One-pot kinetic resolution-Mitsunobu reaction to access optically pure compounds, using silver salts in the substitution protocol

Article abstract of DOI:10.1039/d0nj04802j

A practical method is developed to access chiral arylalkyl carbinols with a high yield from racemic alcohols. A one-pot enzyme mediated Kinetic Resolution followed by Mitsunobu esterification of the unreacted enantiomer of alcohol with metal acetate results in a nearly complete formation of chiral acetate. Substitution with AgOAc was found to be the most efficient, and the use of sub stoichiometric amounts of AgNO3 and excess of NaOAc affords comparable results; the protocol was further extended to introduce azide as a nucleophile.

Full text of DOI:10.1039/d0nj04802j

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One-pot kinetic resolution–Mitsunobu reaction
to access optically pure compounds, using silver
salts in the substitution protocol†
Cite this: New J. Chem., 2020,
44, 21238
Hiten B. Raval and Ashutosh V. Bedekar
*
A practical method is developed to access chiral arylalkyl carbinols with a high yield from racemic
alcohols. A one-pot enzyme mediated Kinetic Resolution followed by Mitsunobu esterification of the
unreacted enantiomer of alcohol with metal acetate results in a nearly complete formation of chiral
acetate. Substitution with AgOAc was found to be the most efficient, and the use of sub stoichiometric
amounts of AgNO3 and excess of NaOAc affords comparable results; the protocol was further extended
to introduce azide as a nucleophile.
Received 29th September 2020,
Accepted 19th November 2020
DOI: 10.1039/d0nj04802j
rsc.li/njc
modification by the Mitsunobu reaction is an effective
approach and it is widely explored in synthetic chemistry.14–20
Introduction
Optically pure secondary alcohols, including arylalkylcarbinols Several useful functional molecules, drug intermediates and
and other derivatives, occupy a significant position in synthetic natural products have been synthesized by the Mitsunobu
organic and pharmaceutical chemistry, primarily due to their reaction. The concept of combining the enzyme mediated KR
easy access and the available methods for their conversion and the Mitsunobu reaction with the acetate ion from acetic
to other functional groups. There are many elegant methods acid has been explored by a couple of groups to afford a
developed to access them in chirally pure forms. One of moderate chemical yield and selectivity.18 However, it hasn’t
the more common and efficient methods to obtain them in been widely explored and investigated as a possible practical
enantiomerically pure forms is by separation of isomers via methodology of accessing chiral secondary alcohols or other
enzyme-mediated kinetic resolution (KR) using enol acetates as functional molecules. In this study, we shall present our
acetylating reagents.1–3 Although the method is quite general investigations to explore the use of a one-pot strategy of
and a ‘‘Green’’ alternative, there remains the major drawback of combining enzyme mediated KR and Mitsunobu esterification
poor atom efficiency, as theoretically only half of the materials with metal acetates as the source of acetate nucleophile. The
can be isolated. The KR approach also requires a purification acetate ion is more nucleophilic in nature in the salt of acetic
step as the free alcohol and the ester need careful separation. acid due to its ionic character and undergoes an efficient
This limitation has been addressed by several ways including substitution reaction. The protocol is extended with MN3 to
dynamic kinetic resolution (DKR)4–8 and dynamic thermody- introduce azide as a new nucleophile to access two functiona-
namic resolution (DTR).9 More than 50% yield of the chiral lized chiral compounds in one-pot operation.
material may be obtained if the unreacted alcohol can be
stereospecifically converted to acetate. This can be achieved
either by separating the alcohol or attaching it with a good
Results and discussion
leaving group and then performing its nucleophilic substitution
In this paper, we shall discuss our approach to use a one-pot
(AcOÀ in the case of enol acetate is used as an acetyl source) with
strategy of combining enzyme mediated KR and Mitsunobu
the inversion of configuration (step-2, Scheme 1).10–13
esterification. In the present reaction, we chose to use metal
This may also be achieved by directly converting the hydroxyl
group to acetate by the Mitsunobu reaction with suitable
carboxylate. Transforming the hydroxyl group without prior
Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of
Baroda, Vadodara 390002, India. E-mail: avbedekar@yahoo.co.in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Separation of isomers by KR.
d0nj04802j
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conversion to acetate 2 was achieved. The product was isolated
and its optical purity was measured by HPLC analysis on a
chiral column. The overall reaction furnished the desired
acetate with an excellent chemical yield and optical purity.
Similarly, Hg(OAc)2, like AgOAc, too has less charge density
on the metal ion and hence will have a weaker metal–acetate
bond, and show good nucleophilic nature. Our results via a
one-pot reaction with Hg(OAc)2 also furnished the product with
good conversion and purity; however, the reaction mixture was
needed to be held at reflux temperature. We extended the study
to compare the efficacy of different metal acetates as a source of
acetate ion for the second step of this one-pot sequence. In
most of the cases, moderate yields were obtained, though good
selectivity was observed. The other metal acetates had stronger
M–OAc bonds and were not as effective; however, their lower
cost and other considerations may offer some advantage.
Another experiment was conducted where the reagents for
the Mitsunobu step were introduced without removing the
biocatalyst. With (R/S)-1, the acetate (R)-2 was isolated with
comparable parameters (89% Y and 92% e.e.).
In an effort to improve the conditions with lesser reactive
metal acetates, we explored the scope of addition of readily
available silver nitrate to the one-pot reaction. We envisaged
the in situ exchange between acetate salt and silver nitrate
leading to the formation of AgOAc, which is more effective for
the Mitsunobu inversion step, and the results are presented
in Table 2. Although the cost of both silver salts does not
differ much, the availability of AgNO3 is more widespread, and
also the protocol can be extended with any derivatives of
carboxylic acids.
Scheme 2 One-pot KR–Mitsunobu with MOAc as a nucleophile.
acetates as a source of nucleophile. The acetate ion is more
readily available in the salt of acetic acid due to its enhanced
ionic character. Conversion of the less reactive isomer of
alcohol to the acetate by inversion of configuration via the
Mitsunobu reaction is done with acetic acid as the source of
acetate ion. The nucleophilicity of acetate ions in the metal salt
of AcOH will be appreciably more and will favor the displace-
ment procedure. With this aim we have screened a number of
metal acetates for the Mitsunobu step in a one-pot sequence
of this reaction. The standard reaction was performed on
1-(3-nitrophenyl)ethan-1-ol (R/S-1), where the first step of KR
was done with a suitable immobilized bio-catalyst and with
vinylacetate as a source of acetylation. After standardizing the
conditions for this step, we performed a parallel set of example,
where the reaction mixture was immediately subjected to
Mitsunobu conditions with metal acetates to convert the
unreacted alcohol to acetate (Scheme 2).
The first step of KR was performed using Novozyme-435 as
the immobilized enzyme and vinyl acetate as the acetylating
agent. The conditions of using excess vinyl acetate (10 eq.),
diethyl ether as a solvent, and the beads of Novozyme-435 (50%
w/w) as a biocatalyst and performing the reaction at room
temperature were optimized after several experiments. After
the KR was achieved, the reaction mixture was filtered to
remove the solid matrix of the immobilized enzyme and the
reaction mixture was treated with metal acetate, DEAD and
Ph3P for the Mitsunobu reaction step (Table 1). The reaction
with AgOAc was smooth at room temperature and a high
In the initial part of this study the conditions for KR were
established and then extended for the one-pot methodology. In
most of the cases we found that Novozyme-435 was found to be
a suitable biocatalyst to bring about highly selective KR, except
3,5-difluoro derivative (R/S)-11, for which Steapsin lipase was
more efficient. In all the cases, the inversion of configuration
was completely controlled under the Mitsunobu conditions.
This also enabled us to compare the two operations and
establish effective stereochemical control in the inversion step.
Table 1 Screening of different MOAc for a one-pot KR–Mitsunobu
reactiona
Table 2 Use of sub-stoichiometric amounts of AgNO3 to activate less
reactive Co(OAc)2 and NaOAca
Acetate (R)-2
No.
MOAc
Yield (%)
e.e.b (%)
Conditions (eq.)
Acetate (R)-2
1
2
3
4
5
6
7
8
9
AgOAc
94
81
70
84
78
82
76
80
81
96.2
91.4
76.2
84.9
86.2
73.9
66.9
83.3
83.6
No.
AgNO3
Co(OAc)2
Yield (%)
e.e.b (%)
Hg(OAc)2
Pb(OAc)2
Cu(OAc)2
Mn(OAc)2
Mg(OAc)2
Co(OAc)2
Ni(OAc)2
NaOAc
1
2
3
—
2.00
1.75
1.50
NaOAc
2.00
1.75
1.50
76
81
88
Yield (%)
81
87
94
66.9
87.8
0.25
0.50
AgNO3
—
0.25
0.50
88.0
e.e. (%)b
83.6
4
5
6
85.2
90.1
a
For (R/S)-1 (0.30 g); vinyl acetate (10.0 eq.); Novozyme-435 (0.15 g; 50%
a
w/w); dry Et2O (10 mL); r.t. (24 h for KR step-1 and 24 h for Mitsunobu
For (R/S)-1 (0.30 g); vinyl acetate (10.0 eq.); Novozyme-435 (0.15 g; 50%
step-2); for step-2: dry CH3CN (15 mL); DEAD (2.0 eq.); Ph3P (2.0 eq.); w/w); Et2O (10 mL); r.t. 24 h for KR step-1 and reflux conditions, 24 h for
MOAc (2.0 eq.). Reaction for step 2 required reflux conditions, except Mitsunobu step-2; for step-2: dry THF (15 mL); DEAD (2.0 eq.); Ph3P
b
(2.0 eq.); rest of the conditions are the same as Table 1. For experimental
for entry 1. Determined by HPLC analysis (Amylose, IPA (5.0%) in
b
hexane; 18.42 min for (R)-1 and 22.37 min for (S)-1). For experimental procedure see the ESI. Determined by HPLC analysis (Amylose, IPA
procedure see the ESI.
(5.0%) in hexane; 18.42 min for (R)-1 and 22.37 min for (S)-1).
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Table 3 Examples of the comparison of KR and the one-pot KR–Mitsunobu reaction as shown in Scheme 2
Timeb Acetate
Acetate Alcohol
e.e. (%) yield (%)
Alcohol
Acetate
yield (%)
Acetated
e.e. (%)
No. ArCH(OH)CH3
(h)
yield (%)
e.e. (%) Ec (c)
One-pot Mitsunobu
with AgOAc
1
24
(R)-2 49.0
98.3
97.8
94.7
98.4
(S)-1 48.0
(S)-3 46.1
(S)-5 45.8
(S)-7 44.5
99.7
499.9
499.9
499.9
4200 (50.35)
(R)-2 94.2
96.1
99.0
96.3
99.0
2
3
4
24
16
48
(R)-4 48.3
(R)-6 48.6
(R)-8 47.0
4200 (50.53)
194 (51.33)
(R)-4 85.5
(R)-6 82.3
(R)-8 83.6
4200 (50.37)
5
50
(R)-10 46.3 499.9
(S)-9 45.5
94.6
99.2
4200 (48.63)
4200 (49.97)
(R)-10 80.0 96.0
(R)-12 89.3 99.0
6e
8 days (R)-12 42.5
99.3
99.4
(S)-11 45.2
7
84
48
(R)-14 44.6
(S)-13 48.9
90.4
4200 (47.62)
4200 (50.12)
(R)-14 89.2 89.2
(R)-16 88.6 94.8
8
(R)-16 45.2
99.4
(S)-15 46.1 499.9
a
b
c
General conditions as per Table 1. Time for KR step 1 of the one-pot procedure, and 24 h for Mitsunobu step 2. E is the enantiomeric ratio and
d
e
c is conversion. Optical purity was determined by converting to alcohols by HCl-mediated hydrolysis. Steapsin lipase (300% w/w); dry THF.
The standard conditions developed for (R)-2 could be extended of the two was optimized to access both chiral products with
to other examples, and in a few cases slightly better optical excellent selectivity and conversion. This modification can gen-
purity of acetate was observed in the one-pot method. Having erate two useful chiral compounds via a single, easy operation
established suitable conditions with AgOAc for the synthesis of with high selectivity.
optically pure (R)-2, by the one-pot combination of KR and the
Mitsunobu reaction, the method was then extended to a
number of examples (Table 3). This study confirms the general-
ity of this method to access the acetates with a high chemical
yield and optical purity.
Chiral secondary azides are important precursors for acces-
sing optically pure amines. Our process was then extended with
azide as the second nucleophile in the Mitsunobu step.21–25
A
standard one-pot reaction with (R/S)-1 was performed with
NaN3 (Scheme 3). The acetate (R)-2 was isolated in the same
way, but the azide (R)-17 was obtained in a poor chemical yield
(Table 4). This probably was due to the low reactivity of NaN3 in
the Mitsunobu step, which prompted us to explore the use of
AgNO3 to enhance the activity of azide. The suitable combination
Scheme 3 Introduction of azide as another nucleophile in this
methodology.
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Table 4 Use of NaN3 and AgNO3 in the Mitsunobu stepa
was stirred under ambient conditions for AgOAc and at reflux
temperature for other acetates (24 h), the solvent was removed
under a reduced pressure and the crude product was purified
by silica-gel column chromatography with ethyl acetate–petro-
leum ether (2 : 98). Colourless liquid was obtained.
Conditions (eq.)
NaN3 [AgNO3]
Acetate (R)-2
Azide (R)-17b
No.
Yield (%)
e.e. (%)
Yield (%)
e.e. (%)
1
2
3
4
5
2.00 [—]
44
45
46
45
45
91.4
91.1
91.4
92.1
91.9
12
24
36
39
41
88.8
91.9
98.9
99.9
99.7
1.75 [0.25]
1.50 [0.50]
1.25 [0.75]
2.00 [0.75]
General procedure for the hydrolysis of acetates
a
The acetates were converted to alcohols for HPLC analysis to
determine the optical purity.
Conditions for KR and characterization of 2 are the same as Table 1.
Determined by HPLC analysis (Chiralcel OD-H), IPA (1.0%) in hexane;
b
17.55 min for (S)-17 and 18.42 min for (R)-17. For experimental
procedure see the ESI.
To a solution of (R)-2 (0.368 g, 1.75 mmol) in methanol
(5 mL), HCl (0.05 mL, 3.50 mmol, 36%) was added. The reaction
mixture was refluxed (3 h). After completion of the reaction
(tlc), MeOH was evaporated under reduced pressure. The
residue was taken in ethyl acetate and washed with water and
brine. The organic layer was dried over sodium sulphate and
concentrated to afford (R)-1 (0.28 g, 94%).
Conclusions
Thus, in this approach we have developed an efficient one-pot
combination of enzyme mediated KR and the Mitsunobu reac-
tion to efficiently access chirally pure arylalkylcarbinols with a
high yield, excellent atom economy and optical purity. The use
of catalytic amounts of readily available silver nitrate increased
the efficiency of acetate for this reaction. The process of using
catalytic quantities of silver nitrate is used to introduce azide as
another nucleophile to produce two different chiral compounds
with a good chemical and optical yield.
(R)-1-(3-Nitrophenyl)ethan-1-ol (1). [a]D = 16 (c = 1.0 CHCl3)
(lit. [a]D = 14 (c = 0.88 CHCl3)).26
1H-NMR: d 1.55–1.56 (d, J = 6.4 Hz, 3H), 2.12 (s, 1H),
5.02–5.07 (q, J = 6.4 Hz, 1H), 7.52–7.56 (t, J = 8.0 Hz, 1H),
7.73–7.75 (d, J = 8.0 Hz, 1H), 8.13–8.16 (m, J = 1.2 Hz, 1H), 8.27–8.28
(t, J = 1.2 Hz, 1H).
(R)91-(4-Chlorophenyl)ethan-1-ol (3). [a]D = 40.86 (c = 1.0 CHCl3)
(lit. [a]D = 42.5 (c = 1.85 CHCl3)).27
1H-NMR d 1.47–1.49 (d, J = 6.4 Hz, 3H), 4.86–4.91 (q, J =
6.4 Hz, 1H), 7.32 (m, 4H).
Experimental section
(R)-1-(4-Bromophenyl)ethan-1-ol (5). [a]D = 32.20 (c = 1.0
CHCl3) (lit. [a]D = 35.3 (c = 0.9 CHCl3)).28
Chemicals and solvents received from commercial sources
were used without further purification. All solvents were pur-
ified as per the standard protocol. Thin layer chromatography
was performed on F254 aluminium coated plates. All the com-
pounds were purified by column chromatography using silica
gel (60–120 mesh). 1H NMR spectra were recorded on a 400
MHz spectrometer (100 MHz for 13C NMR) in CDCl3 as the
solvent and TMS as the internal standard.
1H-NMR: d 1.45–1.53 (d, J = 6.4 Hz, 3H), 4.82–4.87 (q, J =
6.4 Hz, 1H), 7.23–7.25 (d, J = 8.0 Hz, 2H), 7.46–7.48 (d, J =
8.0 Hz, 2H).
(R)-1-(4-Methylphenyl)ethan-1-ol (7). [a]D = 41.96 (c = 1.0
CHCl3) (lit. [a]D = 42.1 (c = 2.94 CHCl3)).29
1H-NMR d 1.50–1.51 (d, J = 6.4 Hz, 3H), 2.37 (s, 3H),
4.86–4.91 (q, J = 6.4 Hz, 1H), 7.18–7.20 (d, J = 8.0 Hz, 2H),
7.28–7.30 (d, J = 8.0 Hz, 2H).
General procedure for the enzymatic resolution
(R)-1-(Naphthalen-2-yl)ethan-1-ol (9). [a]D = 59.76 (c = 1.0 CHCl3)
(lit.[a]D = 68.8 (c = 1.0 CHCl3)).30
To an oven dried flask racemic alcohol (I) (0.3 g, 1.8 mmol) was
taken in dry diethylether (10 mL) and lipase (Novozyme-435)
(0.150 g, 50% w/w) and vinyl acetate (1.54 mL, 18.0 mmol) were
added and stirred at room temperature. The reaction was
followed by TLC. The material was filtered and the filtrate
was concentrated in vacuo. Separation was carried out by
column chromatography over silica gel using petroleum ether
and ethyl acetate as the eluents. Acetate (R)-II was isolated with
ethyl acetate–petroleum ether (2 : 98) and alcohol (S)-I in ethyl
acetate–petroleum ether (5 : 95).
1H-NMR d 1.69–1.71 (d, J = 6.4 Hz, 3H), 5.69–5.74 (q, J =
6.4 Hz, 1H), 7.49–7.70 (m, 3H), 7.70–7.72 (d, J = 8.0 Hz, 1H),
7.80–7.82 (d, J = 8.0 Hz, 1H), 7.89–7.92 (d, J = 8.0 Hz, 1H),
8.13–8.16 (d, J = 8.0 Hz, 1H).
(R)-1-(3,4-Difluorophenyl)ethan-1-ol (11). [a]D = 25.36 (c = 1.0
CH2Cl2) (lit. [a]D = À25.36 (c = 1.0 CH2Cl2)).31
1H-NMR d 1.42–1.44 (d, J = 6.4 Hz, 3H), 4.79–4.84
(q, J = 6.4 Hz, 1H), 7.04–7.19 (m, 3H).
(R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-ol (13). [a]D = 24.1
(c = 1.0 CHCl3) (lit. [a]D = À24.1 (c = 1.0 CHCl3)).32
1H-NMR d 1.56–1.58 (d, J = 6.4 Hz, 3H), 2.01 (s, 1H),
Procedure for one-pot enzymatic KR followed by the Mitsunobu
reaction
The KR was set up as per the above process. After this step 5.05–5.10 (q, J = 6.4 Hz, 1H), 7.81 (s, 1H). 7.87 (s, 2H).
(TLC), the enzyme matrix was filtered off. To the filtrate, metal
(R)-1,2,3,4-Tetrahydronaphthalen-1-ol (15). [a]D
acetates (0.3 g, 1.80 mmol) and triphenyl phosphine (0.71 g, (c = 2.0 MeOH) (lit. [a]D = 28.1 (c = 2.0 MeOH)).33
1.80 mmol) were added under a nitrogen atmosphere followed
1H-NMR d 1.77–1.85 (m, 3H), 1.92–2.03 (m, 3H), 2.75–2.77
=
23.48
by the slow addition of the solution of DEAD (0.49 mL, (m, 1H) 2.82–2.85 (m, 1H), 4.80–4.82 (t, J = 4.0 Hz, 1H) 7.12–7.14
1.80 mmol) in dry CH3CN (10 mL) at 0 1C. The reaction mixture (m, J = 4.0 Hz, 1H), 7.22–7.28 (m, 2H), 7.44–7.47 (m, 1H).
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(R)-1-(3-Nitrophenyl)ethyl acetate (2). [a]D = +69.45 (c = 1.0 analysis on a chiral stationary phase column (Chiralcel-IC) and
in CHCl3).
1H-NMR d 1.56–1.58 (d, J = 6.4 Hz, 3H), 2.11 (s, 1H), 5.91–
compared with the reported data.35b
(R)-1-(1-Azidoethyl)-3-nitrobenzene (17)21
. = +62.8
[a]D
5.96 (q, J = 6.4 Hz, 1H), 7.51–7.55 (t, J = 8.0 Hz, 1H), 7.67–7.69 (c = 1.0 CHCl3).
(d, J = 8.0 Hz, 1H), 8.13–8.16 (m, J = 1.2 Hz, 1H), 8.22–8.23
(t, J = 1.2 Hz, 1H).
1H-NMR d 1.60–1.68 (d, J = 6.8 Hz, 3H), 4.76–4.81 (q, J =
6.8 Hz, 1H), 7.57–7.61 (t, J = 8.0 Hz, 1H), 7.69–7.71 (d, J = 8.0 Hz,
(R)-1-(4-Chlorophenyl)ethyl acetate (4). [a]D = +66.5 (c = 1.0 1H), 8.19–8.23 (m, 2H).
CHCl3) (lit. [a]D = + 68.8 (c = 1.0 CHCl3)).34
IR n 3089, 2924, 2870, 2854, 2090, 1689, 1527, 1350, 1095,
1H-NMR d 1.52–1.54 (d, J = 6.4 Hz, 3H), 2.09 (s, 1H) 5.83–5.88 1072, 902, 810 cmÀ1
(q, J = 6.4 Hz, 1H), 7.28–7.35 (m, 4H).
.
(R)-1-(4-Bromophenyl)ethyl acetate (6). [a]D = +90.12 (c = 1.0
CHCl3) (lit. [a]D = +91.2 (c = 1.1 CHCl3)).34
Conflicts of interest
1H-NMR d 1.52–1.54 (d, J = 6.4 Hz, 3H), 2.09 (s, 1H), 5.81–5.86
(q, J = 6.4 Hz, 1H), 7.24–7.26 (d, J = 8.0 Hz, 2H), 7.48–7.50 (d, J = 8.0
Hz, 2H).
The authors have no conflict of interests.
(R)01-(4-Methylphenyl)ethyl acetate (8). [a]D = +112.32 (c =
1.0 CHCl3) (lit. [a]D = +115.8 (c = 1.1 CHCl3)).34
1H-NMR d 1.54–1.56 (d, J = 6.4 Hz, 3H), 2.08 (s, 1H), 2.37
(s, 3H) 5.85–5.90 (q, J = 6.4 Hz, 1H), 7.18–7.20 (d, J = 8.0 Hz, 2H),
7.27–7.29 (d, J = 8.0 Hz, 2H).
Acknowledgements
We are grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, for the grant [02(0233)/15/EMR-
II] and the Junior Research Fellowship to HBR. We thank
DST-FIST for the NMR facility and Novozymes South Asia
Pvt. Ltd, Bangalore, for the sample of the biocatalyst.
(R)-1-(Naphthalen-2-yl)ethyl acetate (10). [a]D
(c = 1.0 CHCl3) (lit. [a]D = À49.5 (c = 1.0 CHCl3)).33
= +44.32
1H-NMR d 1.70 (d, J = 6.0 Hz, 3H), 2.11 (s, 3 H), 6.65 (t, J = 6.0
Hz, 1H), 7.43–7.61 (m, 4H), 7.79 (d, J = 8.0 Hz, 1H), 7.84–7.88
(m, 1H), 8.08 (d, J = 8.0 Hz, 1H).
Notes and references
(R)1-(3,4-Difluorophenyl)ethyl acetate (12). [a]D = +85.40
(c = 1.0, CH2Cl2) (lit. [a]D = +85.40 (c = 1.0 CHCl3)).31
1H-NMR d 1.51–1.53 (d, J = 6.4 Hz, 3H), 2.09 (s, 3H), 5.80–
5.85 (q, J = 6.4 Hz, 1H), 7.07–7.21 (m, 3H).
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5 H. Pellissier, Adv. Synth. Catal., 2011, 353, 659–676.
6 J. H. Schrittwieser, V. Sattler, J. Resch, F. G. Mutti and
W. Kroutil, Curr. Opin. Chem. Biol., 2011, 15, 249–256.
7 Y. Kim, J. Park and M. J. Kim, ChemCatChem, 2011, 3,
271–277.
(R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethyl acetate (14). [a]D
+54.1 (c = 1.0 MeOH) (lit.66 [a]D = +57 (c = 1.0 MeOH)).32
=
1H-NMR d 1.59–1.60 (d, J = 6.4 Hz, 3H), 2.14 (s, 3H), 5.94–
5.99 (q, J = 6.4 Hz, 1H), 7.81–7.83 (m, 3H).
(R)-1,2,3,4-Tetrahydronaphthalen-1-yl acetate (16). [a]D
+105 (c = 2.0 CHCl3) (lit.66 [a]D = 112 (c = 2.0 CHCl3)).33
=
1H-NMR d 1.82–1.84 (m, 1H), 1.87–1.91 (m, 3H), 2.11 (s, 3H),
2.77–2.81 (m, 1H), 6.01–6.04 (m, 1H), 7.15–7.17 (d, J = 8.0 Hz,
1H), 7.19–7.26 (m, 2H) 7.29–7.31 (m, 1H).
¨
8 O. Verho and J. E. Backvall, J. Am. Chem. Soc., 2015, 137,
3996–4009.
Procedure for the enzymatic reaction followed by the
Mitsunobu reaction with NaN3 (entry 5, Table 4)
9 P. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer,
D. J. Pippel and G. A. Weisenburger, Acc. Chem. Res., 2000,
33, 715–727.
After enzymatic resolution as per the above procedure, the
enzyme matrix was filtered off. To the filtrate, NaN3 (0.3 g, 10 S. Takano, M. Suzuki and K. Ogasawara, Tetrahedron: Asym-
1.80 mmol) and AgNO3 (0.14 g, 0.67 mmol) triphenyl phosphine
metry, 1993, 4, 1043–1046.
(0.71 g, 1.80 mmol) were added under a nitrogen atmosphere 11 A. Steinreiber, A. Stadler, S. F. Mayer, K. Faber and
followed by the slow addition of the solution of DEAD (0.49 mL,
C. O. Kappe, Tetrahedron Lett., 2001, 42, 6283–6286.
1.80 mmol) in dry THF (10 mL) at 0 1C. The reaction mixture 12 A. Wallner, H. Mang, S. M. Glueck, A. Steinreiber, S. F.
was stirred for 24 h. The solvent was removed under reduced
pressure and the crude product was purified by silica-gel
Mayer and K. Faber, Tetrahedron: Asymmetry, 2003, 14,
2427–2432.
column chromatography with ethyl acetate–petroleum ether 13 E. Vanttinen and L. T. Kanerva, Tetrahedron: Asymmetry,
(2 : 98). Colourless liquid was obtained. The azide 17 was
1995, 6, 1779–1786.
converted to amine with Ph3P in aqueous toluene, (reflux 3 h) 14 N. Bouzemi, L. Aribi-Zouioueche and J. C. Fiaud, Tetrahe-
and the crude amine was subjected to acetylation with Ac2O/
dron: Asymmetry, 2006, 17, 797–800.
Et3N in dicloromethane (r.t.; 2 h).35a The optical purity and 15 K. C. Kumara Swamy, N. N. Bhuvan Kumar, E. Balaraman
absolute configuration of this amide were established by HPLC
and K. V. P. Pavan Kumar, Chem. Rev., 2009, 109, 2551–2651.
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