Asymmetric epoxidation of allylic alcohols catalyzed by vanadium-binaphthylbishydroxamic acid complex

Article abstract of DOI:10.1021/acs.joc.5b00185

A vanadium-binaphthylbishydroxamic acid (BBHA) complex-catalyzed asymmetric epoxidation of allylic alcohols is described. The optically active binaphthyl-based ligands BBHA 2a and 2b were synthesized from (S)-1,1'-binaphthyl-2,2'dicarboxylic acid and N-substituted-O-trimethylsilyl (TMS)-protected hydroxylamines via a one-pot, three-step procedure. The epoxidations of 2,3,3-trisubstituted allylic alcohols using the vanadium complex of 2a were easily performed in toluene with a TBHP water solution to afford (2R)-epoxy alcohols in good to excellent enantioselectivities.

Full text of DOI:10.1021/acs.joc.5b00185

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Article
Asymmetric Epoxidation of Allylic Alcohols Catalyzed
by Vanadium–Binaphthylbishydroxamic Acid Complex
Masahiro Noji, Toshihiro Kobayashi, Yuria Uechi, Asami
Kikuchi, Hisako Kondo, Shigeo Sugiyama, and Keitaro Ishii
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00185 • Publication Date (Web): 25 Feb 2015
Downloaded from http://pubs.acs.org on March 2, 2015
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Asymmetric Epoxidation of Allylic Alcohols
Catalyzed by Vanadium–Binaphthylbishydroxamic Acid Complex
Masahiro Noji,* Toshihiro Kobayashi, Yuria Uechi, Asami Kikuchi, Hisako Kondo, Shigeo Sugiyama, and Keitaro
Ishii
Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2ꢀ522ꢀ1 Noshio, Kiyose, Tokyo
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204ꢀ8588, Japan
mnoji@myꢀpharm.ac.jp
GRAPHICAL ABSTRACT
ABSTRACT: A vanadium–binaphthylbishydroxamic acid (BBHA) complexꢀcatalyzed asymmetric epoxidation of
allylic alcohols is described. The optically active binaphthylꢀbased ligands BBHA 2a and 2b were synthesized from
(S)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdicarboxylic acid and NꢀsubstitutedꢀOꢀtrimethylsilyl (TMS)ꢀprotected hydroxylamines via a
oneꢀpot, threeꢀstep procedure. The epoxidations of 2,3,3ꢀtrisubstituted allylic alcohols using the vanadium complex
of 2a were easily performed in toluene with a TBHP water solution to afford (2R)ꢀepoxy alcohols in good to excellent
enantioselectivities.
INTRODUCTION
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The asymmetric epoxidation of allylic alcohols is an attractive method for the synthesis of chiral epoxy alcohols,
which are useful chiral building blocks for the production of pharmaceuticals and agrochemicals.1 The
Katsuki–Sharpless asymmetric epoxidation of allylic alcohols is reliable method of obtaining synthetically useful
chiral epoxy alcohols.2 The epoxidation gives very high asymmetric induction for various types of allylic alcohols.
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The enantioselectivity depends only on the chirality of Lꢀ(+)ꢀ, or Dꢀ(−)ꢀtartrates as ligands, independent of the
structure of the allylic alcohols. Therefore, the absolute configuration of the products can be predicted. Although
the epoxidation is conducted using commercially available titanium tetraisopropoxide, tartrate, and
tertꢀbutylhydroperoxide (TBHP) as an oxidizing agent, it requires strict anhydrous conditions.
Recently, the vanadium–chiral hydroxamic acid (V–HA) complexꢀcatalyzed asymmetric epoxidation of allylic
alcohols with TBHP has also become a highly potent approach to obtaining chiral epoxy alcohols. The advantage of
the V–HA complexꢀcatalyzed method is its simple reaction procedure, which can be conducted in aqueous TBHP
solution, rather than under anhydrous conditions. Since the first report by Sharpless,3 the V–HA complexꢀcatalyzed
system has been extensively studied for the last decade.4–7 Yamamoto has reported C2ꢀsymmetric cyclohexane
diamineꢀbased chiral bishydroxamic acid (BHA) ligands.8 The vanadium–BHA system exhibited excellent
enantioselectivities for a wide range of substituted allylic alcohols. The recent application of BHA ligands for Moꢀ,
Zrꢀ, Hfꢀ, and Wꢀcatalyzed systems demonstrated that the C2ꢀsymmetric chiral BHA ligand was very useful for
asymmetric oxidations of sulfides, simple alkenes, homoallylic alcohols, and allylic amine derivatives.9
Axially chiral C2ꢀsymmetric binaphthyl derivatives have been recognized as a privileged chiral ligand for many
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enantioselective reactions.10 The C2ꢀsymmetric chiral auxiliaries minimize the possibility of diastereomeric
interactions at the transition state and are therefore useful for obtaining high enantiomeric excesses and for elucidating
the mechanism of asymmetric induction. 11 The steric bulkiness and structural rigidity of naphthalene rings would be
effective for the production of large asymmetric space. The flexibility of the binaphthyl axis enable the chiral ligand
to adapt a wide range of substrates. This induced-fit property12 would also be a great advantage for the asymmetric
reaction. Herein, we report the vanadium–binaphthylbishydroxamic acid (BBHA) complexꢀcatalyzed asymmetric
epoxidation of allylic alcohols.
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RESULTS AND DISCUSSION
The BBHA ligands were synthesized via a oneꢀpot, threeꢀstep procedure. The method involved (i) the preparation of
the acid chloride of (S)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdicarboxylic acid13 (1) followed by (ii) the reaction of the
NꢀsubstitutedꢀOꢀTMS protected hydroxylamines and then (iii) the removal of the TMS groups from the amide.
Chromatographic purification and recrystallization gave pure BBHA ligands 2a and 2b in 65% and 54% chemical
yields from (S)ꢀ1 (Scheme 1).
Scheme 1. Synthesis of binaphthylbishydroxamic acid (BBHA)
1H NMR spectra of 2a and 2b in CDCl3 at room temperature showed broad signals, probably because of the
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structural rigidity of the amide linkage and hydrogen bonding. Therefore, most of the 13C NMR signals of 2a and 2b
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were not observed. NMR measurements at 80 °C improved the situation with regard to the broad signals in the H
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and 13C spectra of 2a and 2b. However, the structure assignments on the basis of the aromatic NMR signals
remained difficult. Consequently, singleꢀcrystal Xꢀray diffraction analysis was used to ascertain the structure and
conformation of BBHA ligands 2a and 2b.
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A single crystal of 2a was obtained by slow evaporation from toluene solution at room temperature. Similarly, a
single crystal of 2b was prepared from EtOH–THF solution. The molecular structures of 2a and 2b were determined
by singleꢀcrystal Xꢀray diffraction analysis.14 The crystal prepared from 2a contained one toluene molecule per 2a.
The dihedral angle of the binaphthyl axis, C2ꢀC1ꢀC1′ꢀC2′, of 2a and 2b was 85° and 70°, respectively.
Intramolecular hydrogen bonds between the carbonyl oxygen and hydroxyl group were observed in both structures,
and the oxygen–oxygen distances were 2.6–2.7 Å. In the crystal of 2a with toluene, the hydroxamic acid moieties
were transoid structures and the torsional angles of HO–N–C=O were 170° and 175°. In contrast, cisoid and transoid
structures were observed in the crystal structure of 2b and the torsional angles were 14° and 167°, respectively. The
cisoid hydroxamic groups formed intramolecular stacking structures between the naphthalene and benzene rings.15
BBHA 2a appears to have a larger asymmetric space than 2b, and we employed 2a for initial examination of the
asymmetric epoxidation.
To optimize the epoxidation conditions using BBHA 2a, allylic alcohol 3a was used as a model substrate. The
vanadium/ligand ratio, solvent, and vanadium compounds were investigated using 5 mol% of vanadium compound;
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the results are reported in Table 1. A typical reaction procedure was as follows: BBHA 2a and 5 mol% of vanadium
compound were stirred in the solvent at 20 °C for 24 h, whereupon 1.5 equiv of TBHP water solution and then allylic
alcohol 3a were added. The mixture was stirred at 20 °C until the complete consumption of allylic alcohol 3a or 24
h of reaction time. The reaction was then quenched by adding saturated aqueous Na2SO3 solution; subsequent
extraction and chromatographic purification gave epoxy alcohols 4a and recovered 3a. The enantiomeric excess (ee)
was determined by chiralꢀstationaryꢀphase HPLC analysis. The absolute stereochemistry of (2R,3R)ꢀ4a was
determined by comparison of the chiroptical property with the literature data.16
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Table 1. Optimization of Vanadium/Ligand Ratio, Solvent, and Vanadium Compounds
Bn
OH
N
5 mol% V compound
O
O
BBHA 2a
(S)-
1.5 equiv TBHP (in water)
O
Ph
OH
Ph
OH
solvent (0.1 mol/L)
20 oC, time
N
OH
3a
4a
(2R,3R)-
Bn
BBHA 2a
(S)-
epoxide 4a
vanadium
(5 mol%)
time
(h)
recov. 3a
(%)
BBHA 2a
(mol%)
entrya
solvent
yield
eeb
(%)
86
86
38
80
84
85
72
68
89
87
83
87
(%)
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86
83
78
64
40
20
84
81
62
65
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VO(OEt)3
VO(OEt)3
VO(OEt)3
VO(OEt)3
VO(OEt)3
VO(OEt)3
VO(OEt)3
VO(OEt)3
VO(acac)2
VO(acac)2
VO(acac)2
VO(OiꢀPr)3
10
7.5
3
toluene
toluene
toluene
CHCl3
CH2Cl2
EtOAc
CH3CN
acetone
toluene
CH2Cl2
EtOAc
toluene
24
24
3
9.5
24
24
24
24
6
31
24
0
4
8
20
35
63
7
5
21
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
10
11
12
6
24
24
26
aComplexation time was 24 h. bDetermined by HPLC.
The vanadium/ligand ratio for the best asymmetric induction was examined via the reactions described in entries
1–3. Generally, one hydroxamic acid group (C=O–NOH) serves as one bidentate ligand using two oxygen atoms of
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carbonyl and hydroxyl groups. Because BBHA 2a has two hydroxamic acids and might be potentially tetradendate,
we examined the optimum molar amount of BBHA for 5 mol% of VO(OEt)3 (entries 1–3). The use of 10 mol% of
2a (potentially 20 mol% of coordination sites for 5 mol% of VO(OEt)3) and 7.5 mol% of 2a (potentially 15 mol% of
coordination sites for 5 mol% of VO(OEt)3) gave better asymmetric induction of 86% ee (entries 1 and 2) than the
quantities used in entry 3. Allylic alcohol 3a was recovered in entries 1 and 2; thus, the reaction proceeded more
slowly in the cases of entries 1 and 2 than in the case of entry 3. The vanadium excess condition in entry 3,
VO(OEt)3 5 mol% and BBHA 3 mol% (potentially 6 mol% of coordination sites), appeared to produce ligandꢀfree
vanadium species, which resulted in racemic epoxy alcohol 4a with improved yield and decreased enantioselectivity.
We therefore chose the best ratio of 7.5 mol% BBHA for 5 mol% of vanadium.
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Next, the solvent effect was examined using an excess–ligand condition: 5 mol% of VO(OEt)3 and 7.5 mol% of
BBHA 2a. The epoxidation proceeded rapidly in CHCl3 and CH2Cl2, moderately in toluene and EtOAc, and slowly
in acetonitrile and acetone (entries 4–8). A considerable amount of allylic alcohol 3a was recovered from the
reactions in EtOAc, acetonitrile, and acetone. The best enantioselectivity was observed in toluene in the reaction
involving VO(OEt)3 (entries 2 and 4–7). A similar tendency was observed in the solvent screening reaction
involving VO(acac)2 (entries 9–11). VO(acac)2 is an inexpensive, airꢀstable, and easyꢀtoꢀhandle solid reagent.
Toluene was also the best solvent for the combination of 2a and VO(acac)2. A comparison of the vanadium
compounds revealed that VO(acac)2 exhibited slightly better enantioselectivity than VO(OEt)3 or VO(OiꢀPr)3 (entries
2, 9, and 12). Further optimization of reaction conditions was conducted with 5 mol% of VO(acac)2 and 7.5 mol%
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of BBHA 2a in toluene. The complexation time, oxidant, concentration, and equivalents of TBHP were examined;
the results are summarized in Table 2.
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Table 2. Optimization of the Complexation Time, Oxidant, Reaction Temperature, and Equivalents of TBHP
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Bn
OH
N
5 mol% VO(acac)2
7.5 mol% (S)-BBHA 2a
O
O
O
X equiv Oxidant
Ph
OH
Ph
OH
toluene (Y mol/L)
temp, time
N
OH
3a
(2R,3R)-4a
Bn
(S)-BBHA 2a
epoxide 4a
complexation
time (h)
conc.
(Y mol/L)
oxidant
(X equiv)
reaction
temp. (°C)
reaction
time (h)
recov 3a
(%)
yield
(%)
eea
(%)
entry
oxidant
1
2
3
4
5
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9
TBHP (in water)
TBHP (in water)
TBHP (in water)
TBHP (in nonane)
CHP
TBHP (in water)
TBHP (in water)
TBHP (in water)
TBHP (in water)
TBHP (in water)c
TBHP (in water)
TBHP (in water)
0.1
0.1
0.1
0.1
0.1
0.1
0.25
0.5
1.0
1.0
0.1
0.1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
20
20
20
20
20
0
0
0
0
0
6
4
4
84
88
88
84
67
80
80
77
81
86
87
93
89
89
89
89
83
92
90
90
93
91
92
89
7
4
1
24
6
3
3
3
3
3
3
3
24
24
48
48
48
48
48
48
24
1
27
10
17
21
17
5
10
11
12
3
3
0
0
2
0
3b
aDetermined by HPLC. b5 mol% VO(acac)2 and 5.5 mol% BBHA 2a was used.
During the complexation process in toluene at 20 °C for 24 h (entry 1), darkꢀgreen tolueneꢀinsoluble VO(acac)2
became a darkꢀpurple solution with BBHA 2a. Shorter complexation time was examined for convenience of
epoxidation. Nearly the same change in color was observed at 3 h (entry 3), and the ee of the epoxide 4a was the
same as for 24 h. Three hours was sufficient for the complexation of 2a to obtain the best enantioselectivity in
toluene solution at 20 °C (entries 1−3). Hydroperoxide species were investigated (entries 3−5) under these
complexation conditions. The use of a water solution or nonane solution of TBHP gave the same ee of 89%. The
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use of the nonane solution of TBHP required a longer reaction time of 24 h for the consumption of allylic alcohol 3a
(entry 4). The epoxidation employing cumene hydroperoxide (CHP) in aromatic hydrocarbon proceeded more
slowly, and the enantioselectivity slightly decreased (entry 5). Compared to the epoxidation at 20 °C (entry 3),
reaction at the lower temperature of 0 °C improved the enantioselectivity to 92% ee (entry 6). Next, the substrate
concentration and equivalents of TBHP were examined. Higher substrate concentrations (0.1 vs. 0.25−1 mol/L) did
not improve the yields (entries 6 vs. 7−9), whereas excess TBHP (3 equiv) slightly improved the yields (entries 9−10).
Under TBHP (3 equiv) conditions, no influence of substrate concentration on the yield and enantioselectivity was
observed (entries 10 and 11). Based on the best epoxidation condition in entry 11 (87% yield, 92% ee), more
ligandꢀefficient condition was reꢀexamined. The molar ratio of VO(acac)2/BBHA 2a was changed from 5/7.5 to
5/5.5. Unfortunately, enantioselectivity was decreased to 89% ee, whereas the yield was increased to 93% in 24 h.
The substrate scope of the epoxidation was examined under the optimized reaction conditions (Table 2, entry11)
using BBHA 2a with a complexation time of 3 h. The results are summarized in Table 3. The ee was determined
by chiralꢀstationaryꢀphase HPLC analysis. For the HPLC analysis of aliphatic epoxy alcohols 4f–4k, the epoxy
alcohols were converted into benzoate derivatives. The absolute stereochemistry of the epoxide was determined by
comparison of the chiroptical properties with the literature data.
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Table 3. Epoxidation of Various Allylic Alcohols Using 5 mol% of VO(acac)2 and 7.5 mol% of BBHA 2
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R
OH
N
5 mol% VO(acac)2
7.5 mol% (S)-BBHA 2
O
O
R1
R1
O
3 equiv TBHP-w
R2
OH
R2
OH
(R)
toluene (0.1 mol/L)
0 oC
R3
R3
N
OH
R
3
4
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R = Bn: ( )-BBHA 2a
R = Ph: (S)-BBHA 2b
S
epoxide 4
configurationa
recov. 3
entry ligand time
(%)
yield (%) ee (%)b
1
2
2 d
2 d
87
84
92
16
2
3
2a
2b
4a
4b
3
4
5
4 d
4 d
4 d
95
29
18
87
82
89
1
2a
2a
2a
39
70
4c
4d
4e
4f
6
7
6 d
5 d
20
26
21
0
14
2a
2b
11c
8
9
3 d
3 d
89
95
98d
84d
0
0
2a
2a
4g
10
11
12
13
1 d
1 d
5 d
5 d
60
52
75
86
80d
83d
80d
87d
0
0
2a
2a
2a
2a
4h
4i
8
4j
14
4k
aDetermined by comparison of the chiroptical property with the literature data. bDeteremined by HPLC. cMajor
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product was (S)ꢀ4e. dDetermined by HPLC after benzoylation or mꢀtoluoylation of the isolated products.
The epoxidation of trisubstituted allylic alcohols proceeded faster than the epoxidation of disubstituted allylic
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alcohols (entries 1, 3 vs. entries 4−6 and entries 8−11 vs. entries 12−13). Although the chemical reactivity of the
vanadium complex of BBHA 2b was almost the same as the chemical reactivity of BBHA 2a, enantioselectivity was
low for the epoxidation of 3a (entry 1−2). In the case of the epoxidation of geminal substituted allylic alcohol 3e,
the opposite enantiomer of (S)ꢀ4e was obtained when BBHA 2b were used in the reaction (entries 6−7). The
enantioselectivity of the epoxidation was better in the case of the reaction of trisubstituted allylic alcohols than in the
case of disubstituted allylic alcohols (entries 1, 3 vs. entries 4−6). In the reaction of disubstituted allylic alcohols,
enantioselectivity of the epoxidation increased in the order geminal < trans < cis with respect to the geometry of the
olefin moiety (entries 4−6 and 12−13). Epoxidation of a bulky trisubstituted allylic alcohol, geraniol (3f), showed
excellent enantioselectivity and gave epoxide 4f in 98% ee (entry 8).17 In the epoxidation of geraniol (3f) and nerol
(3g), allylic alcohol moieties were predominantly epoxidized over the trisubstituted alkene moieties, and no
overꢀoxidized products were obtained (entries 8 and 9). The epoxidation of lowꢀmolecularꢀweight allylic alcohol 3h
proceeded with good enantioselectivity to give epoxy alcohol 4h (entry 10). The use of (S)ꢀconfigured BBHA 2a
gave (2R)ꢀepoxy alcohols as the major enantiomers in all cases.
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CONCLUSIONS
We observed that binaphthylꢀbased BBHA 2a was an effective ligand for the vanadiumꢀcatalyzed asymmetric
epoxidation of allylic alcohols. The (S)ꢀBBHA ligands were easily synthesized by the oneꢀpot, threeꢀstep procedure
from (S)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdicarboxylic acid. The combination of the stable and inexpensive VO(acac)2 and a
TBHP water solution as the oxidant in toluene gave the epoxy alcohols in the best enantioselectivities. The reaction
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proceeded faster for trisubstituted allylic alcohols than for disubstituted allylic alcohols. The enantioselectivity was
better for trisubstituted allylic alcohols. The stereochemistry of the epoxy alcohols corresponded to (2R)ꢀstructures
in all cases when (S)ꢀBBHA 2a was used for the epoxidation. Further study of the coordination structure and the
mechanisms of asymmetric induction and further development of other BBHAs are in progress.
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EXPERIMENTAL SECTION
General Experimental Methods. The epoxidations were conducted under air without anhydrous conditions.
Reactions for the syntheses of BBHA ligands and allylic alcohols and for the benzoylation of epoxy alcohols were
conducted in anhydrous conditions under argon atmosphere. All solvents and reagents were used as received. 1H
NMR and 13C{1H} NMR spectra were collected with spectrometers operating at 300 or 500 MHz for proton nuclei in
the solvents indicated. 1H chemical shifts are reported in δ ppm with tetramethylsilane (TMS) as an internal standard.
13C{1H} chemical shifts are reported relative to the central peak of CDCl3 (77.0 ppm) or DMSOꢀd6 (39.52). Infrared
spectra were collected using an FTꢀIR spectrometer. Melting points were measured on a hotꢀplate meltingꢀpoint
apparatus and are uncorrected. Highꢀresolution mass spectra were obtained on a doubleꢀfocusing highꢀresolution
magneticꢀsector mass analyzer operating in a fast atom bombardment (FAB) mode or an electron impact (EI) mode.
Optical rotation was measured on a polarimeter. Chromatographic purifications were performed on silica gel (40–50
ꢀm, spherical) or alumina (activity III). The ee of the products was determined by chiralꢀstationaryꢀphase HPLC on
a
chromatograph equipped with
a
Daicel CHIRALCEL ODꢀH or
a
CHIRALCEL OBꢀH column.
(Z)ꢀ3ꢀPhenylꢀ2ꢀpropenꢀ1ꢀol18
(cisꢀcinnamyl
alcohol)
11
(3d),
2ꢀphenylꢀ2ꢀpropenꢀ1ꢀol19
(3e),
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1ꢀcyclohexenylmethanol20 (3i) were synthesized according to methods reported in the literature.
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Synthesis of BBHA 2a and 2b.
NꢀBenzylꢀOꢀ(trimethylsilyl)hydroxylamine
To
a
solution of
8
9
Nꢀbenzylhydroxylamine hydrochloride (2.82 g, 17.5 mmol), DMAP (109 mg, 877 ꢀmol), and triethylamine (29.2 mL,
210 mmol) in CH2Cl2 (175 mL) was added TMSCl (7.97 mL, 63.1 mmol) at 0 °C. The mixture was gradually
warmed to room temperature and stirred for 18 h. Saturated aqueous NaHCO3 was added, and the mixture was
extracted with CH2Cl2 (100 mL × 3). The combined organic layer was washed with sat. NaCl (100 mL), dried over
MgSO4, and filtered. The filtrate was concentrated, and the residue was purified by bulbꢀtoꢀbulb distillation (160 °C,
11ꢀ12 Pa) to give a colorless oil (3.26 g, 94%): 1H NMR (300 MHz, CDCl3) δ: 7.36–7.26 (5H, m), 5.21 (1H, bs), 4.01
(2H, s), 0.11 (9H, s);21 IR (neat) cm−1: 3255 (m), 2958 (m), 1604 (m), 1249 (s), 880 (m), 843 (m), 749 (m), 698 (m);
EIꢀMS (70 eV) m/z (relative intensity): 195 (M+, 76), 180 (22), 151 (12), 102 (20), 91 (100), 75 (46).
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NꢀPhenylꢀOꢀ(trimethylsilyl)hydroxylamine To a solution of Nꢀphenylhydroxylamine (2.09 g, 19.2 mmol),
DMAP (104 mg, 852 ꢀmol), and triethylamine (11.4 mL, 82.0 mmol) in CH2Cl2 (110 mL) was added TMSCl (5.56
mL, 44.0 mmol) at −20 °C. The mixture was gradually warmed to room temperature and stirred for 30 h. Saturated
aqueous NaHCO3 was added, and the mixture was extracted with nꢀhexane/Et2O = 1:2 (150 mL × 3). The combined
organic layer was washed with sat. NaCl (100 mL), dried over MgSO4, and filtered. The filtrate was concentrated
under reduced pressure at a temperature below 15 °C, and the residue was dried under vacuum. The crude product
was then used without further purification.
(S)ꢀN,N′ꢀDibenzylꢀ1,1′ꢀbinaphtylꢀ2,2′ꢀbiscarbohydroxamic
acid
(2a)
To
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(S)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdicarboxylic acid 1 (1.50 g, 4.38 mmol) in CH2Cl2 (44 mL) were added oxalyl chloride (3.82
mL, 43.8 mmol) and DMF (100 ꢀL) at 0 °C. The mixture was gradually warmed to room temperature. After gas
generation ceased (4 h), the mixture was concentrated under reduced pressure and dried under vacuum. The residue
was dissolved in CH2Cl2 (44 mL). NꢀBenzylꢀOꢀ(trimethylsilyl)hydroxylamine (2.66 g, 13.7 mmol), triethylamine
(3.65 mL, 26.3 mmol), and DMAP (27.0 mg, 221 ꢀmol) were added at 0 °C, and the mixture was brought to room
temperature and stirred for 15 h.
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The mixture was cooled to 0 °C, whereupon tetrabutylammonium fluoride (1 mol/L in THF, 17.5 mL, 17.5 mmol)
was added, and the resulting mixture was stirred for 3.5 h. Water (100 mL) was added, and the mixture was
extracted with CH2Cl2 (150 mL × 3). The combined organic layer was washed with sat. NaCl (100 mL), dried over
MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by
column chromatography (silica gel, 1–50% EtOAc/nꢀhexane + 15% THF) and recrystallization from nꢀhexane and
CHCl3 (1:1) to give 2a as colorless needles (1.58 g, 65%): Rf = 0.20 (silica gel, EtOAc/nꢀhexane/THF = 1:4:1); mp
199–202 °C; 1H NMR (500 MHz, DMSOꢀd6, 80°C) δ: 9.96 (2H, s), 8.10 (2H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.3 Hz),
7.60 (2H, d, J = 8.6 Hz), 7.51 (2H, ddd, J = 8.3, 7.0, 1.2 Hz), 7.26 (2H, ddd, J = 8.6, 7.1, 1.3 Hz), 7.17 (2H, d, J = 8.6
Hz), 7.14 (2H, d, J = 7.4 Hz), 7.12–7.06 (4H, m), 6.71 (4H, br), 4.58 (2H, d, J = 15.6 Hz), 4.51 (2H, d, J = 15.6 Hz);
13C{1H} NMR (125 MHz, DMSOꢀd6, 80°C) δ: 168.4, 135.5, 133.8, 132.6, 132.3, 131.9, 127.6, 127.4, 127.3, 126.8,
126.7, 126.4, 126.3, 125.9, 123.7, 51.2; IR (KBr) cm−1: 3198 (br), 2905 (br), 1609 (s), 1481 (s), 1445 (m), 1421 (m),
1348 (s), 1245 (s), 1147 (s), 819 (s), 755 (s), 628 (m), 488 (m); EIꢀMS (70 eV) m/z (relative intensity): 552 (M+, 75),
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430 (78), 281 (84), 252 (47), 91 (100); HRMS (EI) m/z: M+ Calcd for C36H28N2O4 552.2049; Found 552.2054; Anal.
Calcd for C36H28N2O4: C, 78.24; H, 5.11; N, 5.07. Found: C, 78.14; H, 5.37; N, 5.07; [α]D21 −117 (c 0.496, CHCl3).
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(S)ꢀN,N′ꢀDiphenylꢀ1,1′ꢀbinaphtylꢀ2,2′ꢀbiscarbohydroxamic
acid
(2b)
To
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of
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(S)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdicarboxylic acid 1 (1.00 g, 2.92 mmol) in CH2Cl2 (30 mL) was added oxalyl chloride (2.50
mL, 29.2 mmol) and DMF (100 ꢀL) at 0 °C. The mixture was gradually warmed to room temperature. After gas
generation ceased (1.5 h), the mixture was concentrated under reduced pressure, and dried under vacuum. The
residue was dissolved in CH2Cl2 (30 mL). NꢀPhenylꢀOꢀ(trimethylsilyl)hydroxylamine (1.59 g, 8.76 mmol),
triethylamine (2.43 mL, 17.5 mmol), and DMAP (22.2 mg, 182 ꢀmol) were added at 0 °C and the resulting mixture
was brought to room temperature and stirred for 20 h. The mixture was cooled to 0 °C, whereupon
tetrabutylammonium fluoride (1 mol/L in THF, 11.7 mL, 11.7 mmol) was added, and the resulting mixture was stirred
for 3.5 h. Water (100 mL) was added, and the mixture was extracted with CH2Cl2 (150 mL × 3). The combined
organic layer was washed with sat. NaCl (100 mL), dried over MgSO4, and filtered. The filtrate was concentrated
under reduced pressure. The crude product was purified by column chromatography (silica gel, 2–50%
EtOAc/nꢀhexane + 15% THF) and recrystallization from nꢀhexane and CH2Cl2 (2:1) to give 2b as colorless prisms
(828 mg, 54%): Rf = 0.16 (silica gel, EtOAc/nꢀhexane/THF = 1:4:1); mp 119–123 °C; 1H NMR (500 MHz, DMSOꢀd6,
80 °C) δ: 10.41 (2H, s), 8.03 (2H, d, J = 8.6 Hz), 7.98 (2H, d, J = 8.3 Hz), 7.69 (2H, d, J = 8.6 Hz), 7.52 (2H, ddd, J =
8.0, 6.8, 1.3 Hz), 7.32 (2H, ddd, J = 8.3, 6.7, 1.2 Hz), 7.25–7.16 (10H, m), 7.11–7.06 (2H, m); 13C{1H} NMR (125
MHz, DMSOꢀd6, 80°C) δ: 167.9, 140.5, 134.0, 132.5, 132.3, 132.1, 127.8, 127.8, 127.3, 126.9, 126.3, 125.8, 125.4,
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123.9, 121.5; IR (KBr) cm−1: 3149 (br), 3065 (br), 2918 (br), 2856 (Br), 1617 (s), 1589 (s), 1490 (s), 1389 (m), 828
(m), 754 (m), 680 (m); EIꢀMS (70 eV) m/z (relative intensity): 524 (M+, 2), 492 (12), 416 (13), 400 (14), 372 (23),
325 (11), 281 (100), 252 (40); HRMS (EI) m/z: M+ Calcd for C36H28N2O4 552.2049; Found 552.2054; Anal. Calcd for
C34H24N2O4: C, 77.85; H, 4.61; N, 5.34. Found: C, 77.71; H, 4.68; N, 5.21; [α]D21 +12.1 (c 0.444, CHCl3).
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Synthesis
of
Allylic
Alcohols.
(E)ꢀ2,3ꢀDiphenylꢀ2ꢀpropenꢀ1ꢀol
(3b)22
A
mixture
of
(E)ꢀ2,3ꢀdiphenylꢀ2ꢀpropennoic acid (3.02 g, 13.4 mmol) and powdered KOH (1.24 g, 18.7 mmol) in DMSO (40 mL)
was stirred at room temperature for 1 h. The mixture was cooled to 0 °C, whereupon MeI (1.25 mL, 20.1 mmol) was
added, and the resulting mixture was stirred at room temperature for 42 h. Water (100 mL) was added, and the
mixture was extracted with nꢀhexane/EtOAc (1:1) (100 mL × 3). The combined organic layer was washed with
water (100 mL × 3), dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography (silica gel, 0–4% EtOAc/nꢀhexane) to give methyl
1
(E)ꢀ2,3ꢀdiphenylꢀ2ꢀpropennoate (2.97 g, 92%) as a colorless solid: Rf = 0.22 (silica gel, EtOAc/nꢀhexane = 1:40); H
NMR (300 MHz, CDCl3) δ: 7.85 (1H, s), 7.40–7.33 (3H, m), 7.23–7.12 (5H, m), 7.03 (2H, d, J = 5.5 Hz), 3.79 (3H,
s).
To a solution of (E)ꢀ2,3ꢀdiphenylꢀ2ꢀpropennoate (2.67 g, 11.2 mmol) in Et2O (22 mL) was added DIBAL solution
(0.98 mol/L in hexanes, 25.2 mL, 46.2 mmol) at 0 °C over 20 min. The mixture was warmed to room temperature
and stirred for 4 h. The mixture was then reꢀcooled to 0 °C, and water (100 mL) was carefully added, followed by
brine (50 mL). The white solid that formed was dissolved by the addition of 2 mol/L aqueous HCl. The resulting
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mixture was extracted with Et2O (150 mL × 3). The combined organic layer was washed with brine (100 mL), dried
over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified
by column chromatography (silica gel, 5–32% EtOAc/nꢀhexane) to give allylic alcohol 3b (2.13 g, 90%) as a colorless
oil: Rf = 0.20 (silica gel, EtOAc/nꢀhexane = 1:4); 1H NMR (300 MHz, CDCl3) δ: 7.37–7.28 (3H, m), 7.28–7.19, (2H,
m), 7.16–7.06 (3H, m), 7.20–6.94 (2H, m), 6.69 (1H, s), 4.47 (2H, d, J = 2.9 Hz), 1.64 (1H, br); EIꢀMS (70 eV) m/z
(relative intensity): 210 (M+, 100), 191 (13), 178 (40), 165 (14), 105 (69), 91 (33), 77 (11); IR (KBr) cm−1: 3262 (m),
1445 (m), 1091 (m), 1071 (m), 1004 (m), 916 (m), 694 (m).
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Typical Procedure for the Asymmetric Epoxidation: Epoxidation of 3a (Table 3, Entry 1). A mixture of
VO(acac)2 (6.62 mg, 25.0 ꢀmol) and BBHA 2a (20.7 mg, 37.5 ꢀmol) in toluene (5.00 mL) was stirred at 20 °C for 3 h.
To the resulting darkꢀpurple solution, TBHP in water (70 %, 206 ꢀL, 1.5 mmol, 3.0 equiv) was added at 0 °C; the
resulting mixture was stirred for 10 min. Allylic alcohol 3a (74.6 mg, 500 ꢀmol) was added, and the reaction was
monitored by TLC. Saturated aqueous Na2SO3 solution was added. The mixture was stirred for 30 min and
extracted with Et2O or EtOAc (5 mL × 5). The combined organic layer was dried over MgSO4 and filtered. The
filtrate was concentrated under vacuum. The crude product was purified by column chromatography (silica gel,
5−40% EtOAc/nꢀhexane) to give epoxy alcohol 4a as colorless needles (72.3 mg, 87%). HPLC analysis of 4a
indicated 92% ee. To isolate the volatile aliphatic epoxy alcohols (4h, 4j, 4k), a partially concentrated solution of
crude epoxy alcohols, mostly in toluene, was charged directly to the column for chromatography. Al2O3 (activity III)
was used instead of silica gel for the purification of epoxy alcohols 4d, 4f, 4g, 4h, 4i, 4j, and 4k.
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Benzoylation and mꢀToluoylation of Aliphatic Epoxy Alcohols (4f−4k). To a CH2Cl2 (0.25 mol/L) solution of
epoxy alcohol 4f−4k (1 equiv), DMAP (2 mol%), and NEt3 (3 equiv) was added RCOCl (1.2 equiv) at 0 °C. The
mixture was gradually warmed to room temperature and stirred for 5 h. Saturated aqueous NaHCO3 was added, and
the organic layer was extracted with CH2Cl2. The extracts were dried over MgSO4, filtered, and concentrated. The
crude ester was purified by column chromatography (silica gel, EtOAc/nꢀhexane or EtOAc/nꢀhexane/CH2Cl2) to give
esters of 4f−4hꢀbenzoyl and 4i−4kꢀtoluoyl.
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(2R,3R)ꢀ(2ꢀMethylꢀ3ꢀphenyloxiranꢀ2ꢀyl)methanol (4a) Purified by silica gel column chromatography (5–40%
EtOAc/nꢀhexane) to give 72.3 mg (87%) of colorless needles: mp 50–52 °C (lit.23 52–53 °C); Rf = 0.13 (silica gel,
EtOAc/nꢀhexane = 1:4); 1H NMR (500 MHz, CDCl3) δ: 7.37–7.27 (5H, m), 4.21 (1H, s), 3.85 (1H, dd, J = 12.6, 2.8
Hz), 3.75 (1H, dd, J = 12.6, 8.2 Hz), 2.04 (1H, br), 1.09 (3H, s); 13C{1H} NMR (125 MHz, CDCl3) δ: 135.6, 128.9,
127.6, 126.4, 65.0, 63.6, 60.2, 13.4; IR (KBr) cm−1: 3424 (m), 1451 (m), 1094 (m), 1070 (m), 851 (m), 740 (m), 699
(m), 554 (m), 507 (m); EIꢀMS (70 eV) m/z (relative intensity): 164 (M+, 7), 145 (10), 131 (22), 107 (100), 90 (71), 79
25
(39), 77 (25), 58 (13); HRMS (EI) m/z: M+ Calcd for C10H12O2 164.0837; Found 164.0843; [α]D +13.6 (c 1.28,
25
CHCl3, 92% ee), (lit.16 [α]D −16.9 [c 2.0, CHCl3, (2S,3S)ꢀepoxide, >98% ee]); HPLC conditions: ODꢀH,
nꢀhexane/2ꢀpropanol = 95/5, 0.4 mL/min, 210 nm, 28.2 min (2S,3S), minor, 36.0 min (2R,3R), major.8a
(2R,3R)ꢀ(2,3ꢀDiphenyloxiranꢀ2ꢀyl)methanol (4b)
Purified by silica gel column chromatography (4–40%
EtOAc/nꢀhexane) to give 107.3 mg (95%) of colorless solid: mp 66–69 °C (lit.23 115–116 °C); Rf = 0.13 (silica gel,
1
EtOAc/nꢀhexane = 1:6); H NMR (500 MHz, CDCl3) δ: 7.23–7.15 (5H, m), 7.12–7.09 (3H, m), 7.05–7.01 (2H, m),
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4.51 (1H, s), 4.06–4.00 (2H, m), 2.06 (1H, t, J = 6.7 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ: 134.7, 134.4, 128.3,
127.8, 127.71, 127.66, 127.5, 126.6, 69.1, 65.0, 60.8; IR (KBr) cm−1: 3401 (m), 1496 (m), 1455 (m), 1093 (m), 1036
(m), 1004 (m), 908 (m), 754 (m), 700 (m); EIꢀMS (70 eV) m/z (relative intensity): 226 (M+, 6), 195 (26), 167 (51),
152 (9), 120 (100), 105 (27), 91 (72), 77 (22); HRMS (EI) m/z: M+ Calcd for C15H14O2 226.0994; Found 226.0992;
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[α]D –65.4 (c 1.97, CHCl3, 87% ee), [α]D –55.6 (c 1.08, CH2Cl2, 87% ee), [lit.2a (+)ꢀ(2S,3S)ꢀepoxide (>95% ee)
was reported.]; HPLC conditions: ODꢀH, nꢀhexane/2ꢀpropanol= 95/5, 1 mL/min, 210 nm, 13.5 min (2S,3S), minor,
15.7 min (2R,3R), major.8a,23
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(2R,3R)ꢀ(3ꢀPhenyloxiranꢀ2ꢀyl)methanol (4c)
Purified by silica gel column chromatography (5–40%
EtOAc/nꢀhexane) to give 21.9 mg (29%) of colorless oil: Rf = 0.15 (silica gel, EtOAc/nꢀhexane = 1:3); 1H NMR (500
MHz, CDCl3) δ: 7.37–7.25 (5H, m), 4.04 (1H, ddd, J = 12.8, 5.2, 2.5 Hz), 3.92 (1H, d, J = 2.2 Hz), 3.79 (1H, dd, J =
12.8, 7.6, 4.0 Hz), 3.22 (1H, dt, J = 4.0, 2.0 Hz), 2.09 (1H, dd, J = 7.7, 5.5 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ:
136.7, 128.5, 128.3, 125.7, 62.4, 61.3, 55.6; IR (KBr) cm−1: 3439 (m), 1464 (m), 1398 (m), 1069 (m), 929 (m), 768
(m), 700 (m); EIꢀMS (70 eV) m/z (relative intensity): 150 (M+, 15), 132 (30), 119 (27), 107 (100), 91 (95), 90 (84), 79
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(41); HRMS (EI) m/z: M+ Calcd for C9H10O2 150.0681; Found 150.0680; [α]D +37.2 (c 0.340, CHCl3, 82% ee),
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(lit.16 [α]D −49.6 [c 2.4, CHCl3, (2S,3S)ꢀepoxide, 98% ee]); HPLC conditions: ODꢀH, nꢀhexane/2ꢀpropanol= 90/10,
0.5 mL/min, 210 nm, 24.5 min (2S,3S), minor, 27.1 min (2R,3R), major.8a
(2R,3S)ꢀ(3ꢀPhenyloxiranꢀ2ꢀyl)methanol (4d)
Purified by Al2O3 column chromatography (10–100%
EtOAc/nꢀhexane) to give 13.9 mg (18%) of colorless oil: Rf = 0.15 (silica gel, EtOAc/nꢀhexane = 1:3), 0.20 (Al2O3,
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EtOAc/nꢀhexane = 1:1); 1H NMR (500 MHz, CDCl3) δ: 7.37–7.25 (5H, m), 4.19 (1H, d, J = 4.3 Hz), 3.57–3.52 (1H,
m), 3.48–3.42 (2H, m), 1.57 (1H, br); 13C{1H} NMR (125 MHz, CDCl3) δ: 134.7, 128.3, 127.9, 126.2, 60.5, 58.5,
57.0; IR (neat) cm−1: 3391 (br), 1496 (m), 1454 (s), 1041 (s), 894 (m), 745 (S), 700 (S); EIꢀMS (70 eV) m/z (relative
intensity): 150 (M+, 4), 132 (31), 119 (28), 107 (100), 90 (85), 79 (41), 51 (11); HRMS (EI) m/z: M+ Calcd for
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C9H10O2 150.0681; Found 150.0678; [α]D +35.0 (c 0.344, CHCl3, 89% ee), (lit.24 [α]D −50 [c 3.3, CHCl3,
(2S,3R)ꢀepoxide, 78% ee]); HPLC conditions: ODꢀH, nꢀhexane/2ꢀpropanol= 90/10, 0.5 mL/min, 210 nm, 19.5 min
(2R,3S), major, 24.8 min (2S,3R), minor.8a
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(R)ꢀ(2ꢀPhenyloxiranꢀ2ꢀyl)methanol (4e) Purified by silica gel column chromatography (5–40% EtOAc/nꢀhexane)
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to give 17.4 mg (20%) of colorless oil: TLC Rf = 0.14 (silica gel, EtOAc/nꢀhexane = 1:3); H NMR (500 MHz,
CDCl3) δ: 7.40–7.30 (5H, m), 4.10 (1H, d, J = 12.5 Hz), 4.00 (1H, d, J = 12.5 Hz), 3.26 (1H, d, J = 5.5 Hz), 2.82 (1H,
d, J = 5.5 Hz), 2.12 (1H, br); 13C{1H} NMR (125 MHz, CDCl3) δ: 137.3, 128.5, 128.1, 126.0, 63.1, 60.4, 52.5; IR
(neat) cm−1: 3420 (br, s), 2926 (m), 1496 (m), 1448 (m), 1044 (m), 1024 (m), 761 (s), 699 (s); EIꢀMS (70 eV) m/z
(relative intensity): 150 (M+, 3), 120 (92), 105 (23), 91 (100), 77 (20); HRMS (FAB) m/z: [M+H]+ Calcd for C9H11O2,
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151.0759; Found, 151.0761; [α]D +5.19 (c 0.233, CHCl3, 21% ee), (lit.25 [α]D25 +27.4 [c 1.3, CHCl3, (2R)ꢀepoxide,
77% ee]); HPLC conditions: ODꢀH, nꢀhexane/2ꢀpropanol= 90/10, 1 mL/min, 210 nm, 9.4 min (2S), minor, 11.8 min
(2R), major.8a
(2R,3R)ꢀGeraniolꢀ2,3ꢀepoxide (4f) Purified by Al2O3 column chromatography (7–60% EtOAc/nꢀhexane) to give
76.5 mg (89%) of colorless oil: Rf = 0.13 (Al2O3, EtOAc/nꢀhexane = 3:7), 0.20 (silica gel, EtOAc/nꢀhexane = 1:3); 1H
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NMR (500 MHz, CDCl3) δ: 5.11–5.05 (1H, m), 3.83 (1H, ddd, J = 11.9, 7.8, 4.6 Hz), 3.68 (1H, ddd, J = 11.6, 6.7, 4.6
Hz), 2.98 (1H, dd, J = 6.7, 4.3 Hz), 2.09 (2H, q, J = 7.6 Hz), 1.94 (1H, dd, J = 7.0, 4.9 Hz), 1.74–1.65 (1H, m), 1.69
(3H, d, J = 0.9 Hz), 1.61 (3H, s), 1.48 (1H, ddd, J = 13.8, 9.2, 7.1 Hz), 1.30 (3H, s); 13C{1H} NMR (125 MHz, CDCl3)
δ: 132.1, 123.3, 62.9, 61.4, 61.1, 38.5, 25.6, 23.7, 17.6, 16.7; IR (neat) cm−1: 3419 (br, s), 2968 (s), 1451 (s), 1384 (s),
1036 (s), 865 (m); EIꢀMS (70 eV) m/z (relative intensity): 170 (M+, 1), 152 (3), 139 (5), 121 (7), 109 (100), 95 (26),
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82 (46), 69 (67); HRMS (EI) m/z: M+ Calcd for C10H18O2 170.1307; Found 170.1303; [α]D +4.93 (c 1.44, CHCl3,
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98% ee), (lit.16 [α]D25 –5.3 [c 3.0, CHCl3, (2S,3S)ꢀepoxide, 91% ee]).
(2R,3R)ꢀ2,3ꢀEpoxygeranyl benzoate (4fꢀbenzoyl) Purified by silica gel column chromatography (1–10%
EtOAc/nꢀhexane) to give 99.6 mg (86% based on 422 ꢀmol 4f) of colorless oil: Rf = 0.27 (silica gel, EtOAc/nꢀhexane
= 1:15); 1H NMR (500 MHz, CDCl3) δ: 8.11–8.07 (2H, m), 7.59–7.56 (1H, m), 7.47–7.42 (2H, m), 5.15–5.09 (1H, m),
4.59 (1H, dd, J = 12.2, 4.5 Hz), 4.27 (1H, dd, J = 11.9, 7.1 Hz), 3.13 (1H, dd, J = 6.7, 4.0 Hz), 2.23–2.09 (2H, m),
1.75–1.67 (1H, m), 1.70 (3H, d, J = 0.9 Hz), 1.62 (3H, s) 1.60–1.53 (1H, m), 1.38 (3H, s); 13C{1H} NMR (125 MHz,
CDCl3) δ: 166.4, 133.1, 132.5, 129.8, 129.7, 128.4, 123.2, 63.7, 61.0, 60.8, 33.3, 25.7, 24.2, 22.0, 17.6; IR (neat)
cm−1: 2967 (s), 1723 (s), 1451 (s), 1272 (s), 1109 (m), 712 (m); EIꢀMS (70 eV) m/z (relative intensity): 274 (M+, 1),
256 (1), 192 (14), 134 (9), 105 (100), 77 (18); HRMS (EI) m/z: M+ Calcd for C17H22O3 274.1569; Found 274.1572;
[α]D25 +15.1 (c 1.71, CHCl3, 98% ee), (lit.26 [α]D27 –13.8 [c 1.0, CHCl3, (2S,3S)ꢀepoxide, 99% ee]); HPLC conditions:
ODꢀH, nꢀhexane/2ꢀpropanol= 99/1, 1 mL/min, 254 nm, 10.3 min (2R,3R), major, 15.7 min (2S,3S), minor.
(2R,3S)ꢀNerolꢀ2,3ꢀepoxide (4g) Purified by Al2O3 column chromatography (7–60% EtOAc/nꢀhexane) to give 80.5
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mg (95%) of colorless oil: Rf = 0.16 (Al2O3, EtOAc/nꢀhexane = 3:7), 0.21 (silica gel, EtOAc/nꢀhexane = 1:3); H
NMR (500 MHz, CDCl3) δ: 5.12–5.06 (1H, m), 3.84–3.77 (1H, m), 3.67–3.62 (1H, m), 2.97 (1H, dd, J = 7.0, 4.3 Hz),
2.40 (1H, br), 2.18–2.02 (2H, m),1.69 (3H, s), 1.70–1.63 (1H, m), 1.62 (3H, s), 1.48 (1H, ddd, J = 13.7, 10.1, 7.0 Hz),
1.34 (3H, s); 13C{1H} NMR (125 MHz, CDCl3) δ: 132.4, 123.3, 64.3, 61.5, 61.2, 33.1, 25.6, 24.1, 22.1, 17.5; IR (neat)
cm−1: 3419 (br, s), 2968 (s), 1450 (s), 1380 (s), 1034 (s), 865 (m); FABꢀMS (glycerol) m/z: 171 [M+H]+; HRMS
(FAB) m/z: [M+H]+ Calcd for C10H19O2 171.1385; Found 171.1387; [α]D25 +17.8 (c 1.42, CHCl3, 84% ee), (lit.27 [α]D
+15.4 [c 3.3, CHCl3, (2R,3S)ꢀepoxide, 70% ee]).
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(2R,3S)ꢀ2,3ꢀEpoxyneryl benzoate (4gꢀbenzoyl)
Purified by silica gel column chromatography (1–10%
EtOAc/nꢀhexane) to give 97.3 mg (88% based on 402 ꢀmol 4g) of colorless oil: Rf = 0.29 (silica gel, EtOAc/nꢀhexane
= 1:15); 1H NMR (500 MHz, CDCl3) δ: 8.09–8.06 (2H, m), 7.59–7.55 (1H, m), 7.46–7.43 (2H, m), 5.15–5.10 (1H, m),
4.59 (1H, dd, J = 11.9, 4.0 Hz), 4.28 (1H, dd, J = 11.9, 7.1 Hz), 3.13 (1H, dd, J = 8.0, 5.3 Hz), 2.23–2.10 (2H, m),
1.73–1.65 (1H, m), 1.70 (3H, d, J = 0.9 Hz), 1.62 (3H, s), 1.59–1.53 (1H, m), 1.38 (3H, s); 13C{1H} NMR (125 MHz,
CDCl3) δ: 166.4, 133.1, 132.5, 129.8, 129.7, 128.4, 123.2, 63.7, 61.0, 60.8, 33.3, 25.6, 24.2, 22.0, 17.6; IR (neat)
cm−1: 2967 (m), 1722 (s), 1451 (m), 1272 (s), 1109 (m), 712 (s); EIꢀMS (70 eV) m/z (relative intensity): 274 (M+, 0.2),
191 (5), 134 (9), 105 (100), 77 (22); HRMS (EI) m/z: M+ Calcd for C17H22O3 274.1569; Found 274.1572; [α]D26 +19.1
(c 1.25, CHCl3, 84% ee); HPLC conditions: ODꢀH, nꢀhexane/2ꢀpropanol = 99.7/0.3, 1 mL/min, 230 nm, 11.3 min
(2S,3R), minor, 16.7 min (2R,3S), major.28
(2R)ꢀ(3,3ꢀDimethyloxiranꢀ2ꢀyl)methanol (4h)
Purified by Al2O3 column chromatography (8–66%
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EtOAc/nꢀhexane) to give 30.7 mg (60%) of colorless oil: Rf = 0.16 (Al2O3, EtOAc/nꢀhexane = 1:3); H NMR (500
MHz, CDCl3) δ: 3.83 (1H, dd, J = 12.2, 1.2 Hz), 3.67 (1H, dd, J = 12.2, 7.1 Hz), 2.99 (1H, dd, J = 6.7, 4.3 Hz), 2.89
(1H, br), 1.35 (3H, s), 1.31 (3H, s); 13C{1H} NMR (125 MHz, CDCl3) δ: 63.9, 61.3, 58.8, 24.7, 18.7; IR (neat) cm−1:
3419 (br, s), 1456 (s), 1380 (s), 1033 (s), 858 (m); FABꢀMS (glycerol) m/z: 103 ([M+H]+); HRMS (FAB) m/z: [M+H]+
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Calcd for C5H11O2 103.0759; Found 103.0757; [α]D +13.0 (c 0.417, CHCl3, 80% ee), (lit.29 [α]D −19.4 [c 0.40,
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CHCl3, (2S)ꢀepoxide, 86% ee]).
(2R)ꢀ(3,3ꢀDimethyloxiranꢀ2ꢀyl)methyl benzoate (4hꢀbenzoyl) Purified by silica gel column chromatography
(0–4% EtOAc/nꢀhexane + 2% CH2Cl2) to give 40.7 mg (66% based on 300 ꢀmol 4h) of colorless oil: Rf = 0.09 (silica
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gel, EtOAc/nꢀhexane/CH2Cl2 = 1:40:1); H NMR (500 MHz, CDCl3) δ: 8.09–8.06 (2H, m), 7.60–7.55 (1H, m),
7.47–7.43 (2H, m), 4.59 (1H, dd, J = 12.2, 4.3 Hz), 4.28 (1H, dd, J = 12.2, 6.7 Hz), 3.14 (1H, dd, J = 6.7, 4.3 Hz),
1.390 (3H, s), 1.387 (3H, s); 13C{1H} NMR (125 MHz, CDCl3) δ: 166.4, 133.1, 129.8, 129.7, 128.4, 63.9, 60.6, 58.2,
24.6, 19.0; IR (neat) cm−1: 2965 (m), 1722 (s), 1453 (m), 1273 (m), 1113 (m), 711 (m); FABꢀMS
(mꢀnitrobenzylalcohol) m/z: 207 ([M+H]+); HRMS (FAB) m/z: [M+H]+ Calcd for C12H15O3 207.1021; Found
207.1029; [α]D +22.2 (c 0.573, CHCl3, 80% ee), (lit.30 [α]D –22.2 [c 1.00, CHCl3, (S)ꢀepoxide, 90% ee]); HPLC
conditions: OBꢀH, nꢀhexane/2ꢀpropanol = 90/10, 1 mL/min, 230 nm, 12.5 min (2S), minor, 16.3 min (2R), major.
(1R,6R)ꢀ7ꢀOxabicyclo[4.1.0]heptanꢀ1ꢀylmethanol (4i) Purified by Al2O3 column chromatography (7–60%
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EtOAc/nꢀhexane) to give 33.7 mg (52%) of colorless oil: Rf = 0.16 (Al2O3, EtOAc/nꢀhexane = 1:3); H NMR (500
MHz, CDCl3) δ: 3.68 (1H, d, J = 11.9 Hz), 3.59 (1H, dd, J = 12.2, 7.9 Hz), 3.26 (1H, d, J = 3.4 Hz), 1.98 (1H, dt, J =
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15.6, 7.5 Hz), 1.99–1.77 (3H, m), 1.74–1.66 (1H, m), 1.53–1.42 (2H, m), 1.33–1.22 (2H, m); 13C{1H} NMR (125
MHz, CDCl3) δ: 64.5, 60.1, 55.8, 25.3, 24.4, 19.9, 19.6; IR (neat) cm−1: 3418 (s), 2937 (s), 1434 (m), 1109 (m), 1069
(m), 1034 (m), 917 (m), 835 (m); FABꢀMS (glycerol) m/z: 129 ([M+H]+); HRMS (FAB) m/z: [M+H]+ Calcd for
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C7H13O2 129.0916; Found 129.0915; [α]D +9.64 (c 0.512, CHCl3, 81% ee), (lit.16 [α]D −22.8 [c 2.6, CHCl3,
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(S,S)ꢀepoxide, 93% ee]).
(1R,6R)ꢀ7ꢀOxabicyclo[4.1.0]heptanꢀ1ꢀylmethyl 3ꢀmethylbenzoate (4iꢀtoluoyl) Purified by silica gel column
chromatography (0–4% EtOAc/nꢀhexane + 2% CH2Cl2) to give 43.9 mg (71% based on 251 ꢀmol 4i) of colorless oil:
Rf = 0.09 (silica gel, EtOAc/nꢀhexane/CH2Cl2 = 1:40:1); 1H NMR (500 MHz, CDCl3) δ: 7.87–7.83 (2H, m), 7.38 (1H,
d, J = 7.9 Hz), 7.33 (1H, t, J = 7.7 Hz), 4.46 (1H, d, J = 11.9 Hz), 4.18 (1H, d, J = 11.9 Hz), 3.21 (1H, d, J = 3.4 Hz),
2.41 (3H, s), 2.05–1.95 (2H, m), 1.91–1.84 (2H, m), 1.54–1.44 (2H, m), 1.36–1.23 (2H, m); 13C{1H} NMR (125 MHz,
CDCl3) δ: 166.4, 138.2, 138.9, 130.2, 129.8, 128.3, 126.9, 68.4, 57.8, 56.7, 25.5, 24.3, 21.3, 19.7, 19.5; IR (neat)
cm−1: 2938 (s), 1719 (s), 1590 (m), 1436 (m), 1274 (m), 1197 (s), 1083 (m), 1001 (m), 744 (s); EIꢀMS (20 eV) m/z
(relative intensity): 246 (M+, 0.5), 119 (100); HRMS (EI) m/z: M+ Calcd for C15H18O3 246.1256; Found 246.1254;
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Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.23; H, 7.40; [α]D +11.8 (c 0.624, CHCl3) (81% ee);
HPLC conditions: OBꢀH, nꢀhexane/2ꢀpropanol = 90/10, 1 mL/min, 230 nm, 9.6 min (S,S), minor, 14.2 min (R,R),
major.
(2R,3R)ꢀ(3ꢀPropyloxiranꢀ2ꢀyl)methanol (4j) Purified by Al2O3 column chromatography (7–60% EtOAc/nꢀhexane)
to give 43.9 mg (75%) of colorless oil: Rf = 0.14 (Al2O3, EtOAc/nꢀhexane = 3:7); 1H NMR (500 MHz, CDCl3) δ: 3.91
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(1H, d, J = 12.6 Hz), 3.63 (1H, d, J = 12.2 Hz), 2.96 (1H, td, J = 5.7, 2.4 Hz), 2.92 (1H, dt, J = 4.3, 2.4 Hz), 1.85 (1H,
br), 1.58–1.42 (4H, m), 0.97 (3H, t, J = 7.2 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ: 61.7, 58.4, 55.8, 33.6, 19.2,
13.7; IR (neat) cm−1: 3419 (br, s), 2961 (s), 1665 (m), 1382 (m), 1223 (m), 1065 (m), 1045 (m), 901 (m), 854 (m);
FABꢀMS (glycerol) m/z: 107 ([M+H]+); HRMS (FAB) m/z: [M+H]+ Calcd for C6H13O2, 117.0916; Found, 117.0918;
[α]D23 +27.0 (c 0.694, CHCl3, 80% ee), (lit.31 [α]D25 −46.6 [c 1.0, CHCl3, (2S,3S)ꢀepoxide, 96.8% ee]).
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(2R,3R)ꢀ(3ꢀPropyloxiranꢀ2ꢀyl)methyl 3ꢀmethylbenzoate (4jꢀtoluoyl)
Purified by silica gel column
chromatography (0–4% EtOAc/nꢀhexane + 2% CH2Cl2) to give 44.4 mg (50% based on 378 ꢀmol 4j) of colorless oil:
Rf = 0.14 (silica gel, EtOAc/nꢀhexane/CH2Cl2 = 1:40:1); 1H NMR (500 MHz, CDCl3) δ: 7.88 (1H, d, J = 0.7 Hz), 7.86
(1H, d, J = 7.9 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.33 (1H, t, J = 7.7 Hz), 4.59 (1H, dd, J = 12.0, 3.4 Hz), 4.18 (1H, dd, J
= 12.0, 6.0 Hz), 3.10 (1H, ddd, J = 5.7, 3.4, 2.2 Hz), 2.93 (1H, td, J = 5.7, 2.2 Hz), 2.40 (3H, s), 1.62–1.42 (4H, m),
0.97 (3H, t, J = 7.3 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ: 166.4, 138.1, 133.9, 130.2, 129.6, 128.2, 126.8, 65.1,
56.5, 55.3, 33.5, 21.2, 19.1, 13.8; IR (neat) cm−1: 2960 (s), 1721 (s), 1276 (m), 1199 (m), 1106 (m), 1082 (m), 745
(m); EIꢀMS (70 eV) m/z (relative intensity): 234 (M+, 1), 191 (1), 136 (4), 119 (100), 91 (17); HRMS (EI) m/z: M+
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Calcd for C14H18O3 234.1256; Found 234.1258; [α]D +31.7 (c 0.550, CHCl3, 80% ee); HPLC conditions: OBꢀH,
nꢀhexane/2ꢀpropanol = 98/2, 0.5 mL/min, 230 nm, 30.4 min (2R,3R), major, 34.8 min (2S,3S), minor.8a
(2R,3S)ꢀ(3ꢀPropyloxiranꢀ2ꢀyl)methanol (4k) Purified by Al2O3 column chromatography (7–60% EtOAc/nꢀhexane)
to give 50.5 mg (86%) of colorless oil: Rf = 0.14 (Al2O3, EtOAc/nꢀhexane = 3:7); Rf = 0.14 (silica gel,
1
EtOAc/nꢀhexane = 1:3); H NMR (500 MHz, CDCl3) δ: 3.85 (1H, dd, J = 12.2, 4.0 Hz), 3.67 (1H, dd, J = 12.2, 7.0
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Hz), 3.16 (1H, dt, J = 4.3, 2.1 Hz), 3.07–3.01 (1H, m), 1.59–1.41 (4H, m), 2.37 (1H, br), 0.98 (3H, t, J = 7.0 Hz);
13C{1H} NMR (125 MHz, CDCl3) δ: 60.9, 57.1, 56.9, 29.9, 19.9, 13.8; IR (neat) cm−1: 3408 (br, s), 2962 (s), 1465 (m),
1042 (s), 914 (m), 858 (m), 829 (m), 768 (m); FABꢀMS (glycerol) m/z: 117 ([M+H]+). HRMS (FAB) m/z: [M+H]+
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Calcd for C6H13O2 117.0916; Found 117.0919; [α]D +2.87 (c 0.757, CHCl3, 87% ee), (lit.32 [α]D −4.99 [c 3.64,
22
21.5
CHCl3, (2S,3R)ꢀepoxide, 85.8% ee]).
(2R,3S)ꢀ(3ꢀPropyloxiranꢀ2ꢀyl)methyl 3ꢀmethylbenzoate (4kꢀtoluoyl)
Purified by silica gel column
chromatography (0–4% EtOAc/nꢀhexane + 2% CH2Cl2) to give 50.9 mg (50% based on 435 ꢀmol 4k) of colorless oil:
Rf = 0.16 (EtOAc/nꢀhexane/CH2Cl2 = 1:40:1); 1H NMR (500 MHz, CDCl3) δ: 7.89 (1H, d, J = 0.6 Hz), 7.88 (1H, d, J
= 7.6 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.33 (1H, t, J = 7.6 Hz), 4.58 (1H, dd, J = 11.9, 4.3 Hz), 4.28 (1H, dd, J = 12.2,
7.0 Hz), 3.32 (1H, dt, J = 7.0, 3.5 Hz), 3.08 (1H, td, J = 6.1, 4.3 Hz), 2.41 (3H, s), 1.64–1.46 (4H, m), 1.01 (3H, t, J =
7.2 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ: 166.6, 138.2, 133.9, 130.3, 129.7, 128.3, 126.9, 63.3, 56.4, 53.8, 30.0,
21.2, 19.9, 13.9; IR (neat) cm−1: 2961 (s), 1721 (s), 1457 (m), 1278 (s), 1199 (s), 1107 (m), 1083 (m), 745 (s); EIꢀMS
(70 eV) m/z (relative intensity): 234 (M+, 1), 119 (100), 91 (16); HRMS (EI) m/z: M+ Calcd for C14H18O3 234.1256;
Found 234.1259; [α]D21 +14.2 (c 0.793, CHCl3, 87% ee); HPLC conditions: OBꢀH, nꢀhexane/2ꢀpropanol = 99.8/0.2, 1
mL/min, 230 nm, 19.4 min (2R,3S), major, 28.4 min (2S,3R), minor.9f
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mnoji@myꢀpharm.ac.jp.
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ACKNOWLEDGEMENTS
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M.N. thanks Mr. Kubota and Ms. Ohashi for their technical assistance.
ASSOCIATED CONTENT
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Supporting Information
NMR spectra, HPLC charts, Xꢀray crystal structure details. This material is available free of charge via the Internet
at http://pubs.acs.org.
REFERENCES and FOOTNOTES
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