Vanadium-catalyzed asymmetric epoxidation of allylic alcohols in water

Article abstract of DOI:10.1021/jo900294h

Asymmetric V-catalyzed epoxidation of allylic alcohols can be carried out in water with chiral ligands, which incorporate sulfonamide and hydroxamic acid fragments. Furthermore, the reaction, notorious for its ligand-deceleration effect, in water turned into the ligand-accelerated process. By using this aqueous protocol, a range of allylic alcohols were epoxidized with up to 94% ee.

Full text of DOI:10.1021/jo900294h

Vanadium-Catalyzed Asymmetric Epoxidation of Allylic Alcohols in
Water
Andrei V. Malkov,*,†,‡ Louise Czemerys,† and Denis A. Malyshev†,§
Department of Chemistry, WestChem, Joseph Black Building, UniVersity of Glasgow, Glasgow G12 8QQ,
United Kingdom, and Department of Chemistry, Loughborough UniVersity, Leicestershire,
LE11 3TU, United Kingdom
a.malkoV@lboro.ac.uk
ReceiVed February 10, 2009
Asymmetric V-catalyzed epoxidation of allylic alcohols can be carried out in water with chiral ligands,
which incorporate sulfonamide and hydroxamic acid fragments. Furthermore, the reaction, notorious for
its ligand-deceleration effect, in water turned into the ligand-accelerated process. By using this aqueous
protocol, a range of allylic alcohols were epoxidized with up to 94% ee.
SCHEME 1. Ligand-Deceleration Effect
Introduction
Vanadium-based peroxidases take part in a broad range of
synthetically useful oxidative transformations including asym-
metric epoxidation, sulfoxidation, and benzylic oxidation, which
instigates an interest in designing synthetic biomimetic models
with a vanadium core capable of reproducing the action of the
biological systems.1 Among the oxidation products, chiral
epoxides occupy a pivotal position due to their unique versatility
as synthetic building blocks in the target oriented organic
synthesis.2 Currently, Sharpless Ti-catalyzed epoxidation of
allylic alcohols is the method of choice.3 It is well understood
and capable of delivering reliable and reproducible results;
however, certain limitations, which include a rather high catalyst
loading and requirement for stringently anhydrous conditions,
hamper its wider industrial application.
The alternative methodology, also pioneered by Sharpless,4
utilizes vanadium complexes, which are less sensitive to
moisture, and furthermore, the catalyst loading can be reduced
to 1 mol % or less. However, in V-catalyzed systems the
mechanism of enantiodifferentiation is not clearly understood
and the method is blemished by ligand deceleration effect5
(Scheme 1): ligand-free species A present in equilibrium with
coordinated species B and C is the most reactive but gives a
racemic product. To minimize its presence, a large concentration
of the chiral ligand is used to shift the equilibrium away from
A toward the coordinated species B and C; however, it also
substantially reduces the useful concentration of the desired
catalytically active chiral species B, so that the highest selectivity
is achieved at rather low reaction rates, which impeded the
† University of Glasgow.
‡ Current address: Loughborough University.
§ Visiting student from Higher Chemical College, Russian Academy of
Sciences, 9 Miusskaya square, Moscow 125047, Russia. Current address:
CB262R, The Scripps Research Institute, 10550 North Torrey Pines Road, La
Jolla, California 92037.
(1) For overviews, see: (a) Van de Velde, F.; Arends, I. W. C. E.; Sheldon,
R. A. J. Inorg. Biochem. 2000, 80, 81–89. (b) Van de Velde, F.; Van Rantwijk,
F.; Sheldon, R. A. Trends Biotechnol. 2001, 19, 73–80. (c) Ligtenbarg, A. G. J.;
Hage, R.; Feringa, B. L. Coord. Chem. ReV. 2003, 237, 89.
(2) For overviews, see: (a) Katsuki, T. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Heidelberg, Germany, 1999; Vol. 2, p 621. (b) Katsuki, T. Curr. Org. Chem.
2001, 5, 663. (c) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal.
2001, 343, 5. (d) Adam, W.; Saha-Mo¨ller, C. R.; Ganeshpure, P. A. Chem. ReV.
2001, 101, 3499. (e) Adam, W.; Malisch, W.; Roschmann, K. J.; Saha-Mo¨ller,
C. R.; Schenk, W. A. J. Organomet. Chem. 2002, 661, 3.
(4) (a) Michaelson, R. C.; Palermo, R. E.; Sharpless, K. B. J. Am. Chem.
Soc. 1977, 99, 1990. (b) Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta
1979, 12, 63.
(3) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. (b)
Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
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3350 J. Org. Chem. 2009, 74, 3350–3355
10.1021/jo900294h CCC: $40.75 2009 American Chemical Society
Published on Web 04/03/2009

Asymmetric Epoxidation of Allylic Alcohols in Water
SCHEME 2. Asymmetric Epoxidation
epoxidation is taking place. In these circumstances, the con-
centration of the catalytically active vanadium complex will be
controlled by the concentration of the ligand. Once extracted
from water, vanadium remains in the organic layer as a complex
with hydroxamic acid; the aqueous phase turns out to be
essentially free from the metal after the reaction is complete.
Importantly, the rate of the reaction in water proved generally
slower than that in organic solvents and only our sulfonamide
ligands of type 4 provided an acceptable level of reactivity and
selectivity (up to 72% ee).10b Employing water as a solvent12
offers numerous advantages over traditional organic solvents
including favorable environmental impact and low cost. To-
date, only a handful of reports related to the asymmetric
epoxidation of alkenes in aqueous solutions appeared in the
literature.13,14
To obtain a full return from performing reactions in aqueous
medium, it is important to bring the enantioselectivity to the
practically useful level. Herein, we present a further development
of the asymmetric V-catalyzed epoxidation of allylic alcohols
in water focusing on the synthesis of new chiral ligands and
optimization of the reaction conditions to boost reactivity and
enantioselectivity.
practical use of these systems.4 It is worth noting that even
though species C appears to be inactive in epoxidation, it may
mediate other oxidative processes, such as oxidation of the
allylic alcohols to the corresponding unsaturated aldehydes,6
adding to the complexity of the reacting system.
Following earlier reports on the use of chiral hydroxamic
acids in V-catalyzed asymmetric epoxidation of allylic alcohols,7,8
Yamamoto advanced the field with the discovery of a very
efficient family of bis-hydroxamic acids 3,9 which matched the
Ti systems in terms of the scope and selectivity; however, the
reactivity still remains the issue. In parallel with that, we have
developed a family of sulfonamide ligands 4 which exhibited
high reactivity and promising enantioselectivity in the epoxi-
dation of allylic alcohols in toluene (ee e78%).10
Recently, we discovered that the same reaction (Scheme 2,
1 f 2) can be carried out in water,10b where the costly vanadium
precursor VO(i-OPr)3 and anhydrous t-BuOOH are replaced with
much cheaper alternatives, such as VOSO4 and aqueous
t-BuOOH, respectively. Furthermore, the reaction in water
turned into the ligand accelerated process, where an excess of
the ligand was no longer essential. The epoxidation is likely to
proceed in the organic phase, as water-soluble vanadium salts
exhibited poor conversion. Hydroxamic acid, a well-known key
structural fragment of natural siderophores,11 coordinates to the
vanadium ion and transfers it to the organic phase where
Results and Discussion
A new set of chiral hydroxamic acids 5 and 6 (Scheme 2) is
built around the chiral 1,2-diamine scaffold. Different from
hydroxamic acid 4, the chiral group in 5 and 6 is located in the
hydroxylamine part. All the sulfonamide ligands 4-6 feature
the bulky diphenylmethane substituent in the achiral fragment
as smaller groups tend to considerably reduce enantioselec-
tivity.7c,10a
Ligand Synthesis. General synthetic strategy toward the
hydroxamic acid ligands relies on the coupling of the activated
acid derivatives, such as acid chlorides 7, with hydroxylamines
(12a,b) (Scheme 3). Commercially available monotosylated
derivative 9a was used for the synthesis of hydroxylamine 12a,
while the synthesis of hydroxylamine 12b commenced with the
L-tartrate salt of (R,R)-(+)-8b,15 which after neutralization with
2 M aqueous NaOH was treated with a solution of tosyl chloride
(1.1 equiv) in DCM to afford 9b (86% yield). Further sequence
involved cyanomethylation of the mono-N-tosyldiamines 9a,b
to furnish the respective 10a (70%) and 10b (99%), followed
by oxidation with m-CPBA. The nitrones 11a (92%) and 11b
(75%) thus obtained were treated with hydroxylamine hydro-
chloride to produce the desired hydroxylamines 12a (73%) and
(6) Zeng, W.; Ballard, T. E.; Melander, C. Tetrahedron Lett. 2006, 47, 5923.
(7) (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. (c) Hoshino, Y.; Yamamoto, H. J. Am. Chem.
Soc. 2000, 122, 10452.
(8) (a) Bolm, C.; Ku¨hn, T. Synlett 2000, 899. (b) Bolm, C.; Ku¨hn, T. Isr.
J. Chem. 2001, 41, 263. (c) Bolm, C.; Beckmann, O.; Ku¨hn, T.; Palazzi, C.;
Adam, W.; Rao, P. B.; Saha-Mo¨ller, C. R. Tetrahedron: Asymmetry 2001, 12,
2441. (d) Traber, B.; Jung, Y.-G.; Park, T. K.; Hong, J.-I. Bull. Korean Chem.
Soc. 2001, 22, 547. (e) Wu, H.-L.; Uang, B.-J. Tetrahedron: Asymmetry 2002,
13, 2625. (f) Adam, W.; Beck, A. K.; Pichota, A.; Saha-Mo¨ller, C. R.; Seebach,
D.; Vogl, N.; Zhang, R. Tetrahedron: Asymmetry 2003, 14, 1355. (g) Bryliakov,
K. P.; Talsi, E. P.; Bolm, C.; Ku¨hn, T. New J. Chem. 2003, 27, 609. (h) Bryliakov,
K. P.; Talsi, E. P. Kinet. Catal. 2003, 44, 334. (i) Bryliakov, K. P.; Talsi, E. P.;
Stas’ko, S. N.; Kholdeeva, O. A.; Popov, S. A.; Tkachev, A. V. J. Mol. Catal.
A 2003, 194, 79.
(11) For an overview, see: Wandersman, C.; Delepelaire, P. Annu. ReV.
Microbiol. 2004, 58, 611.
(12) For recent reviews, see: (a) Liu, S.; Xiao, J. J. Mol. Catal. A 2007, 270,
1. (b) Otto, S.; Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 2809. (c)
Lindstro¨m, U. M. Chem. ReV. 2002, 102, 2751. For a related recent contribution,
see: (d) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
(13) (a) Ballistreri, F. P.; Brinchi, L.; Germani, R.; Savelli, G.; Tomaselli,
G. A.; Toscano, R. M. Tetrahedron 2008, 64, 10239. (b) Colladon, M.; Scarso,
A.; Strukul, G. AdV. Synth. Catal. 2007, 349, 797. For the asymmetric epoxidation
of alkenes using aqueous hydrogen peroxide, see: (c) Sawada, Y.; Matsumoto,
K.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 46, 4559. (d) Shimada, Y.; Kondo,
S.; Ohara, Y.; Mataumoto, K.; Katsuki, T. Synlett 2007, 2445. (e) Sawada, Y.;
Matsumoto, K.; Kondo, S.; Watanabe, H.; Ozawa, T.; Suzuki, K.; Saito, B.;
Katsuki, T. Angew. Chem., Int. Ed. 2006, 45, 3478. (f) Matsumoto, K.; Sawada,
Y.; Katsuki, T. Synlett 2006, 3545.
(9) (a) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew.
Chem., Int. Ed. 2005, 44, 4389. (b) Barlan, A.; Zhang, W.; Yamamoto, H.
Tetrahedron 2007, 63, 6075.
(10) (a) Malkov, A. V.; Bourhani, Z.; Kocˇovsky´, P. Org. Biomol. Chem.
2005, 3194. (b) Bourhani, Z.; Malkov, A. V. Chem. Commun. 2005, 4592. (c)
Bourhani, Z.; Malkov, A. V. Synlett 2007, 3525.
(14) For organocatalytic asymmetric epoxidations in aqueous media, see: (a)
Yang, D.; Wong, M. K.; Yip, Y. C.; Wang, X. C.; Tang, M. W.; Zheng, J. H.;
Cheung, K. K. J. Am. Chem. Soc. 1998, 120, 5943. (b) Frohn, M.; Dalkiewicz,
M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. (c) Wang,
Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.
(15) Larrow, J. F.; Jacobsen, E. N. Org. Synth. 2004, 10, 96.
J. Org. Chem. Vol. 74, No. 9, 2009 3351

Malkov et al.
SCHEME 3. Synthesis of Hydroxamic Acids 5 and 6
TABLE 1. Optimization of Aqueous V-Catalyzed Epoxidation of Allylic Alcoholsa
a The reaction was carried out at a 1 mmol scale at 0 °C for 12 h unless stated othervise. The catalyst was generated in situ from VOSO4 and the
ligand (vanadium/ligand ratio 1:1.1). b Determined by chiral GC (see the Experimental Section). c The absolute configuration of all the products was
(S,S) as deduced from their optical rotation (see the Experimental Section). d Reaction time 48 h. e Reference 10b. f The reaction was carried out in a 3:1
mixture of water/DCM. g The reaction was carried out in a 3:1 mixture of water/toluene. h The reaction was carried out at -20 °C for 16 h, using a 5-6
M solution of t-BuOOH in nonane. The catalyst was generated from VO(i-OPr)3 and the ligand (vanadium/ligand ratio 1:1.1).
12b (84%). In the next step, the hydroxylamines were coupled
with commercially available acid chloride 7. To avoid formation
of the unwanted O-acylation products, the OH group in
hydroxylamines 12a,b was first protected in situ by treatment
with a mixture of TMSCl and lutidine16 followed by acylation
with 7 to furnish the target hydroxamic acids 5 (44%) and 6
(67%). Under these conditions, the competing O-acylation of
the hydroxylamine was reduced to a minimum (less than 5%).
Vanadium-Catalyzed Epoxidation. New hydroxamic acids
5 and 6 were examined as chiral ligands in the epoxidation of
2-methylcinnamyl alcohol 1a and 2-phenylcinnamyl alcohol 1i
selected as model substrates to allow direct comparison with
the results obtained with sulfonamide ligand 410 (Table 1).
In the preliminary report,10b the reactions were carried out
with 2 mol % of VOSO4 ·H2O with a slight excess of chiral
ligand (2.2 mol %); on average, the process required 48-60 h
at 0 °C for completion. Following this protocol, epoxidation of
2-methylcinnamyl alcohol 1a with aqueous tert-butyl hydro-
peroxide employing the catalyst based on (R,R)-phenylenedi-
amine ligand 5 after 48 h produced epoxy alcohol 2a with a
slightly improved selectivity (63% yield, 66% ee, entry 2)
compared to the original ligand 4 (69% yield, 59% ee, entry
1), whereas the clear winner was ligand 6 derived from (R,R)-
cyclohexyldiamine giving 2a in 73% yield and 82% ee (entry
4). However, the most dramatic jump in enantioselectivity was
observed in the epoxidation of 2-phenylcinnamyl alcohol 1i:
while ligand 4 afforded epoxide 2i in mere 20% ee (entry 10),
ligand 6 delivered 2i with respectrable 84% ee (entry 13).
Epoxidation in water is generally slower than in organic solvents
due to the heterogeneous nature of the system. The reaction
rate is particularly affected when the substrate allylic alcohol
is a solid, such as 1i, resulting in low conversions (entries 10
and 13). Furthermore, it is important to maintain a high reaction
rate in the aqueous epoxidation since prolonged reaction times
can lead to a competing hydrolytic opening of the epoxide ring,
assisted by a Lewis acidic catalyst, thus affecting the yield of
the target product.17 Therefore, the issues of reactivity were
addressed next.
First, we investigated the effect of catalyst loading. Increasing
the catalyst content from 2 mol % to 5 mol % reduced the
reaction time and increased enantioselectivity. Thus, after just
12 h, the catalyst with ligand 5 afforded epoxy alcohol 2a in
89% yield and 74% ee, while the complex with 6 produced 2a
in 95% yield and 85% ee (entries 3 and 5, respectively). Catalyst
(17) (a) Hanson, R. M. Chem. ReV. 1991, 91, 437. (b) Tetzlaff, H. R.;
Espenson, J. H. Inorg. Chem. 1999, 38, 881.
(16) Jin, Y.; Kim, D. H. Tetrahedron: Asymmetry 1997, 8, 3699.
3352 J. Org. Chem. Vol. 74, No. 9, 2009

Asymmetric Epoxidation of Allylic Alcohols in Water
TABLE 2. Catalytic Epoxidation of Allylic Alcohols in Water with
Ligand 6a
loading of 5 mol % appears to be optimal since a further increase
to 7 mol % offered only marginal benefits (entry 6).
However, the catalyst loading alone cannot cure the problems
associated with inefficient mixing of the organic components
on the aqueous surface, particularly in those cases when both
the substrate alcohol and the ligand are solids. We reasoned
that the homogeneity of the organic phase can be improved by
addition of a small quantity of organic solvent. Furthermore, in
the original aqueous method10b the epoxidation is taking place
in the organic phase consisting predominantly of the starting
alcohol; however, alcohols were shown10a to be poor solvents
for this process. On the other hand, toluene and dichloromethane
(DCM) had a proven record in successful V-catalyzed epoxi-
dation reactions,7-10 therefore they were chosen as additives.
Indeed, addition of DCM to the aqueous mixture in the
epoxidation of 1a with ligand 6 improved reactivity of the
system; however, selectivity was slightly diminished (entry 7).
At the same time, addition of toluene (entry 8) led to a notable
increase in both yield (97%) and selectivity (90% ee). Impor-
tantly, the amount of organic solvent should be kept to a
minimum, since in the organic medium the ligand deceleration
effect comes into play requiring higher ligand-to-vanadium
ratios. Thus, when the reaction was carried out in toluene alone
with 10% excess of ligand over vanadium, the ratio proved
optimal in the aqueous protocol, the selectivity plummeted to
58% ee (compare entries 8 and 9). Epoxidation of 2-phenyl-
cinnamyl alcohol 1i, so far the slowest reacting substrate,
benefited the most from the addition of toluene to the aqueous
mixture: epoxide 2i was obtained in high yield and high
enantioselectivity with both new ligands 5 and 6 (entries 12
and 14), the latter reaching 94% ee.
a The reaction was carried out at 1 mmol scale with 5 mol % of
catalyst (generated from VOSO4 and the ligand in 1/1.1 ratio) at 0 °C
for 24 h in water unless specified otherwise. b Determined by chiral
NMR, GC, or HPLC (see the Experimental Section). c The absolute
configuration of the products was deduced from their optical rotation
(see the Experimental Section). d The reactions were carried out in 3:1
mixture of water/toluene. e The catalyst was generated in situ from
VOSO4 (5 mol %) and the ligand (10 mol %). f The reaction was carried
out with 2 mol % of catalyst at -20 °C for 48 h in a 3:1 water/
methanol mixture.
It is pertinent to note that bis-hydroxamic acid (R,R)-3
introduced by Yamamoto9 and our ligand (R,R)-6 featuring the
same configurations of the stereogenic centers gave rise to
opposite enantiomers of the product 2a, both with high
enantioselectivity ((R,R) 94%9 and (S,S) 90% ee, respectively,
at 0 °C), suggesting that these systems operate by different
mechanisms of enantiodifferentiation. However, we currently
do not have sufficient kinetic, spectroscopic, and computational
data to speculate on the nature of these differences.
synthesized for V-catalyzed aqueous asymmetric epoxidation
of allylic alcohols. Optimization of the reaction conditions led
to development of an efficient protocol that was applied to the
synthesis of a range of epoxy alcohol with up to 94% ee.
The efficacy of the aqueous protocol employing our best
ligand 6 was assessed in the epoxidation of a range of allylic
alcohols (Table 2). The conditions in each case were optimized
to maximize the yield of the target epoxides.
Experimental Section
The reaction proved to be very efficient with all the
2-substitited cinnamyl derivatives 1a-f,i, with the enantiose-
lectivity varying in the range of 83-94% ee (entries 1-6 and
9). It is worth mentioning that alcohols 1d and 1e produced
similar results in both water and water/toluene mixture. In the
case of other 2,3-disubstituted alcohols 1g, 1h, and 1k,
the selectivity displayed a strong dependency on the size of the
substitutents; groups larger than methyl caused a drop in ee
(entries 7, 8, and 11), which is somewhat surprising since bulky
2-phenylcinnamyl alcohol 1i exhibited the highest enantiose-
lectivity (entry 9). Furthermore, alcohols 1h and 1k did not
benefit from the addition of toluene to the reaction mixture
showing slightly higher selectivity in water alone. Other, less
sterically demanding substrates, e.g., 1j and 1l, produced
selectivities similar to those previously reported for ligand 410b
(entries 10 and 12).
Synthesis of N-Hydroxy-N-((1R,2R)-2-(4-methylphenylsul-
fonamido)cyclohexyl)-2,2-diphenylacetamide (6). N-((1R,2R)-2-
Aminocyclohexyl)-4-methylbenzenesulfonamide (9b): Following
a procedure by Ng,18 to a stirred solution of L-tartrate salt 8b15
(4.0 g, 15.14 mmol) in 2 M aqueous NaOH (18 mL) was added
Et3N (2.19 mL, 20.41 mmol) and DCM (130 mL). The mixture
was cooled to 0 °C and a solution of TsCl (3.17 g, 16.65 mmol) in
DCM (90 mL) was added dropwise over 30 min. The mixture was
warmed to room temperature and stirred for 12 h. The resulting
reaction mixture was washed with 2 M aqueous HCl (3 × 50 mL)
and the organic phase was removed. The aqueous phase was
collected and adjusted to pH 9 by addition of 6 M NaOH. The
basic aqueous solution was extracted with DCM (3 × 50 mL). The
combined DCM layers were dried over MgSO4 and evaporated in
vacuo to give 9b as a pale yellow solid (3.5 g, 86%). A small sample
1
was recrystallized from ethyl acetate: pale yellow solid; H NMR
(400 MHz, CDCl3) δ 0.99-1.21 (m, 4H), 1.57-1.66 (m, 3H),
In conclusion, new chiral ligands based on 1,2-diamines
featuring sulfonamide and hydroxamic acid functionalities were
(18) Ng, K. Tetrahedon: Asymmetry 2001, 12, 1719.
J. Org. Chem. Vol. 74, No. 9, 2009 3353

Malkov et al.
1.86-1.95 (m, 1H), 2.37 (s, 3H), 2.42 (dt, J ) 10.3, 3.7 Hz, 1H),
2.66 (dt, J ) 10.3, 3.7 Hz, 1H), (br s, 2H), 7.26 (d, J ) 8.2 Hz,
2H), 7.76 (d, J ) 8.2 Hz); 13C NMR (100.6 MHz, CDCl3) δ 21.5
(CH3), 24.7 (CH2), 25.0 (CH2), 32.4 (CH2), 34.9 (CH2), 54.7 (CH),
60.4 (CH), 127.0 (aromatic CH), 129.7 (aromatic CH), 138.2 (C),
143.1 (C). In agreement with literature data.19
DCM (50 mL). After stirring for 5 min, the resulting precipitate
was collected by filtration and the filter cake was washed with
DCM. The filtrate was neutralized with NaHCO3 (30 mL) and the
organic layer was separated. The aqueous phase was extracted with
DCM (25 mL). The organic phase was washed with brine (30 mL)
and the combined aqueous phases were back-extracted with DCM
(3 × 30 mL). The organic extracts were then dried over MgSO4
and concentrated to give 12b as a pale yellow solid (0.88 g, 84%),
which was used in the next step without further purification. A
small sample was recrystallized from DCM: pale yellow solid, mp
N-((1R,2R)-2-(Cyanomethylamino)cyclohexyl)-4-methylben-
zenesulfonamide (10b): Following a procedure by Fukuyama,20
diisopropylethylamine (2.34 mL, 7.39 mmol) was added to a
solution of monotosyl diamine 9b (1.80 g, 6.72 mmol) in acetonitrile
(30 mL) and the reaulting solution was stirred for 5 min.
Bromoacetonitrile (0.51 mL, 7.39 mmol) was then added via syringe
over 10 min and the mixture was stirred overnight at room
temperature. Then the mixture was concentrated on a rotary
evaporator to give a yellow oil, which was treated with saturated
aqueous NaHCO3 (50 mL). The resulting mixture was extracted
with DCM (50 mL), the organic phase was washed with brine (50
mL), and the combined aqueous phases were extracted with DCM
(3 × 50 mL). The combined organic extracts were dried over
MgSO4 and evaporated in vacuo to give 10b as a yellow solid (1.98
g, 99%), which was used in the next step without further
purification. A small sample was recrystallized from ethyl acetate:
yellow solid, mp 104-105 °C (petroleum ether/ethyl acetate); [R]D
1
100-102 °C (DCM); [R]D -28.9 (c 1.0, acetone); H NMR (400
MHz, CDCl3) δ 0.99-1.18 (m, 4H), 1.45-1.84 (m, 4H), 2.34 (s,
3H), 2.43 (td, J ) 11.3, 3.9 Hz, 1H), 3.0 (m, 1H), 4.74 (br s, 1H),
5.92 (br s, 1H), 7.25 (d, J ) 8.3 Hz, 2H), 7.74 (d, J ) 8.3 Hz,
2H); 13C NMR (100.6 MHz, CDCl3) δ 21.6 (CH3), 24.4 (CH2),
24.7 (CH2), 29.3 (CH2), 33.2 (CH2), 54.4 (CH), 64.2 (CH), 127.1
(aromatic CH), 127.3 (aromatic CH), 129.8 (aromatic CH), 136.9
(aromatic CH), 137.7 (C), 143.6 (C); IR (NaCl) ν 3263.9 (NH),
3155.0 (OH), 2938.0 (CsH), 2253.4 (CdC), 1026.9 (OdSdO);
MS (FAB) m/z (%) 285.2 ((M + H)+ 100), 92.9 (16), 130.4 (15),
92.9 (13); HRMS (FAB) 285.1274 (C13H21N2O3S requires 285.1273).
N-Hydroxy-N-((1R,2R)-2-(4-methylphenylsulfonamido)cyclo-
hexyl)-2,2-diphenylacetamide (6): Following a procedure by
Kim,16 2,6-lutidine (0.58 mL, 4.94 mmol) and TMSCl (0.63 mL,
4.94 mmol) were added to a solution of hydroxylamine 12b (0.70
g, 2.47 mmol) in THF (21 mL) at 0 °C and the resulting mixture
was stirred at room temperature for 6 h. The mixture was cooled
to 0 °C and a solution of diphenyl acetyl chloride (0.57 g, 2.47
mmol) in THF (5.5 mL) was added dropwise. The mixture was
stirred at room temperature overnight. Water (0.9 mL) was added
and the resulting solution was stirred for 1 h at room temperature.
THF was then evaporated in vacuo. Ethyl acetate (20 mL) was
added to the residue and the organic layer was washed successively
with 10% citric acid (30 mL), 5% NaHCO3 (30 mL), and water
(30 mL). The organic solution was then dried over MgSO4 and
concentrated in vacuo to give a yellow sticky oil, which was
recrystallized from methanol to give 6 as a white solid (0.80 g,
67%): mp 183-186 °C (methanol); [R]D + 4.8 (c 0.25, CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.90-1.20 (m, 4H), 1.30-1.74 (m,
4H), 2.35 (s, 3H), 3.10 (m, 1H), 4.30 (td, J ) 11.0, 3.6 Hz, 1H),
4.76 (d, J ) 9.6 Hz, 1H), 5.62 (s, 1H), 7.14-7.31 (m, 12H), 7.61
(d, J ) 8.3 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 20.6 (CH3),
23.3 (CH2), 24.0 (CH2), 27.1 (CH2), 31.1 (CH2), 52.1 (CH), 52.8
(CH), 58.2 (CH), 125.6 (aromatic CH), 125.7 (aromatic CH), 125.8
(aromatic CH), 126.2 (aromatic CH), 126.3 (aromatic CH),
127.3 (aromatic CH), 127.5 (aromatic CH), 127.6 (aromatic CH),
127.7 (aromatic CH), 128.2 (aromatic CH), 128.7 (aromatic CH),
136.5 (C), 138.4 (C), 138.5 (C), 142.5 (C), 172.5 (CdO); IR (NaCl)
ν 3154.0 (OH), 2940.9 (CsH), 2253.4 (CdC), 1709.6 (CdO),
1093.4 (OdSdO); HRMS (EI) m/z 478.1929 (C27H30N2O4S requires
478.1926).
General Procedure for the Asymmetric Epoxidation (Table
2). Hydroxamic acid (4, 5, or 6; 5.5 mol %), vanadyl sulfate (5.0
mol %), and allylic alcohol (1 mmol) were added to distilled water
(3 mL) or a mixture of distilled water (2.25 mL) and toluene (0.75
mL). The mixture was stirred at room temperature for 30 min and
then cooled to 0 °C. A 70% aqueous solution of t-BuOOH (0.15
mL) was added and the mixture was stirred at 0 °C for 48 h. The
reaction mixture was then quenched with a concentrated solution
of Na2SO3 (10 mL) and after being stirred for 1 h at 0 °C it was
extracted with DCM (3 × 20 mL), then the combined organic
extracts were dried over MgSO4 and concentrated in vacuo to give
a brown oil. Purification of the products was accomplished by
column chromatography on silica gel (15 × 3 cm) with a 4:1
mixture of petroleum ether-ethyl acetate. The absolute configu-
ration of the epoxide products was assigned by comparison of their
optical rotations with the literature data; the enantiomeric excess
was determined with analysis by chiral GC, HPLC, or NMR.
1
-9.3 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.90-1.20
(m, 4H), 1.38-1.64 (m, 4H), 1.93-2.01 (m, 1H), 2.36 (s, 3H),
2.40 (dt, J ) 10.8, 3.9 Hz, 1H), 2.77-2.87 (m, 1H), 3.50 (d, J )
17.7 Hz, 1H), 3.63 (d, J ) 17.7 Hz, 1H), 5.10 (d, J ) 8.4 Hz, 1H),
7.26 (d, J ) 8.2 Hz, 2H), 7.72 (d, J ) 8.2 Hz, 2H); 13C NMR
(100.6 MHz, CDCl3) δ 18.7 (CH3), 21.6 (CH2), 24.2 (CH2), 30.4
(CH2), 32.4 (CH2), 34.5 (CH2), 57.4 (CH), 59.5 (CH), 118.1 (C),
126.8 (aromatic CH), 129.8 (aromatic CH), 137.6 (C), 143.6 (CN);
IR (NaCl) ν 3353.6 (NH), 2940.9 (C-H), 2253.4 (CN), 1062.6
(OdSdO); MS (FAB) m/z (%) 281.2 (100), 308.3 ((M + H)+ 55),
153.1 (29), 92.9 (25); HRMS (FAB) 308.1430 (C15H22N3O2S
requires 308.1433).
(1R,2R)-N-(Cyanomethylene)-2-(4-methylphenylsulfonami-
do)cyclohexanamine Oxide (11b): Following a procedure by
Fukuyama,20 m-CPBA (2.14 g, 12.38 mmol) was added in small
portions over 30 min to a solution of 10b (1.52 g, 4.95 mmol) in
DCM (23 mL) cooled to 0 °C in an ice bath. After completion of
addition, the ice bath was removed and the mixture was stirred at
room temperature for 2 h. It was then diluted with DCM (20 mL)
and washed with saturated Na2S2O3 (30 mL) and saturated NaHCO3
(3 × 30 mL). The aqueous phases were extracted with DCM (2 ×
30 mL) and the combined organic extracts were dried over MgSO4
and concentrated in vacuo to give 11b as a white solid (1.19 g,
75%), which was used in the next step without further purification.
A small sample was recrystallized from DCM: white solid, mp
1
152-155 °C (DCM); [R]D -27.3 (c 1.0, acetone); H NMR (400
MHz, CDCl3) δ 1.14-1.40 (m, 4H), 1.62-2.04 (m, 4H), 2.38 (s,
3H), 3.50-3.59 (m, 1H), 3.82 (td, J ) 11.2, 4.4 Hz, 1H), 5.10 (br
s, 1H), 6.60 (s, 1H), 7.25 (d, J ) 8.2 Hz, 2H), 7.64 (d, J ) 8.2 Hz,
2H); 13C NMR (100.6 MHz, CDCl3) δ 23.6 (CH2), 24.3 (CH2),
30.3 (CH2), 33.1 (CH2), 54.5 (CH3), 77.3 (CH), 79.4 (CH), 107.4
(CH), 111.9 (C), 126.8 (aromatic CH), 127.3 (aromatic CH), 129.8
(aromatic CH), 129.9 (aromatic CH), 137.5 (C), 144.2 (CN); IR
(NaCl) ν 3303.5 (NH), 2949.6 (CsH), 2253.4 (CN), 1087.7
(OdSdO), 911.2 (N+sO-); MS (CI) m/z (%) 322.3 ((M + H)+
12), 306.3 (50), 281.3 (40), 125.2 (31); HRMS (CI) 322.1224
(C15H20N3O3S requires 322.1225).
N-((1R,2R)-2-(Hydroxyamino)cyclohexyl)-4-methylbenzene-
sulfonamide (12b): Following a procedure by Fukuyama,20 hy-
droxylamine hydrochloride (1.29 g, 18.5 mmol) was added to a
solution of nitrone 11b (1.19 g, 3.70 mmol) in methanol (32 mL)
and the mixture was heated at 60 °C for 2 h. After that time, the
reaction mixture was cooled to room temperature and diluted with
(19) Balsells, J. Tetrahedon: Asymmetry 1998, 9, 4135.
(20) Tokuyama, H.; Kuboyama, T.; Fukuyama, T. Org. Synth. 2003, 80, 207.
3354 J. Org. Chem. Vol. 74, No. 9, 2009

Asymmetric Epoxidation of Allylic Alcohols in Water
(2-Methyl-3-naphthalene-1-yl-oxiranyl)methanol (2b): Biege
solid, mp 62-65 °C (petroleum ether/ethyl acetate); [R]D -73.4
(c 0.5, CH2Cl2); chiral HPLC (Chiracel IB; 0.70 mL/min; hexane/
2-propanol 95:5, t(-) ) 15.30 min, t(+) ) 22.35 min) showed 83%
ee; 1H NMR (400 MHz, CDCl3) δ 0.95 (s, 3H), 2.02 (dd, J ) 8.2,
4.9 Hz, OH), 3.91-3.93 (m, 2H), 4.61 (s, 1H), 7.39-7.48 (m, 4H),
7.71-7.75 (m, 1H), 7.80-7.88 (m, 2H); 13C NMR (100.6 MHz,
CDCl3) δ 13.9 (CH3), 59.1 (CH), 63.8 (C), 64.9 (CH2), 123.0 (CH),
124.1 (CH), 125.4 (CH), 126.0 (CH), 126.4 (CH), 127.8 (CH), 128.7
(CH), 130.9 (C), 131.9 (C), 133.2 (C); IR (NaCl) ν 3588.9 (OH),
3062.4 (CsH), 2929.3 (CsH), 1598.7 (CdC); MS (EI) m/z (%)
233.1 ((M + H)+ 100), 215.1 (72), 203.1 (40), 175.1 (9); HRMS
(CI) 233.0788 (C11H12O2F3 requires 233.0789).
(3-Methyl-2-phenyloxiranyl)methanol (2g): Yellow oil; [R]D
+33.5 (c 1.0, CH2Cl2); chiral GC (Supelco ꢀ-Dex 120 column, oven
temperature 110 °C for 2 min, then 1 °C/min, tR,R ) 22.65 min, tS,S
) 23.44 min) showed 91% ee; 1H NMR (400 MHz, CDCl3) δ 1.05
(d, J ) 5.5 Hz, 3H), 2.02 (br q, J ) 4.2 Hz, OH), 3.53 (q, J ) 5.5
Hz, 1H), 3.91-4.02 (m, 2H), 7.31-7.42 (m, 5H); 13C NMR (100.6
MHz, CDCl3) δ 14.1 (CH3), 56.9 (CH), 64.6 (CH2), 66.0 (C), 127.0
(aromatic CH), 127.9 (aromatic CH), 128.4 (aromatic CH), 135.7
(C); IR (NaCl) 3449.1 (OH), 2966.0 (CsH), 2252.5 (CdC); MS
(CI) m/z (%) 165.2 ((M + H)+ 14), 147.2 (100), 121.1 (94), 85.2
(31), 69.1 (50); HRMS (CI) 165.0915 (C10H13O2 requires 165.0916).
+
214.1 (M 16), 183.1 (66), 181.0 (19), 141.1 (29), 140.1 (100),
83.9 (26); HRMS (EI) 214.0990 (C14H14O2 requires 214.0994).
[2-Methyl-3-(4-trifluoromethylphenyl)oxiranyl]methanol (2d):
White solid, mp 34-36 °C (petroleum ether/ethyl acetate); [R]D
+7.8 (c 0.5, CH2Cl2); chiral HPLC (Chiracel IB; 0.75 mL/min;
hexane/2-propanol 95:5, t(+) ) 13.37 min, t(-) ) 14.27 min) showed
87% ee; 1H NMR (400 MHz, CDCl3) δ 1.00 (s, 3H), 1.88 (dd, J )
9.1, 4.1 Hz, OH), 3.71 (dd, J ) 12.6, 9.1 Hz, 1H), 3.81 (dd, J )
12.6, 4.1 Hz, 1H), 4.19 (s, 1H), 7.36 (d, J ) 8.1 Hz, 2H), 7.55 (d,
J ) 8.1 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 13.5 (CH3),
60.5 (CH), 64.0 (C), 64.6 (CH2), 125.1 (CH), 125.1 (C), 125.2 (C),
126.8 (CH), 139.9 (C); IR (NaCl) 3566.7 (OH), 3154.0 (CsH),
2999.7 (CsH), 1620.9 (CdC), 1325.8 (CsF); MS (CI) m/z (%)
Acknowledgment. We thank the EPSRC for research grant
GR/R86744, the WestChem for a graduate studentship to L.C.,
and the University of Glasgow for additional support.
Supporting Information Available: General experimental
1
methods, experimental procedures, H and 13C NMR spectra
for new compounds, and GC and HPLC traces for chiral epoxy
alcohols. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900294H
J. Org. Chem. Vol. 74, No. 9, 2009 3355