Synthesis of (S)-ketamine via [1,3]-chirality transfer of a stereocenter created by enantioselective aldol reaction

Article abstract of DOI:10.1246/bcsj.82.1528

The stereocenter in the intermediate alcohol (86% ee), created by enantioselective oxazaborolidinone-promoted aldol reaction, was transferred to the stereocenter in the cyclohexanone ring, necessary for (S)-ketamine, viaallyl cyanate-to-isocyanate rearran

Full text of DOI:10.1246/bcsj.82.1528

1528 Bull. Chem. Soc. Jpn. Vol. 82, No. 12, 1528–1532 (2009)
© 2009 The Chemical Society of Japan
Synthesis of (S)-Ketamine via [1,3]-Chirality Transfer of a Stereocenter
Created by Enantioselective Aldol Reaction
Takeshi Yokoyama,1 Reiko Yokoyama,2 Satoshi Nomura,3 Satoshi Matsumoto,3
Ryoji Fujiyama,3 and Syun-ichi Kiyooka*3
1Department of Dental Anesthesiology, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582
2Department of Anesthesiology and Critical Care Medicine, Kochi Medical School, Oko-cho, Nankoku 783-8505
3Department of Materials Science, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520
Received August 3, 2009; E-mail: kiyooka@kochi-u.ac.jp
The stereocenter in the intermediate alcohol (86% ee), created by enantioselective oxazaborolidinone-promoted
aldol reaction, was transferred to the stereocenter in the cyclohexanone ring, necessary for (S)-ketamine, via allyl cyanate-
to-isocyanate rearrangement. The second asymmetric synthesis of (S)-ketamine has been achieved (87% ee).
Ketamine (1) has been widely used since 1963 as an
anesthetic and analgesic in human and veterinary medicine
under the trade name Ketalar.1 The preparation of racemic
1 was reported by Stevens through thermal isomerization
of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol.2-5
Commercially available ketamine is a racemic mixture of two
enantiomers. The S enantiomer is shown to be more potent with
an approximately 3- to 4-fold anesthetic potency compared
to the R enantiomer. (R)-1 causes undesirable side effects,
including agitation, hallucination, and restlessness in contrast
to (S)-1.6 However, the effective (S)-1 is only obtainable via
optical resolution of the tartaric acid salt,7 leaving the undesired
(R)-1 as a by-product. Therefore, development of an enantio-
selective synthesis for the S enantiomer is highly desirable.
We have recently reported8 the first asymmetric synthesis of
(S)-1 in which the chirality of the precursor allyl alcohol,
introduced by an enantioselective reduction,9 was utilized for
the construction of the nitrogen-substituted quaternary carbon
by an allyl cyanate-to-isocyanate rearrangement.10 The enan-
tioselective reduction supplying chiral allyl alcohols is useful
for the strategy but is limited for the construction of bioactive
compounds having various types of side chains. Then, we
planned to apply an enantioselective aldol reaction for the
purpose of chirality introduction.
(Scheme 1). A precursor nitrile to 2 was prepared from ethyl 2-
chlorobenzoylacetate,11 according to Fleming’s procedure.12
DIBAL reduction of the nitrile at ¹78 °C gave the aldehyde
2 in a good yield.13 The chiral oxazaborolidinone-promoted
enantioselective aldol reaction14 of 2 with 1-phenyloxy-1-
(trimethylsilyloxy)ethene proceeded to give the corresponding
aldol product 3 in 82% yield (Scheme 2), while dimethylketene
methyl trimethylsilyl acetal did not work presumably owing
to its steric bulkiness. The 1H NMR spectra of 3 indicated
that the product was a mixture (ca. 3:2) of diastereomers. The
appearance of the diastereoisomers is evidently attributable to
a new stereocenter associated with atropisomerism15 on the
hindered rotation about the single bond between the ortho
substituted phenyl and cyclohexene rings. The diastereomers
could not be resolved by silica gel column chromatography.
The difficulty of the separation can be suspected to arise
from epimerization around the atropic axis during silica gel
chromatography. When the standard sample of the atropiso-
meric mixture, (aSaR,SR)-3, provided by the corresponding
TiCl4-mediated aldol reaction, was introduced to a chiral HPLC
column, a couple of diastereomeric pairs were observed and
epimerization turned out to take place between the atropiso-
meric pairs, A and B (Figure 1). The aldol products 3 from the
chiral oxazaborolidinone-promoted reaction also underwent the
interconversion so that the chiral HPLC measurement of 3
would not indicate correct values of the enantioselectivity.
Then, the level of the enantioselectivity was determined after
conversion of the aldols (aSaR,SR)-3 to their benzoates
Results and Discussion
The retrosynthesis of (S)-1 suggested that aldehyde 2 is
suitable as a synthetic intermediate for the reaction sequence
O
CH3
O
C
O
Cl
NH2
O
Cl
O
NH
O
N
H
R
Cl
Cl
(S)-Ketamine (1)
2
Scheme 1. Target molecule and retrosynthetic overview.
Published on the web December 10, 2009; doi:10.1246/bcsj.82.1528

T. Yokoyama et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 12 (2009) 1529
DAICEL CHIRALPAK AD-H
Mobile phase: 5% 2-propanol/ n-hexane
Flow rate: 2 mL/min
H
H
OTMS
OPh
H
O
TiCl4
ortho-Cl
ortho-Cl
Detection: UV 254 nm
COOPh
H
0oC/20 min/CH2Cl2
75% yield
OH
Diastereomeric ratio = ca. 2 : 3
(aSaR)-2
(aSaR,SR)-3
B
A
A
O
O
N
H
O
B
H
Ts
ortho-Cl
ortho-Cl
COOPh
H
OH
H
H
OTMS
OPh
-78oC/6 h/CH2Cl2
B
(aSaR)-2
(aSaR,S)-3
86% ee
82% yield
no reaction
Overlaps
Me
Me
OTMS
OMe
Racemate (aSaR,SR)-3 Aldol product 3 from chiral
oxazaborolidinone-promoted
aldol reaction
aldol reaction
H
from TiCl4-promoted
ortho-Cl
BzCl
pyridine
COOPh
OBz
(aSaR,S)-3
93% yield
A:
B:
(aS,S)-3
(aS,R)-3
(aR,S)-3
(aR,R)-3
(aSaR,S)-4
Scheme 2. Introduction of the chiral center necessary for
(S)-ketamine by enantioselective aldol reaction.
(Each peak did not be assigned to each enantiomer in A and B.)
(aSaR,SR)-4 and the chiral HPLC analysis without epimeriza-
tion revealed to be 86% ee as a pair of (aS,S)-4 and (aR,S)-4,
as shown in Figure 2.16 Here the four peaks could not
completely correspond to the structures corresponding to the
four enantiomers but larger peaks be apparently confirmed to S
enantiomers from the results of the absolute configuration and
the level of the enantioselectivity of the final product (S)-1.
In addition, the diastereomeric ratio of 4 changed to ca. 3:1
through epimerization occurring during benzoylation.
Figure 1. Epimerization between two atropisomeric pairs
involving four enantiomers, indicated by the rise of their
base lines, observed during HPLC measurement.
DAICEL CHIRALCEL OD-H
Mobile phase: 0.5% 2-propanol/ n-hexane
Flow rate: 1 mL/min
Detection: UV 254 nm
Diastereomeric ratio = ca. 3 : 1
(S)-enantiomer
Completion of the synthesis directed toward (S)-1 is as
follows (Scheme 3). The aldol 3 was converted by lithium
aluminum hydride reduction to diol 5 (96% yield), followed by
benzylation to give the corresponding mono-benzyl derivative
6 (87% yield). Reaction of 6 with trichloroacetyl isocyanate in
dichloromethane and subsequent hydrolysis with potassium
carbonate in aqueous methanol provided carbamate (aSaR,S)-7
in 95% yield.8,10 The carbamate 7, consisting of the atropiso-
mers, was employed as a precursor of the allyl cyanates 8 for
the successive allyl cyanate-to-isocyanate rearrangement. De-
hydration of 7 was performed with triphenylphosphine, carbon
tetrabromide, and triethylamine at 0 °C for 20 min. During the
one-pot procedure, the expected [3,3]-sigmatropic rearrange-
ment with the 1,3-chirality transfer took place via the transient
(aS,S)- and (aR,S)-8 to give the corresponding isocyanate (R)-9.
The quite stable isocyanate 9 was isolated as a single isomer in
86% yield. Treatment of 9 with lithium aluminum hydride in
THF provided the methylamine (R)-10 in 87% yield. Avoiding
reaction of the basic allylic amino function with the inter-
mediate ozonide, the hydrogen chloride salt of (R)-10 was used
for the ozonolysis in the final step to ketamine.8 Ozonolysis of
10 in methanol at ¹18 °C followed by reductive work-up with
(S)-enantiomer
(R)-enantiomer
(R)-enantiomer
Diastereomeric pairs of
racemate (aSaR,SR)-4
Benzoate 4 derived from the
aldol products, obtained in the
enantioselective aldol reaction
Figure 2. Determination (86% ee of S) of enantioselectivity
by chiral HPLC with the benzoates 4 derived from the
aldols 3.
dimethyl sulfide proceeded smoothly to give the final product 1
as its hydrogen chloride salt which was crystallized from
ethanol/n-hexane in 85% yield. The synthetic ketamine 1

1530 Bull. Chem. Soc. Jpn. Vol. 82, No. 12 (2009)
Synthesis of (S)-Ketamine
H
ortho-Cl
LiAlH4/THF
OH
(aSaR,S)-3
OH
96% yield
(aSaR,S)-5
H
H
ortho-Cl
ortho-Cl
OBn
CCl3CONCO/CH2Cl2
aq K2CO3/MeOH
95% yield
OBn
BnBr/NaH
DMF
O
OH
O
H2N
87% yield
(aSaR,S)-6
(aSaR,S)-7
PPh3/CBr4
Et3N
Cl
Cl
H
H
CH2Cl2/ 0oC
86% yield
OBn
OBn
N C O
N C O
(aS,S)-8 and (aR,S)-8
CH3
O
C
CH3
NH
O3/MeOH
LiAlH4/THF
87% yield
NH
O
N
50 min/Me2S
85% yield
OBn
Cl
Cl
Cl
OBn
(S)-Ketamine 1
(R)-9
(R)-10
87% ee
(R)-10HCl
Scheme 3. Completion of asymmetric synthesis of (S)-ketamine.
(230-400 mesh). Infrared spectra (IR) were recorded on a JASCO
FT/IR-460 and only partial data are listed. Optical rotations were
determined with a JASCO DIP-370 digital polarimeter. H NMR
was determined by chiral HPLC (DAICEL CHIRALCEL
OD-H/5% 2-propanol/n-hexane) analysis to be 87% ee of S
configuration (Figure 3). Throughout the synthetic process,
the optical purity of the compounds: 5, 6, 7, 9, and 10, is
retentively regarded as the same level (86% ee) of 3.
The enantioselectivity of the aldol product was transferred
with the same level to that of the final product where the
stereospecific sigmatropic rearrangement proceeded without
any influence of the ortho-chloro substituent. Thus, the second
asymmetric synthesis of (S)-1 has been accomplished with high
selectivity. Although the aldol moiety was finally eliminated
for the purpose of the ketamine synthesis, this enantioselective
aldol-reaction approach toward the construction of nitrogen-
substituted quaternary carbons will develop profitable routes
extending various side chains in the forthcoming synthesis of
bioactive natural products.
1
spectra were obtained in CDCl3 with a JNM-LA 400 (400 MHz)
spectrometer; chemical shifts (¤) are expressed in ppm relative to
internal standard tetramethylsilane and coupling constants are
reported in Hz. 13C NMR spectra were measured at 100 MHz with
a JNM-LA 400 spectrometer with complete proton decoupling;
chemical shifts are reported in ppm relative to tetramethylsilane
with the solvent resonance as the internal standard (CDCl3, ¤ 77.0).
Enantiomeric excess (ee) was determined by HPLC analysis using
DAICEL CHIRALCEL OD-H and CHIRALPAK AD-H columns.
(aSaR,S)-Phenyl 3-[2-(2-Chlorophenyl)-1-cyclohexenyl]-3-
hydroxypropionate ((aSaR,S)-3) from Chiral Oxazaborolidi-
none-Promoted Enantioselective Aldol Reaction of (aSaR)-2.
To a stirred solution of N-(p-toluenesulfonyl)-(S)-valine (772 mg,
2.85 mmol) in dry CH2Cl2 (8 mL) at 0 °C was added BH3¢THF
(2.59 mL, 2.59 mmol, 1 M in THF). The solution was allowed
to stir for 30 min at 0 °C and an additional 30 min at room
temperature. The solution was then cooled to ¹78 °C and aldehyde
2 (571 mg, 2.59 mmol) [IR (film): 1676 cm¹1; 1H NMR (400 MHz,
CDCl3): ¤ 1.70-1.84 (m, 4H), 2.27-2.32 (m, 1H), 2.34-2.37 (m,
2H), 2.57-2.65 (m, 1H), 7.16-7.21 (m, 1H), 7.28-7.30 (m, 2H),
7.38-7.45 (m, 1H), 9.32 (s, 1H); 13C NMR (100 MHz, CDCl3): ¤
21.3, 21.7, 22.1, 33.1, 126.7, 129.2, 129.7, 130.1, 132.6, 136.4,
138.4, 157.0, 192.8] in CH2Cl2 (1 mL) was added slowly over
Experimental
General. Unless otherwise noted, all reagents were obtained
from commercial suppliers and used without further purification.
All reagent solutions were handled under an argon atmosphere
by using syringes. All reactions unless otherwise noted were
carried out under an argon atmosphere. Merck silica gel 60 TLC
aluminum sheets were used for thin layer chromatography. Flash
column chromatography was carried out with Merck 60 silica gel

T. Yokoyama et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 12 (2009) 1531
were washed with brine and dried (Na2SO4). Concentration under
reduced pressure gave a residue, which was purified by flash
chromatography to afford the corresponding diol (aSaR,S)-5
1
(106 mg, 96%). 5: Colorless oil, IR (film): 3366 cm¹1; H NMR
(400 MHz, CDCl3): a mixture of major and minor isomers; ¤ 1.44-
1.90 (m, 6H), 1.96-2.13 (m, 2H), 2.22-2.41 (m, 2H), 3.15 (brs,
2H), 3.47-3.65 (m, 2H), 4.08-4.14 (m, 1H), 7.10-7.40 (m, 4H);
13C NMR (100 MHz, CDCl3): major: ¤ 22.2, 22.4 (©2), 22.7,
30.9, 35.8, 61.6, 71.9, 126.8, 127.9, 129.2, 129.6, 132.6, 135.7,
141.4; minor: ¤ 22.0, 22.4, 22.8, 23.0, 35.9, 61.0, 71.7, 126.8,
127.9, 129.3, 130.2, 131.7, 132.8, 136.0, 141.3. Anal. Calcd for
C15H19O2Cl: C, 67.54; H, 7.18%. Found: C, 67.359; H, 7.21%.
(aSaR,S)-3-Benzyloxy-1-[2-(2-chlorophenyl)-1-cyclohexyl]-1-
propanol ((aSaR,S)-6). To a DMF-washed solution of excess
NaH (40 mg of 60% dispersion in mineral, 1.00 mmol) in DMF
(7 mL) was added dropwise a solution of diol 5 (160 mg, 0.600
mmol) in DMF (1 mL). The resulting solution was stirred at room
temperature for 1 h. After cooling, a 30% NaOH solution (1 mL)
was added and the mixture was heated at 90 °C for 1 h. A solution
of benzyl bromide (78 mg, 0.662 mmol) was added and the mixture
was heated at 50 °C for 2 h. The reaction mixture was diluted with
water (10 mL) and extracted with ether (10 mL © 3). The com-
bined organic layers were washed with brine and dried (Na2SO4).
Concentration under reduced pressure gave a residue, which was
purified by flash chromatography to afford the corresponding
mono-benzyl compound 6 (186 mg, 87%). 6: Colorless oil, IR
(film): 3434 cm¹1; 1H NMR (400 MHz, CDCl3): a mixture of major
and minor isomers; ¤ 1.60-1.84 (m, 6H), 1.90-2.13 (m, 2H), 2.25-
2.45 (m, 2H), 2.67 (brs, 1H), 3.40-3.62 (m, 2H), 4.12-4.18 (m,
1H), 4.35-4.46 (m, 2H), 7.12-7.39 (m, 9H); 13C NMR (100 MHz,
CDCl3): major: ¤ 22.3, 22.5, 22.8, 31.0, 34.1, 69.4, 71.5, 72.9,
126.9, 127.5 (©2), 127.9, 128.3 (©2), 129.3, 129.8, 130.4, 132.9,
133.2, 135.9, 137.9, 141.7; minor: ¤ 22.0, 22.5, 22.8, 31.4, 34.0,
68.0, 70.1, 72.8, 126.9, 127.4 (©2), 127.9, 128.2 (©2), 129.4,
129.8, 130.4, 132.8, 133.2, 136.2, 138.2, 141.7. Anal. Calcd for
C22H25O2Cl: C, 74.04; H, 7.06%. Found: C, 73.91; H, 7.11%.
(aSaR,S)-3-Benzyloxy-1-[2-(2-chlorophenyl)-1-cyclohexenyl]-
DAICEL CHIRALCEL OD-H
Mobile phase: 5% 2-propanol/n-hexane
Flow rate: 0.5 mL/min
Detection: UV 254 nm
(S)-Ketamine
87% ee
Figure 3. Determination of enantiopurity of synthetic
(S)-ketamine.
5 min. After stirring for 5 min, 1-phenyloxy-1-(trimethylsilyl-
oxy)ethene (593 mg, 2.85 mmol) in CH2Cl2 (1 mL) was added
dropwise over 5 min and the reaction mixture was stirred for 6 h
before quenching with a buffer solution (5 mL, pH 6.86). The
resulting mixture was allowed to warm to room temperature. The
organic layer was extracted with ether, washed with aqueous
saturated NaHCO3 solution and brine. The resulting solution
was dried over MgSO4 and evaporated in vacuo. Flash column
chromatography (20% ethyl acetate/n-hexane) provided a mixture
(4:1) of aldols 3 (758 mg, 82%). 3: Colorless oil, IR (film): 3465,
propyl Carbamate ((aSaR,S)-7).
To a solution of alcohol
(aSaR,S)-6 (152 mg, 0.426 mmol) in CH2Cl2 (3 mL) at 0 °C was
added trichloroacetyl isocyanate (101 ¯L, 0.852 mmol) and the
reaction mixture was stirred at 0 °C for 15 min. After stirring at
room temperature for 15 min, evaporation of the solvent gave a
crude material. The residue was dissolved in an aqueous K2CO3
(474 mg) solution in water (2 mL) and MeOH (3 mL). The reaction
mixture was stirred at room temperature for 1.5 h. After extraction
with ether (10 mL © 3), the combined organic layers were washed
with brine and dried (MgSO4). Evaporation of the solvent under
reduced pressure gave a crude product which was purified by
flash chromatography on silica gel (30% AcOEt/n-hexane) to
afford allyl carbamate (aSaR,S)-7 (161 mg, 95%). 7: Colorless oil,
1
1758 cm¹1; H NMR (400 MHz, CDCl3): a mixture of major and
minor isomers (a hydroxy proton is overlapping); ¤ 1.51-1.73 (m,
4H), 1.96 (m, 2H), 2.12-2.19 (m, 1H), 2.32 (m, 1H), 2.51 (ddd,
J = 15.8, 4.8, 1.8 Hz, 1H), 2.73 (ddd, J = 16.7, 10.6, 8.8 Hz,
1H), 4.34 and 4.95 (major dd, J = 8.4, 5.6 Hz and minor d, J =
2.5 Hz, respectively, 2H), 6.86-7.23 (m, 9H); 13C NMR (100 MHz,
CDCl3): major: ¤ 22.2, 22.4, 22.7, 31.4, 39.1, 67.9, 121.4 (©2),
125.8, 127.1, 128.2, 129.3 (©2), 129.5, 129.5, 132.5, 134.4, 134.5,
141.1, 150.3, 170.0; minor: ¤ 22.1, 22.4, 22.8, 31.4, 39.1, 68.4,
121.4 (©2), 125.8, 127.0, 128.2, 129.3 (©2), 129.5, 129.6, 130.2,
131.7, 133.9, 141.1, 150.4, 171.7. Anal. Calcd for C21H21O3Cl: C,
70.68; H, 5.93%. Found: C, 70.43; H, 6.01%.
(aSaR,S)-1-[2-(2-Chlorophenyl)-1-cyclohexyl]-1,3-propane-
diol ((aSaR,S)-5). To a slurry of large excess LiAlH4 (50 mg,
1.31 mmol) in THF (1 mL) was added dropwise a solution of
(aSaR,S)-3 (148 mg, 0.421 mmol) in THF (1 mL). The resulting
solution was stirred at room temperature for 1 h and then refluxed
for 30 min. After cooling, a 30% NaOH solution (1 mL) was added
and the mixture was stirred for 1 h. The reaction mixture was
extracted with ether (10 mL © 3). The combined organic layers
1
IR (film): 3350, 1715, 1599 cm¹1; H NMR (400 MHz, CDCl3): a
mixture of major and minor isomers; ¤ 1.64-2.15 (m, 10H), 4.32
and 4.40 (dd, J = 20.5, 12.0 Hz and dd, J = 15.0, 12.5 Hz, respec-
tively, 2H), 5.07-5.11 (m, 1H), 7.15-7.35 (m, 9H); 13C NMR
(100 MHz, CDCl3): major: ¤ 22.3, 22.6, 22.8, 30.8, 32.2, 66.7,
72.3, 73.0, 126.8, 127.3, 127.4 (©2), 128.1 (©3), 128.2, 129.2,
130.4, 132.8, 134.3, 138.4, 140.9, 156.1, minor: ¤ 22.3, 22.7, 23.3,
31.2, 33.2, 66.9, 72.6, 72.8, 126.4, 127.4, 127.6, 127.7 (©2), 128.1
(©2), 128.5, 129.5, 130.1, 132.6, 134.9, 138.3, 141.0, 156.1.
(1R,2E)-2-(3-Benzyloxypropylidene)-1-(2-chlorophenyl)-cyclo-
hexyl Isocyanate ((1R,2E)-9). To a solution of carbamate 7
(150 mg, 0.375 mmol), triphenylphosphine (301 mg, 1.15 mmol),

1532 Bull. Chem. Soc. Jpn. Vol. 82, No. 12 (2009)
Synthesis of (S)-Ketamine
and triethylamine (306 ¯L, 2.20 mmol) in CH2Cl2 (6 mL) cooled
to 0 °C was added a solution of carbon tetrabromide (369 mg,
1.11 mmol) in CH2Cl2 (3.5 mL). After stirring at 0 °C for 30 min,
the reaction mixture was diluted with hexane (20 mL). The
resulting reaction mixture was washed with H2O and aqueous
saturated NaHCO3 solution, and dried (MgSO4). Evaporation of
the solvent under reduced pressure gave a crude product which was
purified by flash chromatography on silica gel (20% EtOAc/
n-hexane) to afford isocyanate 9 (123 mg, 86%). 9: Colorless oil,
7.55 (dd, J = 7.5, 1.5 Hz, 1H); 13C NMR (CDCl3): ¤ 21.7, 28.0,
29.0, 38.5, 39.4, 70.0, 126.5, 128.6, 129.3, 131.1, 133.6, 137.7,
209.1.
References
1
a) Ketamine is included as a general anesthetic in the 14th
WHO model list of essential medicines. WHO Technical Report
Series 942, WHO Expert Committee on Drug Dependence: thirty-
fourth report, 2006. b) W. E. Childers, Jr., R. B. Baudy, J. Med.
Chem. 2007, 50, 2557.
18
¹1
½¡ꢀD ¹81.1 (c 1.17, CHCl3); IR (film): 2255 cm
;
1H NMR
(400 MHz, CDCl3): ¤ 1.26-1.57 (m, 1H), 1.74-1.91 (m, 4H), 2.26-
2.42 (m, 3H), 2.61 (dt, J = 14.6, 3.6 Hz, 1H), 2.69-2.76 (m, 1H),
3.40 (t, J = 6.6 Hz, 2H), 4.45 (s, 2H), 5.05 (t, J = 6.6 Hz, 1H),
7.21-7.31 (m, 7H), 7.37 (dd, J = 8.0, 2.0 Hz, 1H), 7.72 (dd, J =
8.0, 2.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): ¤ 22.6, 25.4,
25.5, 28.1, 39.2, 68.9, 69.5, 72.8, 122.5, 126.9, 127.4, 127.5 (©3),
128.3 (©2), 128.8, 129.3, 132.0, 132.9, 138.4, 138.6, 139.8. Anal.
Calcd for C23H24NO2Cl: C, 72.34; H, 6.33%. Found: C, 72.10; H,
6.57%.
2
C. L. Stevens, U. S. Patent 3254124; C. L. Stevens, Chem.
Abstr. 1968, 65, 5414.
3
Amino ketone rearrangement: a) C. L. Stevens, A.
Thuillier, F. A. Daniher, J. Org. Chem. 1965, 30, 2962. b) C. L.
Stevens, H. T. Hanson, K. G. Taylor, J. Am. Chem. Soc. 1966, 88,
2769.
4
¡-Hydroxy imine thermal rearrangement: P. Compain, J.
Goré, J.-M. Vatèle, Tetrahedron Lett. 1995, 36, 4059.
¡-Hydroxyiminium ion semipinacol rearrangement:
(1R,2E)-2-(3-Benzyloxypropylidene)-1-(2-chlorophenyl)-1-
methylaminocyclohexane ((1R,2E)-10). To a slurry of a large
excess LiAlH4 (59 mg, 1.52 mmol) in THF (1 mL) was added
dropwise a solution of isocyanate 9 (83 mg, 0.220 mmol) in THF
(1 mL). The resulting solution was stirred at room temperature for
1 h and then refluxed for 30 min. After cooling, a 30% NaOH
solution (1 mL) was added and the mixture was heated at 90 °C for
1 h. The reaction mixture was extracted with ether (10 mL © 3).
The combined organic layers were washed with brine and dried
(Na2SO4). Concentration under reduced pressure gave a residue,
which was purified by flash chromatography to afford the cor-
responding methyl amine 10 (70 mg, 87%). 10: Colorless liquid,
5
M. D. B. Fenster, B. O. Patrick, G. R. Dake, Org. Lett. 2001, 3,
2109.
6
a) L. A. Nguyen, H. He, C. Pham-Huy, Int. J. Biomed. Sci.
2006, 2, 85. b) J. Liu, X.-Q. Ji, X.-Z. Zhu, Life Sci. 2006, 78, 1839.
c) L. E. Mather, Minerva Anestesiol. 2005, 71, 507. d) C. Nau,
G. R. Strichartz, Anesthesiology 2002, 97, 497.
7
The optical resolution of racemic ketamine is described:
K. Steiner, S. Gangkofner, J.-m. Grunenwald, U.S. Patent
6040479, 2000.
8
R. Yokoyama, S. Matsumoto, S. Nomura, T. Higaki, T.
Yokoyama, S. Kiyooka, Tetrahedron 2009, 65, 5181.
a) R. Noyori, I. Tomino, Y. Tanimoto, J. Am. Chem. Soc.
18
1
½¡ꢀD ¹8.2 (c 0.97, CHCl3); IR (film): 3385, 1101 cm¹1; H NMR
(400 MHz, CDCl3): ¤ 1.45-1.52 (m, 1H), 1.60-1.85 (m, 4H), 1.90
(brs, 1H), 2.04 (s, 3H), 2.27-2.32 (m, 2H), 2.35-2.43 (m, 3H), 3.43
(t, J = 7.4 Hz, 2H), 4.47 (s, 2H), 4.97 (t, J = 7.3 Hz, 1H), 7.17 (dt,
J = 7.1, 1.8 Hz, 1H), 7.23-7.38 (m, 7H), 7.51 (dd, J = 8.0, 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): ¤ 22.4, 25.8, 27.2, 28.1, 29.3,
36.5, 65.6, 70.1, 72.3, 119.8, 126.4, 127.4, 127.5 (©2), 127.6,
128.3 (©2), 130.4, 131.7, 133.9, 138.6, 140.9, 141.5.
9
1979, 101, 3129. b) R. Noyori, I. Tomino, M. Nishizawa, J. Am.
Chem. Soc. 1979, 101, 5843. c) R. Noyori, I. Tomino, Y. Tanimoto,
M. Nishizawa, J. Am. Chem. Soc. 1984, 106, 6709.
10 a) Y. Ichikawa, Synlett 2007, 2927. b) Y. Ichikawa, E.
Yamauchi, M. Isobe, Biosci. Biotechnol. Biochem. 2005, 69, 939.
c) Y. Matsukawa, M. Isobe, H. Kotsuki, Y. Ichikawa, J. Org.
Chem. 2005, 70, 5339. d) E. Roulland, C. Monneret, J.-C. Florent,
C. Bennejean, P. Renard, S. Leonce, J. Org. Chem. 2002, 67, 4399.
e) S. Roy, C. Spino, Org. Lett. 2006, 8, 939. f) P. Kapferer, F.
Sarabia, A. Vasella, Helv. Chim. Acta 1999, 82, 645.
11 M. Messali, L. E. Christiaens, S. F. Alshahateet, F. Kooli,
Tetrahedron Lett. 2007, 48, 7448.
12 F. F. Fleming, L. A. Funk, R. Altundas, V. Sharief, J. Org.
Chem. 2002, 67, 9414.
13 E. Winterfeldt, Synthesis 1975, 617.
14 a) S. Kiyooka, Y. Kaneko, M. Komura, H. Matsuo, M.
Nakano, J. Org. Chem. 1991, 56, 2276. b) S. Kiyooka, Rev.
Heteroat. Chem. 1997, 17, 245. c) S. Kiyooka, M. A. Hena, J. Org.
Chem. 1999, 64, 5511. d) S. Kiyooka, K. A. Shahid, F. Goto, M.
Okazaki, Y. Shuto, J. Org. Chem. 2003, 68, 7967.
(S)-Ketamine 1.
Amine 10 (72 mg, 0.262 mmol) was
dissolved in 10% HCl solution (2 mL). Concentration under
reduced pressure gave the corresponding amine HCl salt. Ozone
was passed into a solution of the amine HCl salt in MeOH (5 mL)
at ¹78 °C, terminating the ozonolysis upon observing the distinc-
tive blue color of ozone. After purging with nitrogen, dimethyl
sulfide (400 ¯L) was added at ¹78 °C. The solution was allowed to
warm up to room temperature and concentrated under reduced
pressure to give a crude material. The crude was dissolved in a
10% NaOH solution (3 mL) and the corresponding amine was
extracted with ether (10 mL). After evaporation of the solvent,
the amine was purified by flash chromatography (50% AcOEt/
n-hexane) to afford (S)-ketamine (63 mg, 85%). The enantio-
meric excess was determined to be 87% by HPLC (DAICEL
CHIRALCEL OD-H column, Mobile phase 5% 2-propanol/
n-hexane, Flow rate 0.5 mL min¹1, Rt (min) 24.3 (R), 27.4 (S)).
15 Special issue of atropisomerism: Tetrahedron 2004, 60,
Issue 20.
16 DAICEL CHIRALCEL OD-H, Mobile phase 0.5% 2-
propanol/n-hexane, Flow rate 1 mL min¹1, Rt (min) 11.6 (aS,R or
aR,R), 13.5 (aS,S or aR,S), 21.8 (aS,R or aR,R), and 27.1 (aS,S or
aR,S).
21
1: Colorless crystals, Mp 120 °C (n-hexane); ½¡ꢀD ¹49.3 (c 1.50,
25
EtOH) (Lit. value, ½¡ꢀD ¹56.9 (c 2.00, EtOH);17 IR (film): 3353,
¹1
1701, 752 cm
;
1H NMR (CDCl3): ¤ 1.72-1.78 (3H, m), 1.82-
1.90 (1H, m), 1.96-2.05 (1H, m), 2.06-2.15 (1H, m), 2.11 (3H, s),
2.44-2.55 (2H, m), 2.76-2.82 (1H, m), 7.24 (dt, J = 7.5, 1.5 Hz,
1H), 7.32 (dt, J = 7.5, 1.5 Hz, 1H), 7.38 (dd, J = 7.5, 1.5 Hz, 1H),
17 Torres Russo Valter Freire, Souza Russo Elisa Mannochio
de, Patent WO 01/98265 A2 (US 2003/0212143 A1).