Studies towards dynamic kinetic resolution of 4-hydroxy-2-methylcyclopent-2-en-1-one and its E-O-trityloxime

Article abstract of DOI:10.1016/j.tet.2016.06.047

Dynamic kinetic resolution through metal complex induced racemization and Candida antarctica lipase mediated enantioselective acetylation of a model hydroxy-ketone: 4-hydroxy-2-methylcyclopent-2-en-1-one and its selected derivatives, has been studied. Racemization of the hydroxy-ketone was efficiently affected by [RuCl₂(cymene)]₂complex–triethylamine while Shvo's catalyst triggered an intramolecular redox process. Kinetic resolution of 4-hydroxy-2-methylcyclopent-2-en-1-one with C. antarctica under conditions compatible with [RuCl₂(cymene)]₂racemization failed to reach the efficiency threshold. However, dynamic kinetic resolution of its O-trityloxime using [RuCl₂(cymene)]₂–triethylamine and C. antarctica lipase–isopropenyl acetate combination, was successfully achieved.

Full text of DOI:10.1016/j.tet.2016.06.047

Accepted Manuscript
Studies towards dynamic kinetic resolution of 4-hydroxy-2-methylcyclopent-2-en-1-
one and its E-O-trityl oxime
Karol Michalak, Jerzy Wicha, Jacek Wójcik
PII:
S0040-4020(16)30569-5
10.1016/j.tet.2016.06.047
TET 27861
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 April 2016
Revised Date: 9 June 2016
Accepted Date: 20 June 2016
Please cite this article as: Michalak K, Wicha J, Wójcik J, Studies towards dynamic kinetic resolution
of 4-hydroxy-2-methylcyclopent-2-en-1-one and its E-O-trityl oxime, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.06.047.
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1
ACCEPTED MANUSCRIPT
Candida antarctica
lipase
AcO
Tr
Tr
O
O
N
N
[RuCl2(cymene)]2
84% yield
>97% ee
(S)
rac.
HO
AcO
Studies towards dynamic kinetic resolution of 4-hydroxy-2-methylcyclopent-2-en-1-one
and its E-O-trityl oxime
Karol Michalak,§ Jerzy Wicha§*
§Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224
Warsaw, Poland
Jacek Wójcik‡
‡Laboratory of Biological NMR, Institute of Biochemistry and Biophysics, Polish Academy of
Sciences, ul. Pawińskiego 5a, 02-106 Warsaw, Poland
Abstract:
Dynamic kinetic resolution through metal complex induced racemization and Candida
antarctica lipase mediated enantioselective acetylation of a model hydroxy-ketone: 4-
hydroxy-2-methylcyclopent-2-en-1-one and its selected derivatives, has been studied.
Racemization of the hydroxy-ketone was efficiently affected by [RuCl2(cymene)]2 complex -
triethylamine while Shvo’s catalyst triggered an intramolecular redox process. Kinetic
resolution of 4-hydroxy-2-methylcyclopent-2-en-1-one with C. antarctica under conditions
compatible with [RuCl2(cymene)]2 racemization failed to reach the efficiency threshold.
However, dynamic kinetic resolution of its O-trityl oxime using [RuCl2(cymene)]2 –

2
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triethylamine and C. antarctica lipase – isopropenyl acetate combination, was successfully
achieved.
Keywords: dynamic kinetic resolution, ruthenium chloride cymene dimer, Shvo’s catalyst, 3-
hydroxyl-cyclopent-2-en-1-one
Introduction
Dynamic kinetic resolution (DKR) of racemic secondary alcohols, pioneered by Williams1
and Bäckvall,2 provides an important connection between racemic and optically active
compounds.3,4 An advanced version of DKR utilizes a lipase as an enantio-differentiating
factor, an acylating agent and metal racemization catalyst. The principles of this method are
illustrated in Scheme 1. The alcohol enantiomers react with chiral acylating agent – enzyme
assembly at different rates, kR and kS generating a non-racemic mixture of the acyl derivatives
and residual alcohols (kinetic resolution, KR). Simultaneously, the metal racemization
catalyst brings about equilibrium between (R)- and (S)-alcohols thus providing the continuous
replenishment of the alcohol enantiomer that is acylated at the higher rate. The process
continues until all available racemate is transformed into the enantiomerically enriched ester.
Ideally, in a case of a large difference between kR and kS, ester of the faster reacting alcohol
would be obtained in a nearly optically pure form and a quantitative yield. For effective DKR
it is important3c that the difference in the reaction rates of enantiomers would be relatively
large (practically, E = kR/kS larger than 20 is required for kR>ks) and that the ratio between
racemization rate (krac) and the slower acylation reaction rate (kS) would be significant (larger
than 10).
Scheme 1. General features of dynamic kinetic resolution (DKR).

3
ACCEPTED MANUSCRIPT
O
X
R3
R3
O
HO H
R1 R2
enzyme
catalyst
O H
R1 R2
metal
catalyst
kR
kS
krac
R3
O
H O
R1 R2
H OH
R1 R2
Several catalysts effecting racemization of secondary alcohols are known,5,6 however only a
few of them have been successfully applied in combination with an acyl donor and an enzyme
preparation. Thermally activated di-ruthenium complex 1 (Fig. 1, Shvo’s catalyst5a) has been
first employed for DKR of racemic secondary alcohols in combination with Candida
antarctica lipase7 B (CALB, Novozyme 435®) and p-chlorophenyl acetate as the acetyl
donor.2 The Kim - Park catalyst5b,5c 2 (activated with tert-BuOK) has been developed for
application in combination with CALB and isopropenyl acetate (IPA). Bäckvall’s catalyst5d,5e
3 (activated with tert-BuOK) was found to function well in combination with CALB and IPA.
Ruthenium cymene dimer 4 activated by triethylamine has been used with a lipase
Pseudomonas cepacia (PCL) and p-chlorophenyl acetate for DKR of allylic alcohols.8 The
same ruthenium complex 4 – in combination with tertiary amine, p-chlorophenyl acetate and
CALB has been applied more recently by the Deca workers9 for DKR of various benzylic
alcohols. These authors have observed that the racemization rate depends significantly upon
the nature of amine used for activation of catalyst and they found that the combination of 4
and N,N,N’,N’-tetramethylpropanediamine provides the best system. Catalysts based upon
ruthenium complex 4 appear to be of particular interest because of its stability towards
atmospheric oxygen and moisture, and availability at relatively low price.
DKR with ruthenium catalysts have been applied to a variety of “functionalized” secondary
alcohols.3a,3c However, there are available only a few reports concerning the racemization of

4
ACCEPTED MANUSCRIPT
hydroxy-ketones,10 in which a competing process - an intramolecular hydride transfer, could
take place.
It was of interest to examine racemization and eventually DKR of the hydroxy ketone, 4-
hydroxy-2-methylcyclopent-2-en-1-one 5 (Scheme 2), which constitutes a convenient starting
material for the terpenoid synthesis.11,12 Recently, we have developed a preparative procedure
for kinetic resolution of rac-5 using CALB and IPA.13,14 However, the attained efficiency (E =
ca. 15 in tert-butyl methyl ether) did not reach the threshold required for the effective DKR.
As an alternative, preparation of derivatives of 5 with anticipated higher E values in the
kinetic resolution and their application in KR in DKR was considered.
In this paper we report the initial studies on racemization of hydroxy-ketone 5 using catalysts
1 and 4, and the preparation, configurational assignments and kinetic resolution of E-O-
trityloxime E-9. The latter derivative, rac-E-9, has been successfully used in the dynamic
kinetic resolution process using catalyst 4, triethylamine, CALB and IPA.
Figure 1. Selected catalysts for the racemization of secondary alcohols.
Ph
Ph
Ph
Ru
O
O
Ph
X
H
H
Ph
Ph
Ph
OC
OC
Ph
Cl
Ph
Ph
Ph
Ph
OC Ru Ru CO
1
2, X = -NH-isopropyl
3, X = phenyl
CO CO
Cl
Cl
Ru
Ru
Cl
Cl
4
Results and Discussion

5
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Racemization of hydroxy-ketone 5.
Heating (S)-5 (98% ee) and the catalyst 1 (2 mol%) in toluene at 70 ºC for 24 h followed by
separation of the products by chromatography afforded dione15 6 and a hydroxy-ketones
fraction in 23% and 74% yields, respectively (Scheme 2). HPLC analysis (chiral column) and
inspection of the 1H NMR spectra of the hydroxy-ketone fraction showed it to consist of (S)-5
(49%), (R)-5 (4%) and two other components to which the structures of (R)- and (S)-7 were
assigned (25% and 22%).16 An analogous reaction of (S)-5 and 1 at 100 ºC afforded 6 (51%)
and the hydroxy-ketone fraction, 13%, containing (S)-5 and (R)-5 in almost equal amounts
(22% and 21%) as well as the enantiomers of 7 (29 and 27%).
Scheme 2. Racemization of (S)-5 using Shvos’s catalyst 1.
In further experiments we examined cymene ruthenium complex 4 (2 mol%) - N,N,N’,N’-
tetramethylpropanediamine (90 mol%).9 MTBE, toluene, chlorobenzene and 1,2-
dichloroethane (DCE) were chosen as the solvents and the reactions were carried out at 40 ºC.
As shown in Table 1, in all of the solvents after 20 h the hydroxy-ketone recovery was high
with only small amounts of the “reversed” isomer 7 formed as a side product. The degree of
racemization expressed as the racemization capacity9 (ꢀee=ee0-eet) depended on the nature of
solvent. The best results were obtained in DCE with ꢀee amounting to 98% after 20 h (entries
7 and 8). Addition of acetone (3 mol equiv) did not affect the reaction outcome (entry 9).
Addition of acetic acid (3 mol equiv) inhibited the racemization (entry 10), which apparently

6
ACCEPTED MANUSCRIPT
reflects protonation of the amine. The 1H NMR spectra of the crude products showed the
presence of only trace contamination, presumably saturated products.
Table 1. Racemization of (S)-5 (98% ee) using cymene ruthenium complex 4, [cymRuCl2]2, 2
mol%, and N,N,N’,N’-tetramethylpropanediamine9 (90 mol%) in selected solvents at 40 ºC.
Solventa T (h) Recov. %b (ee%) ꢀeec (%)
7%d
1
2
3
4
5
6
7
8
9
MTBE
3
20
3
20
3
20
3
20
20
20
-
88
-
91
-
87
-
88
-
-
88
54.
48
5
43
3
29
0
0
10
44
50
93
55
95
69
98
98
0
-
1
1
5
1
5
1
6
6
-
Tol
ClPh
DCE
DCEe
10 DCEf
98
aAbbreviations: MTBE – tert-butyl methyl ether, Tol – toluene, ClPh – chlorobenzene, DCE –
1,2-dichloroethane.
bThe product was isolated and purified by chromatography after 20 h; intermediate
measurements were carried out on samples taken from the reaction mixture.
cRacemization capacity,9 ꢀee=ee0-eet.
dContent in the mixture, HPLC signal of one enantiomer of 7 partly overlapped with that of
(R)-5.
eAdded acetone, 3 mol equiv.
fAdded acetic acid, 3 mol equiv.
The discussed results show that Ru-cymene 4 catalyst is well suited for racemization of the
hydroxy-ketone (S)-5. Our further experiments on applying DKR to rac-5 turned out to be
disappointing because of the E-values in the kinetic resolution in the solvents compatible with

7
ACCEPTED MANUSCRIPT
the racemization catalyst were too low. It was then decided to search for hydroxy-ketone 5
derivatives that could meet the required criteria for both processes, the CALB-mediated
kinetic resolution and the racemization. O-Alkyl/aryl oximes have been chosen. Several
oximes were prepared from 5 and the corresponding hydroxyamine derivatives.17 After series
of preliminary tests trityloxime 9 (Scheme 3) was selected for further studies.
O-Tritylhydroxyamine 8 that was needed for the preparation of 9 (not previously reported, to
the best of our knowledge) was obtained by treating an excess of N-hydroxyphtalimide with
trityl chloride and triethylamine to form N-trityloxyphtalimide followed by hydrazinolysis.
Reaction of rac-5 with trityloxyamine 8 followed by flash chromatography on a silica gel
column afforded two isomeric products identified as E-rac-9 and Z-rac-9 (81% and 17%
yield, respectively).
Rather unexpectedly, Z-9 smoothly isomerized into E-9 on contact with a trace of acid. On the
other hand, a sample of Z-9 was stable on storing and was recovered unchanged after being
heated in toluene at reflux temperature for a few hours (with no acid present). The acid-
induced isomerization can be explained by the hydroxy group participation in weakening of
the carbon-nitrogen double bond and thus lowering the Z-E rotation barrier, as illustrated in
Scheme 3. The relevant intramolecular Michael-type hydroxy group participacion has been
postulated to explain some properties of the parent hydroxy-ketone.18 The corresponding
optically active oximes (S)-E- and (S)-Z-9 were prepared starting from (S)-5 (98% ee).
Scheme 3. Preparation of oximes 9.

8
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Kinetic resolution of rac-E-9
The resolution of rac-E-9 in solvents suitable for the racemization experiments with catalyst
4: toluene, chlorobenzene and dichloroethane at 40 ºC were examined. As shown in Table 2,
resolution of rac-E-9 in DCE was the most efficient with E value of ca. 158. It is noteworthy
that in the resolution of hydroxy oximes rac-E-9 the (S)-epimer is being acetylated at a higher
rate, in contrast to the preference observed in resolution of rac-5. Several cases of similar
kinetic preference reversal as the result of substrate modification have been reported.19
Table 2. Kinetic resolution of rac-E-9 using CALB (10% w/w) and IPA (3 mol equiv) at 40
ºC in selected solvents (3% solution).
Solventa
Tol
T
(h)
2
20
2
20
44
Conv. (S)-OAc (R)-OH Eb
(%)
10
51
6
40
53
ee%
87
74
92
86
ee%
9
80
6
44
88
16
23
ClPh
79

9
ACCEPTED MANUSCRIPT
DCE
2
.4
98
98
98
97
96
4
20
44
72
5d
24
38
44
50
30
58
76
95
158
aSolvent name abbreviations are as in Table 1.
bE values were calculated accordingly to the literature protocol.20
Racemization of E-9 in DCE
In preliminary experiments to assess the affect of catalyst 4 and a tertiary amine on (S)-E-9
and some other hydroxy O-alkyl oximes, no products of the carbon – nitrogen double bond
reduction could be detected. Racemization of (S)-E-9 (98% ee) was examined in DCE at 40
°C using 4 (2 mol%) - N,N,N’,N’-tetramethylpropylidenediamine (0.8 equiv; Scheme 4). The
results are presented in Table 3. As evident, the racemization of (S)-E-9 occurred rapidly at
the beginning and then the reaction proceeded with a decreasing rate. However, the catalyst
activity was sustained throughout the time of measurements. The side product formed during
the process was isolated and identified as the oxo-derivative 10. After 24 h racemization
excess (ꢀee) amounted to 93% and ketone 10 content to 5%. Addition of acetone (3 mol
equiv) accelerated the racemization rate with a slight increase of ketone 10 formation.
Supplementary experiments were also carried out using toluene and chlorobenzene as
solvents. As it is indicated in Table 3, the racemization rate in toluene was slower than in
DCE with a similar rate of ketone 10 formation. Reaction in chlorobenzene gave similar
results to those in DCE.
Scheme 4. Racemization of (S)-E-9 using catalysts 4 and a base.

10
ACCEPTED MANUSCRIPT
Table 3. Racemization of (S)-E-9 using 4 (2 mol%) and N,N,N’,N’-
tetramethylpropylidenediamine, 0.8 equiv. in DCE at 40 oC.
Solventa Time
(S)-OH, ee% ꢀeeb
Ketone 10, %
DCE
5 min
37
25
23
18
14
14
5
22
7
4
2
1
27
14
11
7
61
73
75
80
84
84
93
76
91
93
96
97
71
84
86
91
3
3
3
4
4
5
5
4
7
8
9
10
4
8
3
8
15 min
30 min
1 h
2 h
3 h
24 h
5 min
DCE
acetone 15 min
3 eq
30 min
1 h
2 h
3 h
24 h
Tol
PhCl
3 h
24 h
aSolvent name abbreviations are as in Table 1.
bRacemization capacity,9 ꢀee=ee0-eet.
The N,N,N’,N’-tetramethylpropylidenediamine worked well as a base in the racemization
experiments, however, an operational disadvantage of using that amine was the formation of
viscous mixtures. It was of interest to compare action of N,N,N’,N’-
tetramethylpropylidenediamine to recommended earlier8 triethylamine with respect to (S)-E-9
racemization. The results are compiled in Table 4. As evident, applying triethylamine results
in only slightly lower racemization rate than N,N,N’,N’-tetramethylpropylidenediamine. It
was decided to use triethylamine in combination with 4 in further experiments.
Table 4. Racemization of (S)-E-9 (98 % ee) using 4 and N,N,N’,N’-
tetramethylpropylidenediamine (0.8 mol equiv) or triethylamine (0.8 mol equiv) (DCE, 40
ºC).
Time
Propylidenediaminea
ee% 10(%) ee%
Et3N
∆ee
10(%)
∆ee

11
ACCEPTED MANUSCRIPT
5 min 37
15 min 25
30 min 23
61
73
75
78
82
86
91
3
3
3
4
4
4
7
39
33
30
26
23
22
18
60
65
68
72
75
76
80
3
3
4
5
5
6
10
1 h
2 h
3 h
20
16
12
7
22 h
aN,N,N’,N’-tetramethylpropylidenediamine..
Dynamic Kinetic Resolution of rac-E-9
With the encouraging results for both the kinetic resolution and the racemization of (S)-E-9
carried out separately, we approached the dynamic kinetic resolution. In the first series of
experiments all components of the reaction mixture, the substrate, CALB, IPA, ruthenium
catalyst and triethylamine, were combined at the beginning of the procedure (one-stage
transformation). In complementary experiments rac-9, CALB and IPA were combined and
kinetic resolution was allowed to proceed until ca. 40% of conversion was reached. Only then
catalyst 4 and triethylamine were added. Typical results are shown in Table 5.
Stirring together a mixture of rac-E-9, CALB (10 mol%), IPA (3 mol equiv), 4 (2 mol%) and
triethylamine (0.8 mol equiv) for 3 days afforded the mixture consisting of acetates (61%) in
which (S)-enantiomer predominated (>98% ee), residual alcohols (32%, R/S ratio 2/1) and
ketone 10 (7%; Table 5, entry 1). The extension of reaction time to 6 days caused the
conversion increase to 75% [(S)-E-9, >98 % ee] and the increase of content of ketone 10 to
8% (entry 2). After 10 days the conversion reached 82% [(S)-E-9-acetate, 98% ee] and ketone
10, 10% (entry 3). Carrying the reaction at 60 ºC for 3 days resulted in 66% conversion to
acetate (97% ee) with increase in the amount of ketone 10 to 23% (entry 4). An increase of
amount of CALB to 20% w/w (entry 5) as compared to 10% (entry 1) resulted in an increase
of conversion to 76% (97% ee) with some decrease in amount of 10 (5%). An extension of the
reaction time (entry 6) allowed reaching 88% of conversion (98% ee) with a low 10 content,
6%.

12
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When rac-E-9 was allowed to react with CALB (10% w/w) and IPA for 2 days (R)/(S)-E-9-
acetates content was 37.1 and 0.34% by HPLC (entry 7). At this point catalyst 4 and
triethylamine were added and the mixture was stirred for additional 5 days. After that time (7
days in total) the conversion reached 85% with optical purity of (S)-E-9-acetate >98% ee, and
8% of ketone 10. Similar results were obtained in 3 and 7 days process (10 days in total, entry
8). When compared to the one-stage process (10 days, entry 3) a higher conversion with a
lower content of ketone 10 were recorded. When 20% of CALB was applied and reaction was
carried out in 1 and then 5 days (6 days, entry 9) essentially the same results as in “one stage
process” (entry 6) were obtained. The two-stage process 1 and 3 days (4 days in total, entry
10) at 60 ºC with 20% w/w of CALB gave 84% of acetate of somewhat lower value of ee
(95% ee) and 11% of ketone 10.
Table 5. DKR of rac-E-9 using CALB, IPA (3 mol equiv), catalyst 4 (2 mol%) and
triethylamine (0.8 mol equiv) in DCE.a
1st Stage
2nd Stage
Temp.
Total CALB
time
(days)
(S)-E-9-
Alcohols(%) Ketone
(%w/w) acetate,b %,
(R/S ratio)c
10 (%)
Temp.
(ºC)
40
40
40
60
40
40
40
Time
Time
(days)
-
-
-
-
-
-
(ee%)
(days) (ºC)
1
2
3
4
5
6
7
8
9
3
6
10
3
3
-
-
-
-
-
-
40
40
40
3
6
10
3
3
6
7
10
6
10
10
10
10
20
20
10
10
20
61 (>98)
75 (>98)
82 (>98)
66 (97)
76 (97)
88 (97)
85 (>98)
85 (97)
88 (98)
32 (2/1)
17 (2/1)
8 (2/1)
11 (1/1)
18 (5/1)
7 (5/1)
8 (5/3)
7 (5/2)
6 (4/1)
7
8
10
23
5
6
8
8
7
6
2d
3e
1f
5
7
5
40
40

13
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10
60
1g
60
3
4
20
84 (95)
5 (2/1)
11
aThe experiments were conducted in ca. 0.15 mmol scale [ca. 50 mg of (S)-E-9], in DCE
solution (5%) with magnetic steering, using CALB (as indicated), IPA (3 mol equiv), catalyst
4 (2 mol%) and triethylamine (0.8 mol equiv).
bAverage of at least 3 measurements.
cThe less mobile alcohol enantiomer partly overlapped with the ketone on HPLC analysis.
dContent of 9-acetates (S/R) as 37.1/0.3%.
eContent of 9-acetates (S/R) as 44.8/0.6%.
fContent of 9-acetates (S/R) as 35.6/0.3%.
gContent of 9-acetates (S/R) as 47.1/1.3%.
A larger scale experiment was conducted under conditions analogous to those indicated in
Table 5, entry 7. Thus, starting from rac-E-9 (ca. 300 mg) and using CALB, (10% w/w), IPA
(3 mol equiv), ruthenium catalyst 4 (2 mol%) and triethylamine (0.8 mol equiv) in DCE with
the reaction time 7 days (S)-E-9-acetate was obtained, 84% yield and 97% ee.
Structure of trityloxime 9
The calculated energy difference between Z- and E-9 oxime isomers amounted to 3 kcal/mol,
which led to the presumption that the isolated major product has E-configuration. The
confirmation of structural assignments of isomers was gained from their 13C NMR spectra in
combination with extensive DFT calculations of NMR parameters. The experimental and DFT
calculated chemical shifts (δ) of Z-9 and E-9 carbon nucleus are presented in Table 6.
As shown in Table 6, in Z-9, C2 (proximal to the oxime O-atom) resonance appeared at δ
138.10 ppm whereas for E-9 at 140.72 (∆δ = -2.64); the corresponding values for C-5 are
37.68 (E-9, proximal to the oxime O-atom) and 40.28 (∆δ = -2.60). By the nominal value
these differences are in agreement with the structure assignment criteria. In the fundamental
studies21 on 13C NMR assignment of oxime isomers structure it was determined that the
chemical shift of the carbon α in the position proximal to the oxime OH group appears
systematically at higher field with the magnitude of the effect varying (up to 10 ppm). Those
observations are in line with the data extracted from works on O-alkyl unsymmetrical oxime

14
ACCEPTED MANUSCRIPT
isomers22 and with a recent systematic examination of O-alkyl acetone oximes.23 However,
some other features of the 13C spectra of Z- and E-9 had no literature precedent and indicated
that shielding effects of the oxygen atom vs. the nitrogen atom electron pair may overlap with
shielding effects arising from other parts of the molecule. In particular, (1) chemical shifts of
C1 for Z- and E-9, δ 159.22 and 164.23 ppm, respectively, differ with ꢀδ = δZ-δE = -5.01 ppm,
clearly exceeding the literature values (fitting into the range -0.7 to +0.6 ppm), (2) chemical
shifts of the C6 nuclei for Z-9 and E-9 appeared at δ 18.13 and 12.30 ppm, ∆δ = 5.83, with the
opposite sign of the shift than that observed for C2.
Combination of experimental NMR data and DFT calculations of parameters reflecting the
shielding effects magnitude and direction fully confirmed the structure assignments.
Calculated shielding effects for Z- and E-9 are shown in Table 6. The complete 1H, 13C NMR
experimental data, calculation details and some comments are presented in the Supporting
Information. It should be noted that the propeller-type chirality is inherent to the trityl group.24
The calculated energy barrier between M and P diasteroisomers of Z- or E-(S)-9 do not exceed
0.1 kcal/mol. The measured spectra apparently represent the averaged values of chemical
shifts originating from both diastereomers.
1'
4'
O
N
2'
3'
1
6
5
2
4 3
E/Z-
9
HO
Table 6. Experimental and DFT calculated 13C chemical shifts of oximes 9 in benzene and
corresponding differences ∆δZE (δZ9-δE9).
δ13C /ppm
experimental
calculated
#
1
∆δZ
∆δZ
E
Z-9
E-9
Z-9
E-9
E
159.22 164.23 -5.01 167.51 169.82 -2.31

15
ACCEPTED MANUSCRIPT
2
3
4
5
6
7
138.10 140.72 -2.62 146.17 146.06 0.11
146.36 142.40 3.96 148.03 145.83 2.20
70.93
40.28
18.13
91.77
72.83 -1.90
70.47
39.36
15.41
91.56
72.54
37.37
7.97
-2.07
1.99
7.44
0.61
37.68
12.30
91.67
2.60
5.83
0.10
90.95
1’ 145.52 146.12 -0.60 148.51 148.14 0.37
2’ 127.87 128.47 -0.60 131.16 130.95 0.21
3’ 129.87 130.42 -0.55 127.86
127.9
-0.04
4’ 127.34 127.99 -0.65 126.85 127.27 -0.42
Conclusions
In conclusion, hydroxy ketone rac-5 was transformed into O-trityl oxime rac-E-9, which was
shown to be a good candidate for kinetic resolution using CALB and IPA. Racemization of
(S)-E-9 was executed using easily accessible ruthenium catalyst 4 activated with N,N,N’,N’-
tetramethylpropanediamine or with triethylamine in dichloroethane. The oxo-derivative 10
was identified as the only racemization side product (less than 10% yield). DKR of rac-E-9
was accomplished using catalyst 4 and triethylamine in combination with CALB and IPA
affording (S)-E-9-acetate in 84% yield and 97% ee.
A preliminary study on hydroxy ketone (S)-5 racemization showed that Shvo’s catalyst 1
(toluene, 70 ºC or higher temperatures) affords mixtures of dione 6 and “reversed” hydroxy
ketone 7. However, catalyst 4 - N,N,N’,N’-tetramethylpropanediamine (dichloroethane, room
temperature) gives appreciable racemization results.
Trityloxyamine 8 was prepared and its reaction with 5 leading to E- and Z-9 was investigated.
Experimental
General Experimental Methods.
Melting points were determined on a hot-stage apparatus. Optical rotations were measured for
CHCl3 solutions on a polarimeter using 1 mL capacity cell (10 cm path length). IR spectra
were recorded on FT/IR apparatus. NMR spectra were recorded in CDCl3 or C6D6 solutions

16
ACCEPTED MANUSCRIPT
on a spectrometers: for 1H at 500 MHz/13C at 125 MHz or 400 for 1H at 400 MHz/13C at 100
MHz. Chemical shifts are quoted on the δ scale taking the solvent signal as the internal
standard (CHCl3, 1H, 7.26 ppm; CDCl3, 13C, 77.00 ppm, benzene, 1H, 7.16 ppm, 13C 128.06
ppm). Column chromatography was performed on Merck silica gel 60, 230-400 mesh and
TLC - on aluminum sheets, Merck 60F 254. HPLC analyses were conducted using a chiral
Daicel Chiralcel AD-H® or OD-H® column, n-hexane-isopropanol, flow 1 mL/min, on the
instrument equipped with a changeable UV detector.
Sigma-Aldrich Lipase B from Candida antarctica (CALB) , recombinantly expressed in
Aspargilus niger andimmobilized on acrylic resin was used further referred to as CALB.
Isopropenyl acetate was used as purchased. Kinetic resolution experiments were carried out
using a rotary shaker.
The catalyst [Ru2(CO)4(ꢁ-H)(C4Ph4COHOCC4Ph4)] (1), ruthenium chloride cymene dimer
[Ru(cymene)Cl2]2 (4) and N,N,N’,N’-tetramethylpropanediamine were purchased from
Aldrich. Toluene was dried by distilling from sodium-potassium alloy. Organic extracts were
dried over Na2SO4 and the solvents were evaporated using a rotary evaporator.
Racemization of (S)-4-hydroxy-2-methylcyclopent-2-en-1-one (5) with catalyst 1.
In a flame dry and flashed with argon round bottom flask equipped with a condenser and an
argon inlet, (S)-5 (56 mg, 0.5 mmol, 98% ee), anhyd toluene (2 mL) and 1 (21.7 mg, 2 mol%)

17
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were placed. The mixture was heated for 24 h at the temperature indicated below and then
cooled and transferred into a silica gel column (3 g). Elution of the column with hexane-
EtOAc, 50:50, gave a dione 6; further elution afforded a hydroxy-ketone fraction. The
composition of the hydroxy-ketone fraction was determined by HPLC (Daicel Chiralcel AD-
H® column, hexane-isopropanol, 95:5). The results were as follows:
(1) at 70 °C, 6, 23%, the hydroxy-ketone fraction, 74% yield, consisting of (S)-5 (49%), (R)-5
(4%) and (R)- and (S)-7 (25% and 22%).
(2) at 100 °C, 6 (51%), the hydroxy-ketone fraction, 13% yield containing by HPLC analysis
(S)-5 and (R)-5, 22% and 21%, respectively, and epimers of 7 (29 and 27%).
In the 1H NMR spectra of hydroxy-ketone fractions only trace signals that could correspond to
secondary methyl groups appeared.
2-Methylcyclopent-2-en-1,4-dione (6): IR (film from CHCl3) 1746, 1706, 1618 cm-1; 1H
NMR (400 MHz) 6.99 (q, J = 1.2 Hz, 1 H), 2.86 (s, 2 H), 2.09 (br d, 1.2 Hz, 3 H); 13C NMR
(100 MHz) 201.3, 199.5, 162.5, 146.1, 41.5, 11.2; in agreement with the reported data.15
(R)- and (S)-4-hydroxy-3-methylcyclopent-2-en-1-one (7), diagnostic signals (from a mixture
with 5): 1H NMR (500 MHz) 5.95 (s, 1 H), 4.79 (br d, J = 6.1 Hz, 1 H), 2.18 (s, 3H); 13C
205.8, 177.4, 131.3, 72.5, 45.2, 15.8; in agreement with the reported data.16
Racemization of (S)-5 with [(cymene)RuCl2]2 complex 4 and Me2N(CH2)3NMe2.
Ru-complex 4 (5.5 mg, 2 mol%) was weighted in a 5 mL cylindrical vial and then the solvent
(2 mL) was added and a stirring bar introduced. The mixture was stirred for 15 min and then
were added (S)-5 (98% ee, 50 mg, 0.45 mmol ), and N,N,N’,N’-tetramethylpropanediamine
(67 ꢁL, 49 mg, 0.40 mmol, 90 mol%). The vial was placed in a oil bath at 40 oC (+/-1 oC) and
the mixture was stirred. After 3 h, an aliquot was taken HPLC analysis. After 20 h, the
mixture was cooled and transferred to a silica gel column (3 g). The column was eluted with

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hexane-EtOAc, 50:50 to give the product (87-91% material was recovered). The composition
of the product was determined by HPLC (Daicel Chiralcel AD-H® column, hexane-
isopropanol, 95:5). Signal of one enantiomer of 7 partly overlapped with that of (R)-5. The
results are given in Table 1.
1H NMR spectra of crude products showed the presence of only traces of contaminations.
(less than 5% in total)
Kinetic resolution of rac-5.
Experiments on kinetic resolution of rac-5 were carried using CALB and IPA in TBME as
reported previously.14 It was noted that efficiency of this process depends on content of water
in the solvent: in HPLC-grade commercial MTBE (water content <0.01%) or dried MTBE
kinetic resolution was poor, using CALB preparation as purchased as well as that preliminary
stored over saturated solution of LiCl.5f Using commercial MTBE or the solvent pre-
equilibrated with water the previously reported results were reproduced.
O
O
H2NNH2
CHCl3, MeOH
TrCl, Et3N
DCM
TrONH2
N OH
N OTr
8
O
O
Preparation of O-tritylhydroxylamine (8).
Triethylamine (6.0 mL, 43.1 mmol) was added dropwise, within 5 min, to a stirred solution of
N-hydroxylphthalimide (6.42g, 39.4 mmol) and tritylchloride (10.01 g, 35.8 mmol) in
dichloromethane (55 mL). The mixture was stirred for 1 h and then poured into water (100
mL). The organic layer was separated, washed with water (2 × 100 mL) and dried. The
solvent was evaporated to give N-(trityloxy)phthalimide (white foam, 15.54 g). This product,
without purification, was dissolved in chloroform (320 mL) containing MeOH (32 mL) and
then hydrazine hydrate (5.2 mL, 165.5 mmol) was added dropwise. The mixture was stirred

19
ACCEPTED MANUSCRIPT
for 2 h and then poured into water (400 mL). The organic layer was separated, washed with
water (2 × 300 mL) and dried. The solvent was evaporated and the residue was
chromatographed on silica gel (100 g, hexane - EtOAc, 9:1, ca. 1 L) to give 8 (8.92 g, 90%
from tritylchloride): white crystals, mp 85-86 oC (hexane); 1H NMR (400 MHz): 7.47-7.43
(m, 6 H, aromatic H), 7.37-7.26 (m, 9 H, aromatic H), 4.95 (br s, 2 H, NH); 13C NMR (100
MHz): 143.2, 128.8, 127.8, 127.2, 90.8.
Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.98; H, 6.07, N, 5.02.
TrO
OTr
N
N
HO
HO
E- and Z-(±)-4-Hydroxy-2-methylcyclopent-2-en-1-one O-trityloxime (rac-9).
O-Tritylhydroxylamine (5.62 g, 20.4 mmol) and AcOH (0.1 mL, 1.8 mmol) were added to a
stirred solution of rac-5 (2.08 g, 18.6 mmol) in MeOH (40 mL). The mixture was stirred at rt
for 3 days and then the solvent was evaporated. The residue was dissolved in dichloromethane
- hexane (1:1) and transferred to a silica gel column (150 g). The column was eluted with
hexane – EtOAc (85:15, ca. 3 L) to give E-rac-9 (white foam, 5.52 g, 81%). Further elution
with hexane-EtOAc (8:2, ca. 1L) give Z-rac-9 (white foam, 1.16 g, 17%).
Z-9 partly isomerized into E-9 on dissolving in CDCl3.
Anal. Calcd for C25H23NO2: C, 81.27; H, 6.27; N, 3.79. Found: C, 81.20; H, 6.37, N, 3.56.
In an analogous way from (S)-6 (616 mg, 5.5 mmol) were obtained:
1. E-(S)-9 (thick oil, 1685 mg, 83%); [α]D22 -81.1 (c 1.50);
1H NMR (400 MHz, C6D6, 25 °C) 7.60 (2 H, m, C2’H), 7.16 (2 H, m, C3’H), 7.08 (1 H, m,
3
4
4
C4’H), (couplings in the aromatic protons multiplets: J2’3’=7.9 Hz; J2’4’=1.3 Hz; J3’3’= 1.6
Hz; 4J2’2’= 2.4 Hz; 5J2’3’ = 0.5 Hz), 5.63 (1 H, dq, 3J34 =2.4 Hz; 4J36=1.5 Hz, C3H), 4.29 (1 H,
3
3
3
5
dddq, J45pro(S)=6.7 Hz; J45pro(R) =1.9 Hz; J34 =2.4 Hz; J46=1.3 Hz, C4H), 2.90 (1 H, dd,
2
2J5pro(R)5pro(S) =18.8 Hz; 3J45Hpro(S)=6.7 Hz, C5Hpro(S)), 2.41 (1 H, dd, J5pro(R)5pro(S)=18.8 Hz;

20
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4
5
3J45pro(R) =1.9 Hz, C5Hpro(R)), 1.49 (3 H, dd, J36=1.5 Hz; J46=1.3 Hz, C6H); 13C MNR
(400 MHz, C6D6, 25 °C) 164.23 (C1), 146.12 (C1’), 142,40 (C3), 140.72 (C2), 130.42 (C3’),
128.47 (C2’), 127.99 (C4’), 91.67 (C7), 72.83 (C4), 37.68 (C5), 12.30 (C6).
2. Z-(S)-9 (semicrystalline mass, 303 mg, 15%); [α]D23 -56.2 (c 1.80).
1H NMR (400 MHz, C6D6, 25 °C) 7.69 (2 H, m, C2’H), 7.17 (2 H, m, C3’H), 7.08 (1 H, m,
3
3
4
C4’H), (couplings in the aromatic protons multiplets: J3’4’=7.3 Hz; J2’3’=7.9 Hz; J2’4’= 1.3
4
4
5
3
4
Hz; J3’3’= 1.6 Hz; J2’2’= 2.4 Hz; J2’3’=0.5 Hz), 5.70 (1 H, dq, J34 =2.3 Hz; J36=1.4 Hz,
3
3
5
C3H), 4.11 (1 H, dddq, J45pro(S) = 6.9 Hz; 3J45a = 2.6 Hz; J34 = 2.3 Hz; J46=1.6 Hz, C4H),
2.57 (1 H, dd, J5pro(R)5pro(S) = 17.1 Hz; 3J45pro(S) =6.9 Hz, C5Hpro(S)), 2.27 (3 H, dd, J36= 1.4
Hz; 5J46=1.6 Hz, C6H); 2.08 (1 H, dd, 2J5pro(R)5pro(S) = 17.1 Hz; 3J45pro(R) =2.6 Hz, C5Hpro(R)); δ
13C NMR (400 MHz, C6D6, 25 °C) 159.86 (C1), 147.00 (C3), 146.16 (C1’), 138.74 (C2),
130.51 (C3’), 128.51 (C2’), 127.98 (C4’), 92.41 (C7), 71.57 (C4), 40.92 (C5), 18.77 (C6).
Experimental and DFT calculated chemical shifts for E- and Z-9 in benzene are compiled in
2
4
Table 6. Discussion on chemical shift calculations are presented in the Supporting
Information.
Isomerization of Z-rac-9 into E-rac-9.
Z-rac-9 (40 mg, 0.11 mmol) was dissolved in DCM (1.5 mL) and a solution HCl in DCM was
added (0.01 mL) [prepared by adding TMSCl (0.17 mL, 1.37 mmol) and MeOH (0.06 mL,
1.44 mmol) to DCM (10 mL)]. The mixture was stirred at rt for 5 min and the solvent was
evaporated to give E-rac-9 (40 mg, 100%).
Z-rac-9 was recovered unchanged after heating in toluene for a few hours; heating in xylene
resulted to the substrate decomposition.
Kinetic resolution of rac-E-9, general conditions
To a solution of rac-E-9 in a solvent, containing IPA (3 mol equiv), CALB (10% w/w) was
added and the mixture was shaken at ambient temperature (20 – 25 ºC). Progress of reaction
was followed by HPLC. After the reaction was completed, the solid was filtered off and the

21
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solvent, and the volatiles were removed on a rotary evaporator. The residue was
chromatographed on a silica gel column to afford the product. Average E values were
calculated from a series of consecutive measurements accordingly to the standard protocol.20
The results are combined in Table 2.
HPLC, ODH Chiralcel column, hexane – isopropanol, 94:6, Rt (min): (S)-E-9-acetate, 4.85;
(R)-E-9-acetate, 6.79; (R)-9, 10.04; (S)-9, 12.36 . (Rt values depended upon degree of the
column worn out.)
Racemization of (S)-E-9, general conditions
Catalyst 4 was weighted in a 10 mL vial (3.40-3.70 mg). A magnetic stirring bar, DCE (4 mL)
and (S)-E-9 (98% ee), ca. 100 mg, as calculated taking 2 mol% of 4, were added. The vial was
placed in an oil bath preheated to 40 °C and mixture was briefly stirred (ca. 5 min, until the
solid was dissolved) and then N,N,N’,N’-tetramethylpropylidenediamine (36 ꢁL, 0.8 mol
equiv) was added by a syringe. Stirring at 40 ºC was continued while samples were taken
from the mixture and applied to the HPLC column fitted with a pre-column. The side product
was identified as the oxo-derivative 10 by comparison with a sample was prepared as
described below. The results are shown in Table 3.
In an analogous way experiments using (S)-E-9, catalyst 4 and triethylamine (0.8 mol equiv)
in DCE were carried out. The results are shown in Table 4.
O
N
10
O
Preparation of E-2-methylcyclopent-2-en-1,4-dione 1-O-trityloxime (10).

22
ACCEPTED MANUSCRIPT
Dess-Martin periodinane (150 mg, 0.35 mmol) was added to a solution of (S)-E-9 (109 mg,
0.30 mmol) in DCM (4 mL). The mixture was stirred for 0.5 h and then poured into NaHCO3
solution and extracted with EtOAc (20 mL). The extract was washed consecutively with
Na2SO3 solution, water and brine, and dried (Na2SO4). The solvent evaporated and the
product was chromatographed on silica gel (3 g, 10% EtOAc in hexane) to give 10 (106 mg,
97% yield): mp 148 ºC (hexane); IR (film from CH2Cl2) 1716 cm-1; 1H NMR (500 MHz)
7.35-7.24 (m, 15 H, aromatic H), 6.24 (s, 1H, =C-H), 3.22 (s, 2 H, -CH2-), 1.99 (s, 3 H, Me);
13C NMR (125 MHz) 201.0, 165.4, 157.1, 144.0, 135.9, 129.2, 127.6, 127.3, 91.9, 35.8, 13.2.
Elemental analysis C25H21NO2 (367.45) calcd C, 81.72, H, 5.76, N, 3.81; found C, 81.71, H,
5.62; N, 3.74.
Dynamic kinetic resolution of rac-9, general conditions
One-stage procedure: Alcohol rac-E-9 (55 mg), CALB (10 or 20 %, w/w), DCE (2 mL) and
IPA (52 ꢁL) were placed in a 5 mL vial equipped in a magnetic stirring bar. To the stirred
mixture were added consecutively: 0.5 mL of a solution of 4 in DCE [prepared by dissolving
4 (3.4 mg) in DCE (1 mL)] and Et3N (15 ꢁL). The vial was placed in a preheated oil bath (at
40 or 60 ºC) and stirring was continued. Samples were taken from the mixture and applied to
the HPLC column fitted with a pre-column.
Two-stage procedure was carried out in the same way except that the addition of a solution of
the catalyst 4 and Et3N was delayed by the indicated period of time. The results are given in
Table 5.
Preparative scale experiment: In a 25 mL round-bottomed flask with a magnetic stirring bar
there were placed: rac-E-9 (307 mg, 0.83 mmol), CALB (30 mg) and DCE (12 mL). The
mixture was briefly stirred at rt and then IPA (0.27 mL, 2.45 mmol) was added and the flask
was sealed with a glass stop cork and placed in a pre-heated oil bath at 40 ºC. After 48 h, a

23
ACCEPTED MANUSCRIPT
sample was taken and the composition of the mixture was determined by HPLC as: (S)-E-9-
acetate, 37.10%, (R)-E-9-acetate, 0.34%, (S)-E-9, 49.91%, (R)-E-9, 12.65%. At this point
catalyst 4 (10.1 mg, 0.0165 mmol) and Et3N (0.09 mL, 0.64 mmol) were consecutively added
and stirring was continued for an additional 5 days. The composition of the mixture
determined by HPLC was as follows: (S)-E-9-acetate, 82.59%, (R)-E-9-acetate, 0.64%, (S)-E-
9, 4.82%, (R)-E-9,* 3.53%, 10* 8.41% (*picks partly overlapping). After further 3 days (8
days in total) composition of the mixture was as follows: (S)-E-9-acetate, 86.42%, (R)-E-9-
acetate, 0.60%, (S)-E-9, 2.82%, (R)-E-9 and 10 10.75%.
The solid was then filtered off and the solvent, and volatiles were evaporated. The residue was
transferred to a silica gel column (50 g) and the column was eluted with EtOAc : hexane, 5:95
(1.3 L) to give: (S)-E-9-acetate (288 mg, 84%, 97.4% ee) and 10 (43 mg, 14%) [ODH
Chiralcel column, hexane – isopropanol, 94:6, Rt 11.34 min.]
(S)-E-9-acetate: 1H NMR (500 MHz) 7.35-7.21 (m, 15, aromatic H), 6.12 (s, 1 H, =C-H), 5.65
(br d, J = 5.9 Hz, 1 H, C4-H), 3.27 (dd, J = 18.8, 6.9 Hz, 1 H, CH2A), 2.72 (br d, J = 18.8,
CH2B), 2.05 (s, 3 H, OCOCH3), 1.68 (br s, 3H, Me); 13C NMR (125 MHz) 170.8, 162.0,
144.5, 143.3, 136.4, 129.2, 127.4, 127.0, 90.6, 74.6, 33.7, 21.1, 11.7.
Acknowledgements
This work was supported by the National Science Center (NCN, grant UMO-
2011/01/B/ST5/00827). The calculations were carried out in the Interdisciplinary Center for
Mathematical and Computational Modelling, Warsaw University, Warsaw, Poland (grant
G58-18).We thank Prof. Jadwiga Frelek and Dr. Joanna E. Rode for discussions on chiroptical
properties of O-trityl oximes.
Supporting Information.

24
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Copies of 1H and 13C spectra of compounds 8, E-9, Z-9, and 10; E-9, Z-9, details of NMR
experiments and ab initio calculations.
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(20) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294.
(21) Hawkes, G. E.; Herwig, K.; Roberts, J. D. J. Org. Chem. 1974, 39, 1017.
(22) (a) Wikel, J. H.; Paget, C. J.; DeLong, D. C.; Nelson, J. D.; Wu, C. Y. E.; Paschal J. W.;
Dinner, A.; Templeton, R. J.; Chaney, M. O.; Jones, N. D.; Chamberlin, J. W. J. Med. Chem.
1980, 23, 368; (b) Bozdağ, O.; Gumusel, B.; Demirdamar, R.; Buyukbingol, E.; Rolland, Y.;
Ertan, R. Eur. J. Med. Chem. 1998, 33, 133; (c) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang,
S. J. Am. Chem. Soc. 2014, 136, 4141.
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P.; Gawronski, J. Angew. Chem. Int. Ed. 2009, 48, 7069.

27
ACCEPTED MANUSCRIPT
Tables
Table 1.
Solventa T (h) Recov. %b (ee%) ꢀeec (%)
7%d
1
2
3
4
5
6
7
8
9
MTBE
3
20
3
20
3
20
3
20
20
20
-
88
-
91
-
87
-
88
-
-
88
54.
48
5
43
3
29
0
0
10
44
50
93
55
95
69
98
98
0
-
1
1
5
1
5
1
6
6
-
Tol
ClPh
DCE
DCEe
10 DCEf
Table 2.
Solventa
Tol
98
T
(h)
Conv. (S)-OAc (R)-OH Eb
(%)
10
51
6
40
53
.4
24
38
44
50
ee%
87
74
92
86
79
98
98
98
97
96
ee%
9
80
6
44
88
4
30
58
76
95
2
20
2
20
44
2
20
44
72
5d
16
23
ClPh
DCE
158
Table 3.
Solventa Time
(S)-OH, ee% ꢀeeb
Ketone 10, %
DCE
5 min
15 min
30 min
1 h
2 h
3 h
37
25
23
18
14
14
5
22
7
4
61
73
75
80
84
84
93
76
91
93
96
97
71
3
3
3
4
4
5
5
4
7
8
9
10
4
24 h
5 min
DCE
acetone 15 min
3 eq
30 min
1 h
2 h
2
1
27
Tol
3 h

28
ACCEPTED MANUSCRIPT
24 h
3 h
24 h
14
11
7
84
86
91
8
3
8
PhCl
Table 4.
Time
Propylidenediaminea
Et3N
∆ee
ee%
10(%) ee%
10(%)
3
3
4
5
5
6
10
∆ee
61
73
75
78
82
86
91
5 min 37
15 min 25
30 min 23
1 h
2 h
3
3
3
4
4
4
7
39
33
30
26
23
22
18
60
65
68
72
75
76
80
20
16
12
7
3 h
22 h
Table 5.
1st Stage
2nd Stage
Temp. Time
Total CALB
time
(days)
(S)-E-9-
Alcohols(%) Ketone
(%w/w) acetate,b %,
(R/S ratio)c
10 (%)
Temp.
(ºC)
40
40
40
60
40
40
40
Time
(ee%)
(days) (ºC)
(days)
1
2
3
4
5
6
7
8
3
6
10
3
3
-
-
3
6
10
3
3
6
7
10
6
4
10
10
10
10
20
20
10
10
20
20
61 (>98)
75 (>98)
82 (>98)
66 (97)
76 (97)
88 (97)
85 (>98)
85 (97)
88 (98)
84 (95)
32 (2/1)
17 (2/1)
8 (2/1)
11 (1/1)
18 (5/1)
7 (5/1)
8 (5/3)
7 (5/2)
6 (4/1)
5 (2/1)
7
8
10
23
5
6
8
8
7
-
-
-
-
-
-
-
-
6
-
-
2d
3e
1f
1g
40
40
40
60
5
7
5
3
40
40
60
9
10
11
Table 6.
δ13C /ppm
experimental
calculated
#
∆δZ
∆δZ
Z-9
E-9
Z-9
E-9
E
E
1
2
3
4
5
6
7
159.22 164.23 -5.01 167.51 169.82 -2.31
138.10 140.72 -2.62 146.17 146.06 0.11
146.36 142.40 3.96 148.03 145.83 2.20
70.93
40.28
18.13
91.77
72.83 -1.90
70.47
39.36
15.41
91.56
72.54
37.37
7.97
-2.07
1.99
7.44
0.61
37.68
12.30
91.67
2.60
5.83
0.10
90.95
1’ 145.52 146.12 -0.60 148.51 148.14 0.37
2’ 127.87 128.47 -0.60 131.16 130.95 0.21
3’ 129.87 130.42 -0.55 127.86
127.9
-0.04
4’ 127.34 127.99 -0.65 126.85 127.27 -0.42

29
ACCEPTED MANUSCRIPT
Legends to Tables
Legend to Table 1.
aAbbreviations: MTBE – tert-butyl methyl ether, Tol – toluene, ClPh – chlorobenzene, DCE –
1,2-dichloroethane.
bThe product was isolated and purified by chromatography after 20 h; intermediate
measurements were carried out on samples taken from the reaction mixture.
cRacemization capacity,9 ꢀee=ee0-eet.
dContent in the mixture, HPLC signal of one enantiomer of 7 partly overlapped with that of
(R)-5.
eAdded acetone, 3 mol equiv.
fAdded acetic acid, 3 mol equiv.
Legend to Table 2.
aSolvent name abbreviations are as in Table 1.
bE values were calculated accordingly to the literature protocol.20
Legend to Table 3.
aSolvent name abbreviations are as in Table 1.
bRacemization capacity,9 ꢀee=ee0-eet.
Legend to Table 4.
aN,N,N’,N’-tetramethylpropylidenediamine..
Legend to Table 5.
aThe experiments were conducted in ca. 0.15 mmol scale [ca. 50 mg of (S)-E-9], in DCE
solution (5%) with magnetic steering, using CALB (as indicated), IPA (3 mol equiv), catalyst
4 (2 mol%) and triethylamine (0.8 mol equiv).
bAverage of at least 3 measurements.
cThe less mobile alcohol enantiomer partly overlapped with the ketone on HPLC analysis.
dContent of 9-acetates (S/R) as 37.1/0.3%.
eContent of 9-acetates (S/R) as 44.8/0.6%.
fContent of 9-acetates (S/R) as 35.6/0.3%.
gContent of 9-acetates (S/R) as 47.1/1.3%.
Figures
Figure 1.