Enzymatic kinetic resolution and racemization of 2-(Tetramethylpiperidine- 1-oxyl)ethanols

Article abstract of DOI:10.1002/ejoc.201300661

The Candida antarctica lipase B catalyzed transesterification of 2-(tetramethylpiperidine-1-oxyl)ethanols provides acetates in useful yields with good to high enantiomeric excess values. By taking advantage of the persistent radical effect, the remaining alcohols can be cleanly racemized under mild conditions in the presence of TEMPO [2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl] . The Candida antarctica lipase B (CAL-B)-catalyzed transesterification of 2-(tetramethylpiperidine-1-oxyl)ethanols provides the corresponding acetates in useful yields with good to high enantiomeric excess values. The remaining alcohols can be cleanly racemized under mild conditions in the presence of TEMPO [2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl]; MTBE = methyl tert-butyl ether. Copyright

Full text of DOI:10.1002/ejoc.201300661

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300661
Enzymatic Kinetic Resolution and Racemization of 2-(Tetramethylpiperidine-1-
oxyl)ethanols
Agnes Prechter[a] and Markus R. Heinrich*[a]
Keywords: Enzyme catalysis / Kinetic resolution / Racemization / Chirality / Radicals
The Candida antarctica lipase B catalyzed transesterification
of 2-(tetramethylpiperidine-1-oxyl)ethanols provides acet-
ates in useful yields with good to high enantiomeric excess
values. By taking advantage of the persistent radical effect,
the remaining alcohols can be cleanly racemized under mild
conditions in the presence of TEMPO [2,2,6,6-tetramethyl-
piperidin-1-yl)oxidanyl].
Introduction
Results and Discussion
The interest in 2-(tetramethylpiperidine-1-oxyl)ethanols
as potential substrates for enzymatic reactions arose from
our recent observation that azo alcohols 1 and their corre-
sponding acetates 2 are well accepted as substrates by en-
zymes such as Candida antarctica lipase B (CAL-B) but are
difficult to racemize in a reasonable number of synthetic
steps (Scheme 1).[7,8]
In recent years, enzymatic kinetic resolutions have gained
increasing importance as a versatile way to access enantio-
merically enriched and pure compounds.[1,2] A large variety
of enzymes is nowadays known to convert a multitude of
functional groups enantioselectively, among which alcohols,
esters, carboxylic acids, amines, and amino acids are com-
mon targets in the racemic substrates.[1] One principal draw-
back of such enzymatic kinetic processes, however, is that
only a maximum product yield of 50% can be reached un-
less the substrate simultaneously racemizes under the cho-
sen reaction conditions.[2] Although not as elegantly as
through dynamic kinetic resolution,[3] improved efficacy of
the process can alternatively be reached if the remaining
substrate (with low enantiomeric excess) can be racemized
in a simple way.[2,4] Regarding the commonly used strategies
to achieve racemization, which include thermal racemiza-
tion, base- or acid-catalyzed racemization, enzyme-cata-
lyzed racemization, racemization through redox and radical
reactions, as well as racemization by Schiff bases,[4] reac-
Scheme 1. Racemization of alcohols 3 through homolytic bond
cleavage and recombination.
In contrast, alcohols 3 should undergo racemization at
tions proceeding through homolytic bond cleavage and re- slightly elevated temperatures through homolytic cleavage
combination have so far only played a minor role. A beauti- of the carbon–oxygen bond and subsequent recombination
ful example of dynamic kinetic resolution featuring the ra- of TEMPO [2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl, 4][9]
cemization of amines through reversible hydrogen-atom and stabilized benzylic radical 5. The thermal generation of
transfer to thiyl radicals was recently reported by Gastaldi, carbon-centered radicals from TEMPO adducts and their
Gil, and Bertrand.[5,6] In this communication, we introduce use for olefin functionalization and polymerization has in-
2-(tetramethylpiperidine-1-oxyl)ethanols as new substrates tensively been studied by Studer.[10,11] Beneficially with re-
for kinetic enzymatic resolutions and their racemization un- gard to our studies, alcohol 3a and ring-substituted deriva-
der simple and mild conditions.
tives can be accessed in a one-step synthesis from styrene,
TEMPO (4), and hydrogen peroxide.[12,13] Initial screening
with a variety of enzymes revealed that the transesterifica-
tion of 3a with vinyl acetate can be achieved under signifi-
cantly milder conditions than the hydrolysis or aminolysis
of the corresponding acetate. For the desired transesterifica-
tion, CAL-B[14] again turned out to be the most suitable
enzyme (see the Supporting Information). The results from
[a] Department of Chemistry and Pharmacy, Friedrich-Alexander-
Universität Erlangen-Nürnberg,
Schuhstraße 19, 91052 Erlangen, Germany
E-mail: Markus.Heinrich@fau.de
Homepage: http://www.medchem.uni-erlangen.de/heinrichlab/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300661.
Eur. J. Org. Chem. 2013, 5585–5589
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A. Prechter, M. R. Heinrich
SHORT COMMUNICATION
a screening of different organic solvents are summarized in tion of any other product than desired acetate 7a. The enzy-
Table 1.
matic transesterification thus proceeds very cleanly under
the chosen conditions.
Owing to the superior E value[16,17] of the related trans-
formation (Table 1, entry 7), MTBE was selected as the sol-
vent for further optimization experiments (Table 2). Varia-
tion of the amount of immobilized CAL-B from
400 mgmmol–1 to 200 and 800 mgmmol–1 led to a de-
creased E value (Table 2, entry 1) and no remarkable gain
(Table 2, entry 3), respectively.
Table 1. CAL-B catalyzed transesterification of alcohol 3a with
vinyl acetate (6) in various solvents.[a]
Given that it has been reported that increasing concen-
trations of the acyl transfer reagent can have a positive or
negative influence on the E value of the transformation,[18]
we then turned to investigating this parameter. Interestingly,
a significant improvement was achieved by increasing the
amount of vinyl acetate to 4 equiv. (Table 2, entry 4), but
not further to 6 equiv. (Table 2, entry 5). A slightly higher
reaction temperature (Table 2, entry 6) as well as an ex-
change of the acetyl source from 6 to isopropenyl acetate
(8; Table 2, entry 7) did not give better results. With regard
to the amount of enzyme that was necessary, we were
pleased to find that the enzyme could be reused for further
transformations, which showed comparable E values (see
the Supporting Information).
Entry Solvent
Conversion % eep
% ees
(3a)[d]
E value[e]
[%][b,c]
(7a)[d]
1
2
3
4
5
6
7
acetone
CH3CN
toluene
THF
Ͻ1
8
4
n.d.[f]
n.d.[f]
21
n.d.[f]
n.d.[f]
n.d.[f]
n.d.[f]
12
n.d.[f]
n.d.[f]
n.d.[f]
n.d.[f]
24
Ͻ1
n.d.[f]
91
[TMBA][NTf2] 19 (12)[g]
n-hexane
MTBE
20 (18)
34 (31)
90
91
20
40
23
31
[a] Reaction conditions: rac-3a (0.05 mmol), organic solvent
(2 mL), vinyl acetate (6, 0.10 mmol), CAL-B (20 mg), 40 °C, 3 d.
[b] Conversion determined by 1H NMR spectroscopy. [c] The value
in parentheses is the conversion as determined by the following
equation: conv. = (ees)/(ees + eep). [d] Enantiomeric excess of 3a
and 7a determined by chiral HPLC. [e] E value calculated from the
ee data of alcohol 3a and acetate 7a. [f] n.d.: not determined.
[g] This reaction was performed with 1 mL of [TMBA][NTf2] as
solvent.
With the optimized conditions in hand, we turned to the
evaluation of the substrate scope (Table 3). Transformations
with synthetically useful E values were observed for most
substitution patterns on the aromatic core (Table 3, en-
tries 1–6, 8) with the exception of 2-chloro- and 4-cyano-
Although the use of acetone, acetonitrile, toluene, and substituted derivatives 3g and 3i (Table 3, entries 7 and 9).
tetrahydrofuran led to very low conversions after 3 d For alcohol 3i, we currently assign this to unfavorable inter-
(Table 1, entries 1–4), n-hexane, methyl tert-butyl ether action of the 4-cyano group with the catalytic site of the
(MTBE), and the ionic liquid N-trimethyl-N-butylammon- enzyme, as 3i was not found to be less stable towards
ium–bis(trifluoromethylsulfonyl)imide ([TMBA][NTf2])[15] isomerization than the other alcohols. Again, and was evi-
1
gave acetate 7a in reasonable yields and enantiomeric excess denced by H NMR spectroscopy, all enzymatic reactions
(Table 1, entries 5–7). Investigation of the reaction mixtures proceeded cleanly without the formation of products other
by 1H NMR spectroscopy, which was used to determine the than desired acetates 7. The unsuccessful reaction of 3j
conversion of each experiment, did not indicate the forma- (Table 3, entry 10), however, indicates that alcohols bearing
Table 2. Optimization experiments.[a]
Entry
CAL-B [mgmmol–1]
6/8 (equiv.)
T [°C]
Conversion [%][b,c]
% eep (7a)[d] % ees (3a)[d]
E[e]
1
2
3
4
5
6
7
200
400
800
400
400
400
400
6 (2)
6 (2)
6 (2)
6 (4)
6 (6)
6 (4)
8 (4)
40
40
40
40
40
50
40
19 (15)
34 (31)
52 (46)
39 (40)
35 (33)
50 (48)
25 (23)
83
91
87
93
91
85
92
15
40
74
62
45
80
28
13
31
32
52
33
30
31
1
[a] Reaction conditions: rac-3a (0.05 mmol), MTBE (2 mL), CAL-B (20 mg), 3 d. [b] Conversion determined by H NMR spectroscopy.
[c] The value in parentheses is the conversion as determined by the following equation: conv. = (ees)/(ees + eep). [d] Enantiomeric excess
of 3a and 7a determined by chiral HPLC. [e] E value calculated from the ee data of alcohol 3a and acetate 7a.
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Eur. J. Org. Chem. 2013, 5585–5589

Enzymatic Kinetic Resolution and Racemization of Ethanols
quaternary centers are most probably not tolerated. The ab- mization of the acetates, as exemplified by 7f and 7i, was
solute stereochemistry of acetates 7 was determined by re- achieved under similar conditions. These reactions (Table 4,
ducing the low-enantioenriched, nonconverted alcohol entries 5 and 6) did, however, lead to small amounts of by-
3a (Table 3, entry 1) into corresponding diol
9
products.
(Scheme 2).[19,20]
Table 4. Racemization of alcohols 3a, 3b, 3e, and 3i and acetates
7f and 7i.[a]
Table 3. Substrate scope.[a]
Entry
Alcohol
(R1, R2)
Conv.
[%][b,c]
% eep
% ees
E[e]
(7a–i)[d] (3a–j)[d]
[b]
[d]
Entry Alcohol/acetate (R1) Time [h] % eeinit
% eefinal
1
2
3
4
5
6
3a (H)
3b (OMe)
3e (Cl)
3i (CN)
7f (Br)
7i (CN)
7.5
5.5
6.0
6.0
10.0
10.0
60
62
77
0[b]
0[b]
0[b]
0[b]
0[c]
0[c]
1
2
3
4
5
6
7
8
9
3a (H, H)
40 (39)
3b (4-OMe, H) 42 (40)
92
92
60
62
44
45
93
20
44
30
11
20
13
3c (4-Me, H)
3d (4-F, H)
3e (4-Cl, H)
3f (4-Br, H)
3g (2-Cl, H)
3h (3-Cl, H)
3i (4-CN, H)
3j (H, Me)
31 (27)
42 (39)
47 (46)
25 (28)
13 (13)
49 (48)
42 (42)
Ͻ1
Ͼ97[f]
84[g]
90
36[f]
54
56
91[c]
77[c]
77
91
35
82[f]
80[g]
77[g]
n.d.[h]
12[f]
75
[a] Reaction conditions: 3 (30.0 μmol), TEMPO (4, 1.5–2.5 equiv.),
toluene (1 mL), argon atmosphere, reflux. [b] Enantiomeric excess
was determined by chiral HPLC. [c] Racemization monitored by
optical rotation. [d] No byproducts were detected by 1H NMR
spectroscopy for experiments in entries 1–4. Small amounts of by-
products (5–15%) were found in the experiments with acetates 7f
and 7i.
56
10
n.d.[h]
n.d.[h]
[a] Reaction conditions: rac-3a–j (0.20 mmol), MTBE (8 mL), vinyl
acetate (6, 0.80 mmol), CAL-B (80 mg), 40 °C, 3 d. [b] Conversion
determined by H NMR spectroscopy. [c] The value in parentheses
1
is the conversion as determined by the following equation: conv. =
(ees)/(ees + eep). [d] Unless otherwise stated, the enantiomeric ex-
cess values of alcohols 3 and acetates 7 were determined by chiral
HPLC. [e] E value calculated from the ee data of alcohols 3 and
acetates 7. See also ref.[23] [f] Enantiomeric excess determined after
esterification with methyl 4-chloro-4-oxobutanoate. [g] Enantio-
meric excess determined after conversion to the corresponding
alcohol. [h] n.d.: not determined.
The addition of TEMPO (4) to the alcohols or acetates
was necessary to avoid the formation of decomposition
products. In that way, benzylic radicals 5 (Scheme 1) were
reliably trapped by 4 at the beginning of the racemization
process. The reaction thus takes advantage of the persistent
radical effect (PRE) without having to initially build up an
excess amount of free 4 through partial decomposition of
the alcohols or acetates.[24] Attempts to characterize the
products arising from the thermal decomposition were not
successful owing to the multitude of compounds and the at
same time the small quantities in which they were formed.
To explore the potential of expanding the methodology to
aliphatic substrates, we finally investigated the kinetic reso-
lution of alcohol 10, which was prepared in one step from
tert-butyl acrylate under conditions similar to those used
for the synthesis of alcohols 3 from styrenes (Scheme 3).[12]
Although only a comparably low E value of 5 was deter-
mined for this initial experiment under unoptimized condi-
Scheme 2. Reduction of alcohol 3a to diol 9.
A comparison of the experimental optical rotation values
with values reported in the literature[21] revealed that the
remaining alcohols are of the (S) configuration and that the
transesterification is therefore (R) selective. Moreover, this
reaction shows that the N–O bond can be cleaved under
mild conditions to access the corresponding diols without
a major loss of enantiomeric excess.[22]
The racemization of the nonconverted alcohols pos-
sessing low enantiomeric excess values was studied by in-
creasing the temperature of their solutions in toluene
(Table 4). Under reflux, alcohols 3a, 3b, 3e, and 3i showed
complete and clean racemization after 6–8 h, so that the
starting materials could be recovered in racemic form and
Scheme 3. Kinetic enzymatic resolution of aliphatic TEMPO
in quantitative yield after the given reaction times. The race- alcohol 10 to acetate 11.
Eur. J. Org. Chem. 2013, 5585–5589
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5587

A. Prechter, M. R. Heinrich
SHORT COMMUNICATION
[7]
[8]
[9]
a) F. R. Dietz, A. Prechter, H. Gröger, M. R. Heinrich, Tetra-
hedron Lett. 2011, 52, 655–657; b) A. Prechter, H. Gröger,
M. R. Heinrich, Org. Biomol. Chem. 2012, 10, 3384–3387.
For studies on the racemization of a related azo compound,
see: N. A. Porter, L. J. Marnett, J. Am. Chem. Soc. 1973, 95,
4361–4367.
For recent use of TEMPO in organic synthesis see: a) M. Hart-
mann, Y. Li, A. Studer, J. Am. Chem. Soc. 2012, 134, 16516–
16519; b) Y. Li, A. Studer, Angew. Chem. 2012, 124, 8345–8348;
Angew. Chem. Int. Ed. 2012, 51, 8221–8224.
tions, the reaction nevertheless shows that aliphatic alcohols
are also tolerated by the enzyme. Comparable to styrene-
derived alcohols 3 reported in Table 4, remaining low-en-
antioenriched aliphatic alcohol 10 underwent clean racemi-
zation in boiling toluene.
[10]
[11]
a) C. Wetter, K. Jantos, K. Woithe, A. Studer, Org. Lett. 2003,
5, 2899–2902; b) C. Wetter, A. Studer, Chem. Commun. 2004,
174–175; c) K. Molawi, T. Schulte, K. O. Siegenthaler, C.
Wetter, A. Studer, Chem. Eur. J. 2005, 11, 2335–2350; d) T.
Vogler, A. Studer, Synthesis 2006, 4257–4265.
For review articles, see: a) A. Studer, Chem. Soc. Rev. 2004, 33,
267–273; b) T. Vogler, A. Studer, Synthesis 2008, 1979–1993; c)
L. Tebben, A. Studer, Angew. Chem. 2011, 123, 5138–5174; An-
gew. Chem. Int. Ed. 2011, 50, 5034–5068.
C. Detrembleur, T. Gross, R.-V. Meyer, United States Patent
US2003/0236368A1, 2003; Chem. Abstr. 2003, 140, 60153.
For examples of (partially enantioselective) alternative synthe-
ses, see: a) M. A. A. Ghani, D. Abdallah, P. M. Kazmaier, B.
Keoshkerian, E. Buncel, Can. J. Chem. 2004, 82, 1403–1412;
b) M. P. Sibi, M. Hasegawa, J. Am. Chem. Soc. 2007, 129,
4124–4125; c) K. Akagawa, T. Fujiwara, S. Sakamoto, K.
Kudo, Chem. Commun. 2010, 46, 8040–8042.
Conclusions
In summary, we have shown that 2-(tetramethylpiperi-
dine-1-oxyl)ethanols are well-suited substrates for CAL-B-
catalyzed transesterification with vinyl acetate. Beneficially,
the remaining alcohols can be cleanly racemized under mild
conditions in the presence of TEMPO by exploiting the per-
sistent radical effect (PRE). An initial experiment with an
ester functionality at the place of the radical-stabilizing
phenyl group showed that expansion of the scope towards
aliphatic substrates is possible, although further optimiza-
tion is required for this type of substrate. As a result of the
importance of water activity in many enzymatic reactions,
our current studies are also directed towards evaluation of
this parameter.[25]
[12]
[13]
[14]
[15]
CAL-B was used in the immobilized form of Novozym 435.
For loading and activity, see: J. A. Laszlo, M. Jackson, R. M.
Blanco, J. Mol. Catal. B 2011, 69, 60–65.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures; 1H NMR and 13C NMR
spectra for compounds 3b–j, 7b–i, 10, and 11; and 1H NMR spectra
for compounds 3a and 7a.
For examples of enzymatic reactions in ionic liquids, see: a) A.
Kamal, G. Chouhan, Tetrahedron Lett. 2004, 45, 8801–8805;
b) P. Lozano, T. de Diego, S. Gmouh, M. Vaultier, J. L. Iborra,
Biotechnol. Prog. 2004, 20, 661–669; c) T. de Diego, P. Lozano,
S. Gmouh, M. Vaultier, J. L. Iborra, Biomacromolecules 2005,
6, 1457–1464; d) S. Park, R. J. Kazlauskas, J. Org. Chem. 2001,
66, 8395–8401; e) N. M. T. Lourenço, C. A. M. Afonso, Angew.
Chem. 2007, 119, 8326–8329; Angew. Chem. Int. Ed. 2007, 46,
8178–8181; f) P. Domínguez de María, Angew. Chem. 2008,
120, 7066–7075; Angew. Chem. Int. Ed. 2008, 47, 6960–6968;
g) P. Domínguez de María, Z. Maugeri, Curr. Opin. Chem.
Biol. 2011, 15, 220–225; h) F. van Rantwijk, R. A. Sheldon,
Chem. Rev. 2007, 107, 2757–2785.
Acknowledgments
The authors would like to thank the Universität Bayern e.V. for a
“Bayerische Eliteförderung” fellowship (to A. P.). The authors are
further grateful for the experimental support of Stefanie Kindt and
Dominik Grau as well as for a sample of [TMBA][NTf2] provided
by Dr. Michel Vaultier (Université Bordeaux 1).
[16]
[17]
For a review article on the determination and significance of
E values, see: A. J. J. Straathof, J. A. Jongejan, Enzyme Microb.
Technol. 1997, 21, 559–571.
[1] M. Ahmed, T. Kelly, A. Ghanem, Tetrahedron 2012, 68, 6781–
6802.
[2] U. T. Strauss, U. Felfer, K. Faber, Tetrahedron: Asymmetry
1999, 10, 107–117.
For the most commonly used equations, see: a) C.-S. Chen, Y.
Fujimoto, G. Girdaukas, C. J. Sih, J. Am. Chem. Soc. 1982,
104, 7294–7299; b) J. L. L. Rakels, A. J. J. Straathof, J. J.
Heijnen, Enzyme Microb. Technol. 1993, 15, 1051–1056.
For negative effects of increased acyl donor concentrations on
the E value, see: M. Merabet-Khellasi, L. Aribi-Zouioueche,
O. Riant, Tetrahedron: Asymmetry 2009, 20, 1371–1377; for
positive effects, see: a) A.-B. L. Fransson, Deracemization of
Functionalized Alcohols via Combined Ruthenium and Enzyme
Catalysis, Stockholm University, Stockholm, 2006; b) K. Faber,
S. Riva, Synthesis 1992, 895–910.
[3] For some reviews on dynamic kinetic resolutions, see: a) R. S.
Ward, Tetrahedron: Asymmetry 1995, 6, 1475–1490; b) H.
Stecher, K. Faber, Synthesis 1997, 1–16; c) H. Pellissier, Tetra-
hedron 2003, 59, 8291–8327; d) H. Pellissier, Tetrahedron 2008,
64, 1563–1601; e) N. J. Turner, Curr. Opin. Chem. Biol. 2010,
14, 115–121; f) H. Pellissier, Tetrahedron 2011, 67, 3769–3802;
g) A. Parvulescu, J. Janssens, J. Vanderleyden, D. De Vos, Top.
Catal. 2010, 53, 931–941; h) J. H. Lee, K. Han, M.-J. Kim, J.
Park, Eur. J. Org. Chem. 2010, 999–1015; i) B. Martín-Matute,
J.-E. Bäckvall, Curr. Opin. Chem. Biol. 2007, 11, 226–232.
[4] E. J. Ebbers, G. J. A. Ariaans, J. P. M. Houbiers, A. Bruggink,
B. Zwanenburg, Tetrahedron 1997, 53, 9417–9476.
[5] a) S. Gastaldi, S. Escoubet, N. Vanthuyne, G. Gil, M. P. Ber-
trand, Org. Lett. 2007, 9, 837–839; b) L. El Blidi, M. Nechab,
N. Vanthuyne, S. Gastaldi, G. Gil, M. P. Bertrand, J. Org.
Chem. 2009, 74, 2901–2903; c) L. El Blidi, N. Vanthuyne, D.
Siri, S. Gastaldi, M. P. Bertrand, G. Gil, Org. Biomol. Chem.
2010, 8, 4165–4168.
[18]
[19]
[20]
M. R. Heinrich, A. Wetzel, M. Kirschstein, Org. Lett. 2007, 9,
3833–3835.
For alternative stereoselective synthetic approaches towards
comparable 1-aryl-substituted 1,2-diols, see, for example: a) A.
Archelas, R. Furstoss, Trends Biotechnol. 1998, 16, 108–116; b)
L. Cao, J. Lee, W. Chen, T. K. Wood, Biotechnol. Bioeng. 2006,
94, 522–529; c) X. Tian, G.-W. Zheng, C.-X. Li, Z.-L. Wang,
J.-H. Xu, J. Mol. Catal. B 2011, 73, 80–84; d) M. Edin, B.
Martín-Matute, J.-E. Bäckvall, Tetrahedron: Asymmetry 2006,
17, 708–715; e) R. Zhang, Y. Xu, R. Xiao, B. Zhang, L. Wang,
Microb. Cell Fact. 2012, 11:167; f) T. Shimada, K. Mukaide,
A. Shinohara, J. W. Han, T. Hayashi, J. Am. Chem. Soc. 2002,
124, 1584–1585.
[6] For pioneering work, see: a) S. Escoubet, S. Gastaldi, N. Van-
thuyne, G. Gil, D. Siri, M. P. Bertrand, J. Org. Chem. 2006, 71,
7288–7292; b) S. Escoubet, S. Gastaldi, N. Vanthuyne, G. Gil,
D. Siri, M. P. Bertrand, Eur. J. Org. Chem. 2006, 3242–3250.
5588
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Enzymatic Kinetic Resolution and Racemization of Ethanols
[21] A. Kamal, M. Sandbhor, K. Ahmed, S. F. Adil, A. A. Shaik,
Tetrahedron: Asymmetry 2003, 14, 3861–3866.
[22] Procedure for the reductive cleavage of the N–O bond: M. S.
Tichenor, K. S. MacMillan, J. S. Stover, S. E. Wolkenberg,
M. G. Pavani, L. Zanella, A. N. Zaid, G. Spalluto, T. J. Rayl,
I. Hwang, P. G. Baraldi, D. L. Boger, J. Am. Chem. Soc. 2007,
129, 14092–14099.
[23] Exact determination of the E value becomes increasingly more
difficult as the E value increases in size. Small deviations of the
measured values can therefore lead to significantly changed E
values. U. T. Bornscheuer, R. J. Kazlauskas, Hydrolases in Or-
ganic Synthesis 2nd ed., Wiley-VCH, Weinheim, Germany,
2006.
[24] For review articles on the persistent radical effect, see: a) H.
Fischer, Macromolecules 1997, 30, 5666–5672; b) H. Fischer,
Chem. Rev. 2001, 101, 3581–3610; c) A. Studer, Chem. Eur. J.
2001, 7, 1159–1164.
[25] A. M. P. Koskinen, A. M. Klibanov (Eds.), Enzymatic Reac-
tions in Organic Media, Blackie Academic & Professional, Lon-
don, 1996.
Received: May 6, 2013
Published Online: July 18, 2013
Eur. J. Org. Chem. 2013, 5585–5589
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