Asymmetrie aerobic oxidation of α-hydroxy acid derivatives by C 4-symmetric, vanadate-centered, tetrakisvanadyl(V) clusters derived from N-salicylidene-α-aminocarboxylates

Article abstract of DOI:10.1021/jo070575f

(Chemical Equation Presented) A series of chiral vanadyl(V) methoxides bearing 3-t-butyl-5-substituted N-salicylene-L-valinate and L-t-leucinate as chiral auxiliaries has been prepared. In all cases except the 3,5-di-t-butyl analogue, they exist as monomers both in solution and in the single crystal state. In the case of the 3,5-di-t-butyl analogue, the architectural nature of the vanadyl(V) complex highly depends on the base used during the complex formation event. A pentanuclear C₄-symmetric complex was formed when potassium salts were employed instead of the corresponding sodium salts. A central vanadate(V) unit serves to grip four identical chiral monomelic vanadyl(V) units together, by which a potassium ion sits on top of the four flanking units through carbonyl coordinations and serves to hold the whole cluster by cooperation with the central vanadate(V) unit. In comparison with the corresponding monomelic vanadyl(V) methoxide complex, the cluster complex was utilized to facilitate the asymmetric aerobic oxidations of various racemic α-hydroxyesters, -amides, and -thioesters with excellent selectivity factors (k_rel 40 to >500).

Full text of DOI:10.1021/jo070575f

Asymmetric Aerobic Oxidation of r-Hydroxy Acid Derivatives by
C4-Symmetric, Vanadate-Centered, Tetrakisvanadyl(V) Clusters
Derived from N-Salicylidene-r-aminocarboxylates
Chien-Tien Chen,* Sampada Bettigeri, Shiue-Shien Weng, Vijay D. Pawar, Ya-Hui Lin,
Cheng-Yuan Liu, and Way-Zen Lee*
Department of Chemistry, National Taiwan Normal UniVersity, Taipei, Taiwan,
#88, Section 4, Ding-jou Road, Taipei, Taiwan 11650
chefV043@ntnu.edu.tw; wzlee@ntnu.edu.tw
ReceiVed April 2, 2007
A series of chiral vanadyl(V) methoxides bearing 3-t-butyl-5-substituted N-salicylene-L-valinate and L-t-
leucinate as chiral auxiliaries has been prepared. In all cases except the 3,5-di-t-butyl analogue, they
exist as monomers both in solution and in the single crystal state. In the case of the 3,5-di-t-butyl analogue,
the architectural nature of the vanadyl(V) complex highly depends on the base used during the complex
formation event. A pentanuclear C4-symmetric complex was formed when potassium salts were employed
instead of the corresponding sodium salts. A central vanadate(V) unit serves to grip four identical chiral
monomeric vanadyl(V) units together, by which a potassium ion sits on top of the four flanking units
through carbonyl coordinations and serves to hold the whole cluster by cooperation with the central
vanadate(V) unit. In comparison with the corresponding monomeric vanadyl(V) methoxide complex, the
cluster complex was utilized to facilitate the asymmetric aerobic oxidations of various racemic
R-hydroxyesters, -amides, and -thioesters with excellent selectivity factors (krel 40 to >500).
Introduction
prosthetic groups have been utilized as receptors for chiral
molecular recognition. In marked contrast, C4-symmetric ligands
are relatively unexplored except in the synthetic study of calix-
[4]arenes.4 To date, artificial C4-symmetric oligonuclear orga-
nometallic assemblies that exhibit specific molecular recognition,
biological functions, or asymmetric catalysis have not been
reported.5 As part of our ongoing programs by using vanadyl
and oxometallic species in catalyzing C-C and C-X bond
It is well-documented that vanadyl(V) complexes normally
exist as monomers, µ-oxo-bridged dimers, and tetramers in the
solid state.1 Dependent on solvent polarity, these species may
become monomers and dimers in solution. On the other hand,
to fulfill penta- or hexavalency requirements, the corresponding
vanadyl(IV) complexes may adopt monomeric, dimeric, and
even polymeric frameworks.2 Chiral organometallic complexes
possessing unique C2- and C3-symmetry have been extensively
examined for asymmetric catalysis and molecular recognition.3
In most cases, C2- and C3-symmetric ligands were employed
to capture metal ion centers. Furthermore, several C3-symmetric
(2) (a) Schmidt, H.; Bashirpoor, M.; Rheder, D. J. Chem. Soc., Dalton
Trans. 1996, 3865. (b) Zamian, J. R.; Dockal, E. R.; Castellano, G.; Oliva,
G. Polyhedron 1995, 14, 2411.
(3) (a) You, J.-S.; Yu, X.-Q.; Zhang, G.-L.; Xing, Q.-X.; Lan, J.-B.; Xie,
R.-G. Chem. Commun. 2001, 1816. (b) Kim, J.; Kim, S.-G.; Seong, H. R.;
Ahn, K. H. J. Org. Chem. 2005, 70, 722. (c) Fang, T.; Du, D.-M.; Lu,
S.-F.; Xu, J. Org. Lett. 2005, 7, 2081. (d) Moberg, C. Angew. Chem., Int.
Ed. 1998, 37, 248. (e) McMenimen, K. A.; Hamiltin, D. G. J. Am. Chem.
Soc. 2001, 123, 6453.
* Corresponding authors. Tel.: +886 2-29309095; fax: +886 2-29324249.
(1) (a) Bonadies, J. A.; Butler, W. M.; Pecoraro, V.; Carrano, C. J. Inorg.
Chem. 1987, 26, 1218. (b) Nakajima, K.; Kojima, M.; Toriumi, K.; Saito,
K.; Fujita, J. Bull. Chem. Soc. Jpn. 1989, 62, 760.
10.1021/jo070575f CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/04/2007
J. Org. Chem. 2007, 72, 8175-8185
8175

Chen et al.
formation,6 asymmetric aerobic oxidative dehydrogenation7 and
coupling,8 and photoinitiated DNA cleavage,9 we recently
discovered that a given vanadyl(V) alkoxide complex may self-
assemble into a C4-symmetric pentanuclear cluster under a
special type of N-salicylidene-t-leucinate template and well-
defined complex formation conditions.10 More importantly, the
resultant cluster displays an unprecedented, highly enantiose-
lective asymmetric aerobic oxidation behavior toward a wide
variety of R-hydroxy esters, amides, and thioesters.11 We report
herein our complete results of this finding.
Results and Discussion
Catalyst Preparation. A series of 3-t-butyl-5-substituted
N-salicylidene vanadyl(IV) complexes bearing L-t-leucine or
L-valine can be readily prepared by treatment of in situ generated
N-salicylidene-L-t-leucinate or -L-valinate with NaOAc (2 equiv)
followed by vanadyl(IV) sulfate (1 equiv) in warmed, oxygen-
free MeOH. The respective vanadyl(IV) complexes were
collected from the precipitates by filtration (Figure 1).
Catalyst Crystallographic Analysis. After having been
recrystallized from oxygen-saturated methanol, all the vanadyl-
(IV) centers in the complexes were oxidized to individual
vanadyl(V) methoxides 1-4 (or 1′-4′) bearing a neutral
methanol ligand. The resulting vanadyl(V) complexes as
represented by 1′ and 4′ exhibit a slightly distorted octahedral
geometry (Figure 2). The vanadyl(V) center is configurationally
FIGURE 1. Preparation conditions for complexes 1-4 and 1′-4′.
uniform and is positioned cis to the pendant, pseudo-axial
i-propyl group in the chiral tridentate N-salicylidene-L-valinate
template. The covalently bound methoxide unit is located trans
to the Schiff base imine nitrogen. Coordinated neutral MeOH
is placed trans to the vanadyl oxygen (i.e., VdO).
Cluster Catalyst Structure. In marked contrast, the complex
generated from the corresponding 3,5-di-t-butyl analogue 4 by
using KOH or KOt-Bu as a base led to an unprecedented C4-
symmetric cluster 5. The pentanuclear cluster 5 shows several
unique structural features (see Figure 3 and Table 1). There
exists a C4-symmetric negatively charged vanadate center that
holds four chiral L-t-leucine-based 3,5-di-t-butyl N-salicylidene
vanadyl(V) alkoxides. Four V-O fragments (average length:
1.876 Å, see Table 1) of the central vanadate serve as alkoxides
for covalent attachment to the four peripheral chiral vanadyl-
(V) units and are positioned trans to the respective Schiff base
nitrogens. On the other hand, the lone pair electrons on the four
respective alkoxide oxygens serve to coordinate anti to the next
VdO unit in a counter-clockwise fashion as viewed from the
potassium ion. The average distance for coordination to the
adjacent VdO (i.e., O f V) is 2.454 Å, which is significantly
longer (by ca. 0.10-0.11 Å) than distances in monomers 1′ and
4′ (O f V: 2.342 and 2.351 Å), allowing for better accom-
modation of the central vanadate unit. Notably, the central Vd
O unit (1.547 Å) is pointed away from all four carboxyl units
in the four chiral vanadyl(V) templates (Figure 3a,c).
(4) (a) Andreetti, G. D.; Bohmer, V.; Jordon, J. G.; Tabatabai, M.;
Ugozzoli, F.; Vogt, W.; Wolff, A. J. Org. Chem. 1993, 58, 4023. (b) Pickard,
S. T.; Pirkel, W. H.; Tabatabai, M.; Vogt, W.; Bohmer, V. Chirality 1993,
5, 310. (c) Huan, G.; Jacobson, A. J.; Day, V. W. Angew. Chem., Int. Ed.
Engl. 1991, 30, 422.
(5) (a) For a biological system exhibiting C4-symmetry, see: Orlova, E.
V.; Rahman, M. A.; Gowen, B.; Volynski, K. E.; Ashton, A. C.; Manser,
C.; van Heel, M.; Ushkaryov, Y. A. Nat. Struct. Biol. 2000, 7, 48. (b)
Kaucher, M. S.; Harrell, W. A.; Davis, J. T., Jr. J. Am. Chem. Soc. 2006,
128, 38. (c) Lee, J. Y.; Okumus, B.; Kim, D. S.; Ha, T. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 18938. (d) Collins, R. F.; Frye, S. A.; Kitmitto, A.;
Ford, R. C.; Tonjum, T.; Derrick, J. P. J. Biol. Chem. 2004, 279, 39750.
(6) (a) Weng, S.-S.; Lin, Y.-D.; Chen, C.-T. Org. Lett. 2006, 8, 5633.
(b) Chen, C.-T.; Weng, S.-S.; Kao, J.-Q.; Lin, C.-C.; Jan, M.-D. Org. Lett.
2005, 7, 3343. (c) Chen, C.-T.; Kuo, J.-H.; Ku, C.-H.; Weng, S.-S.; Liu,
C.-Y. J. Org. Chem. 2005, 70, 1328. (d) Chen, C.-T.; Munot, Y. S. J. Org.
Chem. 2005, 70, 8625. (e) Chen, C.-T.; Kuo, J.-H.; Pawar, V. D.; Munot,
Y. S.; Weng, S.-S.; Ku, C.-H.; Liu, C.-Y. J. Org. Chem. 2005, 70, 1188.
(f) See also: Chen, C.-T.; Pawar, V. D.; Munot, Y. S.; Chen, C.-C.; Hsu,
C.-J. Chem. Commun. 2005, 2483.
(7) (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.; Weng,
S.-S.; Bettigeri, S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128,
6308. (c) For a review on metal complex-catalyzed aerobic oxidation, see:
Schultz, M. J.; Sigman, M. S. Tetrahedron 2006, 62, 8227.
(8) (a) Barhate, N. B.; Chen, C.-T. Org. Lett. 2002, 4, 2529. (b) 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. (c) Chen, C.-T.; Kuo, J.-H.; Li, C.-H.; Barhate,
N. B.; Hon, S.-W.; Li, T.-W.; Chao, S.-D.; Liu, C.-C.; Li, Y.-C.; Chang,
I.-H.; Lin, J.-S.; Lin, C.-J.; Chou, Y.-C. Org. Lett. 2001, 3, 3729. (d) For
reviews on olefin and sulfide oxidations mediated by chiral vanadyl
complexes, see: Bolm, C. Coord. Chem. ReV. 2003, 237, 245. (e)
Ligtenbarg, A. G. J.; Hage, R.; Feringa, B. L. Coord. Chem. ReV. 2003,
237, 89.
Intriguingly, the negative charge in the central C4-symmetric
vanadate is balanced by the potassium ion that is situated right
on top of the vanadate center and cooperated with the vanadate
center to stabilize the whole C4-symmetric structure. Moreover,
the potassium ion is sandwiched between the four top water
molecules (H2O f K: 2.76 Å) and the four bottom carbonyl
units (CdO f K av length: 2.40 Å) in the chiral vanadyl(V)
templates in a fashion similar to a 1:2 complex from K+ and
two 12-crown-4 units.12 The C4-symmetry of the pentanuclear
cluster 5 can be visualized by the relative orientation of the
four axially disposed t-butyl groups in the chiral appendages
and the eight C3 and C5 t-butyl groups in the salicylidene
templates (Figure 3b,c). Surprisingly, only the monomeric
vanadyl(V) complex 4 can be utilized for the assembly of the
pentanuclear cluster 5. Other monomeric complexes including
(9) 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.
(10) For a recent example of using a chiral Zr-BINOL cluster (i.e., Zr4-
(m-BINOLate)6(m3-OH)4) in an asymmetric Mannich reaction, see: Saru-
hashi, K.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 11232.
(11) (a) For preliminary studies on the asymmetric aerobic oxidations
of R-hydroxyphosphonates, R -hydroxyesters, and amides by using chiral,
monomeric vanadyl(V) complexes, see ref 7. For a recent asymmetric
aerobic oxidation of R-hydroxyesters, see: (b) Radosevich, A. T.; Musich,
C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 1090.
(12) Dietrich, B.; Viout, P.; Lehn, J.-M., Eds. Macrocyclic Chemistry:
Aspects of Organic and Inorganic Supramolecular Chemistry; Wiley-
VCH: Weinheim, Germany, 1993.
8176 J. Org. Chem., Vol. 72, No. 22, 2007

Asymmetric Aerobic Oxidation of R-Hydroxy Acid DeriVatiVes
FIGURE 2. Chem-3-D presentation for X-ray crystal structures of 1′ and 4′.
FIGURE 3. Diamond and ChemDraw presentations for X-ray crystal structure of the C4-symmetric pentanuclear cluster 5 (hydrogens omitted for
clarity): (a) side view, (b) top view, and (c) bottom view.
4′ do not exert any aggregation effects even when potassium
salts were employed during complex formation. More impor-
tantly, the cluster behavior of 5 remains intact in organic solvents
as evidenced by its 51V NMR spectrum in CDCl3, which shows
two peaks at -536.1 and -609.6 ppm in a 1:4 ratio, respec-
tively, for the central vanadate and the four flanking chiral
vanadyl complexes. Therefore, the vanadyl cluster 5 can be
visualized as a tetravalent receptor or template for the encap-
sulation of potassium vanadate. Furthermore, the central potas-
sium vanadate can be visualized as an unprecedented C4-
symmetric vanadate base.
Comparison of Monomer and Cluster Catalysts in Aerobic
Oxidation Reactivity and Selectivity. Both monomers 1-4
(or 1′-4′) and cluster 5 are readily soluble in toluene and can
J. Org. Chem, Vol. 72, No. 22, 2007 8177

Chen et al.
TABLE 1. Selected Bond Lengths (Å) for Monomers 1′ and 4′ and
TABLE 3. Effects of r-Aryl Groups on Asymmetric Aerobic
Cluster 5
Oxidations of Racemic N-Benzyl-mandelamide 9-15 by Cluster
Catalyst 5
VdO
V-Oa
O f Vb
N f V
CdO f K
V/1
V/4
1.600
1.589
1.547
1.579
1.551
1.581
1.586
1.574
1.778
1.770
1.876d
1.792
1.788
1.772
1.800
1.788
2.342
2.351
2.098
2.101
V(1)c/5
V(2)/5
V(3)/5
V(4)/5
V(5)/5
Σ(V(2 f 5))/4e
2.421
2.456
2.432
2.507
2.454
2.100
2.086
2.083
2.097
2.092
2.374
2.423
2.393
2.410
2.400
time conversion
(h)
% eeb
d
entry
G
(%)a
(yieldc %)
krel
1
2
3
4
5
6
7
C6H5 (7)
23
16
62
81
18
122
4
50
48
48
52
50
54
51
99 (47)
92 (47)
87 (46)
96 (44)
92 (47)
99 (45)
99 (46)
>500
40
a V-O represents the bond trans to the N f V bond. b O f V represents
the bond trans to the VdO unit. c Central vanadate. d Data represent the av
value of all four V-O bonds in the central vanadate. e Av value of all four
identical peripheral vanadyl complexes.
4-CF3C6H4 (9)
4-C1C66H4(10)
2-CH3C6H4 (11)
2-C1C6H4 (12)
1-Np (13)
57
65
79
61
TABLE 2. Effects of Catalysts on Asymmetric Aerobic Oxidation
of Racemic X-Benzyl Mandelate, Mandelamide, and Thiomandelate
6-8
211
8
trans-PhCH )CH(15)
76
50
99 (46)
>500
a Determined by 1H NMR analysis of the reaction mixture. b Determined
by HPLC analysis on a Chiralpak AD-H or AS column. c Isolated, purified
d
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.
with monomer 4, cluster 5 shows essentially similar or better
reactivity and selectivity profiles toward the oxidations of 6-8.
In general, N-benzyl-mandelamide 7 (entries 9-16 in Table 2)
is the most enantioselective substrate for a given catalyst
followed by O-benzyl mandelate 6 (entries 1-8 in Table 2).
On the other hand, S-benzyl thiomandelate 8 (entries 17 and
18 in Table 2) is the least enantioselective.
substrate
(catalyst)
% eeb
d
entry
time (h)
% conversiona
(yieldc %)
krel
76
55
76
167
32
458
63
194
458
458
458
44
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
6 (1)
6 (1′)
6 (2)
6 (3)
6 (3′)
6 (4)
6 (4′)
6 (5e)
7 (1)
7 (1′)
7 (2)
7 (3)
7 (3′)
7 (4)
14.5
20
124
14.5
9
19
19
19
20
20
60
13
11
25
20
23
7
52
53
52
50.5
47.5
50
50.5
50
50
50
50
52
52
50
51
50
97 (46)
97 (42)
97 (45)
97 (50)
78 (48)
98 (46)
92 (46)
96 (46)
98 (48)
98 (48)
98 (50)
93 (43)
80 (43)
99 (47)
98 (43)
99 (47)
78 (47)
95 (46)
Notably, complex 5 can be generated in situ by direct addition
of potassium metavanadate (KVO3, 1.25 equiv) to the freshly
made N-salicylidene-L-t-lencine in oxygen-saturated MeOH. The
resulting complex 5 can be isolated as a dark brown solid after
concentration of the methanol solution to half of its original
volume. ESI-MS analysis of the solid shows only the signal
arising from the pentanuclear complex 5.10 It was also found
that the resulting cluster can be used directly for asymmetric
aerobic oxidation chemistry with intact selectivity profiles.
Cluster Catalyst 5 in Asymmetric Aerobic Oxidation of
R-Hydroxyamides. To probe the substrate scope, we have
selected six different N-benzyl-R-aryl-R-hydroxyacetamides for
further catalytic studies in the presence of 5 (1.25 mol %) (Table
3). Substrates bearing R-phenyl (i.e., 7 in entry 1 in Table 3)
and R-2-thiophenyl (i.e., 14 in entry 7 in Table 3) are the most
selective followed by those bearing the R-2-substituted phenyl
(i.e., 11-13 in entries 4-6 in Table 3) groups. On the other
hand, substrates bearing R-4-substituted phenyl groups are the
least enantioselective (krel 40-57 in entries 2 and 3 in Table
3). As represented in 15 (entry 8 in Table 3), substrates bearing
R-alkenyl groups are also ideal cases for the new asymmetric
aerobic oxidation protocol.
Cluster Catalyst 5 in Asymmetric Aerobic Oxidation of
R-Hydroxythioesters. Since there have not been any studies
on the asymmetric aerobic oxidations of R-hydroxythioesters,
we sought to extend the applications of catalyst 4 and cluster 5
toward resolving this substrate class. As illustrated in entry 17
of Table 2, S-benzyl-thiomandelate 8d is the least-selective
substrate for monomer catalyst 4. By a systematic survey of
five different S-appendages with thiomandelates (G ) Ph) for
their asymmetric aerobic oxidation profiles, we found that
S-ethyl-, isopropyl-, and t-butyl thiomandelates 8a-c are the
most selective substrates by using monomer 4 as the catalyst
16
>500
153
>500
16
7 (4′)
7 (5e)
8d (4)
8d (5e)
51
51
5
82
a Determined by 1H NMR analysis of the reaction mixture. b Determined
by HPLC analysis on a Chiralpak AD-H or AS column. c Isolated, purified
d
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 1.25 mol % catalyst was used.
catalyze the asymmetric aerobic oxidation of X-benzyl man-
delate, mandelamide, and thiomandelate 6-8. In general, the
vanadyl(V) complexes 1′-4′ derived from L-valine are less
enantioselective than those from the corresponding L-t-leucine
(Table 2). The vanadyl(V) complex 3 bearing an electron-
withdrawing nitro group at the C5 position is the most reactive
catalyst. The aerobic oxidations of 6 and 7 catalyzed by 3 can
be completed in 13-14.5 h at about 50% conversion (entries 4
and 12 in Table 2). In marked contrast, the corresponding C5-
methoxy (an electron-donating group) analogue 2 is the least
reactive, which effects 50% conversion of 6 and 7 in 60-124
h (entries 3 and 11 in Table 2). The reactivity profiles (14.5-
25 h) for the vanadyl(V) complexes bearing C5-H (i.e., 1) or
C5-t-butyl groups (i.e., 4 and 5) lie in between those of 2 and
3. Among all the catalysts examined, both 4 and 5 led to the
best selectivity factors in the kinetic resolution process (krel 194
to >500; entries 6, 8, 14, 16, and 18 in Table 2). In comparison
8178 J. Org. Chem., Vol. 72, No. 22, 2007

Asymmetric Aerobic Oxidation of R-Hydroxy Acid DeriVatiVes
TABLE 4. Effects of S-Pendent Groups on Asymmetric Aerobic
Oxidations of Racemic Thiomandelates by Catalyst 4
TABLE 5. Effects of r-Substituents on Asymmetric Aerobic
Oxidations of Racemic S-t-Butyl r-Hydroxythioesters 16-24 by
Catalyst 4 or Cluster 5
% eeb
d
entry
R/catalyst
time (h) conversion (%)a (yieldc %) krel
1
2
3
4
5
6
CH2CH3 (8a)/4
CH(CH3)2 (8b)/4
C(CH3)3 (8c)/4
CH2C6H5 (8d)/4
C6H5 (8e)/4
6
6
6
7
9
7
51
51
50.5
51
52
99 (48)
99 (47)
98 (48)
78 (47)
47 (48)
64 (45)
211
211
230
16
4
C6H5 (8e)/cluster 5
53
7
a Determined by 1H NMR analysis of the reaction mixture. b Determined
by HPLC analysis on a Chiralpak AD-H or AS column. c Isolated, purified
d
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.
(entries 1-3 in Table 4). On the other hand, the asymmetric
oxidation for S-phenyl-thiomandelate 8e is less selective than
that for S-benzyl-thiomandelate 8d (entries 4 and 5 in Table
4). In addition, the enantioselectivity for the asymmetric
oxidation of S-phenyl-thiomandelate (8e) catalyzed by cluster
5 (krel 7, entry 6 in Table 4) is significantly higher than that
catalyzed by monomer complex 4 (krel 4, entry 5 in Table 4).
t-Butylthioesters are popular derivatives of protected acids.
Their t-butyl moiety can be readily unmasked by treatment with
polymer-supported SO3H,13a Br2/aq THF,13b or in aqueous
LiOH/H2O2.14 In addition, t-butylthioesters can be readily
functionalized into amides,15 esters,16 and thioacids.17 Therefore,
a series of R-substituted S-t-butyl R-hydroxythioesters was
further examined in view of their versatility and to fully grip
their kinetic resolution profiles by monomer 4 and cluster 5,
respectively.
a Determined by 1H NMR analysis of the reaction mixture. b Determined
by HPLC analysis on Chiralpak AD-H or AS column. c Isolated, purified
d
Despite that cluster 5 (krel 82) is a better catalyst than
monomer 4 (krel 16) for the kinetic resolution of S-benzylman-
delate 8d (entries 17 and 18 in Table 2), similarly effective
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.
(13) (a) Iimura, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2002, 5, 101.
(b) Sibi, M. P.; Chen, J. Org. Lett. 2002, 4, 2933.
resolutions can now be achieved for both catalysts for the
corresponding S-butyl analogue 8c (entries 1 and 2 in Table 5).
Furthermore, S-t-butyl R-hydroxythioesters bearing electron-
withdrawing and -donating R-aryl (krel 94 to >500, entries 3-12
in Table 5), -naphthyl (krel 81/146, entries 13 and 14 in Table
5), -heteroaryl (krel 458/81, entries 15 and 16 in Table 5),
-alkenyl (krel > 500, entries 17 and 18 in Table 5), and -alkyl (krel
230/116, entries 19 and 20 in Table 5) are all amenable to
aerobic oxidative processes with high to excellent selectivity
factors by using both monomer 4 and cluster 5, respectively.
Consequently, the kinetic resolutions for these S-t-butyl R-hy-
droxythioesters can now be as efficient as those for the
corresponding N/O-benzyl analogues as shown in Table 3.
Rationalization on Enantiocontrol. On the basis of the
structural study of an adduct between N-benzyl-mandelamide
and catalyst 2 in the asymmetric oxidation of R-hydroxyamides,7
we have proposed that the facile perpendicular π-π interaction
between the salicylidene template and the phenyl group in the
N/O-CH2Ph unit plays the dominant role in inducing exclusive
enantiocontrol for the corresponding N/O-benzyl systems 6 and
7. Therefore, it is suggested that the thermodynamically more
stable diastereomeric adduct 25′ as shown in Figure 4 is a
(14) (a) Mann, A.; Quaranta, L.; Reginato, G.; Taddei, M. Tetrahedron
Lett. 1996, 37, 2651. (b) Demarcus, M.; Ganadu, M. L.; Mura, G. M.;
Porcheddu, A.; Quaranta, L.; Reginato, G.; Taddei, M. J. Org. Chem. 2001,
66, 697. (c) Gennari, C.; Vulpetti, A.; Donghi, M.; Mongelli, N.; Vanotti,
E. Angew. Chem., Int. Ed. Engl. 1996, 108, 1809. (d) Gierasch, T. M.; Shi,
Z.; Verdine, G. L. Org. Lett. 2003, 5, 621.
(15) For deprotective amidations by Hg(II), Ag(I), and Cu(I) species,
see: (a) Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48,
1145. (b) Ley, S. V.; Woodward, P. R. Tetrahedron Lett. 1987, 28, 3019.
(c) Schmidt, U.; Steindl, F. Synthesis 1978, 544. (d) Kim, H.-O.; Olsen, R.
K.; Choi, O.-S. J. Org. Chem. 1987, 52, 4531. (e) Poncet, J.; Dufour, M.-
N.; Pantaloni, A.; Castro, B. J. Org. Chem. 1989, 54, 617. For amidation
to primary amides by NH3, see: (f) Otsuka, M.; Narita, M.; Yoshida, M.;
Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 520. (g) Kittaka,
A.; Sugano, Y.; Otsuka, M.; Ohno, M. Tetrahedron 1988, 44, 2811.
(16) For deprotective esterifications by Ag(I) species, see: (a) Lopez-
Alvarado, P.; Avendano, C.; Menendez, J. C. Synthesis 1998, 2, 186. (b)
Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. Tetrahedron Lett. 2001,
42, 4479. (c) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.;
Ueda, K.; Osada, H. J. Med. Chem. 2001, 44, 3216. (d) Clive, D. L. J.;
Hisaindee, S. J. Org. Chem. 2000, 65, 4923. By Tl(ONO2)3, see: (e) Mukai,
C.; Kim, I. J.; Furu, E.; Hanaoka, M. Tetrahedron 1993, 49, 8323. (f) Mukai,
C.; Kim, I. J.; Hanaoka, M. Tetrahedron: Asymmetry 1992, 3, 1007. By
Hg(NO3)2, see: (g) Gennari, C.; Vulpetti, A.; Pain, G. Tetrahedron 1997,
53, 5909.
(17) Bekker, R. A.; Rozov, L. A.; Popkova, V. Y.; Knunyants, I. L. Bull.
Acad. Sci. USSR, DiV. Chem. Sci. (Engl. Transl.) 1982, 31, 2123.
J. Org. Chem, Vol. 72, No. 22, 2007 8179

Chen et al.
FIGURE 4. 4. Proposed two diastereomeric assemblies between catalyst 4 and racemic X-benzyl mandelate.
SCHEME 1
Since the enantioselectivities for the asymmetric oxidations
of S-benzyl- and S-phenyl thiomandelates by cluster 5 are
significantly higher (krel, 82 and 7) and faster (5-7 h) than those
exerted by the corresponding monomer 4 (krel, 16 and 4; time,
7-9 h), there exists a synergistic effect for the cluster during
the asymmetric aerobic oxidation event. One can envisage that
cluser 5 acts like a space station with a central potassium
vanadate core and four docked homochiral, monomer catalysts
4. Upon initial ligand exchange of S-benzyl-thiomandelate 8d
with 5 by nucleophilic attack of (S)-8d to the central vanadate,
one vanadyl(V) hydroxide 4 would dissociate with concomitant
docking of 8d to the vanadate center of the cluster station
(Scheme 2). (S)-8d fits nicely into the chiral pocket that is
created after the departure of one vanadyl(V) hydroxide 4 from
the cluster 5. The docking would involve a seven-membered
chelation of (S)-8d to both a nearby docked monomer unit and
the central vanadate, leading to adduct 28. Subsequent depro-
tonation of the docked (S)-8d by the central VdO with its
concomitant reduction would generate adduct 29 with a reduced
V(III)-OH center. The resulting oxidation product, S-benzyl
benzoyl-thioformate 8d′, would dissociate from 29 to give 30.
A facile disproportionation between either the flanking vanadyl-
(V) unit or the central V(III)-OH in 30 would lead to 31, which
bears one flanking vanadyl(IV) unit and one central vanadyl-
(IV)-OH. These two vanadyl(IV) units in 31 would undergo
spontaneous oxidation in the presence of an oxygen atmosphere
to give a turnover catalyst 32, which possesses recovered
vanadyl(V) states, thus completing the catalytic cycle.
On the other hand, the ligand exchange reaction of cluster 5
by (R)-8d would produce the alternative epimeric adduct 28′.
Subsequent deprotonative oxidation in 28′ would be highly
hindered due to the inaccessibility of the benzylic proton in
docked (R)-8d either by the central vanadate or by prior-
dissociated vanadyl(V) hydroxide 4. The higher oxidation
enantioselectivity with cluster 5 indicates that there exists a
better defined asymmetric environment in the chiral pocket in
32 as compared to that in 4. In addition, the key deprotonative
oxidation is intramolecular in 28 rather than intermolecular when
the reaction is catalyzed by monomer 4, which would secure a
faster reaction and a better enantioselectivity by cluster 5.
At the current stage, we can ignore the possibility of double
or triple ligand exchange between the cluster 5 and the given
substrate (S)-8d since the central vanadate is the only vanadyl-
(V) unit that can participate in the subsequent deprotonative
oxidation. In addition, a loose asymmetric environment would
result from multiple ligand exchange. Therefore, complete
dissociation of all four monomer units from the central
potassium vanadate through quadrupole ligand exchange with
the substrate is unlikely since this event would lead to a random
slower-reacting species toward deprotonative oxidation since
the R-proton in the substrate is less accessible by another
vanadyl complex due to the proximal C3-t-butyl group in the
salicylidene template. On the contrary, the less stable, sterically
more encumbered diastereomeric adduct 25 is faster reacting
for the subsequent R-proton elimination process via a two-
electron oxidation process leading to R-ketothioester 8d′ with
concomitant reduction of the vanadyl(V) species to the corre-
sponding vanadium(III)OH 26 (Scheme 1).
The vanadium(III) hydroxide 26 may disproportionate with
the original vanadyl(V) methoxide 4 catalyst to give two
molecules of vanadyl(IV) complex 27 with the release of
N-benzyl benzoyl-thioformate 8d′ and CH3OH. The vanadyl-
(IV) complex 27 would be oxidized in the presence of oxygen
atmosphere to regenerate the original catalyst 4, thus completing
the catalytic cycle.
In marked contrast, S-ethyl-, isopropyl-, and t-butyl thiom-
andelates 8a-c are the most selective substrates instead of the
corresponding S-benzyl and -phenyl systems 8d and 8e by using
monomer 4 as the catalyst. The longer S-C(O) bond and less
rigid conformation in the S-benzyl and -phenyl thioesters reduce
the stabilization effect of the perpendicular π-π interaction
between the salicylidene template and the phenyl group in the
S-CH2Ph or S-Ph unit, resulting in diminished enantiocontrol
in the asymmetric oxidations of S-benzyl- and S-phenyl-
thiomandelates 8d and 8e by catalyst 4.
8180 J. Org. Chem., Vol. 72, No. 22, 2007

Asymmetric Aerobic Oxidation of R-Hydroxy Acid DeriVatiVes
SCHEME 2
SCHEME 3
unselective attachment of either enantiomeric 8d to the central
vanadate, leading to 33.
2 (Scheme 3). Under such circumstances, the faster deproto-
native oxidation and better enantioselectivity by cluster 5 remain
secured. In addition, to completely shut down the catalytic
pathway mediated by cluster 5 would require a quadrupole
ligand exchange for the alternative mechanism and would result
in the precipitation of K+V(O)(OH)4 from toluene due to its
-
insolubility in organic solvents, which was not observed during
the reaction. A similar mechanistic principle would also hold
for the corresponding S-phenyl thioester case.
Last, the uniformly high enantioselectivities and divergent
relative rates observed for the asymmetric oxidations of S-t-
butyl thioesters by both catalyst 4 and cluster 5 (Table 5) indicate
that both the freely dissociated vanadyl(V) hydroxide 4 and the
turnover cluster catalyst 32 may be operative at the same time
An alternative ligand exchange mechanism between cluster
5 and (S)-8d by nucleophilic attack of (S)-8d to either flanking
vanadyl(V) unit would generate the diastereomeric adduct 25
as in Scheme 1 and the same turnover catalyst 32 as in Scheme
J. Org. Chem, Vol. 72, No. 22, 2007 8181

Chen et al.
2908(w), 2871 (w), 1698 (m), 1613 (s, CdN), 1557 (w, COO),
1477 (w), 1462 (m), 1436 (w), 1414 (w), 1392 (w), 1362 (w), 1322
(w), 1300 (w), 1274 (w), 1252 (w), 1211 (w), 1182 (w), 1078 (w),
982 (w, VdO) cm-1; [R]D25 +36.02 (c 1.0, CH2Cl2); TLC Rf 0.37
(MeOH/CH2Cl2, 1:8); Anal. calcd For [(H2O)MOH]: C, 56.37; H,
7.66; N, 3.13. Found: C, 55.72; H, 7.32; N, 2.71.
due to the increased steric bulk of the substrates, which might
hinder their dockings to the chiral pocket in 32.
Conclusion
We have documented a unprecedented C4-symmetric penta-
nuclear vanadyl(V) cluster 5 bearing one central vanadate and
four identical vanadyl(V) 3,5-di-t-butyl N-salicylene-L-t-leuci-
nates as chiral peripheral units as evidenced by X-ray crystal-
lographic, ESI-MS, and 51V NMR spectroscopic analyses. The
cluster was best produced when potassium t-butoxide was used
as the base instead of NaOAc or NaOt-Bu during the complex
formation. The negative charge in the central vanadate(V) unit
is compensated by a potassium ion sitting on top of the four
flanking units through carbonyl coordinations. Like monomer
4, cluster 5 exhibits a high reactivity and enantioselectivity
profiles toward the asymmetric aerobic oxidations of various
racemic R-aryl- and R-alkenyl-R-hydroxyesters and -amides with
excellent selectivity factors. In the case of S-benzyl- and
S-phenyl-thiomandelates, cluster 5 shows even higher enantio-
controls than those exerted by monomer 4, indicating a potential
cooperative effect18 between three of the four docked vanadyl-
(V) alkoxide units and the central K+V(O)O4- in the cluster 5
during the kinetic resolution event. Conversely, S-t-butyl
R-hydroxythioesters were found to be the best thioester sub-
strates. Uniformly excellent selectivity factors (krel 45 to >200)
were achieved for their asymmetric aerobic oxidations catalyzed
both by monomer 4 and by cluster 5. A handy one-pot recipe
for the preparation of cluster 5 is also established, arguing well
for its practical applications in the kinetic resolution of
R-hydroxy acid derivatives. Investigations on its potential use
as a C4-symmetric chiral vanadate base in asymmetric catalysis
are underway.
Procedure for Preparation of C4-Symmetric Pentanuclear
Vanadyl(V) Cluster 5. In a 50 mL, round-bottomed flask was
placed L-t-leucine (131 mg, 1.0 mmol) and 3,5-di-t-butyl salicy-
ladehyde (234 mg, 1.0 mmol) in anhydrous methanol (5 mL) under
oxygen atmosphere. After having been refluxed at 80 °C for 12 h,
the reaction mixture led to the complete formation of the resultant
Schiff base. A solution of potassium t-butoxide (258 mg, 2.3 mmol)
in anhydrous THF (1 mL) was added dropwise to the Schiff base
at ambient temperature. The reaction mixture was then stirred for
1 h, and a solution of VOSO4-xH2O (203.8 mg, 1.25 mmol) in
anhydrous THF (1 mL) was added gradually. A dark green species
was formed immediately and precipitated out completely in 20 min.
After having been stirred under oxygen atmosphere for an additional
24 h, the dark green reaction mixture was concentrated in vacuo to
half of the original volume. The crude pentanuclear cluster was
collected by filtration and washed sequentially with water (5 ×
25 mL) and cold diethyl ether (5 × 25 mL) and then dried under
vacuum. The pure pentanuclear cluster 5 was obtained by recrys-
tallization from wet MeOH with slow evaporation of MeOH and
then used for asymmetric aerobic oxidation experiments. Single
crystals suitable for X-ray crystallographic analysis was obtained
by recrystallization from MeOH to yield 742 mg (38%) of brown
prism: 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.82 (d, J )
2.0, 1H), 7.50 (d, J ) 2.4, 1H), 4.03 (s, 1H), 1.59 (s, 3H), 1.38 (s,
3H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2, 143.0,
138.1, 132.9, 128.4, 121.2, 86.9, 38.2, 35.2, 34.9, 31.7, 30.4, 30.3,
28.1; 51V NMR (CDCl3) δ -536.14, -609.59; Mw MS (ESI) (M:
C84H132KN4O25V5, 1891.74) 1820 (M-4H2O, 100); IR (KBr) ν 3434
(br, w), 3188 (br, m), 2969 (w), 1619 (s, CdN), 1541 (m, COO),
1510 (m), 1455 (m), 1429 (m), 1390 (m), 1362 (m), 1340 (m),
1309 (m), 1250 (m), 1192 (m), 1164 (m), 1244 (m), 1004 (m, Vd
O), 979 (bs, VdO) cm-1; [R]D25 +66.3 (c 1.0, CH2Cl2); Anal. calcd
for M + 2MeOH (C86H140KN4O27V5): C, 52.81; H, 7.21; N, 2.86.
Found: C, 52.37; H, 6.75; N,2.97.; mp 260-262 °C.
Experimental Section
Representative Preparation Procedure and Analytical Data
for Vanadyl(V) Methoxide (or Hydroxide) Complexes 1-4. In
a 50 mL, two-necked, round-bottomed flask was placed L-t-leucine
(5 mmol) and NaOAc-5H2O (1.17 g, 10 mmol) in degassed water
(10 mL). After having been stirred at 60 °C for 10 min to effect
their complete dissolution, the reaction mixture was treated dropwise
with a solution of respective 2-hydroxybenzaldehyde derivatives
(5 mmol) in degassed EtOH (12.5 mL). The reaction mixture
became homogeneous by heating at 80 °C for 15 min and then
gradually cooled to ambient temperature for 2 h. To the resultant
Schiff base was added a solution of vanadyl(IV) sulfate trihydrate
(1.08 g, 5 mmol) in degassed water (5 mL). The dark green complex
started crashing out in 15 min. The reaction mixture was stirred
for 2 h and then concentrated to half of the original solvent volume.
The crude vanadyl(IV) complex collected by filtration was washed
sequentially with water (5 × 25 mL) and cold ether (5 × 25 mL)
and then dried in vacuo to furnish the pure vanadyl(IV) catalyst.
The corresponding analytically pure vanadyl(V) methoxide (or
hydroxide) complexes were obtained by recrystallization from
oxygen-saturated MeOH and were used for asymmetric aerobic
oxidation experiments. Data for 4: yield: 75%; Mw (M: C21H31-
NO4V) 412; MS (ESI) 881 (M2O + H2O + Na+, 6), 460 (MOCH3
+ H2O+, 77), 444 (M + CH3OH+, 13), 413 (M + H+, 100); 51V
NMR (CDCl3) δ -583.38; IR (KBr) ν 3322 (br, w), 2959 (m),
Representative Procedure for Asymmetric Aerobic Oxidation
of X-Benzyl R-Hydroxyesters, -Amides, and -Thioesters. To a
50 mL, two-necked, round-bottomed flask was placed a vanadyl-
(V) catalyst (0.05 mmol, 5 mol %) in oxygen-saturated toluene
(3 mL) under oxygen atmosphere. The reaction flask was vacuum-
evacuated at 15 Torr for 20 s and then filled with an O2 balloon
(150 mL). A solution of R-hydroxyester, -amide, and -thioester (1
mmol) in oxygen-saturated toluene (2 mL) was added by cannula,
and the resulting dark brown mixture was stirred at ambient
1
temperature. The reaction progress was monitored by H NMR
spectroscopy for percent conversion (142 mg; i.e., 1 mmol of
2-methyl-naphthalene was used as an internal standard). The
enantiomeric excess of the kinetically resolved product was
determined by chiral HPLC analysis after filtration of the reaction
aliquot (100 µL) over a short plug of silica gel (Et2O or CH2Cl2 as
eluent). Upon reaching optimal resolution of the asymmetric
oxidation (50-53% conversion), the reaction was quenched by the
addition of silica gel (150 mg), and the mixture was concentrated
under reduced pressure. The resulting residue was loaded directly
on top of an eluent-filled silica gel column and purified by flash
column chromatography. The enantiomeric excess of the pure,
resolved R-hydroxyester, -amide, and -thioester was analyzed again
by chiral HPLC analysis.
1
S-Benzyl 2-Hydroxy-2-phenyl-thioacetate 8d. H NMR (400
MHz, CDCl3) δ 7.43-7.37 (m, 5H), 7.30-7.27 (m, 5H), 5.21 (s,
1H), 4.16 (d, J ) 13.6, 1H), 4.10 (d, J ) 13.6, 1H), 3.57 (bs, 1H,
OH); 13C NMR (100 MHz, CDCl3) δ 201.4, 137.8, 136.7, 128.8,
128.79, 128.7, 128.6, 127.3, 127.0, 79.7, 33.2; MS (EI, 70 eV)
(C15H14O2S, 258.3) 259 (M + 1+, 5), 213 (23), 124 (26), 107 (100),
(18) For heterobimetallic Ln and Y complexes in multifunctional
asymmetric catalysis, see: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV.
2002, 102, 2187. (b) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 13419.
8182 J. Org. Chem., Vol. 72, No. 22, 2007

Asymmetric Aerobic Oxidation of R-Hydroxy Acid DeriVatiVes
91 (31), 79 (25), 77 (16); HRMS calcd for (C15H14O2S) 258.0715,
found 258.0782; TLC Rf 0.37 (EtOAc/hexane, 1:6); HPLC tR 19.55
min (S), 23.66 min (R) (Chiralcel AD-H, i-PrOH/hexane, 6:94,
1.0 mL/min, λ ) 254 nm). After kinetic resolution: 19.75 min (S,
S-t-Butyl Hydroxyphenyl-thioacetate 8c. 1H NMR (400 MHz,
CDCl3) δ 7.38-7.35 (m, 5H), 5.10 (s, 1H), 3.54 (s, 1H), 1.45 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 201.91, 138.5, 128.6, 127.1,
79.9, 48.9, 29.8; MS (EI, 70 eV) (C12H16O2S, 224.3) 224 (M+, 5),
107 (100), 79 (38), 57 (25); High resolution MS calcd for
(C12H16O2S) 224.0871, found 224.0944; TLC Rf 0.36 (EtOAc/
hexane, 2:8); HPLC tR 10.5 min (S), 12.1 min (R) (Chiralpak AD-
H, i-PrOH/hexane, 6:94, 1.0 mL/min, λ ) 254 nm). After kinetic
28
minor, 2.59%), 23.92 min (R, major, 97.41%). [R]D -82.32 (c
1.0, CHCl3) for 95% ee; [R]D25 +141.9 (c 1.0, MeOH) for 78% ee.
The absolute configuration was deduced to be R according to the
sign of optical rotation; mp 83-85 °C.
S-Benzyl Oxo-phenyl-thioacetate 8d′. 1H NMR (400 MHz,
CDCl3) δ 8.14 (d, J ) 8.0, 2H), 7.66 (td, J ) 8.0, 0.8, 1H), 7.50
(t, J ) 7.6, 2H), 7.38-7.28 (m, 5H), 4.28 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 192.1, 186.0, 136.4, 134.9, 131.6, 130.8, 129.0,
128.8, 128.75, 127.6, 33.3; MS (EI, 70 eV) (C15H12O2S, 256) 256
(M+, 3), 228 (53), 105 (100), 91 (17), 77 (29); TLC Rf 0.39 (EtOAc/
hexane, 1:28); Anal. calcd for C15H13O3S: C, 70.29; H, 4.72.
Found: C, 70.52; H, 4.48.
25
resolution: 10.7 min (minor, 1.38%), 12.2 (major, 98.62%); [R]D
+48.38 (c 1.0, MeOH) for 98% ee; mp 59-61 °C.
S-t-Butyl Oxo-phenyl-thioacetate 8c′. 1H NMR (400 MHz,
CDCl3) δ 8.05 (d, J ) 7.2, 2H), 7.62 (t, J ) 7.4, 1H), 7.49 (t, J )
7.6, 2H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 193.6, 187.1,
134.6, 131.6, 130.5, 128.7, 49.0, 29.6; MS (EI, 70 eV) (C12H14O2S,
222.3) 222 (M+, 13), 105 (100), 219 (29), 77 (22), 57 (18); TLC
Rf 0.45 (EtOAc/hexane, 1:9).
S-t-Butyl Hydroxy-(4-nitrophenyl)-thioacetate 16.19a,b
Representative Procedure for Preparation of S-t-Butyl R-Hy-
droxythioesters. To a solution of a methyl mandelate derivative
(5 mmol) in CH3CN (10 mL) was added VOCl3 (0.09 mL,
0.5 mmol) under oxygen atmosphere. After having been stirred for
several hours, the reaction mixture was concentrated under reduced
pressure, and the crude ketoester product was purified by column
chromatography (eluent: hexane) on silica gel. The purified
R-ketoester (2 mmol) was treated with aqueous KOH (4 mmol,
224 mg in 4 mL of H2O) in EtOH (8 mL) to effect saponification.
After acidification of the reaction mixture with 1 N HCl (5 mL) at
0 °C, the crude acid mixture was then extracted with ether (3 ×
15 mL). The combined organic layers were concentrated, dried
(MgSO4), and evaporated. The resultant R-ketoacid (2 mmol) was
dissolved in CH2Cl2 (5 mL) and was then cooled to 0 °C. To this
solution was added oxalyl chloride (2.5 mL, 2 mmol) under
nitrogen. After having been stirred for 30 min, the reaction mixture
was treated with a cooled mixture of anhydrous t-butanethiol
(1.8 mL, 2 mmol) and dry Et3N (2.7 mL, 2 mmol) at 0 °C and
then gradually warmed to ambient temperature. After completion
of the reaction, the mixture was concentrated under reduced
pressure, and the crude thioester was taken up by ether (30 mL).
The concentrated residue was purified by column chromatography
(hexane/EtOAc, 9:1) on silica gel. The purified R-keto-thioesters
(2 mmol) were dissolved in THF (2 mL) and then treated with
NaBH4 (18.9 mg, 0.5 mmol). After completion of the reaction, the
reaction mixture was acidified with 1 N HCl at 0 °C. Ether
(15 mL) was added, and the organic layer was collected. The
aqueous layer was separated and extracted with ether (3 × 10 mL).
The combined organic layers were dried (MgSO4), filtered, and
evaporated. The crude R-hydroxythioester was purified by column
chromatography (hexane/Et2O, 8:2) on silica gel.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J ) 8.6, 2H), 7.59 (d, J
) 8.7, 2H), 5.21 (s, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 200.4, 147.9, 145.4, 127.8, 123.7, 78.9, 49.5, 29.7 MS (EI, 70
eV) (C12H15NO4S, 269.3) 269 (M+, 4), 153 (100), 57 (85), 136
(30), 106 (20), 77 (15); TLC Rf 0.31 (EtOAc/hexane, 2:8); HPLC
tR 17.2 min (S), 20.6 min (R) (Chiralpak AD-H, i-PrOH/hexane,
6:94, 1.0 mL/min, λ ) 254 nm). After kinetic resolution: 17.0 min
25
(minor, 0.88%), 20.4 min (major, 99.12%); [R]D -40.8 (c 1.0,
MeOH) for 98% ee; mp 73-76 °C.
S-t-Butyl (4-Chlorophenyl)-hydroxythioacetate 17.19a,b
1H NMR (400 MHz, CDCl3) δ 7.53-7.31 (m, 4H), 5.29 (s, 1H),
1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 201.4, 137.0, 134.5,
128.8, 128.5, 79.2, 49.2, 29.8; MS (EI, 70 eV) (C12H15ClO2S, 258.8)
259 (M+, 4), 141 (100), 57 (38), 143 (34), 77 (36), 113 (12); High
resolution MS calcd for (C12H15ClO2S) 258.0481, found 258.0463;
TLC Rf 0.29 (EtOAc/hexane, 2:8); HPLC tR 11.5 min (S), 13.4
min (R) (Chiralpak AD-H, i-PrOH/hexane, 6:94, 1.0 mL/min, λ )
254 nm). After kinetic resolution: 11.0 min (minor, 1.96%), 13.1
25
min (major, 98.04%); [R]D -53.6 (c 1.0, MeOH) for 96% ee;
mp 88-91 °C.
Representative Procedure for Asymmetric Aerobic Oxidation
of S-t-Butyl R- Hydroxythioesters. To a 50 mL, two-necked,
round-bottomed flask was placed monomer catalyst 4 (0.05 mmol,
5 mol %) or cluster 5 (0.0125 mmol, 1.25 mol %) in oxygen-
saturated toluene (3 mL) under oxygen atmosphere. The reaction
flask was vacuum-evacuated at 15 Torr for 20 s and then filled
with an oxygen balloon (150 mL). A solution of a R-hydrox-
ythioester (1 mmol) in oxygen-saturated toluene (2 mL) was added
by cannula, and the resulting dark brown mixture was stirred at
S-t-Butyl Hydroxy-p-tolyl-thioacetate 18.19a,b
1H NMR (400 MHz, CDCl3) δ 7.27-7.17 (m, 4H), 5.07 (s, 1H),
2.35 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.0,
138.4, 135.6, 129.3, 127.1, 79.7, 48.7, 29.8, 21.2; MS (EI, 70 eV)
(C13H18O2S, 238.4) 238 (M+, 4), 121 (100), 93 (30), 77 (17), 57
(15); TLC Rf 0.32 (EtOAc/hexane, 2:8); HPLC tR 12.1 (S) min,
15.8 min (R) (Chiralpak AD-H, i-PrOH/hexane, 6:94, 1.0 mL/min,
λ ) 254 nm). After kinetic resolution: 11.4 min (minor, 3.28%),
1
ambient temperature. The reaction progress was monitored by H
NMR spectroscopy to determine the extent of oxidative conversion.
The enantiomeric excess of the kinetically resolved product was
determined by chiral HPLC analysis after filtration of the reaction
aliquot (100 µL) over a short plug of silica gel (Et2O or CH2Cl2 as
eluent). Upon reaching optimal resolution of the asymmetric
oxidation (50-51% conversion), the reaction mixture was concen-
trated under reduced pressure. The resulting residue was loaded
directly on top of an eluent-filled silica gel column and purified
by flash column chromatography. The enantiomeric excess of the
pure, resolved R-hydroxythioester was analyzed again by chiral
HPLC analysis.
25
15.8 min (major, 96.71%); [R]D -58.6 (c 1.0, MeOH) for 93%
ee; mp 72-75 °C.
(19) (a) Douglas, K. T.; Demircioglu, H. J. Chem. Soc., Perkin Trans. 2
1985, 1951. (b) Creary, X.; Geiger, C. C. J. Am. Chem. Soc. 1982, 104,
4151. (c) Aggarwal, V. K.; Thomas, A.; Franklin, R. J. J. Chem. Soc., Chem.
Commun. 1994, 14, 1653.
J. Org. Chem, Vol. 72, No. 22, 2007 8183

Chen et al.
S-t-Butyl 2-Hydroxy-4-phenyl-but-3-enethioate 23.
S-t-Butyl (2-Chlorophenyl)-hydroxythioacetate 19.
1H NMR (400 MHz, CDCl3) δ 7.42-7.27 (m, 5H), 6.77 (d, J )
15.8, 1H), 6.19 (dd, J ) 15.8, 6.8, 1H), 4.76 (d, J ) 6.8, 1H), 3.41
(bs, 1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 201.4, 136.1,
134.0, 128.6, 128.1, 126.8, 125.7, 78.6, 49.0, 29.9; MS (EI, 70 eV)
(C14H18O2S, 250.4) 250 (M+, 5), 133 (100), 115 (30), 57 (19), 77
(12); High resolution MS calcd for (C14H18O2S) 250.1028, found
250.1033; TLC Rf 0.34 (EtOAc/hexane, 2:8); HPLC tR 29.6 min
(S), 39.9 min (R) (Chiralpak AD-H, i-PrOH/hexane, 2:98, 1.0 mL/
min, λ ) 254 nm). After kinetic resolution: 36.7 min (major, 99%);
1H NMR (400 MHz, CDCl3) δ 7.40-7.35 (m, 2H), 7.29-7.26
(m, 2H), 5.50 (s, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 201.0, 136.3, 133.7, 129.9, 129.8, 129.3, 127.2, 76.9, 49.0, 29.7;
MS (EI, 70 eV) (C12H15ClO2S, 258.8) 259 (M+, 4), 141 (100), 57
(40), 143 (36), 77 (20), 125 (10); High resolution MS calcd for
(C12H15ClO2S) 258.0481, found 258.0470; TLC Rf 0.30 (EtOAc/
hexane, 2:8); HPLC tR 10.4 min (S), 12.1 min (R) (Chiralpak AD-
H, i-PrOH/hexane, 6:94, 1.0 mL/min, λ ) 254 nm). After kinetic
resolution: 10.5 min (minor, 0.44%), 12.2 min (major, 99.50%);
26
[R]D +203.4 (c 1.0, MeOH) for 99% ee; mp 104-106 °C.
25
S-t-Butyl 2-Hydroxy-4-phenyl-thiobutanoate (24).20
[R]D +52.1 (c 1.0, MeOH) for 99% ee; mp 67-68 °C.
S-t-Butyl Hydroxy-(2-methoxy-phenyl)-thioacetate 20.
1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m, 5H), 4.19-4.15
(m, 1H), 3.19 (d, J ) 5.6, 1H, OH), 2.80-2.76 (m, 2H), 2.18-
2.12 (m, 1H), 1.97-1.79 (m, 1H), 1.51 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 203.9, 141.1, 128.5, 128.4, 126.0, 76.8, 48.3, 37.2,
30.8, 29.9; MS (EI, 70 eV) (C14H20O2S, 252.4) 252 (M+, 100),
225 (18), 197 (20), 147 (10), 116 (10), 90 (15), 56 (10); High
resolution MS calcd for (C14H20O2S) 252.1184, found 252.1183;
TLC Rf 0.42 (EtOAc/hexane, 2:8); HPLC tR 19.8 min (S), 22.2
min (R) (Chiralpak AD-H, i-PrOH/hexane, 2:98, 1.0 mL/min, λ )
254 nm). After kinetic resolution: 20.3 min (minor, 1.66%), 22.6
1H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m, 2H), 6.99-6.89
(m, 2H) 5.21 (s, 1H), 3.84 (s, 3H), 1.45 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 202.1, 157.1, 130.0, 129.7, 127.2, 120.8, 111.2,
55.3, 48.0, 29.7; MS (EI, 70 eV) (C13H18O3S, 254.4) 254 (M+, 5),
137 (100), 107 (36), 57 (10); High resolution MS calcd for
(C13H18O3S) 254.0977, found 254.1012; TLC Rf 0.33 (EtOAc/
hexane, 2:8); HPLC tR 16.7 min (S), 18.8 min (R) (Chiralpak AD-
H, i-PrOH/hexane, 6:94, 1.0 mL/min, λ ) 254 nm). After kinetic
25
25
(major, 98.34%); [R]D +88.38 (c 1.0, MeOH) for 97% ee.
S-t-Butyl (4-Nitrophenyl)-oxo-thioacetate 16′.
resolution: 16.7 min (minor, 0.89%) 18.7 (major, 99.11%); [R]D
+84.36 (c 1.0, MeOH) for 98% ee; mp 56-58 °C.
S-t-Butyl Hydroxynaphthalen-1-yl-thioacetate 21.
1H NMR (400 MHz, CDCl3) δ 8.33 (d, J ) 8.5, 2H), 8.26 (d, J
) 8.5, 2H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 192.3,
185.1, 151.0, 136.5, 131.7, 123.7, 49.5, 29.5; MS (EI, 70 eV)
(C12H13NO4S, 267.3) 267 (M+, 4), 57 (100), 150 (57), 104 (25),
76 (21); High resolution MS calcd for (C12H13NO4S) 267.0565,
found 267.0582; TLC Rf 0.42 (EtOAc/hexane, 1:9).
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J ) 7.8, 1H), 7.89-
7.86 (m, 2H), 7.55-7.45 (m, 4H), 5.66 (s, 1H), 3.86 (s, 1H), 1.44
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.7, 134.0, 134.1, 131.0,
129.6, 128.7, 127.4, 126.5, 125.8, 125.1, 123.9, 79.0, 48.9, 29.8;
MS (EI, 70 eV) (C16H18O2S, 274.4) 274 (M+, 5), 156 (100), 129
(54), 120 (38), 118 (22), 57 (10); High resolution MS calcd for
(C16H18O2S) 274.1028, found 274.1020; TLC Rf 0.30 (EtOAc/
hexane, 2:8); HPLC tR 23.0 min (S), 26.6 min (R) (Chiralpak AD-
H, i-PrOH/hexane, 4:96, 1.0 mL/min, λ ) 254 nm). After kinetic
resolution: 21.7 min (minor, 2.41%), 24.8 min (major, 97.59%);
S-t-Butyl (4-Chlorophenyl)-oxo-thioacetate 17′.21
25
[R]D -100.5 (c 1.0, MeOH) for 95% ee; mp 86-89 °C.
S-t-Butyl Hydroxythiophen-2-yl-thioacetate 22.
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J ) 8.6, 2H), 7.46 (d, J
) 8.6, 2H), 1.58 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 193.2,
185.7, 141.4, 132.1, 129.2, 49.1, 29.6; MS (EI, 70 eV) (C12H13-
ClO2S, 256.8) 256 (M+, 5), 139 (100), 144 (38), 111 (36), 57 (25);
TLC Rf 0.41(EtOAc/hexane, 1:9).
S-t-Butyl Oxo-p-tolyl-thioacetate 18′.21
1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J ) 4.7, J ) 1.0, 1H),
7.21 (d, J ) 3.6, 1H), 7.00 (dd, J ) 4.9, 3.6, 1H), 5.35 (s, 1H),
1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 200.6, 141.4, 126.8,
126.5, 126.4, 75.5, 48.9, 29.7 MS (EI, 70 eV) (C10H14O2S, 230.4)
230 (M+, 4), 113 (100), 84 (33), 57 (17); High resolution MS calcd
for (C10H14O2S2) 230.0435, found 230.0432; TLC Rf 0.35 (EtOAc/
hexane, 2:8); HPLC tR 12.3 min (S), 16.1 min (R) (Chiralpak AD-
H, i-PrOH/hexane, 6:94, 1.0 mL/min, λ ) 254 nm). After kinetic
resolution: 11.7 min (minor, 0.73%), 15.1 min (major, 99.27%);
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J ) 8.2, 2H), 7.28 (d, J
) 8.1, 2H), 2.42 (s, 3H), 1.58 (s, 9H); 13C NMR (100 MHz, CDCl3)
(20) For the corresponding S-phenyl thioester, see: Berenguer, R.;
Cavero, M.; Garcia, J.; Munoz, M. Tetrahedron Lett. 1998, 39, 2183.
(21) (a) Lapkin, E. A. J. Org. Chem. USSR (Engl. Transl.) 1977, 13,
915. (b) Ibid, Zh. Org. Khim. 1977, 13, 996.
25
[R]D -47.84 (c 1.0, MeOH) for 98% ee; mp 54-55 °C.
8184 J. Org. Chem., Vol. 72, No. 22, 2007

Asymmetric Aerobic Oxidation of R-Hydroxy Acid DeriVatiVes
δ 193.9, 186.8, 145.9, 130.7, 129.5, 129.1, 48.9, 29.7, 21.9; MS
(EI, 70 eV) (C13H16O2S, 236.3) 236 (M+, 5), 119 (100), 91 (35),
57 (17), 65 (15); TLC Rf 0.42 (EtOAc/hexane, 1:9).
S-t-Butyl Oxo-thiophen-2-yl-thioacetate 22′.22
S-t-Butyl (2-Chlorophenyl)-oxo-thioacetate 19′.
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J ) 3.9, 1H), 7.81 (d, J
) 3.9, 1H), 7.18 (dd, J ) 4.0, 1H), 1.55 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 192.3, 177.7, 138.0, 137.5, 136.1, 128.5, 48.1, 29.4;
MS (EI, 70 eV) (C10H12O2S2, 228.3) 228 (M+, 15), 111 (100), 57
(35); TLC Rf 0.44 (EtOAc/hexane, 1:9).
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J ) 7.6, 2H), 7.49-
7.42 (m, 1H), 7.39-7.35 (m, 1H), 1.57 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 191.7, 188.8, 133.7, 133.5, 133.2, 131.4, 130.4,
126.9, 49.0, 29.5; MS (EI, 70 eV) (C12H13ClO2S, 256.8) 256 (M+,
5), 139 (100), 144 (38), 57 (35), 75 (16); High resolution MS calcd
for (C12H13ClO2S) 256.0325, found 256.0334; TLC Rf 0.41 (EtOAc/
hexane, 1:9).
S-t-Butyl 2-Oxo-4-phenyl-but-3-enethioate 23′.
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J ) 16.1, 1H), 7.64 (dd,
J ) 7.3, 1.3, 2H), 7.44-7.39 (m, 4H), 1.55 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 192.9, 184.0, 148.4, 134.4, 131.6, 129.1, 117.5,
47.8, 29.5; MS (EI, 70 eV) (C14H16O2S, 284.3) 284 (M+, 4), 131
(100), 103 (35), 77 (15), 57 (10); High resolution MS calcd for
(C14H16O2S) 248.0871, found 248.0882; TLC Rf 0.44 (EtOAc/
hexane, 1:9).
S-t-Butyl (2-Methoxyphenyl)-oxo-thioacetate 20′.21
S-t-Butyl 2-Oxo-4-phenyl-thiobutanoate (24′).23
1H NMR (400 MHz, CDCl3) δ 7.73 (d, J ) 7.6, 1H), 7.55 (t, J
) 8.2, 1H), 7.06 (t, J ) 7.6, 1H), 6.97 (d, J ) 8.2, 1H), 3.85 (s,
3H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 193.3, 189.5,
159.8, 135.6, 131.3, 123.2, 121.1, 112.0, 55.7, 48.7, 29.8; MS (EI,
70 eV) (C13H16O3S, 252.3) 252 (M+, 4), 135 (100), 77 (32), 57
(17); TLC Rf 0.43 (EtOAc/hexane, 1:9).
1H NMR (400 MHz, CDCl3) δ 7.30-7.18 (m, 5H), 3.11 (t, J )
7.4, 2H), 2.93 (t, J ) 7.5, 2H), 1.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 195.6, 191.3, 140.2, 128.5, 128.4, 126.3, 47.8, 37.8, 29.4,
29.0; MS (EI, 70 eV) (C14H18O2S, 250.4) 250 (M+, 70), 238 (10),
204 (40), 166 (20), 133 (100), 104 (40), 90 (20), 57 (16); TLC Rf
0.49 (EtOAc/hexane, 2:8).
S-t-Butyl Naphthalen-1-yl-oxo-thioacetate 21′.21
Acknowledgment. We thank the National Science Council
of Taiwan for generous financial support of this research.
1H NMR (400 MHz, CDCl3) δ 8.78 (d, J ) 8.5, 1H), 8.09 (d, J
) 8.2, 1H), 8.04 (d, J ) 7.2, 1H), 7.90 (d, J ) 8.2, 1H), 7.66-
7.53 (m, 3H), 1.62 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 194.1,
189.7, 135.1, 133.9, 133.3, 131.1, 128.74, 128.68, 128.0, 126.8,
125.5, 124.1, 49.1, 29.6; MS (EI, 70 eV) (C16H16O2S, 272.4) 272
(M+, 4), 155 (100), 127 (56), 57 (15); TLC Rf 0.42 (EtOAc/hexane,
2:8).
Supporting Information Available: X-ray data for 1′, 4′, and
5 and spectroscopic characterization for vanadyl(V) complexes 1-4
and 5, kinetic resolution products 6-15, oxidation products 6′-
15′, and HPLC traces of racemic and resolved products 8a-e and
9-24. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070575F
(22) (a) Degani, I.; Dughera, S.; Fochi, R.; Gatti, A. Synthesis 1996, 4,
467. (b) Rybakova, E. A. J. Org. Chem. USSR (Engl. Transl.) 1977, 13,
1360. (c) Ibid, Zh. Org. Khim. 1977, 13, 1476.
(23) Ogura, K.; Katoh, N.; Yoshimura, I.; Tsuchihashi, G.-I. Tetrahedron
Lett. 1978, 375.
J. Org. Chem, Vol. 72, No. 22, 2007 8185