Amino acid-derived hydroxamic acids as chiral ligands in the vanadium catalysed epoxidation

Article abstract of DOI:10.1039/b505324b

New sulfonamide-derived hydroxamic acids 7-11 have been developed as chiral ligands for the V-catalysed asymmetric epoxidation, showing high reactivity at subzero temperatures and moderate to good enantioselectivity. The strong accelerating effect exhibited by the ligands of this type can be attributed to the sulfonamide functionality. A range of cinnamyl type allylic alcohols were epoxidised with up to 74% ee. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505324b

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A R T I C L E
Amino acid-derived hydroxamic acids as chiral ligands in the
vanadium catalysed epoxidation†
Andrei V. Malkov,* Za¨ınaba Bourhani and Pavel Kocˇovsky´
Department of Chemistry, WestChem, Joseph Black Building, University of Glasgow, Glasgow,
Scotland, UK G12 8QQ. E-mail: amalkov@chem.gla.ac.uk
Received 15th April 2005, Accepted 1st July 2005
First published as an Advance Article on the web 27th July 2005
New sulfonamide-derived hydroxamic acids 7–11 have been developed as chiral ligands for the V-catalysed
asymmetric epoxidation, showing high reactivity at subzero temperatures and moderate to good enantioselectivity.
The strong accelerating effect exhibited by the ligands of this type can be attributed to the sulfonamide functionality.
A range of cinnamyl type allylic alcohols were epoxidised with up to 74% ee.
allylic alcohols (1 → 2) with up to 44% ee, which was later
improved to 80% ee (for 2, R1 = R2 = Ph) by using ligand 4
and (i-PrO)3VO as the metal source.9,10 However, in this case,
coordination of the chiral ligands to vanadium resulted in a
significant deactivation of the catalyst, so that this method was
not considered to be of practical use.
The last five years or so, have witnessed the renewed interest
in vanadium(V)-catalysed epoxidation of allylic alcohols. Thus,
Yamamoto described the preparation of hydroxamic acids 5,
derived from 2,2ꢀ-binaphthol, which allowed to achieve 41–
91% ee with a range of allylic alcohols.11 Several other reports
on the application of chiral hydroxamic acids in V-catalysed
epoxidation12 and mechanistic studies13 have then followed.
Recently, while our work was in progress, Yamamoto14 disclosed
the new amino acid-derived ligands, in particular 6b that, for the
first time, came close to the Ti(IV) systems in terms of reactivity
and enantioselectivity.
Introduction
Hydroxamic acid derivatives have been used as ligands in coordi-
nation chemistry of transition metals for a long time.1 However,
only a few examples of their application in asymmetric catalysis
are known, and asymmetric epoxidation is the major object.2
In general, olefin epoxidation has become a powerful tool for
the preparation of chiral intermediates in organic synthesis.3
To-date, the most successful protocols rely on the Ti-catalysed
epoxidation of allylic alcohols, pioneered by Sharpless and
Katsuki,4 Mn-catalysed epoxidation of cis-olefins, developed by
Jacobsen,5 Cr-catalysed epoxidation of trans-olefins designed
by Gilheany,6 and organocatalytic epoxidation of cis- and trans-
disubstituted and trisubstituted olefins introduced by Shi.7
The setbacks of titanium catalysis are the necessity of
strictly anhydrous conditions and high catalyst loading, resulting
in a tedious workup. Compared to the titanium systems,
the use of other metals lags far behind. A few examples
of molybdenum(VI)-catalysed reactions are known, though
the enantioselectivities do not exceed 30–40%.8 Vanadium(V)
complexes, on the other hand, have been more successful.
Thus, Sharpless reported that a complex of hydroxamic acid
3 (Scheme 1) and VO(acac)2 catalysed epoxidation of selected
Herein, we report on the synthesis of chiral hydroxamic acids
with an appended sulfonamide group,15 and demonstrate their
application in vanadium(V)-catalysed asymmetric epoxidation
of allylic alcohols. In particular, the effect of the sulfonamide
moiety on the reactivity and selectivity of the catalyst is
discussed.
Results and discussion
† Electronic supplementary information (ESI) available: Experimental
procedures; 1H and 13C NMR spectra for new compounds. See
http://dx.doi.org/10.1039/b505324b
The selection of chiral hydroxamic acids 7–11, employed in this
work, is shown in Chart 1. We have varied the amino acid
backbone (7a–d, and 10), the sulfonyl group (8a–d), and the
substitution pattern at the stereogenic centre (7a, 9, and 11).
The bulky diphenylmethane substituent at the hydroxylamine
part of the molecule remained constant as the use of smaller
groups led to a considerable reduction in selectivity.11,16
Scheme 1
Chart 1
3 1 9 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 9 4 – 3 2 0 0
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 3
22, selected as model substrates to allow direct comparison with
the results published earlier10–12,14 (Scheme 3).
With ligand 7a, derived from (R)-phenylglycine, the reaction
turned out to be very fast, almost matching the rate observed for
VO(acac)2 alone. Epoxidation of 20 afforded 21 in quantitative
yield and 64% ee at −20 ◦C in 6 h, while the epoxidation of 22
was complete in 24 h, giving 23 in 80% yield and 62% ee, both
with 1 mol% catalyst loading (Table 1, entry 1). The level of
asymmetric induction attained with ligand 7a for geraniol (20)
matched the enantioselectivities obtained with ligand 5c and was
only slightly lower than that reported for ligand 6b. By contrast,
the catalytic system based on ligand 11, lacking the sulfonamide
functionality, proved sluggish, even with geraniol, producing
less than 5% of epoxide 21 of 43% ee (entry 6) after 24 h, which
clearly demonstrates the importance of the toluenesulfonamide
group (as in 7a).
Scheme 2
The influence of the amino acid backbone on the ligand
efficacy was examined next (Table 1). Ligands 7b–d predictably
exhibited excellent reactivities; however only 7d, derived from
tert-leucine, produced enantioselectivity similar to 7a. Surpris-
ingly, ligands 7b–d, despite having the opposite configuration at
the stereogenic centre (compared to 7a), gave rise to the same
enantiomers of the products (though with lower enantioselec-
tivity).
The mechanism of enantiodifferentiation in vanadium(V)-
catalysed epoxidation has not been established in detail. The
NMR investigation of the complexes of V(V) with hydroxamic
acids showed that the axial alkoxide ligand is fairly labile and
rapidly exchanges with neutral alcohol added to the solution.13a,b
It can be assumed that diastereoisomeric complexes A–D
(Chart 2), chiral at vanadium, are the major components
present in solution. With chiral hydroxamic acids, complexes
A/B and C/D form two sets of diastereoisomeric pairs, whose
relative reactivity would be responsible for the observed overall
enantioselectivity of the epoxidation.
It can be suggested that, in the case of sulfonamide ligands,
hydrogen bonding between the sulfonyl group19 and the
approaching allylic alcohol may facilitate displacement of
the labile axial ligand (the i-PrO group or the epoxy alcohol
produced), followed by a fast oxygen transfer (E → F, Scheme 4).
Furthermore, if such an interaction exerts a considerable effect
on the reaction rate, then structures A and B, where the trans-
ferable oxygen of the peroxide and the sulfonamide moiety are
Ligand synthesis
The general synthetic strategy towards the hydroxamic-type
ligands relied on reacting the corresponding amino acid chlo-
rides 15 with benzhydryl hydroxylamine (19) at low temperature
(Scheme 2). Chlorides 15a–i were prepared in two steps from
the respective amino acids 12a–e, which were first N-derivatized
with the corresponding sulfonyl chloride 13a–e in a biphasic
ether–1 M aqueous NaOH system and the resulting sulfon-
amides 14a–i were then converted into acid chlorides 15a–i;
the best results in the latter reaction were obtained with PCl5
in ether. Acid chlorides 15j, k were prepared in a similar fashion
from the corresponding acids.17 Benzhydryl hydroxylamine (19)
was prepared using the published protocol18 that involves
cyanomethylation of benzhydrylamine (16), followed by oxida-
tion with m-CPBA. Treatment of the resulting nitrone 18 with
hydroxylamine hydrochloride furnished the desired benzhydryl
hydroxylamine 19. The reaction of chlorides 15a–k with 19
produced the required hydroxamic acid 7–11. Under these
conditions, the competing O-acylation of the hydroxylamine was
reduced to a minimum (less than 5%). Chiral HPLC analysis of
7a revealed that the latter coupling proceeded without any loss
of the stereochemical integrity (>99% ee).
Vanadium catalysed epoxidation
Hydroxamic acids 7a and 11 were employed as chiral ligands
in the epoxidation of geraniol 20 and 2-methylcinnamyl alcohol
Table 1 Asymmetric epoxidation of allylic alcohols catalysed by V-complexes of chiral hydroxamic acids 7a–d and 10–11 (Scheme 3)a
Geraniol (20)
2-Methylcinnamyl alcohol (22)
Entry
Ligand
Yield (%)
Ee (%), config.b,c
Yield (%)
Ee (%), config.b,c
1
2
3
4
5
6
(R)-7a
(S)-7b
(S)-7c
(S)-7d
(S)-10
(R)-11
95
84
95
93
87
<5
64 (S,S)
15 (S,S)
<5
66 (S,S)
32 (R,R)
43 (S,S)
90
79
88
87
—
—
62 (S,S)
17 (S,S)
<5
51 (S,S)
—
—
a The reaction was carried out in toluene at −20 ◦C for 20 h on a 1 mmol scale. The catalyst was generated in situ from (i-PrO)3VO (1 mol%) and the
ligand (1.8 mol%). b Determined by chiral GC (see the Experimental). c The absolute configuration of the products was deduced from their optical
rotation (see the Experimental).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 9 4 – 3 2 0 0
3 1 9 5

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a steric repulsion between the substituent in the amino acid
backbone and the phenyl group of the hydroxylamine moiety
should force them apart, creating a transition state similar to E,
where the hydrogen atom and the substituent at the stereogenic
centre of the amino acid have traded places (G).
The results of a brief investigation of the effects of solvent,
temperature, and the vanadium : ligand ratio, carried out with
ligand 7a and employing geraniol as substrate, are summarized
in Table 2. Among the solvents, toluene proved to be superior
(entry 1), while the use of other solvents (acetonitrile and
methanol in particular) led to lower selectivities (entries 2–5).
The reaction at room temperature was very fast (complete in
less than 2 h) but non-selective (entry 9); cooling to −20 ◦C
proved to be beneficial but further lowering the temperature
failed to improve the selectivity (compare entries 1 and 10). The
minimum ligand : vanadium ratio that does not adversely affect
the enantioselectivity was identified as 1.5. An increase to 2.4 :
1 did not improve the asymmetric induction, while reduction to
1.2 : 1 resulted in a considerable drop in the enantioselectivity. To
maintain a good reproducibility, the 1.8 : 1 ratio was employed
throughout this work. Loading of vanadium can be reduced to
0.5 mol% without any loss of reactivity or selectivity; on the
other hand, at 0.1 mol%, the enantioselectivity dropped below
50% ee, although good reaction rate was maintained.
Chart 2
An investigation of the effect of additives on this asymmetric
epoxidation revealed that weakly coordinating Lewis-basic
additives (up to 5 mol%), such as DMSO, DMF, and pyridine
N-oxide, slightly decelerated the reaction but did not have an
adverse effect on the enantioselectivity. In fact, pyridine N-
oxide improved the enantioselectivity of geraniol epoxidation (to
68% ee). On the other hand, addition of the coordinating Et3N
resulted in a dramatic decrease in both reactivity and selectivity
(42% ee). It can be hypothesized that the additives assist the
displacement of the product from the axial position but, in the
same time, impair further displacement by the allylic alcohol,
resulting in an overall deceleration of the reaction.
In the Yamamoto imides, the environment of the nitrogen is
flat (Chart 1, ligands 6a,b).14 By contrast, in the sulfonamide
group of our ligands, the sulfur atom adjacent to the nitrogen is
tetrahedral,19 which creates a different spatial environment. Note
that sulfonamide derived ligand 7d and Yamamoto’s ligands 6a,b
sharing the same (S)-tert-leucine backbone produced opposite
epoxide enantiomers.
Scheme 4
positioned cis to each other, should exercise the main influence
on the reaction outcome; the relative reactivity of A and B will
be reflected in the enantioselectivity of the reaction. Note that
methanol, a protic polar solvent, is likely to disrupt intramolec-
ular hydrogen bonding. As a result, the reactivity and selectivity
of ligand 7a in MeOH was reduced to that of the ligand 11
where no functional group is present (compare entry 6, Table 1
and entry 5, Table 2). In addition, p–p interactions between the
phenyl groups of the phenylglycine and the hydroxylamine units
may constitute a significant factor in controlling the structure of
the active complex. These aromatic interactions can be suggested
to account for the observation that the ligands derived from (R)-
phenylglycine and aliphatic (S)-amino acids produced epoxides
of the same configuration (vide supra, Table 1). In the latter case,
The effect of the steric properties of the sulfonamide moiety on
the selectivity of epoxidation of geraniol and 2-methylcinnamyl
alcohol is highlighted in Table 3. It appears from these results
that the aromatic group in the sulfonamide unit plays a key role in
the creation of the chiral cavity, since the smaller methylsulfonyl
group gave nearly racemic products (entry 2).
Recently, we have demonstrated20 that N-methylation of the
amino acid-derived ligands can improve their catalytic per-
formance by inducing favourable conformational restrictions.
Table 2 Effect of temperature, solvent, and ligand : vanadium ratio on the asymmetric epoxidation of geraniol 20 catalysed by V-Complexes with
Ligand 7aa
Entry
Temp./◦C
Ratio ligand : V
Solvent
Yield (%)
Ee (%)b
1
2
3
4
5
6
7
8
9
−20
−20
−20
−20
−20
−20
−20
−20
20
1.8 : 1
1.8 : 1
1.8 : 1
1.8 : 1
1.8 : 1
1.2 : 1
1.5 : 1
2.4 : 1
1.8 : 1
1.8 : 1
toluene
CH2Cl2
CHCl3
MeCN
MeOH
toluene
toluene
toluene
toluene
toluene
98
96
96
95
<5
98
95
82
95c
98
64
47
55
37
39
34
64
64
30
58
10
−40
a The reaction was carried out for 20 h at a 1 mmol scale. The catalyst was generated in situ from (i-PrO)3VO (1 mol%) and ligand 7a. b Determined
by chiral GC (see the Experimental section). c The reaction was complete in less than 2 h.
3 1 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 9 4 – 3 2 0 0

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Table 3 The influence of the sulfonamide group on the asymmetric
24–33 (Table 4). It is pertinent to note that monosubstituted
allylic alcohols, particularly aromatic cinnamyl derivatives 25–
29, are renowned for their poor reactivity in V-catalysed
epoxidation.11,12,14 With the most reactive ligand 6b (reported
to date) it took 80 h at 0 ◦C to achieve 92% conversion
in epoxidation of 25 (58% yield, 87% ee).14a By contrast,
with our catalytic system, based on the sulfonamide-derived
hydroxamic acid 7a, comparable conversion (82%) of 25 into the
corresponding epoxide was attained in 20 h at −20 ◦C (67% yield
and 63% ee, entry 3). Other cinnamyl derivatives, such as 26–
29, behaved in a similar way; a moderate drop in reactivity was
observed for bulky substrates 26 and 29 (entries 4 and 7). All the
cinnamyl derivatives exhibited moderate to good enantioselec-
tivity (entries 4–7). The (E)-3,3-disubstituted allylic alcohols 20,
30, and 31 reacted rapidly, affording the corresponding epoxides
in moderate to good ee (entries 1, 8, and 9), while nerol 24, with
(Z)-configuration of the double bond, showed reduced reactivity
and selectivity (entry 2). In the case of 2,3-disubstituted alcohols
22, 32, and 33, the reactivity was not compromised but selectivity
displayed strong dependency on the size of the 2-substituent.
When ligand 7a was employed, groups larger than methyl caused
ee plummeting (entries 10–12), which contrasts with ligand 6
that gave excellent selectivity for this type of substrates.14a This
comparison serves as an indication that structural changes in
the part of the ligands 6 and 7a,d, seemingly remote from
the active metal centre, can dramatically affect the mechanism
epoxidation of allylic alcoholsa
Geraniol (20)
2-Methylcinamyl alcohol (22)
Entry Ligand Yield (%) Eeb (%) Yield (%)
Eeb (%)
1
2
3
4
5
6
7a
8a
9
8b
8c
8d
95
86
96
55
62
95
64
4
7
41
61
64
90
69
93
52
85
76
62
8
14
39
48
56
a The reaction was carried out in toluene at −20 ◦C for 20 h at a 1 mmol
scale. The catalyst was generated in situ from (i-PrO)3VO (1 mol%) and
the ligand (1.8 mol%). b Determined by chiral GC, the products had
(S,S) absolute configuration deduced from their optical rotation (see
experimental part).
However, in this case, the N-methylated ligand 9 turned out
to exhibit poor enantioselectivity (entry 3). In terms of the
size, p-toluenesulfonamide appears to be optimal, as additional
substituents in the aromatic ring did not bring about any
enhancement of enantioselectivity (entries 4–6). In fact, intro-
ducing ortho substituents decreased the selectivity (entry 4).
The efficacy of the sulfonamide ligand 7a was assessed in
the epoxidation of a range of allylic alcohols 20, 22, and
Table 4 Catalytic epoxidation of allylic alcohols using ligand 7aa
Entry
1
Substrate
Yield (%)
95
Ee (%) config.b,c
20
24
68d (S,S)
2
40
41 (R,S)
3
4
25
26
67
32
63 (R,R)
74 (R,R)
5
6
7
27
28
29
95
91
46
63 (+)
62 (−)
63 (+)
8
9
30
31
49
95
72 (−)
61 (+)
10
11
22
32
90
85
62 (S,S)
20 (S,S)
12
33
55
56 (R,R)
a The reaction was carried out in toluene at −20 ◦C for 20 h at a 1 mmol scale. The catalyst was generated in situ from (i-PrO)3VO (1 mol%) and the
ligand (1.8 mol%). b Determined by chiral GC (see the Experimental section). c The absolute configuration of the products was deduced from their
optical rotation (see the Experimental section). d Pyridine N-oxide was used as an additive (5 mol%).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 9 4 – 3 2 0 0
3 1 9 7

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of enantiodifferentiation, implying that sulfonamide or imido
group might be involved in shaping up the transition state.
In conclusion, new sulfonamide-derived hydroxamic acid
ligands were developed for V-catalysed asymmetric epoxidation,
showing fast reactivity at subzero temperatures and moderate to
good selectivity (in particular, ligand 7a). The strong accelerating
effect exhibited by the ligands of this type can be attributed to
the hydrogen bonding between the sulfonamide moiety and the
incoming alcohol that brings and holds the reactants together.
The reactions only require 1 mol% catalyst loading. A range of
cinnamyl type allylic alcohols (Table 4) were epoxidised with up
to 74% ee.
Step C. A solution of benzhydryl hydroxylamine 19 (200 mg,
1 mmol) in dry dichloromethane (3 mL) was added to a solution
of acid chloride 15a (323 mg, 1 mmol) in dry dichloromethane
(3 mL) under nitrogen atmosphere at −10 ◦C (cryocooler). The
resulting mixture was stirred at −10 ◦C for 30 min and then the
mixture was allowed to warm to room temperature. After 2 h, the
reaction was quenched with triethylamine (150 lL). A saturated
solution of ammonium chloride was added and the mixture was
extracted with dichloromethane. The organic extracts were dried
over MgSO4 and concentrated in vacuo to afford a brown oil.
Purification, using column chromatography on silica gel (15 ×
3 cm) with an n-hexane–ethyl acetate mixture (4 : 1) furnished
7a (115 mg, 24%) as white crystals, which gave positive red-wine
coloured stain with FeCl3 on TLC: mp 172–174 ◦C (hexane–
ethyl acetate), [a]D −58 (c 0.5, CHCl3); Chiral HPLC (Chiralcel
OD-H; 0.75 mL min−1; hexane : 2-propanol 90 : 10, tS = 13.56,
Experimental
General methods
1
tR = 15.43) showed >99% ee; H NMR (400 MHz, CDCl3) d
Melting points were determined on a Kofler block and are
uncorrected. Optical rotations were recorded in CHCl3 at 25 ◦C
unless otherwise indicated with an error of < 0.1. The [a]D
values are given in 10−1 deg cm2 g−1. The NMR spectra were
2.36 (s, 3H), 5.01 (s, 1H), 5.60 (d, J = 8.2 Hz, 1H), 6.08 (d, J =
8.3 Hz, 1H), 6.77 (s, 1H), 6.89 (d, J = 7.3 Hz, 2H), 7.12–7.37 (m,
15H), 7.62 (d, J = 7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) d
22.0 (CH3), 57.8 (CH), 63.5 (CH), 127.4 (CH), 128.1 (CH), 128.3
(CH), 128.4 (CH), 128.7 (CH), 128.8 (CH), 128.9 (CH), 129.0
(CH), 129.1 (CH), 129.2 (CH), 129.8 (CH), 136.3 (C), 137.3 (C),
137.5 (C), 143. 5 (C), 169.6 (CO); IR (KBr) m 3286, 1615, 1496,
1419, 1335, 1163, 1091, 703 cm−1; HRMS (EI) m/z 486.1615
(C28H26O4N2S requires 486.1613).
1
recorded in DMSO-d6 or CDCl3, H at 400 MHz and 13C at
100.6 MHz with chloroform-d1 (d 7.26, 1H; d 77.0 13C) as internal
standard unless otherwise indicated. Various 2D-techniques
and DEPT experiments were used to establish the structures
and to assign the signals. The IR spectra were recorded for
a thin film between KBr plates or for CHCl3 solutions. The
mass spectra (EI and/or CI) were measured on a dual sector
mass spectrometer using direct inlet and the lowest temperature
enabling evaporation. All reactions were performed under an
atmosphere of dry, oxygen-free nitrogen in oven-dried glassware
twice evacuated and filled with nitrogen. Solvents and solutions
were transferred by syringe-septum and cannula techniques. All
solvents for the reactions were of reagent grade and were dried
and distilled immediately before use as follows: diethyl ether
from lithium aluminium hydride; tetrahydrofuran from sodium–
benzophenone; dichloromethane from calcium hydride, toluene
from sodium. Petroleum ether refers to the fraction boiling in
the range of 40–60 ◦C. Yields are given for isolated products
showing one spot on a TLC plate and no impurities detectable
in the NMR spectrum. The identity of the products prepared by
different methods was checked by comparison of their NMR, IR
and MS data and by TLC behaviour. Synthesis of chiral ligands
is illustrated by the synthesis of hydroxamic acid 7a.
General procedure for asymmetric epoxidation
Ligand (1.8 mol%) and (i-PrO)3VO (2.5 lL, 10 lmol) were
dissolved in dry toluene (3 mL) under nitrogen atmosphere
and the resulting deep brown solution was stirred at room
temperature for 30 min. Allylic alcohol (1 mmol) was then
added in one portion and the mixture was stirred for at room
temperature for 10 min and then cooled to −20 ◦C. A 5 M
solution of t-BuOOH in nonane (0.3 mL) was added and the
mixture was stirred at −20 ◦C overnight (∼20 h). The solution
was then washed with water (10 mL), the aqueous phase was
extracted with dichloromethane (2 × 20 mL), 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 an n-hexane–ethyl acetate mixture (4 : 1). The
absolute configuration of the epoxide products was assigned by
comparison of their optical rotations with the literature data; the
enantiomeric excess was determined using chiral GC or HPLC.
Hydroxamic acid (R)-(−)-7a
Epoxidation of geraniol 20. (2S,3S)-(−)-3,7-Dimethyl-2,3-
epoxy-oct-6-en-1-ol (21) was isolated as a clear, colourless oil:
[a]D −1.9 (c 1.00, CHCl3); chiral GC (Supelco a-Dex 120 column,
24.38, tR,R = 24.82) showed 64% ee; 1H NMR (400 MHz, CDCl3)
d 1.34 (s, 3H), 1.41–1.5 (m, 2H), 1.62 (s, 3H), 1.65 (s, 3H), 2.06–
2.12 (m, 2H), 2.23 (bs, 1H), 2.98 (dd, J = 6.6, 4.3 Hz, 1H), 3.68
(dd, J = 12.2, 6.6 Hz, 1H), 3.83 (dd, J = 12.2, 4.1 Hz, 1H), 5.08
(t, J = 6.7 Hz, 1H), consistent with the literature data.22
Step A. A solution of p-toluenesulfonyl chloride 2a (1.372 g,
7.2 mmol) in ether (12 mL) was added to a mechanically stirred
solution of D-(−)-phenylglycine 1 (906 mg, 6 mmol) and NaOH
(600 mg, 15 mmol) in water (12 mL) at room temperature. The
mixture was stirred at room temperature for 16 h and then
acidified to pH ∼2 with 12 M HCl to produce a white precipitate.
The precipitate was separated by filtration and washed with
water. Crystallization from ether afforded acid 14a as a white
solid (1.2 g, 66%), which was used in the next step without
further purification: 1H NMR (400 MHz, DMSO-d6) d 2.33 (s,
3H), 4.86 (d, J = 9.2 Hz, 1H), 7.12–7.29 (m, 7H), 7.61 (d, J =
8.2 Hz, 2H), 8.60 (d, J = 9.2 Hz, 1H), 12.8 (bs, 1H), consistent
with the literature data.21
oven temp. 110 ◦C for 2 min, then 1.0 ◦C min−1 to 200 ◦C, tS,S
=
Epoxidation of alcohol 22. (2S,3S)-(−)-2-Methyl-3-phenyl-
2,3-epoxy-propan-1-ol (23) was isolated as a clear, colourless
oil: [a]D −6.1 (c 1.00, CHCl3); chiral GC (Supelco b-Dex 120
◦
column, oven temp. 110 ◦C for 2 min, then 1.5 C min−1 to
200 ◦C, tR,R = 33.19, tS,S = 33.71) showed 62% ee; H NMR
1
(400 MHz, CDCl3) d 1.12 (s, 3H), 2.16 (bs, 1H), 3.77 (d, J =
12.5 Hz, 1H), 3.88 (d, J = 12.5 Hz, 1H), 4.24 (s, 1H), 7.28–7.39
(m, 5H), consistent with the literature data.22
Step B. Phosphorus pentachloride (0.875 g, 4.2 mmol) was
added portion wise to a stirred solution of acid 14a (1.068 g,
3.5 mmol) in anhydrous ether (8 mL) in a 100 mL round bottom
flask under nitrogen atmosphere. After stirring for 2 h at room
temperature, 35 mL of n-hexane was added and the mixture
was left in a freezer overnight. Precipitated crystals were quickly
separated by filtration and washed with n-hexane. A white solid
of acid chloride 15a (535 mg, 47%) was used immediately in the
next step.
Epoxidation of nerol 24. (2S,3R)-(+)-[3-Methyl-3-(4-methyl-
pent-3-enyl)oxiranyl]-methanol was isolated as a clear, colour-
less oil: [a]D +9.8 (c 1.00, CHCl3); chiral GC (Supelco b-Dex
◦
120 column, oven temp. 110 ◦C for 2 min, then 1.5 C min−1
to 200 ◦C, tS,R = 46.12, tR,S = 46.36) showed 40% ee; 1H NMR
(400 MHz, CDCl3) d 1.28 (s, 3H), 1.38–1.63 (m, 2H) 1.55 (s, 3H),
3 1 9 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 9 4 – 3 2 0 0

View Article Online
1.62 (s, 3H), 1.78 (bs, 1H), 1.96–2.10 (m, 2H), 2.9 (dd, J = 6.8,
4.4 Hz), 3.58 (dd, J = 12.0, 6.9 Hz, 1H), 3.73 (dd, J = 12.0,
4.4 Hz, 1H), 5.01–5.05 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 18.0 (CH3), 22.6 (CH3), 24.6 (CH2), 26.0 (CH3), 33.5 (CH2),
61.7 (CH2), 64.5 (CH), 123.7 (CH-O), 132.9 (C), 138.5 (C-O),
consistent with the literature data.22
J = 12.0, 4.4 Hz, 1H), 7.14–7.31 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 17.8 (CH3), 60.9 (C), 61.3 (CH2), 66.0 (CH), 125.1
(CH), 127.6 (CH), 128.4 (CH), 142.0 (C), consistent with the
literature data.26
Epoxidation of alcohol 31. (+)-(3-Methyl-3-naphthalen-2-
yl-oxiranyl)-methanol was isolated as beige solid: mp 58–60 ◦C
(hexane–ethyl acetate); [a]D +2.4 (c 1.00, CHCl3); chiral HPLC
Epoxidation of cinnamyl alcohol 25. (2R,3R)-(+)-3-Phenyl-
oxiranemethanol was isolated as a beige solid: mp 33–36 ◦C
(hexane–ethyl acetate); [a]D +59 (c 1.00, CHCl3); chiral HPLC
(Chiracel OD-H; 0.7 mL min−1; hexane–2-propanol 90 : 10, t(+)
=
31.46, t(−) = 41.10) showed 61% ee; 1H NMR (400 MHz, CDCl3)
d 1.62 (s, 3H), 1.96 (bs, 1H), 3.01 (dd, J = 6.4, 4.4 Hz, 1H), 3.74
(dd, J = 12.0, 6.4 Hz, 1H), 3.89 (dd, J = 12.0, 4.4 Hz, 1H),
7.14–7.31 (m, 5H); 13C NMR (100 MHz, CDCl3) d 18.0 (CH3),
61.2 (C), 61.4 (CH2), 66.1 (CH), 123.0 (CH), 124.2 (CH) 126.1
(CH), 126.3 (CH), 127.6 (CH), 127.7 (CH), 127.9 (CH), 132.8
(C), 133.1 (C), 139.5 (C); IR (KBr) m 3426, 1631, 1599, 1452,
1388, 1136, 1078, 1027, 862, 826, 743 cm−1; HRMS (EI) m/z
214.0994 (C14H14O2 requires 214.0994).
(Chiracel OD-H; 0.7 mL min−1, hexane–2-propanol 95 : 5, tS,S
=
35.08, tR,R = 39.26) showed 63% ee; 1H NMR (400 MHz, CDCl3)
d 1.77–1.80 (m, 1H), 3.25 (m, 1H), 3.80–3.87 (m, 1H), 3.94 (d,
J = 2.1 Hz, 1H), 4.05–4.17 (m, 1H), 7.28–7.40 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 55.9 (CH), 61.6 (CH2), 62.8 (CH),
126.1 (CH), 128.7 (CH), 128.9 (CH), 137.0 (C), consistent with
the literature data.23
Epoxidation of alcohol 26. (2R,3R)-(–)-(2,4,6-Trimethyl-
phenyl)oxirane-2-methanol was isolated as a white solid: mp 84–
86 ◦C (chloroform); [a]D −12.4 (c 1.00, CHCl3); chiral HPLC
Epoxidation of alcohol 32. (2S,3S)-(–)-2,3-Diphenyl-2◦,3-
epoxy-propan-1-ol was isolated as a white solid: mp 57–59 C
(hexane–ethyl acetate) (lit.27 54–56 ◦C, hexane–diethyl ether);
[a]D −14.2 (c 1.00, CHCl3); chiral HPLC (Chiracel OD-H;
(Chiracel OD-H; 0.7 mL min−1, hexane–2-propanol 95 : 5, tR,R
=
16.13, tS,S = 20.52) showed 74% ee; 1H NMR (400 MHz, CDCl3)
d 1.8 (dd, J = 7.6, 5.6 Hz, 1H), 2.19 (s, 3H), 2.28 (s, 6H), 3.09 (m,
1H), 3.81 (ddd, J = 12.4, 7.2, 4.0 Hz, 1H), 3.88 (d, J = 2.0 Hz,
1H), 4.03 (ddd, J = 12.4, 5.6, 2.4 Hz, 1H), 6.73 (s, 2H); 13C
NMR (100 MHz, CDCl3) d 19.7 (CH3), 20.9 (CH3), 54.4 (CH),
59.7 (CH), 61.5 (CH2), 128.7 (CH), 130.3 (C), 137.0 (C), 137.5
(C), consistent with the literature data.24
0.5 mL min−1; hexane–2-propanol 90 : 10, tR,R = 15.26, tS,S
=
1
16.91) showed 20% ee; H NMR (400 MHz, CDCl3) d 1.97 (s,
1H), 3.96 (s, 2H), 4.44 (s, 1H), 6.96–7.31 (m, 10H), consistent
with the literature data.22
Epoxidation of alcohol 33. (2R,3R)-(+)-(7-Oxa-bicyclo-
[4.1.0]hept-1-yl)-methanol was isolated as a clear, colourless oil:
[a]D +6.7 (c 1.00, CHCl3); chiral GC (Supelco b-Dex 120 column;
Epoxidation of alcohol 27. (+)-(3-Naphthalen-2-yl-oxiranyl)-
methanol was isolated as a beige solid: mp 100–102 ◦C (hexane–
ethyl acetate); [a]D +23.9 (c 1.00, CHCl3); chiral HPLC (Chiracel
OD-H; 0.7 mL min−1; hexane–2-propanol 98 : 2, t(+) = 29.88,
t(−) = 41.68) showed 63% ee; 1H NMR (400 MHz, CDCl3) d 1.83
(dd, J = 7.6, 5.6 Hz, 1H), 3.25 (d, J = 1.8 Hz, 1H), 3.78 (ddd, J =
oven temp. 110 ◦C for 2 min, then 1 ◦C min−1 to 200 ◦C, tS,S
=
13.16, tR,R = 13.41) showed 56% ee; 1H NMR (400 MHz, CDCl3)
d 1.22–1.33 (m, 2H), 1.39–1.52 (m, 2H) 1.66–2.00 (m, 4H), 2.31
(bs, 1H), 3.25 (d, J = 3.2 Hz, 1H), 3.56 (d, J = 12.4 Hz, 1H),
3.67 (d, J = 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 19.6
(CH2), 19.9 (CH2), 25.3 (CH2), 55.9 (CH), 60.3 (CO), 64.6 (CH2),
consistent with the literature data.22
12.0, 7.6, 3.7 Hz, 1H), 4.00–4.05 (m, 3H), 7.15–7.76 (m, 7H); 13
C
NMR (100 MHz, CDCl3) d 56.2 (CH), 61.6 (CH2), 62.8 (CH),
123.2 (CH), 123.3 (CH), 125.8 (CH), 126.6 (CH), 126.8 (CH),
128.2 (CH), 128.8 (CH), 133.5 (C), 133.7 (C), 134.5 (C); IR
(KBr m 3441, 3055, 2926, 1630, 1510, 1400, 1210, 1076, 1018,
824, 745 cm−1; HRMS (EI) m/z 200.0839 (C13H12O2 requires
200.0837).
Acknowledgements
We thank the EPSRC for a research grant GR/R86744, DSM
for a gift of tert-leucine and (S)-(+)-methylphenylglycine, and
the University of Glasgow for an additional support.
Epoxidation of alcohol 28. (−)-(3-Naphthalen-1-yl-oxiranyl)-
methanol was isolated as a colourless oil: [a]D −15.9 (c 1.00,
CHCl3); chiral HPLC (Chiracel OD-H; 0.7 mL min−1; hexane–
2-propanol 98 : 2, t(−) = 30.27, t(+) = 35.79) showed 62% ee; 1H
NMR (400 MHz, CDCl3) d 2.09 (bs, 1H), 3.11–3.13 (m, 1H),
3.86–3.89 (m, 1H), 4.00–4.07 (m, 1H), 4.49 (d, J = 2.1 Hz, 1H),
7.33–8.01 (m, 7H); 13C NMR (100 MHz, CDCl3) d 52.8 (CH),
60.2 (CH2), 60.6 (CH), 121.3 (CH), 121.8 (CH), 124.8 (CH),
124.9 (CH), 125.4 (CH), 127.2 (CH), 127.7 (CH), 130.2 (C),
131.8 (C), 132.2 (C), consistent with the literature data.25
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3 2 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 9 4 – 3 2 0 0