Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

Article abstract of DOI:10.1016/j.tet.2009.05.004

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2

Full text of DOI:10.1016/j.tet.2009.05.004

Tetrahedron 65 (2009) 5181–5191
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective construction of nitrogen-substituted quaternary carbon centers
adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis
of anesthetic (S)-ketamine with high selectivity
Reiko Yokoyama a, Satoshi Matsumoto b, Satoshi Nomura b, Takafumi Higaki b, Takeshi Yokoyama a,
,
Syun-ichi Kiyooka b
*
a Department of Anesthesiology and Critical Care Medicine, Kochi Medical School, Oko-cho, Nankoku 783-8505, Japan
b Department of Materials Science, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl
Received 31 March 2009
Received in revised form 5 May 2009
Accepted 5 May 2009
group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-
ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to
a-ketoxime-ether
acetal 9 bearing chiral auxiliary on the -carbonyl function gave benzyloxyamine 11 major in 83% yield
a
Available online 8 May 2009
with 82% de, which was converted to the corresponding amino ketone 12. However, the reaction of 2-
chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an al-
ternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance,
was designed in which the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by
the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cya-
nate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1
with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis of (S)-ketamine
Nitrogen-substituted quaternary carbon
centers
1. Introduction
compared to (R)-one: this correlates to the higher binding affinity for
the PCP-site of the NMDA-receptor and only (R)-1 is responsible for
Ketamine 1, 2-(2-chlorophenyl)-2-(methylamino)-cyclohexa-
none, has been widely used as an anesthetic and analgesic in human
and veterinary medicine under the trade name Ketalar since 1963.1
The racemic ketamine 1 was prepared by Stevens through thermal
isomerization of 1-[(2-chlorophenyl) (methylimino)methyl]-cyclo-
pentanol.2–5 The commercially available ketamine is a racemic mix-
ture of two enantiomers (Chart 1). The (S)-enantiomer is shown to be
more potent with an approximately 3–4 fold anesthetic potency
agitation, hallucination, and restlessness in contrast to (S)-1.6 The
more active (S)-1 has been increasing in commercially available
preparations. However, the enantiopure compound is only obtained
via optical resolution of the tartaric acid salt,7 leaving the undesired
(R)-1 as a by-product. Therefore, development of an asymmetric
synthesis for the (S)-enantiomer is highly desirable. Recently, Brun-
ner challenged an asymmetric rearrangement of 1-[(2-chlorophenyl)
(methylimino)methyl]-cyclopentanol to optically active ketamine 1
with 2-[4-(S)-tert-butyloxazolin-2-yl]-pyridine coordinated Ni com-
plexes but unfortunately the attempt resulted in failure, only giving
a racemic product.8 To the best of our knowledge, no successful
synthesis of (S)-1 has been reported.
On the other hand, a challenging methodology in organic syn-
thesis prompted us to develop the enantioselective construction of
quaternary carbon centers bearing a nitrogen atom, which are
ubiquitous in naturally occurring pharmaceutical drugs (e.g., alka-
loids),9 but effective approaches are quite limited.10 The difficulty
on the case of (S)-1 can be ascribed in part to the special requisite
that the nitrogen-substituted quaternary carbon has an aryl group
from the carbon and a carbonyl group adjacent to the carbon in the
ring system. As part of our ongoing project to find a new reliable
route to (S)-1, we applied a straightforward methodology, utilizing
CH3
CH3
NH
NH
O
O
Cl
racemic Ketamine 1
Cl
(S)-Ketamine 1
Chart 1. Structure of target molecule.
* Corresponding author. Tel.: þ81 88 844 8295; fax: þ81 88 844 8359.
E-mail address: kiyooka@kochi-u.ac.jp (S.-i. Kiyooka).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.004

5182
R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
O
O
N
R1
O
O
O
C
C
O
O
N
R1
O
NH2
HO
OH
HO
OH
R2
R4
R2
R4
R
R4
1 R2
5
6
R3
R3
R3
O
Scheme 1. 1,3-Chirality transfer via allyl cyanate-to-isocyanate rearrangement.
O
O
O
O
O
p-MeC6H4SO3H
O
O
nucleophilic 1,2-addition to chiral
a-ketoxime-ether acetals. The
benzene
enantioselective 1,2-addition reaction of phenyllithium to the chi-
ral imines proceeded with considerably high diastereoselectivity.
After deprotection, the asymmetric synthesis of the chiral model
compound was established. However, the reaction of 2-chloro-
phenyllithium did not work so that the method could not lead to
the asymmetric synthesis of (S)-1. Then, we employed the plan
using an allyl cyanate-to-isocyanate rearrangement (Scheme 1),
recently developed by Ichikawa,11 independent of the rearrange-
ment developed by Stevens.2 The strategy, with a combination of an
enantioselective reduction and the rearrangement provided a novel
and short route directed toward (S)-ketamine 1. We describe herein
the details of the foregoing 1,2-addition to chiral imines and dis-
close the first asymmetric synthesis of (S)-1 by the sequential
enantioselective reduction-rearrangement strategy.
7
8
O
Ph
O
Ph
O
N
O
N
O
O
HCl H2NOCH2Ph
pyridine, MeOH
O
O
9
10
a-ketoxime-ether acetals.
Scheme 3. Preparation of chiral
construction of nitrogen-substituted quaternary carbon centers. We
chose C2-symmetric diols, (ꢀ)-(2R,3R)-2,3-butanediol and
(ꢀ)-(2S,3S)-1,4-dimethoxy-2,3-butanediol 6, suitable for our pur-
poses. Chiral -ketoxime-ether acetals 9 and 10 were prepared via the
5
a
2. Results and discussion
corresponding 7 and 8, as shown in Scheme 3.
The results of the diastereoselective addition are shown in
2.1. Enantioselective construction of quaternary carbon
centers bearing a nitrogen atom by nucleophilic 1,2-addition
Scheme 4. The reaction of
a-ketoxime-ether acetal 9 with PhLi
proceeded well in toluene (ꢀ78 ꢁC/1 h and then ꢀ17 ꢁC/1 h) to af-
ford a diastereomeric mixture 11 in 83% yield. A diastereoselectivity
of 82% was determined using the methyl proton signals of the
relative acetal moieties in the 1H NMR spectra. After separation
using silica-gel column chromatography, the 11 major was sub-
jected to acid hydrolysis with HCl to afford amino ketone 12 in
a quantitative yield. The enantioselectivity of 12 was confirmed to
be 82% ee by using HPLC with a DAICEL CHIRALPAK IA column
(mobile phase: n-hexane/dichloromethane/diethylamine¼90/10/
0.1, retention times: 19 min for S and 27 min for R under a flow rate
of 1.0 mL/min). Determination of the absolute configuration of the
stereogenic center in 11 major using NMR spectroscopy techniques
was quite difficult because of its quaternary carbon. Then, using fine
crystals recrystallized from n-hexane, the absolute configuration of
the chiral center was determined to be R by X-ray diffraction
analysis,16 as shown in Figure 1.
to chiral a-ketoxime-ether acetals
Whereas chiral quaternary carbon centers have been generally
realized by the asymmetric addition of nucleophiles to ketones, the
enantioselective construction of nitrogen-substituted quaternary
carbon centers by the straightforward addition to ketimines is
regarded to be more difficult because of the poor electrophilic
characteristic of ketimines in comparison with that of ketones.12 As
a model of simple routes to (S)-1, we considered employing nu-
cleophilic addition of RM reagents to N-methylketimines, directly
affording theN-methyl amine function necessary for 1. After some
preliminary studies, however, N-methylketimines turned out to be
inadequate for the purpose because of their inherent instability.
Then, the related ketoxime ethers were chosen as the starting
electrophiles, which have the higher stability toward hydrolysis
and can be efficiently purified by silica-gel column chromatogra-
phy. While there are limited examples of the addition of organo-
metallic reagents to chiral open-chain ketoxime ethers,13,14 no
example for the addition to cyclic ketoxime ethers has been
reported. Thus, diastereoselective nucleophilic 1,2-addition re-
In the result, it was shown that the (R,R)-chiral acetal auxiliary
induces (R)-configuration at the newly created stereocenter. A
stable conformer of the encountered complex, comprised of 9 and
phenyllithium, was optimized by the calculation at the Density
Functional Theory B3LYP/6-31G level: all computations have been
*
actions were designed to the ketoxime ethers modified the a-car-
done using the GAUSSIAN 03 code, 98,17 as shown in Figure 2. The
trajectory of the phenyl anion responsible for the resulting (R)-
configuration can be explained with its approach to the upper site
of the C]N double bond so as to avoid the steric hindrance induced
by the coordinated phenyllithium. On the other hand, the reaction
of 10 with phenyllithium also proceeded with nearly the same de
but the yield was comparatively low presumably owing to the ex-
cessive steric bulkiness of the acetal moiety bearing additional
methoxy groups.
bonyl group with chiral diol auxiliaries, as depicted in Scheme 2.
The availability of the chiral diol auxiliary has been reported15 for
the Grignard addition reactions to a chiral
a-keto acetal and to a chiral
a-aldoxime-ether acetal in the presence of CeCl3. However, the uti-
lization of such a chiral auxiliary has not been reported for the
enantioselective addition to ketimines with regard to the asymmetric
Ph
Ph
Chiral auxiliary
Unexpectedly, the 1,2-addition reaction of chiral
a-ketoxime-
O
O
Ph
O
N
NH
NH
ether acetal 9 with 2-chlorophenyllithium, prepared from 2-bro-
mochlorobenzene with n-butyllithium in THF at ꢀ78 ꢁC,18 did not
proceed because of the increased steric hindrance arising from the
ortho-chloro substituent of the nucleophile (Scheme 5). The addi-
R
R
O
O
O
O
RM
O
2
3
4
19
tion of BF3$OEt2 could not apparently improve the addition re-
Scheme 2. Diastereoselective addition with chiral auxiliaries.
action. This method, based on the enantioselective construction of

R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
Ph
Ph
5183
O
Ph
Ph
O
Ph
O
NH
O
NH
O
N
R
O
PhLi
R
toluene
O
O
O
-78°C/1h→ -17°C/1h
9
11 minor
11 major
83% yield
82% de (from NMR)
O
NH
Ph
HCl
Ph
11 major
O
12
O
O
NH
O
O
O
NH
O
Ph
O
Ph
Ph
Ph
O
N
S
PhLi
O
Ph
O
toluene
-78°C/1h→ -17°C/1h
S
O
O
O
O
O
10
13 minor
13 major
45% yield
80% de (from NMR)
Scheme 4. Diastereoselective addition of phenyllithium to -chiral ketoxime-ether acetals.
a
nitrogen-substituted quaternary carbon centers by the straight-
forward addition to chiral -ketoxime-ether acetals, was conclu-
a
sively found to be less promising for the asymmetric synthesis of
(S)-ketamine 1.
Figure 2. Trajectory of nucleophile to afford (R)-enantiomer.
2.2. Asymmetric synthesis of (S)-ketamine by the strategy of
enantioselective reduction and sequential allyl cyanate-to-
isocyanate rearrangement
2.2.1. Synthetic strategy directed toward (S)-1 and preparation of
synthetic intermediate ketone 18
As appeared in the Stevens’ first synthesis of racemic ketamine, it
looks promising to utilize a rearrangement reaction for constructing
such a structure with highly converged steric features. Recently,
Ichikawa et al. have presented the validity of applying allyl cyanate-
to-isocyanate rearrangement to the construction of quaternary
carbon centers bearing a nitrogen atom.20 They confirmed, through
the adaptation to acyclic systems, that the [1,3]-chirality transfer in
the rearrangement takes place in a stereospecific manner without
any scrambling at the stereogenic centers. The efficiency of the
rearrangement persuaded us to adapt it in an effective and novel
route directed toward (S)-ketamine 1, as shown in Scheme 6. The
retrosynthesis of (S)-1 revealed that ketone 18 is suitable as
a starting material. As outlined in Scheme 7, the synthetic in-
termediate 18 was prepared from ethyl (2-chlorobenzoyl)acetate
14,21 according to Fleming’s procedure.22
Ph
O
N
R
O
Li
R
Cl
O
no reaction
9
Scheme 5. Difficult 1,2-addition of 2-chlorophenyllithium to 9.
Figure 1. ORTEP drawing of 11 major.

5184
R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
O
C
CH3
C
N
NH
N
Cl
O
O
Cl
Cl
1
Cl
OH
Cl
O
18
Scheme 6. Retrosynthesis on synthetic strategy directed toward (S)-ketamine.
2.2.2. Atropisomerism on alcohol 19
Before choosing an appropriate enantioselective reduction of
ketone 18, we prepared racemic alcohol 19 by lithium aluminum
hydride reduction as a standard sample for chiral HPLC analysis to
check the selectivity of the following enantioselective reduction. The
reduction of 18 in diethyl ether or THF occurred without any prob-
lems at room temperature under usual conditions but the product
was found to be a mixture of diastereomers. The appearance of the
diastereoisomers is attributable to a new stereocenter induced by an
atropisomerism23 resulting from hindered rotation about the single
bond between the ortho-substituted phenyl and cyclohexene rings,
which were related to (MP,RS)-19 ((aRaS,RS)-19) and (MP,SR)-19
((aRaS,SR)-19),24 as represented in Scheme 8. The diastereoisomers
had a ratio of almost 1 to 1, which was estimated from the two
doublet peaks corresponding to the methyl groups in the 1H NMR
spectra. The ratio suggests that the reaction stereochemistry in the
reduction was scarcely affected by the direction of the ortho-chloro
substituent. Unfortunately, the diastereoisomers could not be sepa-
rated to each pure state where the interconversion of them took
place under the conditions of silca-gel column chromatography. It
has become apparent that the steric hindrance to rotate could be
considerably low for the isolation of the diastereoisomers.
The phenomenon of the interconversion was confirmed by HPLC
measurement through the interaction of the four enantiomers with
the chiral material packed in the column: the four peaks were
observed in the chromatogram of a DAICEL CHIRALCEL OD-H. Ex-
cessive overlaps were observed in their peaks between I and IV and
between II and III, respectively (Fig. 3). These two pairs correspond
to each distinguishable epimerization on atropisomerism, where
the assignment of the structures; P–S, M–S, M–R, and P–R, to the
corresponding peaks remains unclear at this stage. We observed an
additional interesting finding with regard to the partial epimeri-
zation on the atropic axis that a diastereomer isomerized toward
the more stable another diastereomer in a ratio of 5 to 1 after
standing in the solid state at room temperature for 2 months.25 The
H
H
Cl
O
Cl
Cl
LiAlH4
OH
OH
(MP)-18
(MP,RS)-19
(MP,SR)-19
Scheme 8. Preparation of racemic alcohols 19.
ideal rotational barrier on the atropisomers and the related struc-
tures were investigated by the Density Functional Theory, as
mentioned above.17 The results are illustrated in Figure 4. The cal-
culation of the potential energy was performed every 10ꢁ along the
dihedral angle around the atropic axis. Two stable structures of A
and B were optimized: A was more stable than B by 4.7 kcal/mol,
where in A the ortho-chloro substituent and the alcohol moiety
were situated at opposite side (anti) and the reverse was found for
B (syn). The rotational energy barrier was 22.8 kcal/mol.
As a result, the enantiomeric purity of the product alcohol
obtained in the expected enantioselective reduction could not be
directly determined. Then, in order to enable the determination of
the enantioselectivity by preventing the rotation, the resulting ra-
cemic alcohols 19 were transformed into the corresponding ben-
zoyl derivatives 20 in almost quantitative yields; the mixture of 20
showed only one spot on the TLC, and the two isomers could not be
separated by silica-gel column chromatography. By the 1H NMR
measurement, the isomeric ratio (2.66:1) of 20 was found to be
changed from the original ratio (1:w1) of 19, which is presumably
due to the isomerization during the process of benzoylation. The
more stable isomer of 20 was confirmed to be anti by the calcula-
tion study. However, the interconversion between the two atro-
pisomers of 20 was found to be surely restricted due to the steric
bulkiness of the introduced benzoyl group by checking their
chromatogram of a DICEL CHIRALPAK IA column (mobile phase: n-
O
O
O
O
OEt
CN
OEt
a
Cl
14
Cl
15
CN
c
b
d
Cl
Cl
O
O
CN
Cl
16
17
18
Scheme 7. Synthesis of synthetic intermediate ketone 18. Reagents and conditions: (a) 5-bromovaleronitrile, NaH, NaI, THF, reflux, 24 h, 85%; (b) aq NaOH, 80 ꢁC, 12 h, 76%;
(c) t-BuOK, THF, reflux, 4–5 h, 57%; (d) Mg, MeI, ether then toluene, reflux, 3 h, 82%.

R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
5185
DAICEL CHRALPAK IA
Mobile phase: n-hexane
Flow rate: 2.0 mL/min
Detection: UV 254 nm
II
Epimerization in two atropic pairs
III
IV
A
A
C
H
H
I
Cl
Cl
OH
OH
(M,S)-19
(P,S)-19
B
B
D
H
H
Cl
Cl
OH
OH
(M,R)-19
(P,R)-19
overlaps
DAICEL CHIRALCEL OD-H
Mobile phase: 1% 2-propanol/hexane
Flow rate: 1 mL/min
Detection: UV 254 nm
H
H
four enantiomers of racemic 19
Cl
Cl
Figure 3. Epimerization on diastereomeric atropisomers 19.
OBz
OBz
OBz
hexane, retention times: 6 min for (P,S)-20 and 7 min for (M,R)-20
and 10 min for (M,S)-20 and 14 min for (P,R)-20 under flow rate of
2.0 mL/min), in which the ratios of two diastereoisomers were
observed to be almost the same as those of NMR (Fig. 5).
(P,S)-20 : A
(M,S)-20 : B
H
H
Cl
Cl
OBz
2.2.3. Chirality introduction by enantioselective reduction
On the basis of the above results, we next focused our attention
on the enantioselective reduction of ketone (MP)-18. Our first choice
for the enantioselective reduction was the Noyori’s classical BINAL-H
(M,R)-20 : C
(P,R)-20 : D
Figure 5. Determination (97% ee of S) of enantioselectivity by a chiral HPLC method
with the benzoates 20 derived from the alcohols 19, obtained in (S)-BINAL-H reduction.
reduction,26 which is known to be effective for
a,b-olefinic ketones.
Considering the concerted six-membered cyclic transition state of
1,3-chirality transfer in the subsequent rearrangement, we were
aware that (S)-configuration is necessary for alcohol 19 for the
asymmetric synthesis of (S)-1, and therefore (S)-BINAL-H is a suitable
reagent. Treatmentof 18 with (S)-BINAL-H inTHFat ꢀ100 ꢁC resulted
in the production of atropisomeric alcohols 19 in 85% yield, as shown
in Scheme 9. The resulting alcohols were transferred into the cor-
responding benzoyl derivatives 20 in a quantitative yield in order to
determine the enantioselectivity of the reduction. Judging from the
methyl signals of the 1H NMR spectra of 20, the diastereomeric ratio
was determined to be 1.93:1. Needless to say, the change of the ratio
can be ascribed to the epimerization on the atropisomerism during
the benzoylation process. Determination of the enantiomeric purity
was performed by chiral HPLC analysis using a mixture of 20, as
shown in Figure 5. By direct comparison with an authentic chro-
matogram of the racemates, the major pair (A and C) and the minor
pair (B and D) of the diastereisomers turned out to have 96% ee of
(S)-isomer and >99% ee of (S)-isomer, respectively. As a whole, the
total enantioselectivity in the (S)-BINAL-H reduction of 18 was cal-
culated to be 97% ee. This excellent enantioselection suggests that
the newly created chiral center is almost completely controlled by
the chirality of the catalyst,27 regardless of the stereochemistry of the
substrate ketone concerned with the atropisomeric ortho-chloro
substituent. In addition, we explored Noyori’s ruthenium-catalyzed
asymmetric transfer hydrogenation28 of 18 as a more practical cat-
alytic method. [(1R,2R)-N-(p-Toluenesulfonyl)-1,2-diphenylethane-
diamine]-(p-cymene)ruthenium(II), Ru[(R,R)-Ts-DPEN](p-cymene),
served as an efficient catalyst for the enantioselective reduction of 18
to (S)-alcohol in a 5 to 2 formic acid-triethylamine azeotropic mix-
ture at 40 ꢁC. The enantioselectivity of the conversion, however, was
not excellent (77% ee).
B (syn): (M,S)- or (P,R)-19
A (anti): (P,S)- or (M,R)-19
22.8 kcal/mol
B
4.7 kcal/mol
A
-68.2°
0
Dihedral angle
75.1°
Figure 4. Rotaional barrier and optimized structures of atropisomers (B3LYP/6-31G
*
level).

5186
R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
-
Li
+
O
H
Al
O
OEt
O
H
H
Cl
ortho-Cl
Cl
(S)-BINAL-H
-100 °C/THF
OH
OH
(MP)-18
major (P,S)-19
85% yield, 97% ee
(M,S)-19
the corresponding benzoate 20
Ts
N
Ru
N
H
Ru[(R,R)-Ts-DPEN](p-cymene)
major (P,S)-19
(M,S)-19
40 °C/HCOOH-triethylamine
68% yield, 77% ee
Scheme 9. Stoichiometric and catalytic ‘Noyori’ enantioselective reductions of ketone 18.
2.2.4. Completion of asymmetric synthesis of (S)-ketamine
The reaction sequence from the diastereomeric optically active
alcohols (MP,S)-19 to (S)-ketamine 1 is as follows (Scheme 10).
Reaction of 19 with trichloroacetyl isocyanate in dichloromethane
at 0 ꢁC and subsequent hydrolysis with potassium carbonate in an
aqueous methanol provided carbamate (MP,S)-21 in 96% yield. The
carbamate 21 was also a diastereomeric mixture of the atro-
pisomers and without further purification was employed as a pre-
cursor to the cyanates, (P,S)-22 and (M,S)-22, for the successive allyl
cyanate-to-isocyanate rearrangement. According to Ichikawa’s
procedure,11,20 dehydration of 21 was carried out with triphenyl-
phosphine, carbon tetrabromide, and triethylamine at 0 ꢁC for
20 min as to provide the transient allyl cyanate. During the one-pot
procedure, the expected sigmatropic rearrangement took place to
convert 22 to the corresponding isocyanate (R)-23. Fortunately, the
isocyanate was quite stable for the isolation process using an
aqueous work-up and isolated as a single isomer in 98% yield. The
stability of 23 is ascribed to its clearly inherent sterically hindered
structure. This easy isolation of 23 led to a shortening of the re-
action path to the methyl amine moiety necessary for ketamine. In
practice, treatment of 23 with lithium aluminum hydride in THF
provided the methyl amine (R)-24 in 92% yield.
The final stage toward ketamine is only the conversion of the
functional group from the double bond to the carbonyl group.
Ozonolysis of 24 in dichloromethane at ꢀ18 ꢁC followed by a re-
ductive work-up with dimethyl sulfide resulted in a miserable
mixture. Presumably, the participation of the basic allylic amino
function to the intermediate ozonide might have disturbed the
normal ozonolysis. Then, the hydrogen chloride salt of 24 was
furnished for the ozonolysis in methanol. Expectedly, the reaction
proceeded smoothly to give the final product of 1, as the hydrogen
chloride salt, which was crystallized from ethanol-n-hexane in 95%
yield. The synthetic ketamine 1 was determined to be >99% ee with
the almost complete enantiomeric purity of the (S)-configuration
by chiral HPLC analysis, as illustrated in Figure 6. Here, the first
asymmetric synthesis of (S)-ketamine has been accomplished via
a short path with excellent selectivity. On the basis of the pro-
duction of (S)-1 in maintaining the level of the chirality of the
H
H
ortho-Cl
ortho-Cl
a
O
OH
O
NH2
(MP,S)-19
(MP,S)-21
Cl
Cl
H
H
b
CH3
CH3
N
C O
N C O
(P,S)-22 and (M,S)-22
O
CH3
NH
C
c
N
d
complex mixtures
Cl
Cl
(R)-23
(R)-24
CH3
-
CH3
Cl
NH2
e
NH
O
Cl
Cl
(S)-Ketamine 1
(R)-24-HCl
Scheme 10. Completion of asymmetric synthesis of (S)-ketamine via rearrangement.
Reagents and conditions: (a) CCl3CONCO, CH2Cl2, aq K2CO3/MeOH, 96%; (b) PPh3, CBr4,
Et3N, CH2Cl2, 0 ꢁC, 98%; (c) LiAlH4, THF, 92%; (d) O3, CH2Cl2, 50 min, Me2S; (e) O3,
MeOH, 50 min, Me2S, 95%.
starting alcohol 19, the 1,3-chirality transfer in the [3,3]-sigma-
tropic rearrangement was reevaluated to be stereospecific with the
concerted mechanism via the six-membered cyclic transition state
in this investigation. Optically pure (R)-ketamine was also synthe-
sized by starting with (R)-alcohol 19 from the enantioselective re-
duction of ketone 18 with (R)-BINAL-H.

R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
5187
using Merck 60 silica-gel (230–400 mesh). Unless otherwise noted,
all infrared spectra (IR) are reported in wave number (cmꢀ1). 1H and
13C NMR spectra are reported; chemical shifts are expressed in
parts per million relative to internal standard tetramethylsilane
(coupling constants: Hz). High resolution mass spectra (HRMS) are
reported in m/z.
DAICEL CHIRALCEL OD-H
Mobile phase: 5% 2-propanol/n-hexane
Flow rate: 0.5 mL/min
Detection: UV 254 nm
4.2. Synthesis of ketones having an acetal moiety
A solution of 1,2-cyclohexanedione (22.4 mmol, 2.51 g) and diol
(22.4 mmol) in benzene (30 mL) was refluxed overnight with p-
TsOH (8 mg) under a Dean–Stark water separator. Ether (30 mL) was
added and unchanged diketone was extracted with 10% NaOH (aq)
(15 mL). The organic layer was washed with brine and dried over
anhydrous Na2SO4, and the solvent was evaporated. The residual oil
was purified by flash column chromatography on silica-gel.
4.2.1. 2-Oxocyclohexanone (1R,2R)-1,2-dimethylethylene acetal (7)
Colorless oil; (3.62 g, 88%): [
a]
22 15.0 (c 1.00, CHCl3); IR (neat):
D
2972, 2870, 1735 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d 1.23 (3H, d,
J¼7.3), 1.28 (3H, d, J¼7.3), 1.82–1.97 (6H, m), 2.48–2.54 (1H, m),
2.58–2.62 (1H, m), 3.61–3.73 (2H, m); 13C NMR (100 MHz, CDCl3)
d
16.0, 16.4, 22.2, 25.9, 37.6, 39.2, 78.6, 78.7, 105.7, 206.0.
4.2.2. 2-Oxocyclohexanone (1S,2S)-1,2-dimethoxyethylene
acetal (8)
22
Colorless oil; (4.45 g, 80%): [
a
]
ꢀ29.0 (c 1.00, CHCl3); IR (neat)
D
2939, 1736 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 1.70–1.79 (1H, m),
1.80–1.92 (3H, m), 1.95–2.05 (2H, m), 2.48–2.55 (1H, m), 2.59–2.67
(1H, m), 3.37 (3H, s), 3.40 (3H, s), 3.43 (1H, d, J¼4.4), 3.51–3.56 (3H,
m), 4.01–4.05 (2H, m); 13C NMR (100 MHz, CDCl3)
39.7, 59.3, 59.5, 72.4, 73.2, 77.8, 78.5, 107.9, 206.8.
d 22.6, 26.4, 37.9,
racemic Ketamine
(S)-Ketamine
Figure 6. Determination of enantiopurity of synthetic (S)-ketamine.
4.3. Synthesis of a-ketoxime-ether acetals
3. Conclusion
To a solution of ketone (10.2 mmol) in MeOH (30 mL) were
added HCl$H2NOCH2Ph (10.2 mmol, 1.63 g) and pyridine
(30.6 mmol, 3 mL). The reaction mixture was refluxed for 30 min.
After solvent evaporation, water (15 mL) was added to the residue.
The mixture was extracted with ether (30 mL). The organic layer
was washed with brine and dried over anhydrous MgSO4. The so-
lution was concentrated under reduced pressure. The crude prod-
uct was subjected to flash column chromatography on silica-gel.
The enantioselective construction of nitrogen-substituted qua-
ternary carbon centers in the ring like (S)-ketamine was a very
difficult challenge. First, we have established a straightforward
method for the construction of a chiral nitrogen-substituted qua-
ternary carbon center using an enantioselective 1,2-addition re-
action of phenyllithium to chiral
10, having -chiral acetal auxiliary. After deprotection, the ap-
proach provided the chiral compound with a nitrogen-substituted
quaternary carbon bearing -carbonyl group. However, the reaction
a-ketoxime-ether acetals, 9 and
a
4.3.1. 2-Benzyloxyiminocyclohexanone (1R,2R)-1,2-
a
dimethylethylene acetal (9)
of 2-chlorophenyllithium did not work so that this route was un-
available for the synthesis of (S)-ketamine 1. An alternative strategy
was adapted to the synthesis, consisting of the enantioselective
reduction of the atropisomeric intermediate ketone 18 and the
sequential allyl cyanate-to-isocyanate rearrangement with 1,3-
chirality transfer. The enantioselective reduction using (S)-BINAL-H
gave (S)-alcohol 19 with 97% ee. Subsequently, the complete 1,3-
chirality transfer of the carbamate 21, derived from the alcohol, was
observed to afford the corresponding isocyanate 23 in the [3,3]-
sigmatropic allyl cyanate-to-isocyanate rearrangement. Thus, the
first asymmetric synthesis of (S)-ketamine 1, after reduction and
ozonolysis, was accomplished with excellent selectivity (>99% ee).
22
Colorless oil; (2.51 g, 85%): [
a
]
ꢀ24.2 (c 0.33, CHCl3); IR (neat):
D
2970, 2935, 2865, 1496, 1454 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.13 (3H, d, J¼5.6), 1.23 (3H, d, J¼5.6), 1.62–1.52 (2H, m), 1.70–1.76
(2H, m), 1.85–1.90 (2H, m), 2.56 (1H, ddd, J¼14.0, 7.4, 5.5), 2.67 (1H,
ddd, J¼14.0, 7.4, 5.5), 3.6 (1H, dq, J¼8.9, 5.6), 3.63 (1H, dq, J¼8.9,
5.6), 5.14 (2H, dd, J¼14.0, 12.0), 7.27–7.34 (5H, m); 13C NMR
(100 MHz, CDCl3)
d 16.4, 16.7, 22.8, 24.1, 24.9, 38.5, 75.6, 78.0, 79.2,
105.5, 127.5, 128.0, 138.3, 158.7; HRMS (FAB) calcd for C17H23NO3
[MþH]þ 290.1757, found 290.1763.
4.3.2. 2-Benzyloxyiminocyclohexanone (1S,2S)-1,2-
dimethoxyethylene acetal (10)
25
Colorless oil; (2.73 g, 76%): [
a]
ꢀ18.0 (c 1.00, CHCl3); IR (neat):
D
4. Experimental
4.1. General
3030, 2934 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.53–1.61 (2H, m),
1.72–1.78 (2H, m), 1.88–1.91 (2H, m), 2.53–2.62 (1H, m), 2.64–2.73
(1H, m), 3.16 (1H, dd, J¼10.0, 5.0), 3.34–3.41 (1H, m), 3.26 (3H, s),
3.38 (3H, s), 3.51 (2H, d, J¼4.4), 3.90–3.96 (2H, m), 5.13 (2H, dd,
All reactions unless otherwise noted were carried out under an
argon atmosphere. Flash column chromatography was carried out
J¼14.8, 11.8), 7.26–7.37 (5H, m); 13C NMR (100 MHz, CDCl3)
d 22.8,
24.0, 24.9, 38.3, 59.2, 59.4, 72.8, 73.6, 75.5, 78.0, 78.1, 107.2, 127.6,

5188
R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
128.0, 128.3, 138.5, 158.5; HRMS (FAB) calcd for C19H27NO5 [MþH]þ
4.6. Ethyl (2-chlorobenzoyl) (4-cyanobutyl)acetate (15)
350.1968, found 350.1977.
Ethyl (2-chlorobenzoyl)acetate 14 (3.20 g, 14.1 mmol), [IR (film)
2982,1741, 1687 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.24–1.27 (3H, t,
4.4. Typical 1,2-additon reaction of PhLi to chiral
ether acetals
a
-ketoxime-
J¼7.7), 4.00 (2H, s), 4.19–4.25 (2H, q, J¼7.7), 7.47–7.96 (5H, m)], was
added dropwise to a stirred THF (60 mL) slurry of NaH (408 mg,
17.0 mmol) at 0 ꢁC. To the resulting solution were added 5-bro-
movaleronitrile (2.12 mL, 18.3 mmol) and solid NaI (417 mg,
2.8 mmol) and then the reaction mixture was heated at reflux. After
24 h, the reaction was allowed to cool, a saturated aqueous NH4Cl
solution (20 mL) was added. The organic layer was separated and
the aqueous layer was extracted with AcOEt (20 mLꢂ3). The com-
bined organic layers were dried (Na2SO4). After concentration of
the solvent under reduced pressure, the residue was purified by
flash chromatography on silica-gel (20% AcOEt/hexane) to afford
ketoester 15 (3.69 g, 85%). IR (film) 2245, 1736, 1702 cmꢀ1; 1H NMR
To
a stirred solution of chiral a-ketoxime-ether acetal 9
(0.98 mmol, 283 mg) in toluene (5 mL) was PhLi (2.94 mmol) at
ꢀ78 ꢁC. The solution was stirred for 1 h at ꢀ78 ꢁC and then was
allowed to warm to ꢀ17 ꢁC. After stirring for 1 h, the reaction
mixture was quenched by the addition of satd NaHCO3 (aq) (5 mL)
at ꢀ7 ꢁC. The reaction mixture was extracted with Et2O (10 mL). The
combined organic layers were dried over anhydrous K2CO3. After
evaporation of the solvent, the resulting residue was purified by
silica-gel column chromatography to give a mixture of 11 (305 mg,
83% yield). The diastereoselectivity of 11 was determined to be 82%
de by using the relative methyl doublet signals (7.25 (major) and
8.23 (minor) ppm) in its 1H NMR spectrum. The isomers were
separated by silica-gel column chromatography. The major isomer
was recrystallized from n-hexane to afford the fine crystals (mp
78 ꢁC), adequate for X-ray study.
(CDCl3):
d
1.16 (keto: 3H, t, J¼6.8), 1.37 (enol: 3H, t, J¼6.8), 1.45–1.60
(m), 1.69–1.74 (m), 1.98–2.04 (m), 2.16 (enol: 2H, t, J¼7.2), 2.36
(keto: 2H, t, J¼7.2), 4.13 (keto: 2H, q, J¼6.8), 4.27 (enol: 1H, t, J¼6.8),
4.34 (enol: 2H, q, J¼6.8) 7.30–7.50 (4H, m). 13C NMR (CDCl3):
d Keto
form: 13.8, 16.8, 25.1, 26.4, 27.3, 57.3, 61.4, 119.3, 126.8, 129.2, 130.3,
130.5, 132.1, 138.1, 173.0, 197.6; Enol form: 14.1, 16.6, 24.6, 25.5, 28.3,
60.9, 102.4, 119.4, 126.7, 129.6, 129.8, 130.8, 132.0, 133.9, 168.6,168.9.
4.4.1. (2R)-2-Benzyloxyamino-2-phenylcyclohexanone (1R,2R)-1,2-
dimethylethylene acetal ((R,R,R)-11)
4.7. 2-Chlorophenyl 5-cyanopentyl ketone (16)
23
Colorless crystals; Mp 78 ꢁC (n-hexane): [
a
]
24.5 (c 2.00,
D
CHCl3); IR (KBr) 2950, 2927, 2898, 2859, 1496, 1445 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
An aqueous NaOH (2 M, 14 mL) solution was added to an etha-
nolic solution (5 mL) of 15 (5.49 g, 17.8 mmol). The reaction mixture
was heated at 80 ꢁC for 12 h. The resulting solution was acidified at
0 ꢁC by 1 M HCl until a pH of 2. The organic layer was separated, the
aqueous layer was extracted with EtOAc (10 mLꢂ3). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica-gel (10% EtOAc/hexane) to afford cyanoketone 16 (3.19 g,
d
0.72 (3H, d, J¼6.5), 0.91 (3H, d, J¼6.5), 1.43 (1H,
d, J¼12.8), 1.53–1.70 (3H, m), 1.92 (1H, tq, J¼12.7, 3.1), 2.03 (1H, dt,
J¼12.7, 5.7), 2.15–2.24 (1H, m), 2.25–2.27 (2H, m), 3.34 (1H, dq,
J¼8.6, 5.7), 4.74 (2H, dd, J¼20.8, 11.5), 6.46 (1H, m), 7.20–7.34 (8H,
m), 7.50–7.52 (2H, m); 13C NMR (100 MHz, CDCl3)
d 15.3, 16.9, 20.7,
23.8, 29.5, 33.7, 68.6, 76.3, 77.3, 78.7, 108.6, 126.3, 126.9, 127.4, 128.1,
128.2, 128.8, 138.6, 140.8; HRMS (FAB) calcd for C23H29NO3 [MþH]þ
368.2227, found 368.2231.
76%). IR (film) 2245, 1699 cmꢀ1
1.74 (4H, oct, J¼7.0), 2.37 (2H, t, J¼7.0), 2.97 (2H, t, J¼7.0), 7.30–7.45
(4H, m); 13C NMR (CDCl3):
17.0, 23.2, 25.3, 28.1, 119.6, 127.0, 128.7,
; d 1.54 (2H, m),
1H NMR (CDCl3):
4.4.2. (2S)-2-Benzyloxyamino-2-phenylcyclohexanone (1S,2S)-1,2-
d
dimethoxyethylene acetal ((S,S,S)-13)
130.6, 130.8, 131.7, 139.5, 203.1.
Colorless paste: IR (KBr) 2928, 1497, 1454 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
1.51–1.54 (2H, m), 1.69 (2H, br s), 1.86–1.91 (1H,
4.8. 1-(2-Chlorophenyl)-2-cyano-1-cyclohexene (17)
m), 1.86–1.91 (1H, m), 1.98–2.01 (1H, m), 2.22–2.25 (1H, m), 2.29–
2.36 (1H, m), 2.70 (2H, br s), 2.74–2.78 (1H, m), 3.21 (3H, s), 3.24–
3.30 (2H, m), 3.28 (3H, s), 3.72–3.75 (1H, m), 4.70 (2H, dd, J¼22.0,
13.0), 6.46 (1H, s), 7.23–7.38 (8H, m), 7.51 (2H, d, J¼8.0); 13C NMR
Solid t-BuOK (602 mg, 5.37 mmol) was added to a refluxing THF
solution of 16 (900 mg, 4.47 mmol) in THF (200 mL). After 5 h, the
solution was cooled to room temperature. A saturated aqueous
NH4Cl (30 mL) was added and the organic layer was separated. The
aqueous layer was extracted with ether (30 mLꢂ3). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica-gel (20% EtOAc/hexane) to give nitrile 17 (555 mg, 57%). IR
(100 MHz, CDCl3)
d 20.7, 23.7, 29.4, 33.8, 59.1, 59.3, 68.6, 72.8, 73.3,
76.3, 77.1, 78.8, 111.6, 126.5, 127.0, 127.1, 127.3, 127.4, 128.2, 138.6,
140.9; HRMS (FAB) calcd for C25H33NO5 [MþH]þ 428.2438, found
428.2431.
(film) 2211, 1470, 1431 cmꢀ1; 1H NMR (CDCl3):
(1H, br s), 2.42 (2H, br s), 2.59 (1H, br s), 7.16–7.22 (1H, m), 7.26–
7.34 (2H, m), 7.41–7.50 (1H, m); 13C NMR (CDCl3):
21.2, 21.5, 27.4,
d 1.79 (4H, br s), 2.24
4.5. (2R)-2-Benzyloxyamino-2-phenylcyclohexanone (12)
from deacetalization of (R,R,R)-11
d
30.9, 111.0, 118.4, 127.1, 129.1, 129.6, 129.9, 131.6, 139.2, 154.5; HRMS
To a stirred solution of (R,R,R)-11 (100 mg, 0.27 mmol) in MeOH
(3.6 mL) was added 36% HCl (aq) (5.7 mL). The solution was stirred
at 50 ꢁC overnight. After solvent evaporation, the resulting mixture
was extracted with ether (10 mL). The organic layer was washed
with satd K2CO3 (aq) (3 mL) and dried over anhydrous Na2SO4. The
(FAB) calcd for C13H12NCl [MþH]þ 218.0737, found 218.0726.
4.9. 1-Acetyl-2-(2-chlorophenyl)-1-cyclohexene (18)
To an ethereal solution (1.5 mL) containing magnesium turning
crude was purified by flash column chromatography on silica-gel to
(104 mg, 4.31 mmol) was added a solution of methyl iodide (335 mL,
23
give 12 (271 mg, 92% yield). Colorless oil: [
a]
ꢀ163.0 (c 2.00,
5.0 mmol) in Et2O (1.0 mL). When the reaction was complete, dry
toluene (4.5 mL) was added. After the ether solvent was evacuated
under reduced pressure, nitrile 17 (468 mg, 2.15 mmol) was added.
The resulting solution was stirred at 100 ꢁC. After cooling, 5 M
hydrochloric acid (5 mL) was added. Then, the mixture was stirred
at 90 ꢁC for 12 h. The separated organic layer was washed with
a dilute aqueous NaHCO3 solution (5 mL) and dried (MgSO4). After
D
CHCl3); IR (neat) 2943, 2864 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.72
(2H, m), 1.84 (1H, m), 1.94 (1H, m), 2.29 (2H, m), 2.49 (1H, m), 2.75
(1H, ddd, J¼14.4, 5.6, 3.2), 4.59 (2H, s), 6.35 (1H, s), 7.40–7.24 (10H,
m); 13C NMR (100 MHz, CDCl3)
d 21.8, 26.9, 32.9, 40.5, 73.8, 77.2,
127.5, 127.6, 128.2, 128.3, 128.4, 128.9, 136.8, 137.7, 210.7; HRMS
(FAB) calcd for C19H21NO2 [MþH]þ 296.1651, found 296.1650.

R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
5189
concentrated under reduced pressure, the crude was purified by
flash chromatography on silica-gel (10% EtOAc/hexane) to give
to give benzoates 20 (42 mg, 98%). Colorless oil: IR (film) 1717,
1271 cmꢀ1 1H NMR (CDCl3):
;
d
(minor) 1.32 (3H, d, J¼7.0), (major)
ketone 18 (439 mg, 87%). IR (film) 1663 cmꢀ1
;
1H NMR (CDCl3):
1.33 (3H, d, J¼7.0), 1.70–1.79 (4H, m), 2.00–2.20 (1H, m), 2.23–2.35
(3H, m), (major) 5.40 (1H, q, J¼7.0), (major) 5.42 (1H, q, J¼7.0), 7.18–
7.40 (4H, m), 7.43 (2H, t, J¼6.8) 7.53 (1H, q, J¼6.8), 8.00 (2H, t,
d
1.67–1.76 (1H, m), 1.73 (3H, s), 1.98–2.00 (1H, m), 2.10–2.24 (1H,
m), 2.25–2.33 (2H, m), 2.52–2.56 (2H, m), 7.08 (1H, dd, J¼3.1, 5.4),
7.23 (2H, dd, J¼3.1, 5.4), 7.38 (1H, dd, J¼3.1, 5.4); 13C NMR (CDCl3):
J¼6.8); 13C NMR (CDCl3): (major)
d
18.3, 22.3, 22.4, 22.7, 30.9, 72.0,
d
21.9, 22.2, 25.7, 29.6, 32.1, 127.2, 128.7, 129.6, 129.7, 137.8, 141.8,
127.0, 128.1, 128.2, 129.3, 129.4, 130.0, 141.1, 165.3: (minor) d19.0,
143.0 (ꢂ2), 203.1; HRMS (FAB) calcd for C14H15OCl [MþH]þ
22.5, 22.8, 23.0, 31.1, 71.4, 126.5, 128.1, 128.2, 129.5, 129.7, 129.9,
141.0, 165.2.
235.0890, found 235.0883.
4.10. Major (P,S)- and minor (M,S)-1-[2-(2-chlorophenyl)-1-
cyclohexenyl]ethanol ((P,S)-19 and (M,S)-19) from (S)-BINAL-H
reduction of 18
4.13. Major (P,S)- and minor (M,S)-1-[2-(2-Chlorophenyl)-1-
cyclohexenyl]ethyl carbamate ((PM,S)-21)
To a solution of alcohol (MP,S)-19 (170 mg, 0.729 mmol) in
To a 2.4 M THF solution (2.95 mL, 7.10 mmol) of LiAlH4 at 0 ꢁC
was added dropwise a solution of ethanol (330 mg, 7.18 mmol) of
THF (3.5 mL). After stirring for 10 min, a solution of (S)-binaphthol
(2.07 g, 7.21 mmol) in THF (10 mL) was added and the resulting
mixture was stirred for 30 min at room temperature. The reducing
agent was cooled to ꢀ100 ꢁC. A solution of ketone 18 (500 mg,
2.14 mmol) in THF (12 mL) was added dropwise over a period of
5 min at ꢀ100 ꢁC. The resulting mixture was stirred for an addi-
tional 6 h at the temperature and at ꢀ78 ꢁC for 24 h. After addition
of 2 M HCl (20 mL), the mixture was extracted with ether. The li-
gand, (S)-binaphthol, was recovered in a quantitative level without
lowing the enantiopurity by extracting the ethereal solution with 5%
NaOH (20 mLꢂ3). The organic layer was dried (MgSO4) and con-
centrated under reduced pressure. A residual oil was purified by
flash chromatography on silica-gel (20% AcOEt/hexane) to afford
the optically active alcohol 19 (395 mg, 78%). IR (film) 3301, 1469,
CH2Cl2 (4.6 mL) at 0 ꢁC was added trichloroacetyl isocyanate
(172 m
L, 1.46 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 (811 mg) solution in water (2 mL) and MeOH
(5 mL). The reaction mixture was stirred at room temperature for
1.5 h. After extraction with ether (10 mLꢂ3), 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/
hexane) to afford allyl carbamate 21 (195 mg, 96%). IR (film) 3454,
1734, 1723 cmꢀ1
;
1H NMR (CDCl3):
d
1.19 (3H, d, J¼6.7), 1.68–1.78
(4H, m), 1.99–2.03 (1H, m), 2.17 (2H, brs), 2.30–2.35 (1H, m), 4.79
(2H, br s), 5.04 (1H, q, J¼6.9), 7.15–7.35 (4H, m); only distinguish-
able methyl doublet 1.21 (3H, d, J¼6.7) of minor diastereomer
shows the ratio (3: 1) of the atropisomers; 13C NMR (CDCl3): (ma-
758 cmꢀ1; 1H NMR (CDCl3):
d
1.12 (minor: 3H, d, J¼6.8), 1.17 (major:
jor)
d
18.3, 22.2, 22.3, 22.6, 30.8, 72.0, 126.8, 128.0, 129.2, 130.1,
18.9, 22.4, 22.7, 22.8, 31.0,
3H, d, J¼6.8), 1.52 (minor isomer: 1H, s), 1.60 (major isomer: 1H, s),
132.6, 133.4, 133.5, 141.1, 156.3: (minor)
d
1.62–1.80 (4H, m), 2.00–2.40 (4H, m), 4.16 (1H, m), 7.05–7.40 (4H,
71.6, 126.5, 128.0, 129.6, 129.9, 132.4, 133.5, 133.6, 141.0, 156.4;
HRMS (FAB) calcd for C15H18NO2Cl [MþH]þ 280.1105, found
280.1083.
m); 13C NMR (CDCl3): Two isomers
d
20.0, 20.5, 21.4, 21.5, 22.5 (ꢂ2),
22.8, 23.0, 31.1, 31.3, 67.9 (ꢂ2), 126.8, 1269, 127.9 (ꢂ2), 129.4, 129.5,
129.6, 130.3, 131.9, 132.2, 132.8, 133.0, 136.7, 137.2, 141.7, 141.8;
HRMS (FAB) calcd for C14H17OCl [MþH]þ 237.1047, found 237.1023.
The enantiomeric excess was determined to be 97% by HPLC analysis
(DAICEL CHIRALPAK IA) after conversion of the alcohol into the cor-
responding benzoate.
4.14. (1R,2E)-1-(2-Chlorophenyl)-2-ethylidenecyclohexyl
isocyanate ((R)-23)
To a solution of carbamate 23 (100 mg, 0.357 mmol), triphe-
nylphosphine (288 mg, 1.10 mmol), and triethylamine (290 mL,
4.11. Major (P,S)- and minor (M,S)-19 from Ru[(R,R)-Ts-
DPEN](p-cymene) reduction of 18
2.10 mmol) in CH2Cl2 (6 mL) cooled to 0 ꢁC was added a solution of
carbon tetrabromine (353 mg, 1.06 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, an 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
To an azeotropic (5: 2) mixture29 of formic acid and triethyl-
amine (1 mL) was added
a solution of ketone 18 (50 mg,
0.214 mmol) in CH2Cl2 (1 mL). A solution of (R,R)-Ru-[N-(tosyl)-1,2-
diphenylethylenediamine](p-cymene) (6.4 mg, 0.011 mmol) in
CH2Cl2 (1 mL) was added to the mixture at room temperature. After
stirring at 40 ꢁC for 15 h, the resulting solution was concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica-gel to give the optically active alcohols 19
(34 mg, 68%). The enantiomeric excess was determined to be 77%
by HPLC analysis after conversion of the alcohol into the corre-
sponding benzoate.
(20% AcOEt/hexane) to afford isocyanate 23 (92 mg, 98%). Colorless
19
oil: [
a
]
D
ꢀ116.0 (c 1.00, CHCl3); IR (film) 2256, 1464, 1431 cmꢀ1; 1H
NMR (CDCl3):
d
1.48–1.56 (1H, m), 1.59 (3H, dd, J¼6.5, 1.3), 1.77–1.88
(4H, m), 2.23–2.29 (1H, m), 2.62–2.76 (2H, m), 5.04 (1H, dq, J¼6.7,
1.9), 7.24 (1H, dt, J¼7.6, 1.7), 7.30 (1H, dt, J¼7.6, 1.7), 7.37 (1H, dd,
J¼7.6, 1.7), 7.73 (1H, dd, J¼7.6, 1.7); 13C NMR (CDCl3):
d 12.9, 22.6,
24.8, 25.2, 39.0, 69.0, 120.9, 124.7, 126.8, 128.7, 129.2, 131.9, 132.8,
137.3, 140.1; HRMS (FAB) calcd for C15H16NOCl [MþH]þ 262.1000,
found 262.9987.
4.12. (PM,S)-1-(1-Benzoylethyl)-2-(2-chlorophenyl)-1-
cyclohexene ((PM,S)-20)
4.15. (R)-1-(2-Chlorophenyl)-2-ethylidene-1-
methylaminocyclohexane ((R)-24)
To a solution of alcohols 19 (30 mg, 0.127 mmol), obtained from
enantioselective reduction, in CH2Cl2 (1 mL) was added pyridine
(30
chloride (29
m
L). After stirring at room temperature for 15 min, benzoyl
To a slurry of large excess LiAlH4 (50 mg, 1.31 mmol) in THF
(1 mL) was added dropwise a solution of isocyanate 23 (150 mg,
0.57 mmol) in THF (1 mL). The resulting solution was stirred at
room temperature for 1 h and then reflux for 30 mn. After cooling,
a 30% NaOH solution (1 mL) was added and the mixture was heated
m
L, 0.255 mmol) was added to the solution. The
resulting solution was sirred for 2 h. The mixture was quenched
with 10% HCl (1 mL) and extracted with CH2Cl2 (5 mL). The organic
layer was dried (MgSO4) and concentrated under reduced pressure

5190
R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
to 90 ꢁC for 1 h. The reaction mixture was extracted with ether
(10 mLꢂ3). 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
4.
5.
a-Hydroxyimine thermal rearrangement: (a) Vate`le, J.-M.; Dumas, D.; Gore´, J.
´
`
Tetrahedron Lett. 1990, 31, 2277; (b) Compain, P.; Gore, J.; Vatele, J.-M. Tetra-
hedron Lett. 1995, 36, 4059.
a
-Hydroxyiminium ion semipinacol rearrangement: Fenster, M. D. B.; Patrick,
B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109.
6. (a) Nguyen, L. A.; He, H.; Pham-Huy, C. Int. J. Biomed. Sci. 2006, 2, 85; (b) Liu, J.;
Ji, X.-Q.; Zhu, X.-Z. Life Sci. 2006, 78, 1839; (c) Mather, L. E. Minerva Anestesiol.
2005, 71, 507; (d) Nau, C.; Strichartz, G. R. Anesthesiology 2002, 97, 497; (e)
Powell, J. R.; Ambre, J. J.; Ruo, T. I. The efficacy and toxicity of drug stereoiso-
mers. In Drug Stereochemistry. Analytical Methods and Pharmacology, 1st ed.;
Wainer, I. W., Ed.; Marcel Dekker: New York, NY, 1988; pp 245–270.
7. The racemic separation of ketamine was described in U. S. Patent 6040479 (DE
2062620, WO 97/43244, 01/98265).
8. Brunner, H.; Kagan, H. B.; Kreutzer, G. Tetrahedron: Asymmetry 2003, 14, 2177.
9. (a) Cordell, G. A. In The Alkaloids: Chemistry and Biology; Elsevier: San Diego, CA,
2003; Vol. 60; (b) Yamamura, S. In The Alkaloids; Brossi, A., Ed.; Academic: New
York, NY, 1986; Vol. 29.
corresponding methyl amine 24 (131 mg, 92%). Colorless liquid:
20
[
a]
ꢀ48.8 (c 1.67, CHCl3); IR (film) 1427, 1039, 753 cmꢀ1; 1H NMR
D
(CDCl3):
d
1.46–1.50 (1H, m), 1.59 (3H, d, J¼6.2), 1.60–1.83 (4H, m),
1.96 (1H, br s), 2.05 (3H, s), 2.27–2.40 (3H, m), 4.99 (1H, q, J¼6.9),
7.16 (1H, dt, J¼7.7, 1.7), 7.25 (1H, dt, J¼7.7, 1.7), 7.32 (1H, dd, J¼7.7,
1.7), 7.51 (1H, dd, J¼7.7, 1.7),; 13C NMR (CDCl3):
d 12.7, 22.5, 25.3,
26.9, 29.3, 36.4, 65.6, 118.1, 126.4, 127.5, 130.4, 131.7, 133.9, 139.7,
141.7; HRMS (FAB) calcd for C15H20NCl [MþH]þ 250.1364, found
250.1366.
10. (a) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873; (b) Wu, G.;
Huang, M. Chem. Rev. 2006, 106, 2596; (c) Ikeda, D.; Kawatsuda, M.; Uenishi, J.
Tetrahedron Lett. 2005, 46, 6663; (d) Garcı´a Ruano, J. L.; Alema´n, J.; Parra, A. J.
Am. Chem. Soc. 2005, 127, 13048; (e) Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam,
P. C.-H. J. Am. Chem. Soc. 2003, 125, 11482; (f) Masaki, Y.; Arasaki, H.; Iwata, M.
Chem. Lett. 2003, 32, 4; (g) Steinig, A. G.; Spero, D. M. Org. Prep. Proced. Int. 2000,
32, 205; (h) Bloch, R. Chem. Rev. 1998, 98, 1407; (i) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1977, 8, 1895; (j) Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem., Int. Ed. 1996, 35, 2708.
4.16. (S)-Ketamine (1)
Amine 24 (85 mg, 0.30 mmol) was dissolved in 10% HCl solution
(2 mL). Concentration under reduced pressure gave the corre-
sponding amine HCl salt. Ozone was passed into a solution of the
amine HCl salt in MeOH (5 mL) at ꢀ78 ꢁC, terminating the ozo-
nolysis upon observing the distinctive blue color of ozone. After
11. Ichikawa, Y. Synlett 2007, 2927.
12. Steinig, A. G.; Spero, D. M. Org. Prep. Proced. Int. 2000, 32, 205.
13. (a) Marco, J. A.; Carda, M.; Murga, J.; Gonza´lez, F.; Falomir, E. Tetrahedron Lett.1997,
38, 1841; (b) Marco, J. A.; Carda, M.; Murga, J.; Rodrı´guez, S.; Falomir, F.; Oliva, M.
purging with nitrogen, dimethyl sulfide (400 mL) was added at
ꢀ78 ꢁC. The solution was allowed to warm up to room temperature
and concentrated under reduced pressure to give the crude mate-
rial, which was dissolved in EtOH (2 mL). When hexane was added,
´
Tetrahedron: Asymmetry 1998, 9, 1679; (c) Carda, M.; Murga, J.; Rodrıguez, S.;
Gonza´lez, F.; Castillo, E.; Marco, J. A. Tetrahedron: Asymmetry 1998, 9, 1703.
14. (a) Moody, C. J.; Gallagher, P. T.; Lightfoot, A. P.; Slawin, A. M. Z. J. Org. Chem.
1999, 64, 4419; (b) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. Synlett 1997, 659.
15. (a) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477; (b) Fujioka,
H.; Fuji, M.; Okaichi, Y.; Yoshida, T.; Annoura, H.; Kita, Y.; Tamura, Y. Chem.
Pharm. Bull. 1989, 37, 602; (c) Tamura, Y.; Annoura, H.; Yamamoto, H.; Kondo,
H.; Kita, Y.; Fujioka, H. Tetrahedron Lett. 1987, 28, 5709; (d) Johnson, W. S.;
Harbert, C. A.; Stipanovic, R. D. J. Am. Chem. Soc. 1968, 90, 5279.
the HCl salt of (S)-1 was immediately crystallized: Colorless crys-
20
tals; Mp 276 ꢁC (ethanol-n-hexane): [
a
]
þ91.7 (c 2.00, H2O);30 IR
D
(film) 1722, 773 cmꢀ1; 1H NMR (CD3OD):
d 1.69–1.82 (2H, m), 1.90–
2.00 (2H, m), 2.10–2.15 (1H, m), 2.50–2.59 (2H, m), 3.42 (1H, dd,
J¼14.2, 2.8), 7.60–7.70 (3H, m), 7.97 (1H, d, J¼6.8); 13C NMR
16. X-ray diffraction data for 11 major, (2 R,3 R,6 R)-6-benzyloxyamino-
2,3-dimethyl-6-phenyl-1,4-dioxaspiro[4,5]decane: X-ray diffraction data were
collected using a Rigaku RAXIS RAPID diffractometer with graphite-mono-
(CD3OD): d 22.8, 28.0, 31.0, 37.5, 40.8, 73.7, 129.2, 129.7, 133.2, 133.3,
133.9, 135.8, 208.3. The salt was again 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/hexane) to afford (S)-
ketamine (68 mg, 95%). The enantiomeric excess was determined
chromated Cu-K
a
radiation (
l
¼1.54187 Å). The data of the crystal were col-
lected at ꢀ180ꢃ1 ꢁC to a maximum 2
q
value of 136.5ꢁ. A total of 144 oscillation
images was collected. Of the 36,672 reflections that were collected, 3612 were
unique (Rint¼0.025). The structure was solved by direct method (SHELX 97)
and expanded using Fourier techniques (DIRDIF 99). Chemical formula:
C23H29NO3(FW: 367.49); crystal color, habit: colorless, block; crystal system;
orthorhombic; lattice parameters; a¼0.26164(11) Å, a¼0.26164(11) Å, b¼17.
to be >99% by HPLC analysis (DAICEL CHIRALCEL OD-H column).
20
Colorless crystals; Mp 122 ꢁC (n-hexane); [
a
]
ꢀ56.3 (c 1.20,
D
7250(3) Å, c¼17.8039(7) Å, V¼1976.01(9) Å3; space group¼P212121(#19);
Z
EtOH);30 IR (film) 3353, 1701, 752 cmꢀ1 1H NMR (CDCl3):
; d 1.72–
value¼4; Dcalc¼1.235 g/cm3;
00
m
(CuK
a
)¼6.432 cmꢀ1
; residuals: R1 (I>2.
s
(I))¼0.0319; residuals: R (all reflections)¼0.0354; residuals: wR2 (all re-
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 (1H, dt,
J¼7.5, 1.5), 7.32 (1H, dt, J¼7.5, 1.5), 7.38 (1H, dd, J¼7.5, 1.5), 7.55 (1H,
flections)¼0.0752; goodness of fit indicator¼1.172. Crystallographic Data has
been deposited with Cambridge Crystallographic Data Centre: Deposition
number CCDC-689370. Copies of the data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conls/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge, CB2 1FZ, UK; Fax:
þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.jp).
dd, J¼7.5, 1.5); 13C NMR (CDCl3):
d 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.
17. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03 Re-
vision C.02; Gaussian,: Wallingford, CT, 2004.
Acknowledgements
This work was supported by Grand-in-Aid for Scientific Re-
search (C) of Japan Society for the Promotion of Science. We are
grateful to Messrs. Motoo Shiro and Mikio Yamasaki of X-ray Re-
search Laboratory and Application Laboratory, Rigaku Corporation
for X-ray crystallographic measurement.
References and notes
1. (a) Ketamine is included as a general anethetic in the 14th WHO model list of
essential medicines. ‘Critical review of ketamine’, WHO Expert Committee on
Drug Dependence: thirty-fourth report 2006 (WHO Technical Report Series
942). (b) Childers, W. E.; Baudy, R. B. J. Med. Chem. 2007, 50, 2557; (c) Chizh, B.
A.; Headley, P. M. Curr. Pharm. Des. 2005, 11, 2977; (d) Leung, A.; Wallance, M. S.;
Ridgeway, B.; Yaksh, T. Pain 2001, 91, 177.
18. Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1956, 78, 2217.
19. (a) Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org. Chem. 2005, 70, 2335; (b) Moody,
C. J.; Gallagher, P. T.; Lightfoot, A. P.; Slawin, A. M. Z. J. Org. Chem. 1999, 64, 4419;
(c) Uno, H.; Terakuwa, T.; Suzuki, H. Synlett 1991, 559; (d) Uno, H.; Okada, S.;
Shiraishi, Y.; Shimokuwa, K.; Suzuki, H. Chem. Lett. 1988, 1165; (e) Keck, G. E.;
Enholm, E. J. J. Org. Chem. 1985, 50, 146.
2. Stevens, C.L. U.S. Patent 3254124: Chem. Abstr. 1968, 65, 5414.
20. (a) Ichikawa, Y. J. Chem. Soc., Perkin Trans. 1 1992, 2135; (b) Ichikawa, Y.; Ya-
mazaki, M.; Isobe, M. J. Chem. Soc., Perkin Trans. 1 1993, 2429; (c) Ichikawa, Y.;
Yamauchi, E.; Isobe, M. Biosci. Biotechnol. Biochem. 2005, 69, 939; (d) Matsu-
kawa, Y.; Isobe, M.; Kotsuki, H.; Ichikawa, Y. J. Org. Chem. 2005, 70, 5339; (e)
Kopferer, P.; Sarabia, F.; Vesella, A. Helv. Chim. Acta 1999, 82, 645; (f) Roulland,
E.; Monneret, C.; Florent, J.-C.; Bennejean, C.; Renard, P.; Leonce, S. J. Org. Chem.
2002, 67, 4399; (g) Roy, S.; Spino, C. Org. Lett. 2006, 8, 939.
3. Aminoketone rearrangement: (a) Stevens, C. L.; Thuillier, A.; Daniher, F. A. J. Org.
Chem. 1965, 30, 2962; (b) Stevens, C. L.; Klundt, I. L.; Munk, M. E.; Pillai, M. D.
J.Org. Chem. 1965, 30, 2967; (c) Stevens, C. L.; Ash, A. B.; Thuillier, A.; Amin, J. H.;
Balys, A.; Dennis, W. E.; Dickerson, J. P.; Glinski, R. P.; Hanson, H. T.; Pillai, M. D.;
Stoddard, J. W. J. Org. Chem. 1966, 31, 2593; (d) Stevens, C. L.; Hanson, H. T.;
Taylor, K. G. J. Am. Chem. Soc. 1966, 88, 2769; (e) Stevens, C. L.; Pillai, M. D.;
Munk, M. E.; Taylor, K. G. Mech. Mol. Migr. 1971, 3, 271.

R. Yokoyama et al. / Tetrahedron 65 (2009) 5181–5191
5191
21. Messali, M.; Christiaens, L. E.; Alshahateet, S. F.; Kooli, F. Tetrahedron Lett. 2007,
48, 7448.
S.-i.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37, 2597; (e) Kobayashi, S.;
Ohtsubo, A.; Mukaiyama, T. Chem. Lett. 1991, 20, 831.
22. Fleming, F. F.; Funk, L. A.; Altundas, R.; Sharief, V. J. Org. Chem. 2002, 67, 9414.
23. Atropisomer: (a) Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145; (b)
AtropisomerismClayden, J., Ed. Tetrahedron (Tetrahedron Symposium-in-Print
Number 103) 2004, 60, 4325; (c) Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bardia, M.;
28. (a) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197; (b) Eustache, F.;
Dalko, P. I.; Cossy, J. Org. Lett. 2002, 4, 12635; (c) Noyori, R.; Yamakawa, M.;
Hashiguchi, S. J. Org. Chem. 2001, 66, 7931; (d) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2001, 40, 40; (e) Matsumura, K.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738; (f) Hashiguchi, S.; Fujii, A.; Haack,
K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288;
(g) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. 1997, 36, 285; (h) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521; (i) Uematsu, N.; Fujii, A.; Hashiguchi, S.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916; (j) Hashiguchi, S.; Fujii,
A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562; (k) Za-
notti-Gerosa, A.; Hems, W.; Groarke, M.; Hancock, F. Platinum Met. Rev. 2005,
49, 158; (l) Bierenstiel, M.; Dymarska, M.; de Jong, E.; Schlaf, M. J. Mol. Catal. A:
Chem. 2008, 290, 1.
´
´
Pickworth, M.; Solans, X.; Sole, D.; Vallverdu, L. Org. Biomol. Chem. 2005, 3, 3173.
24. The description of M and P, which correspond to aR and aS, respectively, for
compounds with chirality axes has been effectively used in the following re-
port: Lloyd-Williams, R.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145.
25. Sakurai, R.; Suzuki, S.; Hashimoto, J.; Baba, M.; Itoh, O.; Uchida, A.; Hattori, T.;
Miyano, S.; Yamaura, M. Org. Lett. 2004, 6, 2241.
26. (a) Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979, 101, 3129; (b)
Noyori, R.; Tomino, I.; Nishizawa, M. J. Am. Chem. Soc. 1979, 101, 5843; (c)
Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106,
6709; (d) Brunel, J. M. Chem. Rev. 2005, 105, 857; (e) No¨th, H.; Schlegel, A.;
Suter, M. J. Organomet. Chem. 2001, 621, 231.
27. Catalyst control: (a) Tomioka, K. Pure Appl. Chem. 2006, 78, 2029; (b) Kagan, H.;
Lagasse, F.; Tsukamoto, M.; Welch, C. J. Am. Chem. Soc. 2003, 125, 7490; (c)
Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003, 5, 3741; (d) Kiyooka,
29. Narita, K.; Sekiya, M. Chem. Pharm. Bull. 1977, 25, 135.
25
25
30. (S)-Ketamine: [
a
]
D
ꢀ56.9 (c 2.00, EtOH) and the HCl salt: [
a
]
þ92.6 (c 2.00,
D
H2O); Torres Russo Valter Freire; Souza Russo Elisa Mannochio de, Patent WO
01/98265 A2 (US 2003/0212143 A1).