of benzoin. These are asymmetric aerobic oxidation catalyzed
by Co(II) or Cu(II) bearing BINAM type ligands (krel
)
Table 1. Effects of Substituents on the Asymmetric Aerobic
Oxidations of Racemic R-Phenyl-R-hydroxyl-ketones 5-10 and
R-Hydroxy-benzyl-ketones 11-13 Catalyzed by 2b
8-23) in the presence of TEMPO.7,8 Notably, the consis-
tency of the optical purity of the benzoins was hampered by
easy tautomerization and racemization, even under mild basic
conditions. Substrate classes possessing alkyl and heteroaryl
R-hydroxy-ketones with a diverse array of R-substituents
were also relatively unexplored.
As part of our ongoing programs of using chiral oxido-
vanadium(V) methoxide complexes in catalyzing asymmetric
oxidative couplings of 2-naphthols,9 site-selective DNA
photocleavage,10 asymmetric aerobic oxidation of R-hydroxy-
carboxylic acid and phosphonic acid derivatives,11 and
synergistic metal-specific ion transport,12 we sought to extend
their scope13 to the asymmetric oxidation of R-hydroxy-
ketones bearing alkyl, aryl, and heteroaryl groups, particularly
those bearing 2-pyrrolyl appendages. Herein we describe the
results of this highly enantioselective, kinetic resolution
process.
d
substrate
t (h)
conv (%)a
% eeb (yield,c %)
krel
Benzoin 5 was first used as a test asymmetric aerobic
oxidation substrate with oxidovanadium(V) methoxide 2b
derived from 3,5-dibromo-N-salicylidene-L-tert-butylglycine,
which was the best catalyst identified by us for the asym-
metric aerobic oxidation of R-hydroxy-phosphonates.11b The
extent of oxidation for benzoin reached 51% conversion after
8 h in toluene at ambient temperature, but the enantiomeric
purity of the recovered (R)-benzoin 5 was only 41% ee
(krel ) 3, Table 1).14 We then turned our attention to different
types of ketone. Replacing the phenyl group attached to the
ketone part of benzoin 5 by alkyl groups, as in substrates
6-9, led to significant increases in the enantiomeric excess
of the kinetic resolutions, presumably due to the enhanced
5
6
7
8
8
2.5
3
2.2
2
13
3.5
1.5
1
51
55
51
54
50
49
51
54
47
41 (47)
91 (40)
>99 (43)
85 (40)
92 (48)
40 (45)
90 (46)
83 (44)
84 (42)
3
21
>211
17
79
4
9
10
11
12
13
42
15e
98
a Determined by 1H NMR analysis of the reaction mixture. b Determined
by HPLC analysis on Chiralcel OD, OD-H, AD, or AD-H column. c Isolated,
d
purified material for the alcohol by column chromatography. krel ) ln[(1
- C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C ) conversion and ee )
enantiomeric excess. e The selectivity factor was 41 (98% ee) when the
reaction was performed at 15 °C after 3.5 h.
(7) (a) Alamsetti, S. K.; Mannam, S.; Mutupandi, P.; Sekar, G.
Chem.sEur. J. 2009, 15, 1086. (b) Alamsetti, S. K.; Muthupandi, P.; Sekar,
G. Chem.sEur. J. 2009, 15, 5424. (c) Muthupandi, P.; Alamsetti, S. K.;
ketone coordination strength of these substrates to the
catalyst. The order of selectivity factors followed the order
of sterics of G:15 7 (G ) CH2C6H5; krel > 211) > 9 (G )
CH(CH3)2; krel ) 79) > 6 (G ) CH2CH3; krel ) 21) and 8
(G ) CH2CH2C6H5; krel ) 17). In marked contrast, the
enantiomeric selectivity dropped to 40% ee (krel ) 4) in the
case of alkynyl ketone 10 (G ) Ct CC6H5) presumably due
to reduced steric encumbrance of the alkynyl unit.
Based on the excellent kinetic resolution of benzyl ketone
7, we screened through two more substrates derived from 7
that possessed para- substituents in the R-phenyl moiety (i.e.,
R ) 4-ClC6H4 and 4-MeC6H4). In these two cases, substrate
12 (krel ) 15) bearing an electron-donating, para-methyl
group was less enantioselective than substrate 11 (krel ) 42),
which bore an electron-withdrawing, para-chloro group,
despite the higher solubility of 12 in toluene. This electronic
effect is consistent with our previous findings.11 Nevertheless,
the selectivity factor in the case of 12 could be improved to
41 (98% ee) when the kinetic resolution was performed at
15 °C (reaction time 3.5 h). Furthermore, the most difficult
substrate, 13, which bears the least sterically demanding
R-methyl group, also proceeded smoothly in 1 h with
excellent enantiocontrol (krel ) 98) under the same reaction
Sekar, G. Chem. Commun. 2009, 3288
.
(8) For a review and representative works on metal complex-catalyzed
aerobic oxidation of alcohols, see: (a) Schultz, M. J.; Sigman, M. S.
Tetrahedron 2006, 62, 8227. (b) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.;
Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008,
130, 13745, and references therein. (c) Sun, W.; Wang, H.; Xia, C.; Li, J.;
Zhao, P. Angew. Chem., Int. Ed. 2003, 42, 1042
.
(9) (a) Hon, S.-W.; Li, C.-H.; Kuo, J.-H.; Barhate, N. B.; Liu, Y.-H.;
Wang, Y.; Chen, C.-T. Org. Lett. 2001, 3, 869. (b) Barhate, N. B.; Chen,
C.-T. Org. Lett. 2002, 4, 2529.
(10) Chen, C.-T.; Lin, J.-S.; Kuo, J.-H.; Weng, S.-S.; Cuo, T.-S.; Lin,
Y.-W.; Cheng, C.-C.; Huang, Y.-C.; Yu, J.-K.; Chou, P.-T. Org. Lett. 2004,
6, 4471.
(11) (a) 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. (b) Pawar, V. D.;
Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006,
128, 6308. (c) Chen, C.-T.; Bettigeri, S.; Weng, S.-S.; Pawar, V. D.; Lin,
Y.-H.; Liu, C.-Y.; Lee, W.-Z. J. Org. Chem. 2007, 72, 8175.
(12) Chen, C.-T.; Lin, Y.-H.; Kuo, T.-S. J. Am. Chem. Soc. 2008, 130,
12842.
(13) (a) Bolm, C. Coord. Chem. ReV. 2003, 237, 245. (b) Hirao, T. Pure
Appl. Chem. 2005, 77, 1539. (c) Takizawa, S.; Katayama, T.; Sasai, H.
Chem. Commun. 2008, 4113.
(14) The absolute stereochemistry for the resolved alcohols 5 and 6 were
found to be (R) by comparing their signs of optical rotations with those
from the literature: (a) Roger, R. HelV. Chim. Acta 1929, 12, 1060. (b)
¨
Demir, A. S.; S¸es¸enoglu, O.; Eren, E.; Hosrik, B.; Pohl, M.; Janzen, E.;
Kolter, D.; Feldmann, R.; Du¨nkelmann, P.; Mu¨ller, M. AdV. Synth. Catal
2002, 344, 96. (c) The absolute configuration for 20 was identified as (R)
by converting the naturally occurring (-)-(S)-mandelic acid to (S)-20 and
comparing their signs of optical rotations. The absolute configurations for
the other resolved alcohols 21-30 were assigned as (R) as analogy. (d)
See Supporting Information for details.
(15) G stands for the substituent attached directly to the ketone moiety.
Org. Lett., Vol. 13, No. 1, 2011
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