Development and application of versatile bis-hydroxamic acids for catalytic asymmetric oxidation

Article abstract of DOI:10.1016/j.tet.2007.03.071

In this article, we describe the development and preliminary results of our new designed C₂-symmetric bis-hydroxamic acid (BHA) ligands and the application of the new ligands for vanadium-catalyzed asymmetric epoxidation of allylic alcohols as well as homoallylic alcohols. From this success we demonstrate the versatile nature of BHA in the molybdenum catalyzed asymmetric oxidation of unfunctionalized olefins and sulfides.

Full text of DOI:10.1016/j.tet.2007.03.071

Tetrahedron 63 (2007) 6075–6087
Development and application of versatile bis-hydroxamic
acids for catalytic asymmetric oxidation
*
Allan U. Barlan, Wei Zhang and Hisashi Yamamoto
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Received 24 January 2007; revised 7 March 2007; accepted 12 March 2007
Available online 16 March 2007
Abstract—In this article, we describe the development and preliminary results of our new designed C2-symmetric bis-hydroxamic acid
(BHA) ligands and the application of the new ligands for vanadium-catalyzed asymmetric epoxidation of allylic alcohols as well as homo-
allylic alcohols. From this success we demonstrate the versatile nature of BHA in the molybdenum catalyzed asymmetric oxidation of
unfunctionalized olefins and sulfides.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric epoxidation of allylic alcohols. The success of
the catalyst design comes from the design of C2-symmetric
bis-hydroxamic acid (BHA) ligand. The new BHA design
has accomplished the asymmetric oxidation of allylic alco-
hols,7 homoallylic alcohols,8 unfunctionalized olefins,9 and
sulfides10 (Scheme 1). BHA metal complexes can serve as a
new and versatile tool for asymmetric oxidation in modern
organic synthesis. In this article we describe the develop-
ment and preliminary results of the BHA leading to the
versatile nature of the BHA.
Today, the rapidly developing small molecule, chiral tech-
nology industry is witnessing a flurry of activity. While
traditional methods of chiral production such as resolution
and chiral pool chemistry are firmly established, emerging
asymmetric catalyses are generating strong interest and are
the focus of intensive research. Among these, asymmetric
oxidation is one of the most important processes for drug
synthesis.
Enantiomerically enriched epoxides, which are versatile
building blocks for the synthesis of natural products and
biologically active substances, could be provided by many
efficient protocols,1 especially by the Sharpless asymmetric
epoxidation that applied the chiral titanium–tartrate com-
plex as the catalyst.2 Our studies began with the intention
that it would be more practical of this type of protocol if
the following conditions could be fulfilled: (1) ligand design
to achieve high enantioselectivities for wide scope of allylic
and homoallylic alcohols, (2) low catalyst loading (such
as 1 mol %), (3) mild reaction conditions at 0 ꢀC to room
temperature for fewer hours, (4) application of commer-
cially available aqueous TBHP (tert-butyl hydroperoxide)
or CHP (cumene hydroperoxide) as an achiral oxidant in-
stead of anhydrous TBHP, and (5) easy work-up procedure
for obtaining small epoxy alcohols with high purity.3–6
R2
R2
O
BHA, Vanadium (1 mol%)
aqueous TBHP or CHP
R1
OH
n
R1
OH
n
(1)
R3
R2
R3
R1
R2
BHA, MoO2(acac)2, (2 mol%)
(2)
O
R1
R3
R3
R2
TBHP, CHP, or THP
RT, Air, DCM
R4
R4
BHA, MoO2(acac)2(2 mol%)
R1
R1
R2
S
(3)
S
THP, CH2Cl2
0 °C, Air
O
Scheme 1. BHA metal complexes’ asymmetric oxidation reactions.
2. Results and discussion
Recently, a series of chiral hydroxamic acid ligands have
been developed by our group. These ligands were de-
monstrated to be effective for the vanadium-catalyzed
Recently, a series of chiral hydroxamic acid ligands have
been developed by our group.11–13 These ligands were
demonstrated to be effective for the vanadium-catalyzed
asymmetric epoxidation of allylic and homoallylic alcohols
(Scheme 2). These results suggested that several structural
features of the hydroxamic acid were very suitable to
* Corresponding author. Tel.: +1 773 702 5059; fax: +1 773 702 0805;
e-mail: yamamoto@uchicago.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.071

6076
A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
HO
N
ring to minimize steric interaction and restrict its coordina-
tion with the metal. A second aspect is that the attachment
of additional ligands to vanadium will also be restricted for
steric reasons. Thus, doubly or triply coordinated species,
which are believed to be inactive, should not be generated
with this bis-hydroxamic acid ligand, and consequently the
ligand deceleration effect with the vanadium–3 catalyst
system should not be problematic.
O
R
Ph
Ph
O
N
N
O
Ar
OH
OH
O
N
N
Ar
OMe
O
OH
O
R
1
2
3
Scheme 2. Hydroxamic acid ligands.
2.1. Synthesis of BHA ligands
generate reactive complex with vanadium and the complex
significantly enhanced the enantioselectivities of the epoxy
alcohols. However, the ligand deceleration effect was still
observed in these cases.11,12,14 To exclude this effect, we
planned to design a new C2-symmetric BHA incorporating
several features: (1) with an additional binding site, 3 is ca-
pable of chelating as an bi-dentate ligand to the metal center
to complete the generation of chiral vanadium–ligand com-
plex more efficiently than monohydroxamic acids 1 and 2;
(2) when the R group of amide in 3 is sufficiently large, it will
direct the amide carbonyl oxygen toward the cyclohexane
To prove the veracity of our hypothesis, we devised a syn-
thetic protocol for C2-symmetric BHA 3 from readily avail-
able chiral diamine tartrate salt (Scheme 3). These reaction
sequences can be conducted with satisfactory yield for every
step to provide 6, which is used to react with different acid
chlorides to provide our designed ligands. Based on this pro-
tocol, we have prepared a wide array of diverse ligands 3 and
several of them have been demonstrated to be highly effi-
cient to the vanadium-catalyzed asymmetric epoxidation
reaction (Scheme 3).7,8
OMe
O
+
1. p-anisaldehyde,K2CO3
NH3
N
EtOH, H2O, reflux
L-tartrate
2. Oxone, KHCO3,
THF, MeCN
NH2
+
N
O
5
4
OMe
.
1. BnONH2 HCl,
HCl, MeOH
2. Et3N, Imidazole, DMAP
i
Pr2SiCl2, CH2Cl2
O
O
R
1. Acid Chloride, DIEA
CH2Cl2
H
N
N
i
N
O
O
Pr
Pr
OH
OH
Si
i
2. 3N HCl
N
H
R
3
6
R
O
3c R = phenyl
CR3
O
O
3d R = 4-Methylphenyl
R
N
3e R = 4-isopropylphenyl
OH
OH
N
N
3f R = 4-tert-Butylphenyl
OH
OH
3g R = 4-(2,4,6-trimethylphenyl)phenyl
3h R = 4-(2,4,6-triethylphenyl)phenyl
N
CR3
O
R
R
3a R = Ph
3b R = 3,5-dimethylphenyl
CPh3
O
O
CPh3
OH
N
N
O
OH
OH
N
O
N
HO
Ph3C
O
O
CPh3
7a
7b
Scheme 3. Preparation of BHA ligands.

A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
Table 2. Asymmetric epoxidation of allylic alcohols
6077
2.2. Asymmetric epoxidation of allylic alcohol
R2
R2
1 mol% VO(O-iPr)3;
2 mol% ligand 3
R1
R1
OH
OH
Our first ligand 3a was tested for the vanadium-catalyzed
asymmetric epoxidation of allylic alcohol 8a (Table 1).
The complex, which was generated with different ratio of
ligand 3a to VO(OiPr)3, was applied as the catalyst to per-
form the epoxidation in toluene in the presence of aqueous
TBHP. Similar yields and ee values were provided even if
the ratio of ligand to vanadium was increased to 3:1, which
have shown us that the negative effect of dynamic ligand ex-
change was not observed in the vanadium–bis-hydroxamic
acid catalyst system (entry 1–6).11,12,14 We then performed
the reaction with 1 mol % of vanadium reagent and 2 mol %
of ligand 3a in different solvent and CH2Cl2 was the best one
for both high yield and enantioselectivity (entry 7–10). Use
of anhydrous TBHP increased neither yield nor ee value (en-
try 12) and slow reactivity was surmounted by performing
the epoxidation at 0 ꢀC or at room temperature without sig-
nificant loss of enantioselectivity (entry 7, 14). When cata-
lyst loading was decreased to 0.2 mol %, both reactivity
and enantioselectivity were kept, which confirmed the high
efficiency of our chiral catalyst.
O
R3
R3
TBHP(70% aq.), CH2Cl2
8
9
Entrya
Epoxy alcohol
Ligand Temp,
time
Yieldb eec (%),
(%)
config.d
Ph
ꢁ20 ꢀC,
97,
(2R,3R)
9b
O
O
1
3a
84
OH
OH
48 h
Me
Ph
ꢁ20 ꢀC,
97,
(2R,3R)
9c
2
3
4
3a
3a
3a
53
56
51
60 h
C3H7
ꢁ20 ꢀC,
95,
(2R,3R)
9d
O
OH
72 h
C5H11
ꢁ20 ꢀC,
95,
(2R,3R)
9e
O
OH
72 h
9f
O
O
0 ꢀC,
12 h
OH
5
6
3a
3a
73
79
95, (R)
Ph
ꢁ20 ꢀC,
95,
(2R,3R)
With the modified reaction conditions and several designed
ligands in hand; we then performed the epoxidation of a
wide scope of allylic alcohols in CH2Cl2 with 1 mol % of va-
nadium reagent and 2 mol % of 3. As expected, the complex
of vanadium with 3 provided epoxy alcohols with both high
enantioselectivities and good yields (Table 2). The catalyst
derived from vanadium and 3a invariably induced excellent
enantioselectivity during the epoxidation of trans-
9g
OH
48 h
C6H13
0 ꢀC,
72 h
95,
(2R,3S)
9h
O
7
8
3c
3c
3c
60
24
64
OH
Ph
ꢁ20 ꢀC,
97,
(2R,3S)
9i
O
OH
5 d
Me
O
Ph
O
ꢁ20 ꢀC,
96,
(2R,3R)
9j
9
Table 1. Modification of conditions for asymmetric epoxidation of allylic
alcohols
OH
48 h
Ph
O
VO(O-i-Pr)3 1.0 mol%
ligand 3a
Ph
9k
ꢁ20 ꢀC,
95,
(2R,3S)
10
3c
62
68
OH
Ph
OH
Ph
OH
48 h
oxidant, solvent
ꢁ20 ꢀC,
95,
(2R,3R)
9a
8a
Entrya Ratiob Solvent
9l
O
11
3b
OH
48 h
Temp (ꢀC), Yieldc eed (%),
a
config.e
All reactions were carried out in dichloromethane in the presence of
1.5 equiv of tert-butylhydroperoxide (TBHP) (70% aqueous solution)
unless otherwise indicated.
Isolated yield after chromatographic purification.
ee values were determined by either chiral HPLC or GC and the detailed
time (h)
(%)
1
2
3
4
5
6
7
8
1:1
2:1
3:1
1:1
2:1
3:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
Acetone
Ethyl acetate 0, 12
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt, 6
rt, 6
rt, 6
0, 15
0, 15
0, 15
0, 12
0, 12
0, 12
96
96
95
90
87
84
93
95
48
93
95
91
90
91
90, (2R,3R)
92, (2R,3R)
93, (2R,3R)
93, (2R,3R)
94, (2R,3R)
93, (2R,3R)
94, (2R,3R)
83, (2R,3R)
85, (2R,3R)
92, (2R,3R)
93, (2R,3R)
94, (2R,3R)
95, (2R,3R)
97, (2R,3R)
b
c
information was provided in our published paper.7
Determined by comparison of reported optical rotation.
d
disubstituted and trisubstituted allylic alcohols. The most
gratifying aspect of this catalyst system was the excellent
enantioselectivity during epoxidation of cis-substituted al-
lylic alcohols with catalyst derived from vanadium and 3b.
Reactions were performed under air at 0 ꢀC to ꢁ20 ꢀC with
aqueous solution of TBHP to obtain all the above results.7
9
10
11f
12g
13h
14
0 w rt
0, 12
0, 12
ꢁ20, 48
a
All reactions were carried out in the presence of 1.5 equiv of tert-butyl-
hydroperoxide(TBHP)(70%aqueoussolution)unlessotherwiseindicated.
Ratio was the mole ratio of ligand 3a to VO(OiPr)3 when VO(OiPr)3 was
1.0 mol % of substrate in the reaction.
2.3. Asymmetric epoxidation of small allylic alcohol
b
c
Our vanadium–bis-hydroxamic acid ligand system was next
applied to asymmetric synthesis of small epoxy alcohols, a
long-standing problem for asymmetric oxidation.2 Since
our vanadium–3 complex was very difficult to be decom-
posed by water and very soluble in organic solvent, the prod-
uct was extracted with water to give the enantiopure epoxy
alcohols after the reaction (Table 3).15
Isolated yield after chromatographic purification.
d
ee values were determined by either chiral HPLC or chiral GC and the
detailed information was provided in our published paper.7
Determined by comparison of reported optical rotation.
0.2 mol % VO(OiPr)3 and 0.4 mol % ligand were used, reaction was per-
formed at 0 ꢀC for 6 h and then warmed to rt to complete the conversion.
3.5 M TBHP in dichloromethane was used.
e
f
g
h
VO(acac)2 was used.

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A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
Table 3. Asymmetric epoxidation of small allylic alcohols
Table 4. Ligand screening for asymmetric epoxidation of homoallylic alco-
hols
R2
R2
1 mol% VO(O-iPr)3;
2 mol% ligand 3
R1
R1
VO(O-i-Pr)3 (1 mol%)
OH
OH
Ph
Ph
O
ligand 3 (2 mol%)
R3
R3
OH
OH
CHP(88%), CH2Cl2
O
8
9
CHP
10a
11a
eec
Entrya
Epoxy alcohol
Ligand Temp, time Yieldb eec (%),
(%)
Entrya
Ligand
Solvent
Temp,
time (h)
Yieldb
(%)
config.d
(%)
0 ꢀC, 12 h;
wrt, 12 h
0 ꢀC, 24 h;
wrt, 24 h
1e
3b
3b
78
70
97, (R)
96, (R)
1
2
3
4
5
6
3a
3b
3c
3f
3g
3h
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
rt, 12
rt, 12
rt, 12
rt, 12
rt, 12
rt, 12
23
48
52
56
60
61
10
53
71
90
92
96
O
9n
OH
OH
2e,f
0 ꢀC, 12 h;
wrt, 12 h
9n
3
4
5
3a
3c
50
71
93, (2R,3R)
92, (2R,3S)
O
a
All reactions were carried out in toluene in the presence of 1.5 equiv of
cumene hydroperoxide (CHP) (88%) unless otherwise indicated.
Isolated yield after chromatographic purification.
0 ꢀC, 12 h;
wrt, 12 h
O
9o
OH
b
c
ee values were determined by either chiral HPLC (AD-H) or GC and the
0 ꢀC, 12 h;
wrt, 12 h
detailed information was provided in our published paper.8
9p 3a
68
73
95, (2R,3R)
94, (S)
O
OH
0 ꢀC, 12 h;
wrt, 12 h
6e
3b
O
9q
Table 5. Asymmetric epoxidation of homoallylic alcohols
OH
R2
R2
O
a
All reactions were carried out in dichloromethane in the presence of
1.5 equiv of cumene hydroperoxide (CHP) (88%) unless otherwise indi-
cated.
1 mol% VO(O-iPr)3;
R1
R1
2 mol% ligand 3f
OH
OH
R3
R3
b
c
CHP(70% aq.), toluene
rt, 24h
See Section 4.
ee values were determined by chiral GC and the detailed information was
10
11
provided in our published paper.7
d
e
f
Determined by comparison of reported optical rotation.
Toluene was used as solvent.
(ee; yield)
0.5 mol % VO(OiPr)3 and 0.6 mol % ligand were used.
H
O
H
Ph
Ph
C2H5
OH
OH
O
O
2.4. Asymmetric epoxidation of homoallylic alcohol
HO
H
H
11b
(99%; 85%)
H
11c
11a
We broadened our study to the asymmetric epoxidation of
homoallylic alcohols, which was more challenging than
allylic alcohols.2,6,13 Compared with the catalyst system
of allylic alcohols, several different modified conditions
were: (1) CHP was better than TBHP to facilitate and
complete the transformation; and (2) toluene was used as
solvent to inhibit cyclization of the produced epoxide to
the corresponding tetrahydrofuran by-product. Based on
modified conditions, all the three ligands that applied to
epoxidation of allylic alcohols (3a, 3b, and 3c) were tested
for homoallylic alcohol 10a. Ligand 3c was demonstrated
to be highly effective. With this promising result in hand,
we then modified ligands based on 3c. Ligand 3f was syn-
thesized and its vanadium complex increased the enantio-
selectivity dramatically. Finally, 3h, which was introduced
with a more hindered substituted phenyl group, was found
to be excellent for the reaction; 96% ee was obtained on
10a while the rate of the reaction was also facilitated
(Table 4).
(96%; 90%)
(93%; 85%)
H
H
C5H11
C6H13
OH
O
H
OH
OH
O
O
H
H
C2H5
11f
11d
11e
(98%; 92%)
H
(95%; 92%)
(96%; 89%)
H
H
H
H
H
OH
OH
O
OH
O
O
C5H11
C4H9
C3H7
11i
11g
(97%; 90%)
11h
(99%; 90%)
(99%; 91%)
alcohols and epoxy alcohols were obtained with satisfactory
enantiopurity. For the case of homoallylic alcohols, it should
also be noted that this kinetic resolution gave us an oppor-
tunity to generate asymmetric carbon in a completely new
scheme.7,8,15
The scope of the reaction was investigated with 3h under
the modified conditions. Gratifyingly, both trans- and cis-
substituted epoxides were achieved with virtually complete
enantioselectivities and satisfactory yields (Table 5).8,15
1 mol% VO(O-iPr)3;
O
2 mol% ligand 3a
OH
Ph
OH
Ph
OH
+
2.5. Kinetic resolution of allylic and homoallylic alcohols
TBHP (70% aq.)
Ph
CH2Cl2, 0 °C
51% conversion
With the successful results of the asymmetric epoxidation of
allylic and homoallylic alcohols, this catalyst system was ap-
plied to the kinetic resolution of these alcohols with out-
standing selectivities (Schemes 4 and 5). Both the starting
95% ee
93% ee
rac.
12
13
14
Scheme 4. Kinetic resolution of allylic alcohol.

A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
6079
0.5 mol% VO(O-iPr)3;
for trans-substituted allylic alcohols. On the other hand, the
additional flexibility of ligand 3c allows the cis-substituted
allylic alcohols enough space to fit in the chiral pocket
resulting in high selectivity.
O
R
1.0 mol% ligand 3h
HO
HO
HO
+
R
R
0.7 equiv. CHP;
toluene, rt, 30h
15
16a R=C2H5
17a R=C2H5
95%ee, 51% yield 95%ee, 48% yield
2.7. Asymmetric epoxidation of olefin
16b R=C4H9
17b R=C4H9
96%ee, 51% yield 97%ee, 48% yield
In a previous survey of metal BHA complexes to perform
oxidations of allylic alcohols, an interesting reaction was
observed. During the epoxidation of geraniol with molybde-
num–3c in the presence of TBHP, it was noticed that the
reaction provided a 1:1 mixture of 2,3-epoxygeraniol and
6,7-epoxygeraniol.7,16 These results suggested that a MoVI
complex of BHA in the presence of an organic hydroper-
oxide is a stronger oxidizing agent than VV complex and
that the former does not require substrate metal coordination
during the catalytic cycle.17 This prompted us to explore
enantioselective oxidation of olefins with Mo–BHA catalyst.
Scheme 5. Kinetic resolution of homoallylic alcohols.
2.6. Proposed transition state
To explain the enantioselectivity, we propose the following
possible intermediate during epoxidation (Scheme 6).
From the structural features of chiral cyclohexyl diamine,
the second and fourth quadrants are more crowded than
the first and third quadrants. The transition state assembly
of the ligand, allylic alcohol (or homoallylic alcohol), and
TBHP (or CHP) is governed by the following factors: (a) ste-
ric repulsion of the carboxylate side chain and cyclohexane
ring to direct the carbonyl inside the ring; (b) trans approach
of the allylic alcohol (or homoallylic alcohol) and TBHP (or
CHP) to minimize the steric hindrance, and (c) spiro overlap
of olefin and oxygen. For the case of allylic alcohol, the ste-
ric bulk at the alpha position of the carboxylate plays an im-
portant role, which is greater in the case of 3a, and suitable
Industrial use of molybdenum–peroxo complex for epoxida-
tion of alkenes has been extensively explored over the last 40
years beginning with homogeneous MoVI catalysts in the
Halcon and Arco processes.18 Consequently, considerable
effort has been directed toward the development of enantio-
selective epoxidation with chiral molybdenum catalysts.19,20
However, due to weak coordination of ligands with the
molybdenum, very little success has been achieved. The
H
O
V
O
N
O
N
O
C
*
HO
O
HO
O
O
N
C
N
O
O
O
Et
Et
Et
Et
Et
Et
Me
R
R
R
O
N
O
N
O
O
H
C
*
Et
HO
HO
O
R2
V
Et
Et
O
O
N
Et
C
N
R1
Et
O
O
O
Et
R
R
R
Et
Et
Et
Et
Et
Et
Scheme 6.

6080
A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
Table 7. Oxidation of olefins with different substitution patternsa
Table 6. Effect of achiral oxidant and liganda
MoO2(acac)2 (2 mol%)
O
R2
R2
MoO2(acac)2
O
R1
CH2Cl2, RT,17 h
R1
R3
R3
CH2Cl2
R4
RT, 15-46 h
R4
18
19
18a-n
19a-n
Entry
Oxidant
Ligand
Yieldb (%)
eec (%)
Entry
Epoxide
Ligand Oxidant Time Yieldb ee (%),c
(h) (%) config.d
1
2
3
4
5
6
7
8
9
TBHP (aq)
TBHP (aq)
CHP
THP
CHP
3a
3c
3c
3c
3e
3f
3g
7a
7b
20
15
72
27
92
82
91
17
13
28
42
66
96
80
87
58
91
42
O
19a
1
2
3
3d
3c
3d
THP
THP
THP
18 81
19 87
20 19
96, (S,R)
91, (S,R)
90, (S,R)
CHP
O
O
TBHP
THP
THP
19b
a
All reactions were carried out in CH2Cl2 in the presence of 1.5 equiv of
oxidant and 2 mol % of molybdenum catalyst at rt in air unless otherwise
indicated.
Isolated yield after chromatographic purification.
Determined by chiral HPLC or GC.
19c
b
c
O
19d
4
5
6
3e
3f
3c
TBHP 20 13
93, (R,R)
64, (R,S)
70, (R)
O
O
Mo–BHA complex successfully performed the catalyzed
asymmetric oxidation of mono-, di-, and trisubstituted ole-
fins under mild conditions in air at room temperature to
give epoxides in high yields and up to excellent selectivity.9
CHP
THP
22 77
19e
O
19f
36
7
In early experiments of the epoxidation of olefin 18, we
found that ligand 3c provided a higher selectivity over ligand
3a in the presence of aqueous TBHP (Table 6, entries 1–2).
Changing the oxidant to CHP or tritylhydroperoxide (THP)
did improve the selectivity, but reactivity was slower when
bulkier THP was utilized. Furthermore, oxidation of 18a
with bulkier ligands (3c–f) or a bulkier oxidant provided
good to excellent selectivity (entries 4–6). However, we
found that there is a ligand–oxidant relationship, whereas
a ligand that is too bulky 3g will decrease selectivity (entry
7). Additionally, we investigate the use of different BHA
backbones such as 7a and 7b, but the selectivities realized
were either slightly less or decreased, respectively (entries
8 and 9).
O
19g
7
3f
TBHP 36 29
72, (R)
O
8
9
3e
3f
CHP
23 70
60, (R)
43, (R)
19h
O
19i
TBHP 40 77
C6H13
Ph
O
10
11
3f
3f
CHP
36 89
50, (R,S)
81, (S,S)
19j
Under optimized conditions, we examined the scope of the
reaction, which proceeded in air at room temperature; Table
7 shows our preliminary results in olefin oxidation. More
notably, the size of ligands and the number of alkene substit-
uents play a crucial role in determining the rate of the oxida-
tion. As illustrated in Table 7, all cis-substituted olefins
gave excellent selectivity during oxidation (entries 1–4). It
is noteworthy that the epoxidation of 18c realizes only cis
product; no trans product is detected (entry 3). Trisubstituted
and terminal alkenes also provided good selectivity (entries
6–8, 10, 11). Another important aspect of this Mo–BHA
catalyst is that it selectively oxidizes the most electron rich
alkene in the presence of multiple double bonds (entries
12–13). Encouraged by the selectivity observed during myr-
cene (18m) oxidation, squalene (18o), an important bio-
genetic precursor of steroids and polycyclic terpenoids, was
subjected to similar reaction conditions (Scheme 7).21 To
our delight, Mo–3f complex in the presence of 1 equiv of
CHP selectively provided 2,3-epoxysqualene with good
enantioselectivity (69% ee). It is noteworthy that the synthe-
sis of 18o often requires multiple steps.
Ph
O
19k
TBHP 36 41
O
33, de
trans/cis
19l
12
13
3f
3f
3f
TBHP 46 47
CHP
44 91
75, (R)
19m
O
O
14
TBHP 17 13
43
19n
a
All reactions were carried out in CH2Cl2 in the presence of 1.5 equiv of
oxidant and 2 mol % of molybdenum catalyst at rt unless otherwise indi-
cated.
Isolated yield after chromatographic purification.
Determined by chiral HPLC or GC.
b
c
d
Configurations determined by comparison of specific rotation to the liter-
ature.

A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
6081
Table 8. Asymmetric oxidation of sulfidesa
BHA 3f
2, MoO2(acac)2
MoO2(acac)2 (2 mole%)
R1
R2
R1
R2
S
S
THP, CH2Cl2
O
CHP (1 eq), CH2Cl2, RT
33% , 69% ee
20a-g
21a-g
18o
2
Entry
Sulfide
Ligand Time Yieldb ee (%),c
(h)
(%)
config.d
1
2
3
4
5
3ce
3cf
3c
3d
3e
17
26
20
18
16
77
89
83
60
81
54, (S)
65, (S)
68, (S)
79, (S)
79, (S)
S
O
CH3
20a
19o
Scheme 7. Regio- and enantioselective oxidation of squalene.
S
CH3
6
7
3d
3e
17
20
99
75
65, (S)
81, (S)
2.8. Proposed transition state for Mo–BHA
20b
We believe that the mechanism follows the concerted metal
alkyl peroxide mechanism supported by Sharpless.22 The
BHA–Mo complex combines with the achiral oxidant to ox-
idize the olefin in a concerted fashion by transfer of oxygen
from the metal peroxide to the olefin. To explain the enantio-
selectivity, we propose the following possible intermediate
during epoxidation, noting the importance of the bulky achi-
ral oxidant (Scheme 8). From the structural features of chiral
cyclohexyl diamine, the second and fourth quadrants are
more crowded than the first and third quadrants, similar to
the V–BHA proposed earlier.
S
S
8
9
CH3
3d
3e
17
19
76
76
66, (S)
75, (S)
20c
20d
10
11
3d
3e
18
18
99
81
68, (S)
82, (S)
S
S
12
20e
3e
24
66
62, (R)
CH3
13
14
3e
17
21
82
71
86, (S)
82, (S)
3ef
20f
2.9. Asymmetric oxidation of sulfides and disulfides
S
CH3
To demonstrate further the versatility of the BHA, we pro-
ceeded to investigate its utility in the oxidation of sulfides.
Metal catalyzed asymmetric oxidation of sulfides, a powerful
strategy for the rapid preparation of enantiopure sulfoxides,
has garnered extensive attention from the synthetic commu-
nity.23–27 However, to date, application of molybdenum as
a catalyst for the asymmetric oxidation of sulfide remains
under-explored.29 Here, we report the first successful cata-
lytic asymmetric oxidation of sulfides and disulfides utiliz-
ing a catalytic amount of a chiral molybdenum complex in
the presence of an achiral oxidant under mild conditions.10
15
3e
19
83
72, (S)
20g
a
AllreactionswerecarriedoutinCH2Cl2 inthepresenceof1.0 equivofTHP
and 2 mol % of molybdenum catalyst at 0 ꢀC unless otherwise indicated.
Isolated yield after chromatographic purification.
ee values were determined by chiral HPLC.
Configurations determined by comparison of optical rotation to the liter-
ature.
b
c
d
e
f
1.0 equiv TBHP.
1.0 equiv CHP.
enantioselectivity (entry 2) under similar reaction condi-
tions. Highest enantioselectivity was obtained when bulkier
BHA 3e was utilized. It is important to note here that, isopro-
pyl phenyl sulfide (20e), which usually provides relatively
low enantionselectivity,23a,24e also provided good selectivity
(entry 12).
To evaluate the general applicability of BHA as a ligand for
asymmetric oxidation of various sulfides, phenyl methyl sul-
fide 20a was explored with our early results in Table 8.10 At
this stage, an array of ligands, reaction conditions, and oxi-
dants were surveyed. We found that 2 mol % of molybde-
num catalyst in the presence of THP is optimal for the
high enantioselectivity (entry 3). CHP also provided good
High enantioselectivity during sulfide oxidation is often due
to kinetic resolution of the newly formed sulfoxides by
R
R
R
O
N
O
N
O
O
C
*
HO
O
HO
Mo
O
O
N
C
N
O
O
O
R
R
R
Scheme 8. Proposed transition state for Mo–BHA.

6082
A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
Table 9. Asymmetric oxidation with kinetic resolutiona
High-performance liquid chromatography (HPLC) was per-
formed on a Varian ProStar Series equipped with a variable
wavelength detector using chiral stationary columns (Chira-
cel, AD, AS, OB, OB-H, OD, or OD-H, 0.46 cmꢂ25 cm)
from Daicel. Optical rotations were measured on a JASCO
DIP-1000 digital polarimeter. Analytical gas-liquid chroma-
tography (GLC) was performed on a Shimadzu GC-17A
instrument equipped with flame ionization detector and a
capillary column using chiral columns G-TA (0.25 mmꢂ
25 m) or BDP (0.25 mmꢂ25 m) using nitrogen as carrier
gas. All reactions were carried out in oven-dried glassware
with magnetic stirring unless otherwise noted. Analytical
thin layer chromatography (TLC) was performed on Merck
pre-coated TLC plates (silica gel 60 GF254, 0.25 mm). Flash
chromatography was performed on silica gel E. Merck 9385
or silica gel 60 extra pure (for all the bis-hydroxamic acids).
Dichloromethane (CH2Cl2) and toluene (PhCH3) were
purchased from Acros as anhydrous solvents. N,N-Diisopro-
pylethylamine and triethylamine were stored over KOH
pellets. Substrates were purchased from commercial vendors
or have been previously prepared by reported procedures
and characterized. Olefins and products in Table 7 have
been previously isolated and characterized. Sulfides and
products in Table 8 have been previously isolated and char-
acterized. References can be found elsewhere and within this
paper. Anhydrous tritylhydroperoxide (THP) was prepared
according to the literature procedure. All other reagents
and starting materials, unless otherwise noted, were pur-
chased from commercial vendors and used without further
purification. High-resolution electro spray ionization
(HRMS-ESI) mass spectra were obtained on a Micromass
Q-TOF-2, quadruple time-of-flight mass spectrometer at
the University of Illinois Research Resources Center in
positive mode.
Entry Sulfide Oxidant Sulfoxide:sulfone Yieldb ee (%),c
(%)
config.
1
2
3
20a
20b
20d
20g
THPg
THPd
CHPe
THPg
THP
81:19
81:19
49:51
82:18
74:26
46:54
80:20
72:28
32:68
76:24
50:50
68
66
43
74
55
37
69
51
31
50
47
92, (S)
92, (S)
96, (S)
87, (S)
94, (S)
95, (S)
91, (S)
96, (S)
97, (S)
93, (S)
99, (S)
CHPe
THPg
THP
CHPf
THP
4
CHPe
a
All reactions were carried out in CH2Cl2 in the presence of 1.5 equiv of
THP and 2 mol % of molybdenum–3d catalyst at ꢁ40 ꢀC, 19 h then
0 ꢀC, 24 h unless otherwise indicated.
Isolated yield after chromatographic purification.
ee values were determined by chiral HPLC.
ꢁ40 ꢀC, 44 h then 0 ꢀC, 47 h.
b
c
d
e
f
1.55 equiv CHP.
1.75 equiv CHP.
2 mol % of molybdenum–3e.
g
generating a significant amount of sulfones.24–28 We found
that the oxidation of phenyl methyl sulfoxide (20a) was slow,
but molybdenum–3d complex selectively oxidized one of
the enantiomers. We were pleased to find that the R isomer
of 21a, which is the minor isomer produced during oxidation
of 20a, was oxidized in a faster rate.
The results of this study are listed in Table 9. Both oxidants
CHP and THP provided excellent selectivity during the pro-
cess (ee 87–99%).
3. Conclusion
4.2. Preparation of ligands
In conclusion, we have designed a series of new C2-sym-
metric bis-hydroxamic acid ligands and developed a new
catalyst system for the asymmetric oxidation of allylic alco-
hols, homoallylic alcohols, unfunctionalized olefins, and
sulfides. In addition, kinetic resolution of allylic alcohols,
homoallyic alcohols, and sulfides enhances its versatility as
an asymmetric catalyst. Mechanistic understanding and
study of further applications of bis-hydroxamic acid ligands
in asymmetric reactions are on going.
4.2.1. Preparation of (R,R)-N,N0-bis-(4-methoxybenzyl-
idene)-cyclohexane-1,2-diimine. A mixture of diammo-
nium salt (4) (26.4 g, 100 mmol), K2CO3 (27.6 g,
200 mmol), and de-ionized water (130 mL) was stirred until
dissolution was achieved, and then ethanol (420 mL) was
added. The resulting cloudy mixture was heated to reflux,
and a solution of p-anisaldehyde (27.5 g, 200 mmol) in eth-
anol (40 mL) was added in a steady stream over 30 min. The
yellow slurry was stirred at reflux for 5 h before heating was
discontinued. The reaction mixture was cooled to room tem-
perature, and the water phase was separated and discarded.
The organic phase was concentrated and dissolved in di-
chloromethane. It was then removed any trace of water,
dried over Na2SO4, and filtered. The filtrate was removed
of solvent to provide crude diimine as light yellow solid,
which was purified by recrystallization from dichloro-
methane and hexanes as white solid (31.5 g, 90% yield).
FTIR (film) nmax 2929, 2855, 1643, 1606, 1579, 1512,
4. Experimental
4.1. General methods
Infrared (IR) spectra were recorded on a Nicolet 20 SXB
FTIR. 1H NMR spectra were recorded on a Bruker Avance
400 (400 MHz) or Bruker Avance 500 (500 MHz) spectro-
meter. Chemical shift values (d) are expressed in parts per
million downfield relative to internal standard (tetramethyl-
silane at 0 ppm). Multiplicities are indicated as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), and br
(broad). 13C NMR spectra were recorded on a Bruker
Avance 400 (100 MHz) and Bruker Avance 500 (125 MHz)
spectrometer and are expressed in parts per million using
solvent as the internal standard (CDCl3 at 77.23 ppm).
1463, 1303, 1250, 1165, 1032, 831 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 8.12 (s, 2H), 7.52 (d, J¼8.8 Hz,
4H), 6.82 (d, J¼8.8 Hz, 4H), 3.78 (s, 6H), 3.37–3.32 (m,
2H), 1.87–1.77 (m, 6H), 1.49–1.46 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 161.5 (C), 160.5 (CH), 129.7 (CH),
114.0 (CH), 74.0 (CH3), 55.5 (CH), 33.3 (CH2), 24.8
(CH2); HRMS-ESI calcd for C22H27O6N2 [M+H]+
351.2073, found 351.2076.

A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
6083
4.2.2. Preparation of dioxaziridine 5. To a stirred solution
of diimine (10.5 g, 30.0 mmol) in MeCN (180 mL) and THF
(360 mL), at room temperature, was added an aqueous solu-
tion (300 mL) of KHCO3 (50.5 g, 504 mmol) followed by an
aqueous solution (300 mL) of oxone (44 g, 72 mmol). After
stirring for 3 h, the reaction mixture was diluted with
CH2Cl2 (600 mL). The biphasic mixture was separated
and the aqueous portion was extracted with CH2Cl2
(2ꢂ100 mL) and the combined organic extracts were dried
over Na2SO4 and filtered. The filtrate was concentrated
under reduced pressure to provide crude dioxaziridine 5
(10.3 g, 90% yield) as light yellow solid, which was used
in the following step without further purification. Pure prod-
uct, which was applied to determine the structure, was
obtained by recrystallization from dichloromethane and
hexane as white solid. FTIR (film) nmax 2935, 1615, 1517,
by washing with the mixture of EtOAc/hexanes (5:95) to
provide 6 (3.85 g, 61% yield), which was used in the follow-
ing step without further purification. H NMR (400 MHz,
CDCl3) d 5.17 (br, 2H), 2.83–2.77 (m, 2H), 1.76–1.74 (m,
2H), 1.54–1.50 (m, 2H), 1.30–1.26 (m, 2H), 1.12–1.03 (m,
16H).
1
4.2.5. General procedure for preparation of bis-hydroxa-
mic acids. To a stirred solution of 6 (570 mg, w2.0 mmol)
obtained from the previous reaction and DIEA (1.04 mL,
6.00 mmol) in CH2Cl2 (20 mL) was added acid chloride
(6.00 mmol, dissolved in 10 mL CH2Cl2) under nitrogen.
After 72 h, the reaction mixture was treated with 3 N HCl
(or 1 M HCl/MeOH). After stirring for 30 min the reaction
mixture was extracted with CH2Cl2, washed with brine,
dried over Na2SO4, and filtered. The filtrate was concen-
trated under reduced pressure and the residue was purified
by flash column chromatography on silica gel to provide
the bis-hydroxamic acid.
1
1309, 1456, 1437, 1310, 1252, 1171, 1031, 821 cmꢁ1; H
NMR (400 MHz, CDCl3) d 6.81–6.78 (m, 4H), 6.58–6.54
(m, 4H), 4.37 (s, 2H), 3.78 (s, 6H), 2.39–2.37 (m, 2H),
2.21–2.18 (m, 2H), 1.83–1.80 (m, 2H), 1.58–1.51 (m, 2H),
1.31–1.27 (m, 2H). 13C NMR (125 MHz, CDCl3) d 160.7
(C), 129.0 (CH), 126.5 (C), 113.8 (CH), 81.6 (CH), 72.4
(CH3/CH), 55.4 (CH3/CH), 30.3 (CH2), 24.1 (CH2);
HRMS-ESI calcd for C22H26O4N2Na [M+Na]+ 405.1788,
found 405.1790.
4.2.5.1. Ligand 3a. Yield 55%; white solid; Rf 0.5
(EtOAc/hexanes, 3:7); FTIR (film) nmax 3195, 3062, 3029,
2961, 2940, 2862, 1750, 1687, 1658, 1620, 1600, 1495,
1451, 1401, 1309, 1251, 1166, 1079, 1032, 909, 733,
699 cmꢁ1 1H NMR (400 MHz, CDCl3) d 9.04 (s, 2H),
;
7.32–7.04 (m, 20H), 5.50 (s, 2H), 4.56–4.55 (m, 2H), 1.78
(m, 6H), 1.24 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 175.2 (C]O), 139.4 (C), 139.2 (C), 129.5 (CH), 128.9
(CH), 128.8 (CH), 128.7 (CH), 127.3 (CH), 127.1 (CH),
56.7 (CH), 53.4 (CH), 27.9 (CH2), 24.6 (CH2); HRMS-ESI
calcd for C34H34O4N2Na [M+Na]+ 557.2416, found
557.2438; [a]2D8.4 +93.47 (c 1.0, CHCl3). Mp 229–231 ꢀC.
4.2.3. Preparation of dihydroxylamine dihydrochloride.
To a mixture of the unpurified product 5 (10.3 g) obtained
from the previous oxidation reaction and benzyloxyhydroxyl
amine hydrochloride (8.80 g, 55.1 mmol) was treated with
anhydrous methanol (250 mL), and then 1 M HCl in
MeOH (94 mL, 94 mmol) was added immediately. The re-
sulting mixture was stirred for 20 min. The reaction mixture
was then concentrated under reduced pressure to dryness.
Et2O (200 mL) and de-ionized water (100 mL) was added.
The bi-layer was separated and the organic part was ex-
tracted with de-ionized water (20 mL). Combined aqueous
portion was washed with Et2O (2ꢂ100 mL). The aqueous
portion was concentrated to 60–75 mL and the resulting
white solid (BnONH2$HCl) was filtered off, then filtrate
was concentrated under reduced pressure to provide bis-hy-
droxylamine dihydrochloride (6.10 g, 90% yield) as an oily
solid, which contained 5–10% of BnONH2$HCl. This mate-
rial was utilized in the next step without any purification. 1H
NMR (400 MHz, D2O) d 3.66–3.62 (m, 2H), 2.02–1.98 (m,
2H), 1.69–1.66 (m, 2H), 1.41–1.37 (m, 4H), 1.20–1.15 (m,
2H); 13C NMR (100 MHz, D2O) d 58.6 (CH), 25.1 (CH2),
22.1 (CH2).
4.2.5.2. Ligand 3b. Yield 20%; Rf 0.5 (EtOAc/hexane,
1:4); FTIR (film) nmax 3172, 3007, 2919, 2861, 1621,
1602, 1452, 1404, 1309, 1264, 1233, 1166, 1132, 1037,
958, 897, 851, 823, 790, 770, 736, 710, 688, 660 cmꢁ1; 1H
NMR (400 MHz, CDCl3) d 8.42 (s, 2H), 6.87–6.72 (m,
12H), 5.35 (s, 2H), 4.52–4.50 (m, 2H), 2.27 (s, 12H), 2.14
(s, 12H), 1.89–1.77 (m, 6H), 1.26 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 175.0 (C]O), 139.2 (C), 139.0 (C),
137.9 (C), 137.5 (C), 128.6 (CH), 128.5 (CH), 126.8 (CH),
126.4 (CH), 56.5 (CH), 53.0 (CH), 27.7 (CH2), 24.5
(CH2), 21.4 (CH3), 21.3 (CH3); HRMS-ESI calcd for
C42H50O4N2Na [M+Na]+ 669.3668, found 669.3668.
4.2.5.3. Ligand 3c. Yield 72%; white solid; Rf 0.63
(EtOAc/hexanes, 1:3); FTIR (film) nmax 3150, 2938, 2859,
1
1616, 1493, 1446, 1419, 1170, 769, 700 cmꢁ1; H NMR
4.2.4. Preparation of O-protected dihydroxylamine 6. To
a stirred suspension of unpurified bis-hydroxylamine dihy-
drochloride (6.10 g) obtained from the previous reaction in
CH2Cl2 (100 mL) under nitrogen at room temperature was
added Et3N (11.1 mL, 76.8 mmol). After 1 h, to the resulting
cloudy white suspension, DMAP (180 mg, 1.47 mmol), imi-
dazole (2.00 g, 29.4 mmol) followed by dichlorodiisopro-
pylsilane (5.00 mL, 27.7 mmol) were added and stirring
was continued for 2 h, and then poured into an aqueous so-
lution of NaHCO3 (5.16 g, 61.4 mmol) and extracted with
EtOAc (2ꢂ100 mL). The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was dissolved in a small amount of di-
chloromethane and filtered through a small plug of silica gel
(400 MHz, CDCl3) d 8.26 (s, 2H), 7.28–7.17 (m, 30H),
4.19 (d, J¼16.1 Hz, 2H), 3.94–3.92 (m, 2H), 3.55 (d,
J¼16.1 Hz, 2H), 1.68–1.65 (m, 2H), 1.50–1.38 (m, 4H),
1.12–1.07 (m, 2H); 13C NMR (100 MHz, CDCl3) d 173.6
(C]O), 147.2 (C), 129.6 (CH), 127.8 (CH), 126.3 (CH),
56.2 (C), 55.2 (CH), 42.5 (CH2), 27.5 (CH2), 24.6 (CH2);
HRMS-ESI calcd for C48H46O4N2Na [M+Na]+ 737.3355,
found 737.3379; [a]D28.4 +22.12 (c 1.0, CHCl3). Mp 235–
237 ꢀC.
4.2.5.4. Ligand 3d. Yield 72%; white solid; (EtOAc/hex-
anes, 1:3); FTIR (film) nmax 3166, 2921, 2861, 2360, 2339,
1616, 1456, 1418, 1239, 1172, 1021, 910, 811, 732,
570 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.75 (s, 2H),
;

6084
A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
7.11 (d, J¼7.5 Hz, 12H), 7.03 (d, J¼7.5 Hz, 12H), 4.14 (br
d, J¼14.5 Hz, 2H), 3.98 (br m, 2H), 3.56 (br d, J¼14.5 Hz,
2H), 2.3 (s, 18H), 1.97 (m, 2H), 1.69 (m, 2H), 1.55–1.47 (m,
4H); 13C NMR (125 MHz, CDCl3) d 174.0, 144.5, 135.6,
129.2, 128.5, 55.1, 54.8, 42.8, 27.5, 24.5, 21.0. Mp 232–
233 ꢀC; HRMS: M+H 799.447 observed, 799.44693 ex-
pected.
(CH2), 43.66 (CH), 37.62 (CH2), 36.67 (C); FTIR (film)
nmax 3431, 2916, 2848, 2338, 2112, 1642, 1492, 1472,
1446, 1416, 1265, 1186, 1034, 910, 700, 576 cmꢁ1; Mp
139–142 ꢀC; HRMS: M+H 745.3274 observed, 745.32721
expected.
1
4.2.5.10. Ligand 7b. Yield 90%; H NMR (500 MHz,
CDCl3) d .18 (24H, m), 7.12 (6H, m), 6.36 (2H, br s), 4.88
(2H, m), 4.31 (2H, d), 3.92 (4H, s), 3.79 (2H, t), 3.72 (2H,
m); 13C NMR (100 MHz, CDCl3) d 168.4 (C]O), 143.0
(C), 129.6 (CH), 127.8 (CH), 126.3 (CH), 56.2 (C), 43.1
(CH), 27.5 (CH2), 24.6 (CH2); FTIR (film) nmax 3436,
3057, 2939, 2860, 2361, 2336, 1617, 1493, 1421, 1241,
4.2.5.5. Ligand 3e. Yield 72%; white solid; Rf 0.62
(EtOAc/hexanes, 1:3); FTIR (film) nmax 3126, 2958, 2870,
1616, 1507, 1457, 1418, 1240, 1173, 1057, 1019, 910,
1
828, 734, 584 cmꢁ1; H NMR (400 MHz, CDCl3) d 8.40
(s, 2H), 7.14 (d, J¼7.5 Hz, 12H), 6.97 (d, J¼7.5 Hz, 12H),
4.07 (br d, J¼14.5 Hz, 2H), 3.80–3.78 (br m, 2H), 3.59 (br
d, J¼14.5 Hz, 2H), 2.85–2.79 (m, 6H), 1.54–1.50 (m, 2H),
1.29–1.15 (m, 40H), 0.95–0.91 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 173.6, 146.3, 144.9, 129.6, 125.7,
55.8, 55.0, 42.2, 33.7, 27.4, 24.5, 24.3, 24.1. Mp 193–
195 ꢀC; HRMS: M+H 967.6357 observed, 967.63474
expected.
1170, 1029, 737, 561 cmꢁ1
.
4.3. General procedure for asymmetric epoxidation
of allylic alcohols in the presence of VO(OiPr)3
and ligand 3
To a solution of 3 (0.0210 mmol) in dichloromethane
or toluene (1 mL) was added VO(OiPr)3 (0.0025 mL,
0.0104 mmol), and the mixture was stirred for 1 h at room
temperature. The resulting solution was cooled to 0 ꢀC,
and then 70% aqueous tert-butylhydroperoxide (TBHP)
(0.22 mL, 1.59 mmol) and allylic alcohol 8 (1.05 mmol)
were added and stirring was continued at the same tempera-
ture for several hours. The process of epoxidation was mon-
itored by TLC. Saturated aqueous Na2SO3 was added, and
the mixture was stirred for 1 h at 0 ꢀC. The mixture was
then allowed to warm to room temperature, extracted with
Et2O, dried over Na2SO4, and concentrated under reduced
pressure. The remaining residue was purified by flash column
chromatography on silica gel to provide epoxy alcohol 9.
4.2.5.6. Ligand 3f. Yield 45%; white solid; Rf 0.50
(EtOAc/hexanes, 1:6); H NMR (400 MHz, CDCl3) d 8.08
1
(br, 2H), 7.23–7.21 (m, 12H), 7.16–7.14 (m, 12H), 4.23–
4.20 (m, 2H), 4.13–4.11 (m, 2H), 3.67–3.64 (m, 2H),
1.60–1.00 (m, 8H), 1.27 (s, 54H); 13C NMR (100 MHz,
CDCl3) d 173.5 (C]O), 148.3 (C), 144.2 (C), 129.0 (CH),
124.4 (CH), 55.0 (C), 54.9 (CH), 42.3 (CH2), 34.3 (C),
31.4 (CH3), 27.4 (CH2), 24.3 (CH2); HRMS-ESI calcd for
C72H95O4N2 [M+H]+ 1051.7286, found 1051.7267. Mp
225–227 ꢀC.
4.2.5.7. Ligand 3g. Yield 40%; white solid; Rf 0.35
(EtOAc/hexanes, 1:6); H NMR (400 MHz, CDCl3) d 7.56
1
(s, 2H), 7.30–7.28 (m, 12H), 7.00–6.98 (m, 12H), 6.89 (s,
12H), 4.52 (d, J¼16.4 Hz, 2H), 4.11–4.10 (m, 2H), 3.70
(d, J¼16.4 Hz, 2H), 2.28 (s, 18H), 1.97 (s, 36H); 13C
NMR (100 MHz, CDCl3) d 174.6 (C]O), 145.6 (C),
138.8 (C), 138.6 (C), 136.4 (C), 136.0 (C), 129.6 (CH),
128.8 (CH), 128.3 (CH), 55.8 (C), 55.0 (CH), 43.7 (CH2),
27.6 (CH2), 24.4 (CH2), 21.0 (CH3), 20.8 (CH3). Mp 212–
213 ꢀC; HRMS: M+H 1423.82057 observed, 1423.82254
expected.
4.4. General procedure for asymmetric epoxidation
of small allylic alcohols in the presence of VO(OiPr)3
and ligand 3
To a solution of 3 (0.0125 mmol) in dichloromethane or
toluene (1 mL; for the case of 8q, only 0.25 mL of toluene
was used as solvent) was added VO(OiPr)3 (0.0025 mL,
0.0104 mmol), and the mixture was stirred for 1 h at room
temperature. The resulting solution was cooled to 0 ꢀC,
and then 88% cumene hydroperoxide (CHP) (0.25 mL,
1.50 mmol) and small allylic alcohol 8 (0.086 mL,
1.00 mmol) were added and stirring was continued at the
same temperature for 12 h. Reaction mixture was then al-
lowed to warm to room temperature and stirring was contin-
ued at room temperature for another 12 h to make sure that
the epoxidation was complete. It was then extracted with
de-ionized water (3ꢂ0.5 mL). To the combined aqueous
portion, saturated aqueous NaHCO3 (0.010 mL) was added
to prevent the hydrolysis of the epoxy alcohol 9 and the mix-
ture was extracted with toluene (3ꢂ1.0 mL) to remove resi-
dual cumene hydroperoxide and 2-phenyl-2-propanol. All the
above extractions were performed by utilizing the vortex
mixer to achieve efficient mixing and at 0 ꢀC to prevent
the hydrolysis of epoxy alcohol 9. To the aqueous portion,
fresh distilled anhydrous THF (5 mL) was added and con-
centrated under reduced pressure with rotary evaporator at
room temperature. To the concentrate (w2 mL), additional
THF (5 mL) was added and solvent was removed under the
same conditions. This process was repeated for eight times
4.2.5.8. Ligand 3h. Yield 40%; white solid: Rf 0.45
(EtOAc/hexanes, 1:6); H NMR (400 MHz, CDCl3) d 7.39
1
(s, 2H), 7.29–7.27 (m, 12H), 7.04–7.01 (m, 12H), 6.93 (s,
12H), 4.51 (d, J¼16.4 Hz, 2H), 4.11–4.10 (m, 2H), 3.73
(d, J¼16.4 Hz, 2H), 2.65 (q, J¼7.6 Hz, 12H), 2.32 (q,
J¼7.5 Hz, 24H), 1.78–1.74 (m, 6H), 1.28 (q, J¼7.6 Hz,
18H), 1.22–1.20 (m, 2H), 0.99 (t, J¼7.5 Hz, 36H); 13C
NMR (100 MHz, CDCl3) d 174.7 (C]O), 145.6 (C),
143.1 (C), 142.1 (C), 138.2 (C), 137.8 (C), 129.2 (CH),
128.9 (CH), 125.1 (CH), 55.7 (C), 54.8 (CH), 43.7 (CH2),
28.6 (CH2), 27.6 (CH2), 26.9 (CH2), 24.4 (CH2), 15.5
(CH3), 15.4 (CH3); HRMS-ESI calcd for C120H143O4N2
[M+H]+ 1676.1042, found 1676.1040.
1
4.2.5.9. Ligand 7a. Yield 34%; H NMR (500 MHz,
CDCl3) d 7.22 (30H, m), d 5.28 (2H, dd), 4.06 (2H, d),
3.85 (2H, m), 2.18 (2H, m), 1.95 (2H, m), 1.72 (2H, m);
13C NMR (100 MHz, CDCl3) d 169.80 (C]O), 136.4 (C),
129.24 (CH), 127.68 (CH), 123.4 (CH), 70.57 (CH), 54.1

A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
6085
and all the solvent was removed at the final time to provide
the product as colorless liquid, which contained a mixture of
epoxy alcohol 9 and THF (mole ratio was determined by 1H
NMR). GC analysis: distribution of the product was above
97% epoxy alcohol 9.
(g-TA), injection 120 ꢀC, column 100 ꢀC, pressure
100 kPa, 29.6 min (minor) (3S,4R), 36.8 min (major)
(3R,4S).
1
Compound 11g: yield 90%; H NMR (400 MHz, CDCl3)
d 3.90–3.84 (m, 2H), 3.11–3.08 (m, 1H), 2.97–2.96 (m,
1H), 1.89–1.87 (m, 2H), 1.72–1.70 (m, 1H), 1.54–1.50 (m,
4H), 1.00 (t, J¼7.6 Hz, 3H); 97% ee, GC (g-TA), injection
140 ꢀC, column 120 ꢀC, pressure 100 kPa, 18.4 min (minor),
19.6 min (major).
4.5. General procedure for asymmetric epoxidation of
homoallylic alcohols in the presence of VO(OiPr)3 and
ligand 3h
To a solution of 3h (35.2 mg, 0.0210 mmol) in toluene
(0.25 mL) was added VO(OiPr)3 (0.0025 mL, 0.0104 mmol),
and the mixture was stirred for 8 h at room temperature.
Eighty-eight percentage of cumene hydroperoxide (CHP)
(0.25 mL, 1.50 mmol) and homoallylic alcohol 10
(1.05 mmol) were then added and the stirring was continued
at the same temperature for 24 h. The process of epoxidation
was monitored by TLC. The mixture was then allowed to be
purified by flash column chromatography on silica gel to
provide epoxy alcohol 11.
1
Compound 11h: yield 91%; H NMR (400 MHz, CDCl3)
d 3.90–3.85 (m, 2H), 3.11–3.08 (m, 1H), 2.96–2.95 (m,
1H), 1.86–1.85 (m, 2H), 1.70–1.67 (m, 1H), 1.56–1.38 (m,
6H), 0.94 (t, J¼7.5 Hz, 3H); 99% ee, GC (g-TA), injection
140 ꢀC, column 120 ꢀC, pressure 100 kPa, 26.1 min (minor),
28.4 min (major).
1
Compound 11i: yield 90%; H NMR (400 MHz, CDCl3)
d 3.80–3.78 (m, 2H), 3.50 (br, 1H), 3.10–3.07 (m, 1H),
2.96–2.95 (m, 1H), 1.85–1.83 (m, 1H), 1.69–1.66 (m, 1H),
1.54–1.52 (m, 4H), 1.36–1.33 (m, 4H), 0.92 (t, J¼6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 60.2 (CH2), 56.9
(CH), 54.9 (CH), 31.4 (CH2), 30.6 (CH2), 27.8 (CH2), 26.1
(CH2), 22.5 (CH2), 13.9 (CH3); 99% ee, GC (g-TA), injec-
tion 140 ꢀC, column 120 ꢀC, pressure 100 kPa, 41.8 min
(minor), 45.1 min (major).
1
Compound 11a: yield 90%; H NMR (400 MHz, CDCl3)
d 7.35–7.26 (m, 5H), 3.88–3.87 (m, 2H), 3.74 (d,
J¼2.1 Hz, 1H), 3.17–3.14 (m, 1H), 2.14–2.09 (m, 1H),
1.90–1.85 (m, 1H), 1.80 (br, 1H); 96% ee, HPLC (AD-H),
hexanes/isopropanol¼95:5, flow rate¼1 mL/min, 15.0 min
(major), 17.6 min (minor).
1
Compound 11b: yield 85%; H NMR (400 MHz, CDCl3)
4.6. Procedure for kinetic resolution of secondary allylic
alcohols in the presence of VO(OiPr)3 and ligand 3
d 7.38–7.29 (m, 5H), 4.14 (d, J¼4.2 Hz, 1H), 3.80–3.76
(m, 2H), 3.42–3.38 (m, 1H), 1.61–1.51 (m, 3H); 99% ee,
HPLC (AD-H), hexanes:isopropanol¼98:2, flow rate¼
0.7 mL/min, 54.3 min (major), 57.7 min (minor).
To a solution of 3a (0.0420 mmol) in dichloromethane
(1 mL) was added VO(OiPr)3 (0.0050 mL, 0.0208 mmol),
and the mixture was stirred for 1 h at room tempera-
ture. The resulting solution was cooled to 0 ꢀC, and then
70% aqueous tert-butylhydroperoxide (TBHP) (0.44 mL,
3.18 mmol) and secondary allylic alcohol 12 (2.10 mmol)
were added and stirring was continued at the same tempera-
ture for 12 d. [The process of conversion was monitored by
HPLC: saturated aqueous Na2SO3 was added to a small por-
tion of reaction mixture (0.05 mL), and the mixture was
stirred for 30 min at 0 ꢀC. The mixture was then allowed
to warm to room temperature, extracted with Et2O, dried
over Na2SO4, and concentrated under reduced pressure.]
Saturated aqueous Na2SO3 was added when the conversion
was over 51%, and the mixture was stirred for 1 h at 0 ꢀC.
The mixture was then allowed to warm to room temperature,
extracted with Et2O, dried over Na2SO4, and concentrated
under reduced pressure. The remaining residue was purified
by flash column chromatography on silica gel to provide the
secondary allylic alcohol 13 and the epoxy alcohol 14. ee
values of 13 and 14 were determined by chiral HPLC.7
1
Compound 11c: yield 85%; H NMR (400 MHz, CDCl3)
d 3.82–3.76 (m, 2H), 2.90–2.85 (m, 1H), 2.78–2.74 (m,
1H), 2.00–1.90 (m, 1H), 1.76–1.63 (m, 1H), 1.58 (br, 1H),
1.00 (t, J¼16.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 59.8 (CH2), 56.5 (CH), 56.5 (CH), 34.3 (CH2), 25.9
(CH2), 9.8 (CH3); 93% ee, GC (g-TA), injection 120 ꢀC, col-
umn 100 ꢀC, pressure 100 kPa, 41.8 min (major) (3R,4R),
45.3 min (minor) (3S,4S).
1
Compound 11d: yield 89%; H NMR (400 MHz, CDCl3)
d 3.80–3.79 (m, 2H), 2.87–2.86 (m, 1H), 2.81–2.80 (m,
1H), 2.01–1.92 (m, 1H), 1.91 (br, 1H), 1.71–1.65 (m, 1H),
1.55–1.52 (m, 2H), 1.44–1.40 (m, 2H), 1.34–1.30 (m, 4H),
0.92 (t, J¼5.8 Hz, 3H); 96% ee, GC (g-TA), injection
120 ꢀC, column 100 ꢀC, pressure 100 kPa, 36.7 min (major),
38.0 min (minor).
1
Compound 11e: yield 92%; H NMR (400 MHz, CDCl3)
d 3.80–3.79 (m, 2H), 2.87–2.86 (m, 1H), 2.81–2.80 (m,
1H), 2.04–1.94 (m, 1H), 1.90 (br, 1H), 1.73–1.63 (m, 1H),
1.55–1.52 (m, 2H), 1.45–1.43 (m, 2H), 1.36–1.30 (m, 6H),
0.90 (t, J¼6.6 Hz, 3H); 98% ee, GC (g-TA), injection
120 ꢀC, column 100 ꢀC, pressure 100 kPa, 61.8 min (major),
63.0 min (minor).
4.7. Procedure for kinetic resolution of homoallylic
alcohols in the presence of VO(OiPr)3 and ligand 3h
To a solution of 3h (35.2 mg, 0.0210 mmol) in toluene
(0.25 mL) was added VO(OiPr)3 (0.0025 mL, 0.0104 mmol),
and the mixture was stirred for 8 h at room temperature.
Eighty-eight percentage of cumene hydroperoxide (CHP)
(0.37 mL, 1.47 mmol) and homoallylic alcohol 15 (racemic,
2.10 mmol) were then added and stirring was continued
at the same temperature for 30 h. [The process of conversion
1
Compound 11f: yield 92%; H NMR (400 MHz, CDCl3)
d 3.84–3.81 (m, 2H), 3.10–3.09 (m, 1H), 2.91–2.89 (m,
1H), 2.16 (br, 1H), 1.85–1.83 (m, 1H), 1.70–1.67 (m, 1H),
1.58–1.50 (m, 2H), 1.05 (t, J¼7.6 Hz, 3H); 95% ee, GC

6086
A. U. Barlan et al. / Tetrahedron 63 (2007) 6075–6087
€
Roschmann, K. J.; Saha-Moller, C. R.; Schenk, W. A.
J. Organomet. Chem. 2002, 661, 3; (f) Lattanzi, A.; Scettri,
A. J. Organomet. Chem. 2006, 691, 2072; (g) Shi, Y. Acc.
Chem. Res. 2004, 37, 488; (h) Shi, Y.; Frohn, M. Synthesis
2000, 14, 1979.
was monitored by GC.] Saturated aqueous Na2SO3 was
added when the conversion reached 50%, and the mixture
was stirred for 1 h at 0 ꢀC. The mixture was then allowed
to warm to room temperature, extracted with Et2O, dried
over Na2SO4, and concentrated under reduced pressure.
The remaining residue was purified by flash column chro-
matography on silica gel to provide the homoallylic alcohols
16 and the epoxy alcohols 17, ee values of 16 and 17 were
determined by chiral GC.8
2. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974; (b) Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1984,
49, 3707; (c) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765.
3. For recent reports on chiral vanadium catalyst for epoxidation,
see: (a) Bryliakov, K. P.; Talsi, E. P. Kinetics and Catalysis
(Translation of Kinetika i Kataliz) 2003, 44, 334; (b) Bolm,
C.; Kuhn, T. Synlett 2000, 899; (c) Traber, B.; Jung, Y. G.;
Park, T. K.; Hong, J. I. Bull. Korean Chem. Soc. 2001, 22,
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2002, 13, 2625; (e) Bourhani, Z.; Malkov, A. V. Chem.
Commun. 2005, 4592; (f) Lattanzi, A.; Piccirillo, S.; Scettri,
A. Eur. J. Org. Chem. 2005, 1669.
4.8. General procedure for asymmetric oxidation of
olefins in the presence of MoO2(acac)2 and ligand 3
To a solution of BHA (0.022 mmol) in dichloromethane
(1 mL) was added MoO2(acac)2 (5 mg, 0.02 mmol), and
the mixture was stirred for 1 h at room temperature. To the
resulting solution, olefin 18 (1.0 mmol) and alkyl hydroper-
oxide (1.5 mmol) were added and stirring was continued at
the same temperature for several hours. The process of oxi-
dation was monitored by TLC. Saturated aqueous Na2SO3
was added, and the mixture was stirred for 30 min at room
temperature. The mixture was extracted with CH2Cl2, dried
over Na2SO4, and concentrated under reduced pressure. The
remaining residue was purified by flash column (ethyl ace-
tate/hexanes 1:50) chromatography on silica gel to provide
epoxide 19.
4. For recent reports on achiral metal catalyst and chiral oxidant,
€
see: (a) Adam, W.; Alsters, P. L.; Neumann, R.; Saha-Moller,
C. R.; Seebach, D.; Beck, A. K.; Zhang, R. J. Org. Chem.
2003, 68, 8222; (b) Adam, W.; Beck, A. K.; Pichota, A.;
€
Saha-Moller, C. R.; Seebach, D.; Vogl, N.; Zhang, R.
Tetrahedron: Asymmetry 2003, 14, 1355; (c) Adam, W.;
€
Alsters, P. L.; Neumann, R.; Saha-Moller, C. R.; Seebach, D.;
Zhang, R. Org. Lett. 2003, 5, 725.
5. For recent reviews on vanadium, see: (a) Hirao, T. Chem. Rev.
1997, 97, 2707; (b) Bolm, C. Coord. Chem. Rev. 2003, 237,
245.
4.9. General procedure for asymmetric oxidation of
sulfides in the presence of MoO2(acac)2 and ligand 3
6. For Zr catalyzed epoxidation of homoallylic alcohols, see: (a)
Ikegami, S.; Katsuki, T.; Yamaguchi, M. Chem. Lett. 1987,
83; (b) Okashi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85.
7. Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H.
Angew. Chem., Int. Ed. 2005, 44, 4389.
8. Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286.
9. Barlan, A.; Bask, A.; Yamamoto, H. Angew. Chem., Int. Ed.
2006, 45, 45849.
To a solution of BHA (0.03 mmol) in dichloromethane
(3 mL) was added MoO2(acac)2 (5 mg, 0.015 mmol), and
the mixture was stirred for 1 h at room temperature. The
resulting solution was cooled to 0 ꢀC, and then sulfide 20
(0.75 mmol) and THP (207 mg, 0.75 mmol) were added
and stirring was continued at the same temperature for sev-
eral hours. The process of oxidation was monitored by TLC.
Saturated aqueous Na2SO3 was added, and the mixture was
stirred for 30 min at 0 ꢀC. The mixture was then allowed to
warm to room temperature, extracted with CH2Cl2, dried
over Na2SO4, and concentrated under reduced pressure.
The remaining residue was purified by flash column chroma-
tography on silica gel to provide sulfoxide 21.
10. Basak, A.; Barlan, A.; Yamamoto, H. Tetrahedron: Asymmetry
2006, 17, 508.
11. (a) Murase, N.; Hoshino, Y.; Oishi, M.; Yamamoto, H. J. Org.
Chem. 1999, 64, 338; (b) Hoshino, Y.; Murase, N.; Oishi, M.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 1653.
12. Hoshino, Y.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
10452.
13. Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed.
2003, 42, 941.
Acknowledgements
14. Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 107, 1159; Angew. Chem., Int. Ed. Engl. 1995,
34, 1059.
Support for this research was provided by SORST project of
the Japan Science and Technology Agency (JST), GAANN,
National Institutes of Health (NIH) GM068433-01, Merk
Research Laboratories, and a starter grant from The Univer-
sity of Chicago.
15. See Section 4.
16. Vanadium–3c complex in the presence of TBHP selectively
oxidized geraniol to generate 2,3-epoxygeraniol.
17. Bortolini, O.; Campestrini, S.; Furia, E.; Modena, G. J. Org.
Chem. 1987, 52, 5093.
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