Oxidative kinetic resolution of racemic alkyl aryl carbinols by an electronically tuned chiral nitroxyl radical

Article abstract of DOI:10.1016/j.tetlet.2014.02.005

A method for oxidative kinetic resolution of racemic alcohols catalyzed by chiral nitroxyl radical (R,R)-1 has been developed. This method is especially effective for the kinetic resolution of tert-butyl aryl carbinols (s = up to 23).

Full text of DOI:10.1016/j.tetlet.2014.02.005

Tetrahedron Letters 55 (2014) 1943–1945
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Tetrahedron Letters
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Oxidative kinetic resolution of racemic alkyl aryl carbinols
by an electronically tuned chiral nitroxyl radical
⇑
Shohei Hamada, Yoshiyuki Wada, Takahiro Sasamori, Norihiro Tokitoh, Takumi Furura, Takeo Kawabata
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for oxidative kinetic resolution of racemic alcohols catalyzed by chiral nitroxyl radical (R,R)-1
has been developed. This method is especially effective for the kinetic resolution of tert-butyl aryl carbi-
nols (s = up to 23).
Received 10 December 2013
Revised 31 January 2014
Accepted 4 February 2014
Available online 12 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Nitroxyl radical
Oxidation
Kinetic resolution
Alcohols
Hydride shift
Kinetic resolution of racemic alcohols is an alternative to asym-
metric reduction of the corresponding ketones for obtaining opti-
cally active alcohols. An advantage of kinetic resolution is being
able to produce optically active compounds with extremely high
enantiomeric purity under the proper control of the reaction con-
version.1 Acylative kinetic resolution of racemic alcohols has been
extensively developed.2 Oxidative kinetic resolution of racemic
alcohols has also been well developed employing organometallic
catalysts.3 On the other hand, oxidative kinetic resolution using
metal-free oxidation catalysts have been relatively unexplored.
Several chiral nitroxyl radical oxidation catalysts have been devel-
oped and effectively used for the oxidative kinetic resolution of
racemic alcohols.4 Here, we report a new method for oxidative ki-
netic resolution of racemic alcohols with chiral nitroxyl radical oxi-
dation catalyst 1.
We have developed racemic-1 as a nitroxyl radical oxidation
catalyst based on the electronic tuning strategy.5,6 Although cata-
lyst 1 has tetrasubstituted carbons adjacent to the nitroxyl radical
catalytic center, which usually resulted in poor catalytic activity
for the oxidation of secondary alcohols due to the steric reasons,7
1 could effectively promote oxidation of various secondary alco-
hols8 because of the presence of electron-withdrawing ester
groups (electronic tuning effect).5 A rate-determining hydride
transfer mechanism was proposed for the oxidation of bezylic
alcohols catalyzed by 1 based on the kinetic isotope effects and
Figure 1. Hydride shift (A) and nucleophilic attack of the oxygen atom (B) at the
key step of the oxidation of alcohols with the oxoammonium species derived from
nitroxyl radical oxidation catalysts.
Hammet plots. (Fig. 1).5,9 A hydride attached to the chiral center
of the substrate alcohol was supposed to be transferred directly
to the oxoammonium species derived from 1. On the other hand,
in most cases of the oxidation reactions catalyzed by nitroxyl rad-
icals, the reaction proceeds via a nucleophilic attack of an oxygen
atom of the hydroxy group to the oxoammonium species (B) fol-
lowed by proton-abstraction.4,7,8,10 The difference in the oxidation
mechanisms depending on the catalysts may result in the differ-
ence in the substrate scope of the oxidative kinetic resolution.
These stereochemical backgrounds prompted us to develop a
method for oxidative kinetic resolution of racemic alcohols pro-
moted by optically active 1.
⇑
Corresponding author. Tel.: +81 774 38 3190; fax: +81 774 38 3197.
E-mail address: kawabata@scl.kyoto-u.ac.jp (T. Kawabata).
http://dx.doi.org/10.1016/j.tetlet.2014.02.005
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1944
S. Hamada et al. / Tetrahedron Letters 55 (2014) 1943–1945
catalyst (R,R)-1 ((À)-1) was prepared by oxidation of (+)-2 (99%
ee) with oxone.12
Optically active (+)-2 (99% ee), a precursor for optically active 1, was
prepared according to Einhorn’s procedure (Fig. 2).6 Because the
absolute configuration of (+)-2 has not been determined yet,6 we
initiated our study by determining the absolute configuration of
(+)-2. An X-ray structure of the p-bromoanilide 2a derived from
(+)-2 is shown in Figure 2.11 The absolute configuration of (+)-2
was thus determined to be (R,R). Chiral nitroxyl radical oxidation
Since racemic-1 was found to promote chemoselective oxida-
tion of benzylic alcohols effectively, oxidative kinetic resolution
of benzylic alcohols 3–10 was examined (Table 1). Although oxida-
tion of racemic-3 proceeded quantitatively (58% conversion) by
treatment with 0.6 equiv of phenyl iodonium bis(trifluoroacetate)
(PIFA) and K2CO3 in the presence of 10 mol % of (R,R)-1, it gives
recovered 3 as a racemate (entry 1). Oxidative kinetic resolution
of racemic-4 proceeded also in a low selectivity (s = 1.9, entry 2).
On the other hand, highly selective oxidative kinetic resolution of
racemic tert-butyl phenyl carbinol (5) was observed (s = 15, entry
3).13 Oxidative kinetic resolution of several racemic tert-butyl aryl
carbinols 6–10 was examined, and moderate to high selectivity
was observed (s = 5.6 ꢀ 23, entries 4–8). The highest selectivity
was obtained by the oxidative kinetic resolution of tert-butyl 1-
naphthyl carbinol (10). Treatment of racemic-10 with 0.8 equiv of
PIFA and K2CO3 in the presence of 10 mol % of (R,R)-1 gave (R)-10
in 97% ee at 58% conversion, which corresponds to s = 23 (entry
8). Alkyl aryl carbinols with S-configuration react faster in all of
the cases, and the alcohols with R-configuration were recovered
(entries 2, 3, 5, 7, 8). The oxidative kinetic resolution of allylic alco-
hol 11 resulted in a low selectivity (s = 1.1, entry 9). Aliphatic sec-
ondary alcohol 12 showed only moderate selectivity (s = 4.7) in the
oxidative kinetic resolution (entry 10).
In conclusion, we have developed a method for oxidative ki-
netic resolution of racemic alcohols promoted by chiral nitroxyl
radical oxidation catalyst (R,R)-1. This method is especially effec-
tive for the oxidative kinetic resolution of tert-butyl aryl
carbinols.
Figure 2. Preparation and an X-ray structure of 2a.
Table 1
Oxidative kinetic resolution of racemic alcohols
Entry
Substrate
Conversion (%)
ee of the recovered alcohol (%)
Absolute configuration
Selectivity (s)
1a
2a
3
4
5
6
7
8
9
3
4
5
6
7
8
9
10
11
12
58
57
66
62
66
42
50
58
73
47
2
ND
R
R
ND
R
ND
R
1.0
1.9
15
26
99
96
94
42
78
97
7
14
9.4
5.6
19
23
1.1
4.7
R
R
10
45
1S,2R
a
PIFA (0.6 equiv) and K2CO3 (2.4 equiv) were used.

S. Hamada et al. / Tetrahedron Letters 55 (2014) 1943–1945
1945
6. Nitroxyl radical 1 and its meso-isomer were prepared by Einhorn and co-
workers in 2000, see: Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. Synth.
Commun. 2000, 30, 1837–1848. To the best of our knowledge, however, the
catalytic properties as an oxidation catalyst had never been reported prior to
our report (Ref. 5).
7. For reviews on TEMPO-catalyzed oxidation, see: (a) de Nooy, A. E. J.; Besemer,
A. C.; van Bekkum, H. Synthesis 1996, 1153–1174; (b) Sheldon, R. A.; Arends, I.
W. C. E. Adv. Synth. Catal. 2004, 346, 1051–1071; (c) Tebben, L.; Studer, A.
Angew. Chem., Int. Ed. 2011, 50, 5034–5068.
8. Powerful nitroxyl radical catalysts for the oxidation of sterically hindered
secondary alcohols have been developed, see: (a) Shibuya, M.; Tomizawa, M.;
Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128, 8412–8413; (b) Demizu, Y.;
Shiigi, H.; Oda, T.; Matsumura, Y.; Onomura, O. Tetrahedron Lett. 2008, 49, 48–
52; (c) Shibuya, M.; Osada, Y.; Sasano, Y.; Tomizawa, M.; Iwabuchi, Y. J. Am.
Chem. Soc. 2011, 133, 6497–6500.
9. A hydride transfer mechanism has also been proposed in TEMPO-mediated
oxidation of alcohols under acidic conditions by computational studies, see:
Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B. J. Org. Chem. 2007, 72, 4504–4509.
10. Iwabuchi and co-workers reported highly selective oxidative kinetic resolution
(Ref. 4g), in which both the formation of the tetrahedral intermediate by
nucleophilic attack of the oxygen atom of the alcohol as shown in B and the
collapse of the tetrahedral intermediate by proton-abstraction were claimed to
be important for the selectivity.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Advanced Molecular Transformation
by Organocatalysts’ from The Ministry of Education, Culture,
Sports, Science, and Technology, Japan, and by Grant-in-Aid for
JSPS Fellows to S.H.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
02.005.
References and notes
1. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–331.
2. For reviews, see: Furuta, T.; Kawabata, T.; pp 497–496, and Smith, A. D.; Woods,
P. A. pp 547–590. Science of Synthesis, Asymmetric Organocatalysis 1, Lewis Base
and Acid Catalysts: List, B. Eds.; George Thieme Verlag KG: Stuttgart, New York,
2012.
11. Crystallographic
data
for
2a:
C20H21Br2N3O2,
M = 495.22,
0.10 Â 0.02 Â 0.02 mm, trigonal, P32(#145), a = 20.3466(3) Å, b = 20.347 Å,
c = 12.8283(2) Å,
calcd = 1.609 g cmÀ3
measured, 11,412 unique (Rint = 0.0808),
a
,
= 90°, b = 90°,
2hmax = 25.50°, T = 103(2) K, 49404 reflections
= 3.986 mm–1, The final R1 and wR
c
= 120°, V = 4599.21(10) Å3, Z = 9,
q
3. For selective examples of transition-metal-catalyzed oxidative kinetic
resolution of alcohols, see: (a) Hashiguchi, S.; Fujii, A.; Haack, K. J.;
Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288–
290; (b) Masutani, K.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000, 41,
5119–5123; (c) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–
7726; (d) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123,
7475–7476; (e) Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 1090–1091; (f) Weng, S. S.; Shen, M. W.; Kao, J. Q.; Munot, Y.-S.; Chen, C. T.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3522–3527; (g) Kunisu, T.; Oguma, T.;
Katsuki, T. J. Am. Chem. Soc. 2011, 133, 12937–12939.
4. (a) Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org. Chem. 1996, 61,
1194–1195; (b) Kashiwagi, Y.; Kurashima, F.; Kikuchi, C.; Anzai, J.; Osa, T.;
Bobbitt, J. M. Tetrahedron Lett. 1999, 40, 6469–6472; (c) Kuroboshi, M.;
Yoshihisa, H.; Cortona, M. N.; Kawakami, Y.; Gao, Z.; Tanaka, H. Tetrahedron
Lett. 2000, 41, 8131–8135; (d) Graetz, B.; Rychnovsky, S.; Leu, W.-H.; Farmer,
P.; Lin, R. Tetrahedron: Asymmetry 2005, 16, 3584–3598; (e) Demizu, Y.; Shiigi,
H.; Mori, H.; Matsumoto, K.; Onomura, O. Tetrahedron: Asymmetry 2008, 19,
2659–2665; (f) Shiigi, H.; Mori, H.; Tanaka, T.; Demizu, Y.; Onomura, O.
Tetrahedron Lett. 2008, 49, 5247–5251; (g) Tomizawa, M.; Shibuya, M.;
Iwabuchi, Y. Org. Lett. 2009, 11, 1829–1831.
l
were 0.0785 and 0.1567 (all data). The residual electron densities (peak and
hole) were 1.323 and À0.835 e ÅÀ3. These data have been deposited in the
Cambridge Crystallographic Data Center as CCDC973587.
12. Preparation of enantiopure (À)-1 and (+)-1 was reported in detail by Einhorn
et al. See Ref. 6.
13. Typical procedure for kinetic resolution of alcohol (Table 1, Entry 3): To a mixture
of recemic-5 (15.3 mg, 0.093 mmol), (R,R)-1 (2.1 mg, 9.3 lmol, 10 mol %), and
K2CO3 (38.6 mg, 0.28 mmol, 3.0 equiv) in DCM (1.5 mL) was added PIFA
(31.8 mg, 0.074 mmol, 0.8 equiv) at 0 °C. The resulting mixture was stirred at
the same temperature for 6 h. The reaction was quenched with saturated aq.
Na2S2O3 and extracted with CHCl3. The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo to give
a residue. The yield of the
corresponding ketone was determined by 1H NMR integration with sorbic
acid (10.3 mg, 0.093 mmol) as an internal standard. The residue was purified
by prep. TLC (AcOEt/n–hexane = 1/5) to give recovered 5, whose ee and
absolute configuration were determined by HPLC analysis with
stationary phase (See Supplementary data).
a chiral
5. Hamada, S.; Furuta, T.; Wada, Y.; Kawabata, T. Angew. Chem., Int. Ed. 2013, 52,
8093–8097.