cl.
The aqueous layer was extracted twice with ether. The com-
bined organic layer dried over anhydrous MgSO4 and con-
centrated under reduced pressure. The residue was purified
by flash silica gel chromatography (1:3 EtOAc–hexane) to
give the desired product as a yellow oil (yield 0.26 g, 85%).
IR (KBr): 3310, 3257 (NH), 3059, 1310, 1189, 1097, 1048,
951, 893, 879, 751, 700 cm−1. 1H NMR (250 MHz, CDCl3,
TMS) δ: 1.25 (s, 9 H), 1.33–2.32 (m, 8H), 3.58–3.64 (m,
1H), 4.15(m, 4 H), 6.86–7.78 (m, 4 H) ppm. 13C NMR
(62.5 MHz, CDCl3) δC : 22.6, 23.6, 22.9, 28.82, 31.7, 38.6,
62.0, 65.8, 68.0, 122.3, 126.3, 128.7, 130.7, 131.0, 132.3,
133.6, 140.1 ppm. α: +179 (c 1.2 CHCl3). de = 90% by
HPLC analysis (DAICEL CHIRALCEL OD-H column).
Mass spectrum (EI, 70 eV), m/z (Irel, %): [М] + 371 (13),
344 (13), 336 (7), 311 (13), 266 (20), 239 (27), 191 (27), 57
(100); elemental analysis for C18H26ClNO3S: calculated C
58.13, H 7.05, N 3.77, found C 58.22, H 7, N 3.77%.
Preparations of (S,E)‑2‑methyl‑N‑(1,4‑dioxas‑
piro[4.5]decan‑6‑ylidene)propane‑2‑sulfinamide (2)
A mixture containing 1 (0.312 g, 2 mmol), Ti(OEt)4
(0.912 g, 4 mmol) in THF (20 mL) was reacted under a
N2 atmosphere. Then, (S)-tert-butanesulfinamide (0.27 g,
2.2 mmol) was added and the reaction mixture was refluxed
for 6 h. After completion of the reaction (monitored by
TLC), the reaction mixture was poured into (20 mL) brine
while rapidly stirring. The resulting suspension was filtered
through a plug of Celite and the filter crude was washed with
EtOAc (30 mL). The filtrate was transferred to a separatory
funnel. The organic layer was washed with brine (3 10 mL).
The brine layer was extracted with EtOAc (10 mL). Then,
the combined organic layer dried over anhydrous MgSO4
and concentrated under reduced pressure. The sulfinylim-
ine 2 was purified by silica gel flash chromatography (1:3
EtOAc–hexane) (brown oil, yield 0.47 g, 90%). IR (KBr):
3340 (NH), 3253, 2952, 2873, 2714, 1668, 1620, 1579, 1455,
1363, 1311, 1188, 1096, 1048, 951, 891, 820 cm−1. 1H NMR
(250 MHz, CDCl3, TMS) δ: 1.25 (s, 9 H), 1.32–2.53 (m,
8 H), 4.00 (m, 4 H) ppm. 13C NMR (62.5 MHz, CDCl3) δC:
22.1, 22.6, 26.2, 31.3, 37.3, 58.9, 64.7, 116.0, 182.6 ppm. α:
+153 (c 1.2 CHCl3). Mass spectrum (EI, 70 eV), m/z (Irel,
%): [М]+259 (3), 232 (7), 199 (22), 154 (19), 139 (16), 98
(47), 57 (100); elemental analysis for C12H21NOS: calcu-
lated C 55.57, H 8.16, N 5.40, found C 55.59, H 8.1, N 5.4%.
Preparation of (S)‑N‑((S)‑6‑argio‑1,4‑dioxaspiro[4.5]
decan‑6‑(2‑cholorophenyl)‑N,2‑dimethylpro‑
pane‑2‑sulfinamide (4)
A solution of sulfinamide 3 (1 g, 2.7 mmol) in 20 mL ace-
tone was homogenized at room temperature. Then, K2CO3
(1.11 g, 8.1 mmol) was added and the reaction mixture was
refluxed for 2 h. Methyl iodide (1.52 g, 5.34 mmol) was
added dropwise over 30 min. After the addition was com-
pleted, the mixture was stirred for 1.5 h. The mixture was
filtered and concentrated under reduced pressure. The oil
obtained was extracted twice with 25 mL n-hexane. The
combined organic layers were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The prod-
uct obtained was purified by silica gel column chromatog-
raphy (2:2 EtOAc–hexane) (yellow oil, yield 1.45 g, 70%).
IR (KBr): 3079, 2913, 2892, 1597, 1467, 1428, 1363, 1310,
1189, 1097, 1048, 951, 893, 879, 751, 700 cm−1. 1H NMR
(250 MHz, CDCl3, TMS) δ: 1.25 (s, 9 H), 1.33–2.32 (m,
8H), 2.48 (s, 3H), 4.11–4.18 (m, 4 H), 6.86–7.78 (m, 4 H)
ppm. 13C NMR (62.5 MHz, CDCl3) δC : 22.9, 23.5, 28.8,
31.8, 38.0, 38.9, 58.4, 63.5, 68.1,125.7, 127.8, 128.7, 130.3,
132.4, 140.7 ppm. α: +152 (c 1.2 CHCl3). Mass spectrum
(EI, 70 eV), m/z (Irel, %): [М]+385 (3), 371 (7), 311 (7), 266
(7), 251 (7), 206 (18), 111 (21), 98.2 (100), 84 (25), 55 (36);
elemental analysis for C19H28ClNO3S: calculated C 59.13, H
7.31, N 3.63, found C 59.22, H 7.27, N 3.63%.
Preparation of (S)‑N‑((S)‑6‑argio‑1,4‑dioxas‑
piro[4.5]decan‑6‑(2‑cholorophenyl)‑2‑methylpro‑
pane‑2‑sulfinamide (3)
A solution of imine 2 (0.22 g, 0.84 mmol) in dry THF
(5 mL) at − 78 °C under N2 was added dropwise from a
dropping funnel to solution of 2-chlorophenyl magnesium
bromide (0.38 g, 2 mmol) in 5 mL THF. The mixture was
stirred at −78 °C for 1 h. Then, the mixture reaction was
Preparations of (S)‑2‑(2‑cholorophenyl) 2‑methyl‑
amino cyclohexan‑1‑one (S‑ketamine) (5)
A solution of sulfinamide 4 (0.386 g, 1 mmol) in metha-
nol (20 mL) was added slowly to 3.5 mL hydrochloric acid
1 3

Journal of the Iranian Chemical Society
2. B.A. Chizh, P.M. Headley, Curr. Pharm. 11(23), 2977–2994
(2005)
(36%). The reaction mixture was stirred at 70 °C for 5 h.
After completion of the reaction (monitored by TLC), the
volatiles were removed under reduced pressure. Then, reac-
tion mixture was cooled to 25 °C and was added 10 mL
aqueous saturated NaHCO3 solution was added. Next,
ammonia was added dropwise to reach PH = 6. The amine
obtained was extracted twice with 25 mL EtOAc and con-
centrated to pale yellow liquid. The combined organic layers
were washed with brine and dried with anhydrous magne-
sium sulfate. Concentration under reduced pressure gave a
residue, which was purified by flash silica gel chromatogra-
phy (1:3 EtOAc–hexane) to afford the corresponding amine
(S-ketamine), (yield 0.2 g, 82%). The enantiomeric excess
was determined to be > 80% by HPLC analysis (DAICEL
CHIRALCEL OD-H column). IR (KBr): 3050, 2842, 2624,
2624, 2555, 2428, 1723, 1597, 1467, 1428, 1363, 1310,
1189, 1097, 1048, 751 cm−1. 1H NMR (250 MHz, CDCl3,
TMS) δ: 1.51–1.82 (m, 4H), 1.82–2.05 (m, 1H), 2.10 (s,
3H), 2.25–2.8 (m, 3H), 2.82–3.1 (m, 1H), 7.2–8.1 (4H) ppm.
13C NMR (125.75 MHz, CDCl3): δC = 23.8, 28.8, 30.4,
38.6, 39.7, 71.5, 127.6, 128.8, 130.3, 132.5, 134.4, 137.5,
3. A. Leung, M.S. Wallance, B. Ridgeway, T. Yaksh, Pain 91(1),
177–187 (2001)
4. M.L. Cohen, A.J. Trevor, Anesthesiology 39(4), 370–376 (1973)
5. M.P. Marietta, W.L. Way, N.J. Castagnoli, A.J. Trevor, J. Pharma-
col. Exp. Ther 202(1), 157–165 (1977)
6. D.A. Cathy, G. Chen, D.H. Kaump, C. Ensor, J. New Drugs 5(1),
21–33 (1965)
7. M.L. Cohen, A.J. Trevor, J. Pharmacol. Exp. Ther. 189(2), 351–
358 (1974)
8. M.W. Tyler, H.B. Yourish, D.F. Ionescu, S.J. Haggarty, ACS
Chem. Neurosci. 8(6), 1122–1134 (2017)
9. K. Hirota, D.G. Lambert, Br. J. Anaesth. 77(4), 441–444 (1996)
10. L.A. Nguyen, H. He, C. Pham-Huy, Int. J. Biomed. Sci. 2, 85–100
(2006)
11. J. Liu, X.-Q. Ji, X.-Z. Zhu, Life Sci. 78(16), 1839–1844 (2006)
12. L.E. Mather, Minerva Anestesiol. 71(9), 507–516 (2005)
13. C. Nau, G.R. Strichartz, Anesthesiology 97(2), 497–502 (2002)
14. J.R. Powell, J.J. Ambre, T.I. Ruo, Anal. Methods Pharmacol.
41, 245–270 (1988)
15. P.F. White, J. Ham, W. Way, A.J. Trevor, Anesthesiology 52,
231–239 (1980)
16. C.L. Stevens, U.S. Patent 3254124: Chem. Abstr. 65, 5414–5423
(1968)
17. C.L. Stevens, R.D. Elliott, B. Winch, L, J. Am. Chem. Soc. 85,
1464–1470 (1963)
ο
208.0 ppm; Mp 123 C; α: − 53.6 (c 2 EtOH) [56]. Mass
18. C.L. Stevens, I.L. Klundt, M.E. Munk, M.D. Pillai, J. Org.
Chem. 30, 2967–2973 (1965)
spectrum (EI, 70 eV), m/z (Irel, %): [М]+237 (12), 222 (28),
186 (24), 167 (28), 149 (100), 139 (44), 111 (44), 85 (72),
57 (64); elemental analysis for C13H16ClNO: calculated C
65.68, H 6.78, N 5.89, found C 65.82, H 6.75, N 5.9%.
19. C.L. Stevens, A.B. Ash, A. Thuillier, J.H. Amin, A. Balys, W.E.
Dennis, J.P. Dickerson, R.P. Glinski, H.T. Hanson, M.D. Pillai,
J.W. Stoddard, J. Org. Chem. 31(8), 2593–2601 (1966)
20. C.L. Stevens, H.T. Hanson, K.G. Taylor, J. Am. Chem. Soc.
88(12), 2769–2774 (1966)
21. J.M. Vate, D. Dumas, J. Gore, Tetrahedron Lett. 31(5), 2277–
2280 (1990)
Conclusions
22. P. Compain, J. Gore, J.M. Vate, Tetrahedron Lett. 36(23), 4059–
4062 (1995)
23. M.D.B. Fenster, B.O. Patrick, G.R. Dake, Org. Lett. 3(13),
2109–2112 (2001)
We have presented a new strategy for the synthesis of (S)-
ketamine as anesthesia drug. The synthetic strategy included
the construction of a chiral nitrogen-substituted quaternary
carbon center using an enantioselective 1,2-addition reac-
tion of 2-cholorophenyl magnesium bromide to chiral α-N-
sulfinylimine-ether acetal, having α-chiral sulfinylimine
auxiliary. The use of (S)-tert-butanesulfinamide chiral aux-
iliary is one advantageous in the current strategy because the
tert-butanesulfinyl group activates the imine for nucleophilic
addition and serves as a powerful chiral inductive group. The
chiral compound with a nitrogen-substituted quaternary car-
bon bearing α-carbonyl group was obtained after deprotec-
tion. Thus, the asymmetric synthesis of (S)-ketamine, after
methylation and deprotection, was accomplished with 82%
yield and 70% ee.
24. C.L. Stevens, U.S. Patent. No. 3254124 (1966)
25. R.S. Sulake, C. Chen, H.R. Lin, A.C. Lua, Bioorg. Med. Chem.
Lett. 21(19), 5719–5721 (2011)
26. A. Podgors, S. Stavber, M. Zupan, J. Green Chem. 9(5), 1212–
1218 (2007)
27. C.L. Stevens, B. Peter, M.J. Morton, Org. Chem. 28, 331–336
(1963)
28. C.L. Stevens, T. Andre, Org. Chem. 30(4), 2967–2975 (1965)
29. P. Irina, V. Andrei, Coord. Chem. Rev 248, 2337–2342 (2004)
30. S. Kiyooka, S. Matsumoto, S. Nomura, T. Higaki, T. Yokoyama,
R. Yokoyama, Tetrahedron 65(27), 5181–5191 (2009)
31. M. Biermann, K.I. Hardcastle, N.V. Moskalev, P.A. Crooks,
Acta. Crystallogr. E67, 0936 (2011)
32. D.A. Cogan, G. Liu, K. Kim, B.A. Backes, J.A. Ellman, J. Am.
Chem. Soc. 20, 8011–8019 (1998)
33. G. Liu, D.A. Cogan, J.A. Ellman, J. Am. Chem. Soc. 119, 9913–
9914 (1997)
34. D.A. Cogan, J.A. Ellman, J. Am. Chem. Soc. 121, 268–269
(1999)
35. G. Liu, D.A. Cogan, T.D. Owens, T.P. Tang, J.A. Ellman, J. Org.
Chem. 64, 1278–1284 (1999)
36. D.A. Cogan, G. Liu, J.A. Ellman, Tetrahedron 55, 8883–8904
(1999)
References
37. G. Borg, D.A. Cogan, J.A. Ellman, Tetrahedron Lett. 40, 6709–
6712 (1999)
1. W.E. Childers, R.B. Baudy, J. Med. Chem. 50, 2557–2562 (2007)
1 3

Journal of the Iranian Chemical Society
38. G. Borg, M. Chino, J.A. Ellman, Tetrahedron Lett. 42, 1433–1436
(2001)
49. H. Elhawi, H. Eini, A. Douvdevani, G. Byk, Molecules 17, 6784–
6807 (2012)
39. T.P. Tang, J.A. Ellman, J. Org. Chem. 64, 12–13 (1999)
40. T.P. Tang, J.A. Ellman, J. Org. Chem. 67, 7819–7832 (2002)
41. T.P. Tang, S.K. Volkman, J.A. Ellman, J. Org. Chem. 66, 3707–
3709 (2001)
50. B. Gregoire, M.C. Carre, P. Caubere, J. Org. Chem. 51, 1419–
1427 (1986)
51. X. Verdaguer, I. Marchueta, J. Tormo, A. Moyano, M.A. Pericas,
A. Riera, Helv. Chim. Acta 81(1), 78–84 (1998)
52. X. Lv, Q. Xiang, Q. Zeng, Org. Prep. Proc. Int. 46, 164–175
(2014)
42. S. Chandrasekhar, P. Mrunal, M. Chandrashekar, S.M. Akondi,
P.S. Mainkar, Tetrahedron Lett. 53, 1292–1295 (2012)
43. C.L. Harrison, M. Krawiec, R.E. Forslund, W.A. Nugent, Tetra-
hedron 67, 41–47 (2011)
53. K. Owsianik, W. Wieczorek, A. Bali, M. Mikołajczyk, Heteroat.
Chem 25(6), 690–697 (2014)
44. H. Mei, Y. Xiong, J. Han, Y. Pan, Org. Biomol. Chem. 9, 1402–
1406 (2011)
54. A.C. Cope, R.D. Bach, A. DeMeijere, K.B. Wiberg, Org. Synth.
5, 315–317 (2003)
45. J.P. McMahon, J.A. Ellman, Org. Lett. 6(10), 1645–1647 (2004)
46. M.T. Robak, M.A. Herbage, J.A. Ellman, Chem. Rev. 110, 3600–
3740 (2010)
55. D. Lednicer, C.R. Hauser, B.C. McKusick, W.A. Sheppard, R.D.
Vest, H.F. Mower, Org. Synth. 5, 434–738 (2003)
56. (S)-Ketamine:[α]25: –56.9 (c 2.00, EtOH) and the HCl salt:[α]25:
D
D
47. H. Xu, S. Chowdhury, J.A. Ellman, Nat. Protoc. 8(11), 2271–2280
(2013)
92.6 (c 2.00, H2O); Torres Russo Valter Freire; Souza Russo Elisa
Mannochio de, Patent WO01/98265 A2 (US 2003/0212143 A1)
48. J.A. Ellman, Pure Appl. Chem. 75(1), 39–46 (2003)
1 3