Highly enantioselective organocatalytic oxidative kinetic resolution of secondary alcohols using chirally Modified AZADOs

Article abstract of DOI:10.1021/ol900441f

A highly enantioselective organocatalytic oxidative kinetic resolution (OKR) of racemic secondary alcohols has been accomplished using asymmetric organocatalysis. A panel of chirally modified 2-azaadamantane N-oxyls (AZADOs) exhibit superior catalytic act

Full text of DOI:10.1021/ol900441f

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1829-1831
Highly Enantioselective Organocatalytic
Oxidative Kinetic Resolution of
Secondary Alcohols Using Chirally
Modified AZADOs
Masaki Tomizawa, Masatoshi Shibuya, and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received March 4, 2009
ABSTRACT
A highly enantioselective organocatalytic oxidative kinetic resolution (OKR) of racemic secondary alcohols has been accomplished using
asymmetric organocatalysis. A panel of chirally modified 2-azaadamantane N-oxyls (AZADOs) exhibit superior catalytic activity and high
enantioselectivity, allowing us to obtain optically active secondary alcohols with a krel value up to 82.2.
Enantioselective oxidation of racemic secondary alcohols offers
chemists an attractive strategy for delivering optically active
alcohols, which should play indispensable roles in the synthesis
of various biologically active compounds.1 In recent years, remark-
able progress has been made, especially in transition-metal-
catalyzed oxidation systems in the presence of asymmetric ligands.2
Meanwhile, the development of non-transition-metal-catalyzed
systems has attracted attention as a significant challenge because
of their environmentally benign and user-friendly characteristics.
Although many endeavors employing asymmetric organocatalysts,
especially based on the chirally modified nitroxyl radicals,3 have
been carried out, the design of catalysts capable of applying a wide
range of substrates with satisfactory selectivity has remained
elusive. Our own interest in this field stems from our development
of the azaadamantane-type of organocatalysts, AZADO and 1-Me-
AZADO, which served as powerful oxidation catalysts for a wide
range of secondary alcohols.4 In this paper, we disclose the highly
enantioselective organocatalytic oxidative kinetic resolution (OKR)
of secondary alcohols using chirally modified AZADOs. The
method reported here demonstrates the successful example of an
(1) For reviews on the preparation of optically active alcohols, see: (a)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons:
New York, 1994. (b) Kagan, H. B.; Flaud, J. C. Kinetic Resolution. Top.
Stereochem. 1988, 18, 249–330. (c) Vedejs, E.; Jure, M. Angew. Chem.,
Int. Ed. 2005, 44, 3974–4001.
(2) For selective examples of transition-metal-catalyzed OKR, see: (a)
Hashiguchi, S.; Fujii, A.; Haak, K.-J.; Matsumoto, K.; Ikariya, T.; Noyori,
R. Angew. Chem., Int. Ed. 1997, 44, 288–289. (b) Masutani, K.; Uchida,
T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000, 41, 5119–5123. (c) Jensen,
D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475–
7476. (d) Ferrcira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–
7726. (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) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem., Int. Ed.
2008, 47, 2447–2449, and references therein.
(3) For selective examples of chiral nitroxyl-radical-catalyzed OKR, see:
(a) Ma, Z.; Huang, Q.; Bobbitt, J. M. J. Org. Chem. 1993, 58, 4837–4843.
(b) Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org. Chem. 1996,
61, 1194–1195. (c) Kashiwagi, Y.; Kurashima, F.; Chiba, S.; Anzai, J.;
Osa, T.; Bobbitt, J. M. Chem. Commun. 2003, 114–115. (d) Rychnovsky,
S.; Leu, W.-H.; Farmer, P.; Lin, R. Tetrahedron: Asymmetry 2005, 16, 3584–
3598. (e) Shiigi, H.; Mori, H.; Tanaka, T.; Demizu, Y.; Onomura, O.
Tetrahedron Lett. 2008, 49, 5247–5249.
(4) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, I. J. Am. Chem.
Soc. 2006, 128, 8412–8413.
10.1021/ol900441f CCC: $40.75
Published on Web 03/26/2009
2009 American Chemical Society

organocatalysts with a high level of enantioselectivity comparable
to that of transition-metal-mediated systems, enabling the highly
enantioselective OKR of a wide range of racemic secondary
alcohols even under mild chemical conditions.5
Figure 2. Panel of chiral AZADOs.
Table 1).10 An initial attempt carried out using catalyst 1, which
has no substituent group, with TCCA11 under -40 °C in CH2Cl2
Table 1. OKR of (()-8 Using a Panel of Chiral AZADOs
The designed motif, namely, 4-aryl-1-alkyl-AZADO, relies
on the generally accepted mechanism of TEMPO-catalyzed
alcohol oxidation proposed by Semmelhack6a and Bobbitt,6c
in which the key feature of the concept consists of the following
two steps: (1) addition of the substrate to the oxoammonium
species and (2) H-abstraction via a Cope-like planar five-
membered cyclic transition state. Thus, we expected that in the
first stage the cation-π interaction between N+dO and the aryl
group effectively shielded one side of the oxoammonium moiety
to exhibit face selectivity,7,8 and the alkyl group flanking the
nearby catalytic center played an important role in the dis-
crimination of racemic alcohols during the course of the
oxidation (Figure 1).
entry catalyst t [h] convn [%]a ee [%]b config (alcohol)b krel
1
2
3
4
5
6
7
1
2
3
4
5
6
7
3
3
52
55
52
38
50
29
55
8
96
S
S
S
S
R
R
S
1.2
32.0
82.2
7.8
11.7
4.5
32.8
3
98
3
41
24
24
3
-70
-23
98
a Conversion was estimated from isolated yields of alcohols. b Determined
by chiral HPLC analysis.
resulted in rapid oxidation with no selectivity (entry 1, kR/kS12
) 1.2). On the other hand, for catalyst 2 with a methyl group,
good selectivity was observed under the same reaction condi-
tions (entry 2), and with the more sterically effective n-Bu type
of catalyst 3 the oxidation proceeded in 52% conversion with
excellent selectivity (entry 3, kR/kS ) 82.2). Additionally, the
configuration of recovered alcohols depended on the position
of the alkyl substituent group (entries 5 and 6), suggesting that
the R-substituent group of chiral AZADO is essential for the
(7) For examples of cation-π interaction, see: (a) Kawabata, T; Nagato,
M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169–3170. (b) Li,
X.; Liu, P.; Houk, K. N.; Birman, V. B. J. Am. Chem. Soc. 2008, 130,
13836–13837. (c) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303–
1324.
(8) An interesting paper, in which the effects on the π-facial diastereo-
selectivity of the substituent in the 4-position of adamantin-2-one were
investigated, has been reported; see:(a) Barboni, L.; Filippi, A.; Fraschetti,
C.; Giuli, S.; Marcolini, M.; Marcantoni, E. Tetrahedron Lett. 2008, 49,
6065–6067.
Figure 1. Working hypothesis of OKR catalyzed by chiral AZADO.
(9) In preliminary experiments, chiral AZADO and chiral AZADOH
(its corresponding hydroxylamine), which is a synthetic precursor of chiral
AZADO, afforded similar kR/kS values for OKR. In view of its availability,
we chose the chiral AZADOH catalyst for further study.
(10) See Supporting Information for details of the preparation of the
catalysts and screening for reaction conditions in OKR.
To assess our hypothesis, we synthesized a panel of chiral
AZADOs and their corresponding hydroxylamine catalysts (see
Supporting Information)9 and evaluated their selectivity in OKR
using trans-2-phenyl-cyclohexanol 8 as a substrate (Figure 2,
(11) (a) Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3,
3041–3044. (b) Luca, L. D.; Giacomelli, G.; Masala, S.; Porcheddu, A. J.
Org. Chem. 2003, 68, 4999–5001.
(12) For details of kR/kS values, see: (a) Kagan, H. B.; Flaud, J. C. In
Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York,
1988; Vol. 18, pp 249-330. (b) Vedejs, E.; Jure, M. Angew. Chem., Int.
Ed. 2005, 44, 3974–4001.
(5) Osa and Bobbitt reported a highly enantioselective OKR using a
chiral TEMPO (1-azaspiro[5.5]undecane N-oxyl radical) modified electrode
system; however, the chiral TEMPO itself is not applicable to simple
chemical conditions.3c,e
(6) (a) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. S. Tetrahedron
Lett. 1986, 27, 1119–1122. (b) de Nooy, A. E. J.; Basemer, A. C.; van
Bekkum, H. Synthesis 1996, 1153–1174. (c) Bobbitt, J. M.; Wiberg, K. B.
J. Org. Chem. 2007, 72, 4504–4509, and references therein.
(13) The sterically congested i-Pr group of the catalyst decreased catalytic
activity and enantioselectivity. We consider that flexibility of the substituent
group as normal butyl group is essential for the generation of broad
asymmetric reaction space. This assumption was supported by the fact that
catalyst 2 with a Me group gave low selectivity with other secondary
alcohols (see Supporting Information).
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Org. Lett., Vol. 11, No. 8, 2009

enantiodiscrimination of the substrates.13 These results strongly
support the validity of our working hypothesis and provide
useful experimental insight into the proposed mechanism of
nitroxyl radical mediated alcohol oxidation.6
ketone via enol formation, thus allowing easy access to
enantiomerically enriched carbonyl compounds (Scheme 1).
Scheme 1
.
Preparation of Enantiomerically Enriched
Having developed the optimal catalyst, we investigated the
substrate scope of the oxidative kinetic resolution. As described
in Table 2, 3/TCCA systems attained good to excellent levels
(2S)-Ketone 9
Table 2. Scope of Substrates Employing the 3/TCCA System
Unfortunately, a seven-membered ring substrate could not be
resolved efficiently (entry 6). The resolution can also be ac-
complished with 2-alkyl- or 2-alkoxyl-substituted cyclohexanols
in moderate to good selectivity (entries 7-9). On the other hand,
the resolution of acyclic substrates resulted in low selectivity,
although a substrate having a sterically congested adamantyl group
affords a good result (entries 10 and 11), indicating importance of
the steric interaction for enantioselectivity.15
In conclusion, we have disclosed the efficient kinetic resolu-
tion of racemic secondary alcohols catalyzed by chiral AZADOs
and their corresponding hydroxylamine catalyst. Our catalytic
system recorded the highest krel value comparable to that of
the transition-metal-mediated process when R-substituted cy-
clopentanol and cyclohexanols were employed as the substrates.
Even though limited substrates could be applicable to our system
to date, this research provided useful insights for development
of more efficient catalytic systems applicable to a wider range
of substrates. Further studies are in progress to expand the
scope of chirally modified AZADOs on the oxidative desym-
metrization of meso-diols.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (B) (No. 17390002) from
the Japan Society for the Promotion of Science, Grant-in Aid
for the Research Fellowship for Young Scientists (M.T.), Grant-
in-Aid for Young Scientists (B) (No. 19790005), and Grant-
in-Aid for the Grobal COE Program for “International Center
of Research & Education for Molecular Complex Chemistry”
from Ministry of Education, Culture, Sports, Science, and
Technology, Japan and a research grant from Uehara Memorial
Fundation for the Promotion of Life Science. We thank Dr.
Chizuko Kabuto (Tohoku University) for her helpful discussion.
a Conversion was estimated from isolated yields of alcohols. b Determined
by chiral HPLC analysis. c For etermination of the absolute configurations,
see Supporting Information. d 3 (3 mol %), PhI(OAc)2 (0.7 equiv), CH2Cl2,
-5 °C.
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900441F
(14) Optically active 2-substituted cyclohexanols and cyclohexane diol
derivatives are reliable tools as chiral reagents, especially as auxiliaries,
for asymmetric synthesis; see: (a) Whitesell, J. K. Chem. ReV. 1992, 92,
953–964. (b) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656–
4661. (c) Sakai, K.; Suemune, H. Tetrahedron: Asymmetry 1993, 4, 2109–
2118. (d) Laumen, K.; Breitgoff, D.; Seemayer, R.; Schneider, M. P.
J. Chem. Soc., Chem. Commun. 1989, 148–150. (e) Tanyeli, C.; Turkut,
E.; Akhmedov, I. M. Tetrahedron: Asymmetry 2004, 15, 1729–1733.
(15) The resolution of less hindered secondary alcohols such as 1-phenyl-
ethanol or indanol proceeds with low selectivity (krel < 4) and with rapid
oxidation rate, indicating that substituent size at C-1 of chiral AZADO plays
essential roles for the efficient resolution.
of asymmetric induction with several nonactivated classes of
alcohols. Cyclopentanol and cyclohexanol having an aryl
substituent group serve especially well as substrates14 for
resolution, with selectivity factors as high as 82.2 (entries 1-5).
Note that the OKR of 8 using 3 with 0.133 equiv of TCCA
(0.4 equiv as Cl+) afforded (2S)-ketone 9 in 40% yield and
with excellent enantiopurity (97% ee), indicating that the
3/TCCA system is mild enough to prevent an epimerization of
Org. Lett., Vol. 11, No. 8, 2009
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