Asymmetric oxidation of enol phosphates to α-hydroxy ketones using Sharpless reagents and a fructose derived dioxirane

Article abstract of DOI:10.1016/j.tetasy.2012.09.012

The asymmetric oxidation of a variety of differently substituted, acyclic and cyclic enol phosphates using the Sharpless AD-reagents AD-mix-α and AD-mix-β, and a fructose derived chiral ketone as a catalyst, afforded the corresponding α-hydroxy ketones in high enantioselectivity and good yield. The influence of steric and electronic factors of the substrates on the facial stereoselectivity in the reported oxidations was studied.

Full text of DOI:10.1016/j.tetasy.2012.09.012

Tetrahedron: Asymmetry 23 (2012) 1480–1489
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Tetrahedron: Asymmetry
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Asymmetric oxidation of enol phosphates to
a-hydroxy ketones using
Sharpless reagents and a fructose derived dioxirane
⇑
_
Ewa Krawczyk , Grazyna Mielniczak, Krzysztof Owsianik, Jerzy Łuczak
´
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2012
Accepted 19 September 2012
The asymmetric oxidation of a variety of differently substituted, acyclic and cyclic enol phosphates using
the Sharpless AD-reagents AD-mix-
a and AD-mix-b, and a fructose derived chiral ketone as a catalyst,
afforded the corresponding -hydroxy ketones in high enantioselectivity and good yield. The influence
a
of steric and electronic factors of the substrates on the facial stereoselectivity in the reported oxidations
was studied.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Recently we have described an efficient asymmetric synthesis
of chiral a-hydroxy carbonyl compounds via the oxidation of read-
Chiral
a
-hydroxy ketones are important building blocks for the
ily available acyclic and cyclic enol phosphates using Jacobsen’s
asymmetric synthesis of natural products.1 Among the methods for
their synthesis, the asymmetric oxidation of various enol deriva-
tives plays an important role.2 For this purpose, different chiral oxi-
dizing agents, such as N-sulfonyl-oxazirididines2a or Sharpless
catalyst.14 With the aim of improving efficiency in the asymmetric
synthesis of various cyclic and acyclic
a-hydroxy derivatives, we
decided to extend our studies to the oxidation of enol phosphates
using other chiral reagents. Initially we selected commercially
reagents:3 AD-mix-
a
1a and b 1b (Fig. 1) as well as chiral catalysts
available Sharpless reagents AD-mix-
a
-1a (‘OsO4ꢀ(DHQ)2PHAL’),
such as (salen) Met complexes, which were designed by Jacobsen4
and modified by Berkessel,5 have been used. The fructose-derived
ketone 2 has been reported to be a very efficient catalyst for the
asymmetric epoxidation of di-trans and trisubstituted acyclic ole-
fins6 and has also been applied to the oxidation of enol deriva-
tives.7 New catalysts, analogues of ketone 2, were prepared by
Shi for his studies of metal-free asymmetric epoxidations.8 These
chiral ketones were successfully applied to the asymmetric epoxi-
dation of other differently substituted unsaturated compounds.8
As part of our interest in the application of organophosphorus
derivatives in the synthesis of functionalized polycyclic com-
pounds,9 we have elaborated upon a methodology based on an-
other type of enol derivative, namely enol phosphates, for an
AD-mix-b-1b (‘OsO4ꢀ(DHQD)2PHAL’), and the chiral oxidant dioxi-
rane 3, generated in situ from ketone 2 (Fig. 1).
2. Results and discussion
Enol phosphates are easy to prepare from simple reagents
such as the corresponding alkyl aryl ketones and dialkyl- or
diarylphosphorochloridates.14 For our investigation, we selected
a set of acyclic phosphates 4a–h and cyclic enol phosphates
5a–d, which were synthesized from the corresponding phospho-
rochloridates and enolate anions, generated in situ from the
appropriate ketones by the action of LDA.14b Acyclic enol phos-
phates 4 were formed as single Z-isomers except for 4e, which
was obtained as a mixture of Z- and E-isomers in a 5:1 ratio.
(Scheme 1). The Z-configuration of enol phosphate 4f was estab-
lished on the basis of the observation of a positive nuclear Over-
hauser effect (NOE); 3% increase in the area for the vinyl proton
cis to the phenyl.15 The Z-configuration of the other enol phos-
phates was determined by comparison of the chemical shift of
the vinyl protons and the coupling constant (4JPH) observed for
4f and for compounds 4a–d, and g, h. Additionally a NOESY
experiment was carried out on compound 4e.14b
alternative synthesis of cyclic
a
-hydroxy carbonyl compounds.10
Enol phosphates are known to exhibit biological activity, the most
important example being phosphoenol pyruvate.11 Bicyclic enol
phosphates such as cyclophostin and cyclipostin P,12 show a potent
inhibition of acetyl cholinesterase or hormone sensitive lipases. In
the last few years, diversely substituted enol phosphates have been
used as versatile intermediates for the construction of complex or-
ganic molecules.13
The corresponding bi- and tricyclic phosphates 5 (Fig. 2) con-
taining an aromatic system fused with a cyclic enol phosphate
moiety with an E-configuration, were prepared according to the
procedure described above.
⇑
Corresponding author. Tel.: +48 42 680 32 16; fax: +48 42 680 32 61/42 680 32
60.
E-mail address: ewakrsoj@cbmm.lodz.pl (E. Krawczyk).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.012

E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
1481
Et
Et
Et
Et
N
N
N
N
N
N
N
N
O
O
O
O
H
H
H
H
OMe
MeO
MeO
OMe
N
N
O
N
N
(DHQ)2PHAL
(DHQD)2PHAL
1a
1b
O
O
O
O
O
(S)
(S)
O
(R)
(R)
O
O
O
O
O
O
3
2
Figure 1. Ligands, fructose derived ketone, and chiral dioxirane designed for our study.
Yield
4a R1=Me, R=Et, Ar=C6H5,
4b R1=Me, R=Ph, Ar=C6H5
91%
85%
O
O-Li+
H
O
(RO)2PO
4c R1=Me, R=Et, Ar=p-MeOC6H4 85%
LDA
(RO)2P(O)Cl
-78°C
R1
R1
4d R1=Et, R=Et, Ar=C6H5
4e R1=Ph, R=Et, Ar=C6H5
4f R1=Pr, R=i-Pr, Ar=C6H5
90%
75%
90%
Ar
Ar
R1
-78°C
Ar
H
H
4g R1=Pr, R=p-ClC6H4, Ar=C6H5 50%
Ar = Ph, p-MeOC6H4
R1 = Me, Et, Ph, Pr
R = Et, i-Pr, Ph
p-ClC6H4
4h R1=Pr, R=p-MeOC6H4, Ar=C6H
5 78%
4a-h
p-MeOC6H4
Scheme 1. General synthesis of enol phosphates 4.
O
O
O
R1
H
OP(O)(OR)2
Ar
OP(O)(OR)2
(EtO)2PO
AD-mix α
AD-mix β
R1
OP(O)(OEt)2
Me
R1
Ar
Ar
or
OH
(R)-6a,c,d,e
OH
(S)-6a,c,d
4a-e
X
5a R=Et, X=CH2, 85%
5b R=Et, X=O, 78%
5c, 85%
5d, 87%
Scheme 2. Asymmetric oxidation of enol phosphates 4 with AD-mix-
a and AD-
Figure 2. Cyclic E-enol phosphates 5.
mix-b.
2.1. Asymmetric oxidation of enol phosphates 4 and 5 with AD-
mix- and AD-mix-b—Sharpless AD-reaction
The mixture of Z/E (5:1) enol phosphate 4e, containing phenyl
groups at both the - and b-positions, only reacted with AD-mix-
a
a
b to give (R)-(ꢁ)benzoin 6e with 100% ee, albeit in very low yield.
(Table 1, entry 5). The composition of the crude post-reaction mix-
ture [(Z/E 2:1) of the remaining phosphate 4e] revealed that only
the Z-isomer of 4e had reacted, although the conversion was low.
In the first set of experiments, we studied the asymmetric oxi-
dation of enol phosphates according to the Sharpless AD-proce-
dure.3a We examined this process using acyclic 4a–e and cyclic
enol phosphates 5a, b. The reactions of 4a–e were carried out with
Furthermore, the reaction of 4e with AD-mix-a afforded a mixture
commercially available AD-mix-
a
and AD-mix-b which utilize the
of unidentified compounds among which only benzil [PhC(O)-
C(O)Ph] was identified.
(DHQ)2-PHAL16 and (DHQD)2-PHAL16 ligands, in t-BuOH–H2O (1:1)
or in CH3CN–H2O (1:1), and methanesulfonamide as an additive, at
The asymmetric dihydroxylation of cyclic enol phosphate 5a,
0 °C for 24 h. The product,
a
-hydroxy ketones 6 were isolated by
derived from tetralone, with AD-mix-a and AD-mix-b, carried out
flash chromatography (Scheme 2).
Phosphates 4a–d, with an alkyl substituent b to the phosphate
group, when treated with AD-mix-
under standard conditions, led to the formation of the correspond-
ing 2-hydroxy tetralone 9a in modest yields and enantioselectivity
(Table 1, entries 6,7). A few attempts at the oxidation of chroma-
none derived enol phosphate 5b under various conditions, were
unsuccessful. However, in an experiment using double the amount
of commercial AD-mix-b and sodium persulfate as a co-oxidant,17
a
or with AD-mix-b, afforded
-hydroxy
a-hydroxy ketones 6a,c,d with an (S)-configuration and
a
ketones 6a,c,d with an (R)-configuration, with very high enantiose-
lectivity (92–100%) and in reasonable yields (Table 1, entries 1–4).

1482
E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
Table 1
Enantioselective synthesis of
a
-hydroxy ketones 6, 9 by catalytic asymmetric dihydroxylation (AD) of (Z)-acyclic 4a–e and of (E)-cyclic enol phosphates 5a, b
Entry
Substrate
Product
AD-mix-
Configb
a
AD-mix-b
eea (%)
Yieldc (%)
eea (%)
Configb
Yieldc (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
6a
6a
6c
6d
6e
9a
9a
9b
98.6
94
100
92
(S)-(ꢁ)
(S)-(ꢁ)
(S)-(ꢁ)
(S)-(ꢁ)
47
40
67
60
99
94
100
95
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(ꢁ)
60
54
75
50
14
4ed
5ae,f
5ae,g
5be,g,h
100
34
13
(R)-(+)
(R)-(+)
29
18
31
12
(S)-(ꢁ)
(S)-(ꢁ)
25
30
a
b
c
Determined by HPLC (Chiracel OD, see Section 4).
Absolute configurations were determined by comparison of sign of the specific rotation with the literature data (see Section 4).
Yield of isolated product.
Ratio of isomers: (Z/E 5:1).
E Isomers.
Conditions: solvent: t-BuOH/H2O.
d
e
f
g
h
Conditions: solvent:CH3CN.
According to Marcune17 conditions: CH3CN, Na2S2O8, ꢁ10 ? 0° C, 1 h, +5 °C, 24 h.
OP(O)(OEt)2
O
X
O
OH
OH
AD-mix α
or
X
X
(R)-9a
AD-mix-β
Scheme 3. Asymmetric oxidation of cyclic enol phosphates 5 with AD-mix-
5a X=CH2
(S)-9a,b
5b X=O
a
and AD-mix-b.
the product, 3-hydroxychroman-4-one 9b was formed, though in
30% yield and with only 12% ee (Table 1, entry 8) (Scheme 3).
The results presented in Table 1 show that those acyclic enol
phosphates 4 are suitable substrates for the AD process. The ste-
reochemical outcome of these reactions and the high level of asym-
metric induction are in agreement with those observed for (Z)-
methyl enol ethers or the silyl enol ethers of aryl alkyl ketones
studied by Sharpless et al.3a In order to understand this high face
stereoselectivity in the AD reactions of acyclic enol phosphates 4,
the mechanistic models proposed for these processes were
analyzed.
The initially proposed empirical model, a ‘mnemonic device for
predicting enantiofacial selection’18 was later modified so that ‘the
southwest quadrant is regarded as being an attractive area, well
suited to accommodate flat aromatic substituent, the northeast
and southeast quadrants retain open and severely crowded, and
the northwest quadrant which exhibits modest steric restriction,
but can play an attractive role for some olefinic substrate’19d
(Scheme 4).
aim of rationalizing some mechanistic aspects of the Sharpless
asymmetric dihydroxylation reactions.19 They allowed us to pro-
pose the updated mnemonic device which differs from the original
one, indicating that only one quadrant (SE) is crowded while the
NW quadrant is open and not subject to weak crowding. This mod-
el improves the predictivity, especially for trisubstituted
alkenes.19l,m
Thus, our results show that acyclic a-hydroxy ketones 6 of (R)-
and of (S)-configuration were formed from (Z)-acyclic enol phos-
phates 4, according to the updated Sharpless mnemonic.19l,m Enol
phosphate 4 is positioned as illustrated in Scheme 5, with the phe-
nyl substituent placed in the SW quadrant, which is assigned as the
most important for attractive interactions with the catalyst ligand.
The bulky phosphoryl group occupies the open northwest
quadrant.
It was also mentioned that, ‘if the substituent oriented toward
NW corner is long and flexible it can wrap around and experience
moderate steric stabilization from any nearby group’.19l This could
be the case of the phosphoryl group.
Over the last two decades, extensive studies, including compu-
tational and kinetic investigations, have been undertaken with the
Corey extended the scope of the AD reaction, using the pyrida-
zine-linked ligand, [(DHQD)2PYDZ], to the polycyclic olefinic
(DHQD)2-PHAL
OH
H
HO
RS
[O]
NE
NW
RM
RL
RS
RL
RM
(R,R)
attractive
area
H
RL
H
RM
RS
SW
SE
[O]
(DHQ)2-PHAL
HO
OH
(S,S)
Scheme 4. Sharpless mnemonic device for the prediction of AD selectivity.

E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
1483
(DHQD)2-PHAL
open
NW
attractive
NE
O
AD-mix-β
O
Alk
Ar
O
O
P
OH
O
Alk
(R)
O
H
Alk
Ar
(S)
AD-mix-α
SE
SW
attractive
OH
repulsive
(DHQ)2-PHAL
Scheme 5. Updated mnemonic device for the AD oxidation of acyclic enol phosphates 4.
substrates containing an aromatic framework. Several (R,R)-poly-
cyclic diols with an aromatic moiety were obtained with high
enantioselectivity.19g A few years later, Marcune et al. applied a
modified AD procedure to accomplish the asymmetric synthesis
with an aromatic moiety, we focused our attention on an organo-
catalyst—a fructose derived ketone 2, readily available from D-fruc-
tose via a simple two step synthesis.6,20 The chiral oxidant,
dioxirane 3, is usually generated in situ from ketone 2 and Oxone
(potassium peroxomonosulfate).6
of cyclic
a
-hydroxy ketones from enol ethers of cyclic ketones.17
The (R)- and (S)-enantiomers of 2-hydroxy tetralone 9a and (S)-
3-hydroxychroman-4-one 9b were obtained using the
(DHQD)2PHAL and the (DHQ)2PHAL ligands, respectively, with high
enantioselectivity and in good yield. The facial stereoselectivity
was found to be the same as that observed for polycyclic diols.
On the contrary, our attempt to synthesize enantiomerically en-
riched 3-hydroxychroman-4-one 9b and 2-hydroxy tetralone 9a,
according to the modified AD procedure was less successful. Using
our substrates, cyclic enol derivatives 5a, 5b, containing a phos-
Adam et al. described the utility of this method for the conver-
sion of acyclic silyl enol ethers into the corresponding optically ac-
tive
modified derivatives, for the preparation of many enantiomeric
mono- and bicyclic enol epoxides.7b,8c,f Further transformations,
under acidic or thermal conditions, afforded enantiomerically en-
a
-hydroxy ketones.21 Shi et al. applied ketone 2 and its
riched
a-acyloxy-, a-alkoxy, or a-aryloxy ketones. In some cases,
one enantiomer of an epoxide could be converted into either enan-
tiomer of these ketones by the choice of proper reaction
conditions.7b
phoryl group, the corresponding
a-hydroxy ketones 9a and 9b
were obtained in low yield and enantioselectivity. Moreover these
compounds 9a, 9b were formed not only in low enantiomeric pur-
ity, but the sense of these asymmetric inductions was [(S)-config-
uration] opposite to that [(R)-configuration] observed by
Marcune for the cyclic enol ethers.
To test the utility of chiral dioxirane 3 in asymmetric oxidations,
we examined the reactivity of the enol phosphate derived from
chroman-4-one 5b. (Scheme 6, Table 2).
From the reaction with excess dioxirane 3, generated in situ
from chiral ketone 2 and Oxone, the desired (R)-(+)-3-hydroxy-
chroman-4-one 9b was obtained directly in good yield and with
high enantioselectivity (92% ee, Table 2, entry 2). The same process,
carried out under catalytic conditions (Table 2, entry 3) afforded
product 9b with similar enantioselectivity (82% ee) albeit in lower
yield. Therefore, the next set of experiments with phosphates 5a, c,
2.2. Asymmetric epoxidation of enol phosphates 4 and 5 with
chiral dioxirane 3
Searching for another effective catalyst for the asymmetric oxi-
dation of enol phosphates, in particular cyclic compounds fused
d
containing cyclic, aromatic substituents, as well as with
O
(EtO)2(O)PO
OP(O)(OEt)2
dioxirane 3
O
O
OH
OH
(R)
H+
dioxirane 3
(R)
O
X
(R,R)-8a
(EtO)2(O)PO
(R)-(+)-9a
5a,b,d
(R)-(+)-9b
OP(O)(OEt)2
CH3
O
O
OH
H+
(S)
dioxirane 3
(S)
CH3
(S)
CH3
5d
(S,S)-8d
(S)-(-)-9d
OH
O
(S)
(EtO)2(O)PO
(EtO)2(O)PO
O
(S)
H+
dioxirane 3
5c
(S,S)-8c
(S)-(-)-9c
Scheme 6. Asymmetric epoxidation of cyclic enol phosphates 5 with chiral dioxirane 3 and subsequent epoxides conversion into cyclic a-hydroxy ketones 9.

1484
E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
Table 2
Enantioselective synthesis of
a
-hydroxy ketones 6, 9 via enantioselective epoxidation of cyclic 5 and acyclic enol phosphates 4 with a fructose-derived dioxirane 3a
Entry
Substrate (E) or (Z)
Epoxideb
Configc
Yieldd (%)
50
Product
Yielde (%)
eef (%)
Configg.
1
2
3
4
5
6
7
8
9
10
5a
5b
5bh
5c
5d
4a
4b
4f
8a
(R,R)
9a
9b
9b
9c
9d
6a
6a
6f
50
60
40
48
25
33
48
50
18
40
88
92
83
84
12
76
68
66
76
69
(R)-(+)
(R)-(+)
(R)-(+)
(S)-(ꢁ)
(S)-(ꢁ)
(R)-(+)
(S)-(ꢁ)
(R)-(+)
(S)-(ꢁ)
(S)-(ꢁ)
8c
8d
7a
7b
7f
(S,S)
(S,S)
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
48
28
33
48
55
20
50
4g
4h
7g
7h
6f
6f
a
b
c
General non-catalytic reaction conditions: substrate (1 equiv), ketone 2 (3 equiv), Oxone (5 equiv), and K2CO3 (15 equiv) in CH3CN/aq Na2-(EDTA) at 0 °C.
Not isolated but characterized by 31P and 1H NMR data and compared with the literature data.14b
The absolute configurations were tentatively assumed by comparing the absolute configurations of the resulting a-hydroxy ketones 6 and 9, determined by the sign of the
specific rotation of 6 and 9 and chiral HPLC data.14b
d
By 31P NMR spectroscopy of the crude reaction mixture.
Yield of isolated products.
Determined by chiral HPLC (Chiracel OD).
Absolute configurations were determined by comparison of the sign of the specific rotation with the literature data (see Section 4).
e
f
g
h
Conditions: substrate (1 equiv), ketone 2 (0.3 equiv), Oxone (1.38 equiv), and K2CO3 (5 equiv) in CH3CN/buffer [0.05 M Na2O4O7.10 H2O in aq Na2-(EDTA)] at 0 °C.
dialkyl- 4a, f and diaryl-substituted 4b, g, h acyclic enol phos-
mized transition state is the spiro-like TS model presumably ‘due
to the stabilizing interaction of a dioxirane oxygen lone pair with
the p⁄ orbital of the alkene. (In the planar TS, that interaction is
not possible owing to its geometry)’. The electronic factors of a
substituent on the olefin, such as phenyl, can lower the energy of
the p⁄ orbital of the alkene and enhance these stabilizing interac-
tions.7c Based on stereochemical analysis of a few possible spiro
and planar transition states, it can be concluded that two of them,
one spiro and one planar, are sterically favored. In these models, the
steric repulsions of the dioxirane and olefin substituents are
minimized.7b
phates, were performed under non-catalytic conditions (entries
1, 4–10). In most cases, the corresponding enol phosphate epoxides
7 and 8 were formed in good to moderate yields (Table 2, entries 1,
4, 6–9) as determined by 31P NMR. The substrates 4g and 5d were
less reactive under the epoxidation reaction conditions to give the
epoxides 7g, 8d in very low yield. (Table 2, entries 5, 10). Any at-
tempts to isolate all of the intermediate epoxides 7, 8, including
an Et3N-buffered silica gel column, were unsuccessful. For this rea-
son, the crude reaction mixtures were hydrolyzed using trifluoro-
acetic acid in ether/H2O solution to give
a-hydroxy carbonyl
derivatives 6a, f, 9a, c, d, which have been isolated in pure form.
The degrees of conversion of all enol phosphate epoxides 7, 8 to
The application of the spiro model of the TS to the E-configured
cyclic enol phosphates 5a, b allowed us to predict the proper (R,R)
facial stereoselectivity in this epoxidation process.6,7 Following
Shi’s mechanistic proposal for the epoxidation of cyclic enol
ethers,7b the arrangement of this bicyclic system containing a
phosphate group and an aromatic moiety is illustrated in Figure 3.
The phosphoryl group is positioned over the fructose ring so that it
can avoid the steric repulsion with the exo-dioxolane ring (Fig. 3a).
a-hydroxy ketones 6, 9 were nearly quantitative as concluded from
31P NMR data. High enantioselectivities (88–82%) were observed
for the epoxidation of cyclic phosphates 5a, c but for product 9c,
the (S)-configuration prevailed. Enol phosphate 5d was converted
into nearly racemic 2-hydroxy-2-methyl-indanone 9d in low yield.
The stereoselectivity of the epoxidation of the Z isomers of acyclic
enol phosphates 4a, b, f, g, h was good (ee 76–66%), but lower
compared to the cyclic ones 5a–c (ee 92–83%).22 While the enol
phosphates with alkoxy substituents on the phosphoryl group
4a,f led to (R)-configured final products 6a and 6f, (Scheme 7, Ta-
ble 2, entries 6, 8) the substrates bearing aryloxy groups at phos-
The
a-hydroxy ketone of opposite configuration (S)-9c was
formed from the enol phosphate derivative of 2,3-dihydro-phenan-
thren-4-one 5c. In this case, the steric interactions of the bulkier
aromatic substituent with the fructose moiety in the spiro transi-
tion state prevailed. (Fig. 3b). Hence, we assume that the (S)-con-
phorus 4b, g,
h
afforded the (S)-enantiomers of
a-hydroxy
figured product was formed as a result of the epoxidation
according to the planar TS (Fig. 3c).
ketones 6a and 6f23 (Scheme 7, Table 2, entries 7, 9, 10).
The results of the asymmetric epoxidation of acyclic 4 and cyc-
lic enol phosphates 5, using chiral ketone-catalyst 2, show that the
degree of enantioselectivity and absolute configuration of a-hydro-
xy ketones obtained, are dependent on the geometry (E/Z) and sub-
stitution pattern of the starting phosphates, which is in agreement
with earlier observations by Shi6,7b and Adam.21 Two mechanistic
models with spiro or planar transition states were proposed for
the dioxirane-mediated epoxidation of differently substituted ole-
fins.6 Calculations performed by Bach et al.24 show that the opti-
The spiro transition state model, in which the planar Ph group is
directed over the plane of the dioxirane ring, can explain the (R,S)
facial stereoselectivity of the epoxidation of acyclic enol phos-
phates 4a, f containing a dialkoxy phosphoryl group and an alkyl
substituent in the cis position. Hydrolysis of the resulting epoxides
7a, f, with CF3C(O)OH, led to the observed
with an (R)-configuration (Table 2, entries 6, 8), (Scheme 8). How-
ever, in contrast to these (R)- -hydroxy ketones 6a and 6f, the (S)-
-hydroxy ketones 6a and 6f were formed from phosphates 4b, g,
a-hydroxy ketones 6a, f
a
a
O
O
R1
H
OP(O)(OR)2
Ph
R1
H
OP(O)(OR)2
Ph
2, oxone
H+
R1
R1
Na2CO3 or K2CO3
Ph
Ph
or
O
OH
(S)-6a,f
OH
(R)-6a,f
7a,b,f-h
4a,f R=Et
4b,g,h R=Ar
Scheme 7. Enantioselective synthesis of acyclic a-hydroxy ketones 6 via epoxidation of acyclic enol phosphates 4.

E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
1485
O
O
O
O
O
O
(R,R)
H
O
RO
RO
O
O
O
H
O
H
OP(O)(OEt)2
O
O
O
O O
O
O
O
O
(S,S)
O
O
R=P(O)(OEt)2
b
a
c
Figure 3. Proposed spiro and planar transition states for the epoxidation of cyclic enol phosphates 5 with chiral dioxirane 3.
OH
Ph
R1
O
Ph
R1
O
H
O
R=Alk
O
O
Ph
H
(R)-6a,f
O
OP(OR)2
O
R1
OP(OR)2
O
OH
O
R=Ar
O
Ph
O
(R,S)-7a,b,f,g,h
R1
O
R = Et, Ph, iPr, p-ClC6H4, p-MeOC6H4
(S)-6a,f
R1 = CH3, C3H7
Scheme 8. Mechanistic proposal for the epoxidation of enol phosphates 4 by fructose derived chiral dioxirane 3.
h bearing aryloxy phosphoryl groups (Table 2, entries 7, 9, 10).
Although the absolute configurations of the enol phosphate epox-
ides 7a, b, f, g, and 7h were not determined due to their instability,
the stereochemical course of these epoxidations was assumed to
be the same in both cases, based on the preferred spiro transition
state model discussed above (Scheme 8).
of the CF3C(O)Oꢁ anion at this atom. Hence, the reaction occurs
at the less substituted carbon atom. Subsequent hydrolysis affords
a-hydroxy ketone (S)-6a,f with inversion of configuration at that
carbon. It should be also mentioned that an analogous phenome-
non was observed in the asymmetric oxidation of aryloxy substi-
tuted enol phosphates using Jacobsen’s catalyst.14
Therefore, it seems reasonable to assume that a reversal of con-
figuration leading to (S)-a-hydroxy ketones 6a, f, takes place over
the course of the acidic hydrolysis of the enol diaryloxyphosphate
3. Conclusion
epoxides 7b, g, and h.
Two tentatively considered mechanisms for the hydrolysis of
enol phosphate epoxides 7 are shown in Scheme 9.
We have demonstrated that readily available enol phosphates 4
and 5 are good synthons for the stereoselective synthesis of differ-
ently substituted
a-hydroxy carbonyl derivatives. It has been
Under the acidic conditions of this reaction, it is the O-proton-
ated epoxide which undergoes hydrolysis. In the case of dialkoxy
phosphoryl epoxides, attack of an anion at the phosphorus atom
facilitates the cleavage of the phosphorus-oxygen bond. Conse-
shown that Sharpless AD reagents 1a and 1b, are complementary
to fructose-derived ketone 2 in the asymmetric oxidation of (Z)-
acyclic enol phosphates 4 and of (E)-cyclic enol phosphates 5
respectively. AD-mix-
very effective reagents for the enantioselective oxidation of acyclic
enol phosphates 4 giving -hydroxy ketones with excellent ees. In
a 1a and AD-mix-b 1b have appeared to be
quently,
a-hydroxy ketones (R)-6a,f of retained configuration are
formed. The presence of bulky aryloxy substituents at the phos-
phorus atom in compounds 7b, g, and 7h can impede the attack
a
turn cyclic enol phosphates 5, containing an aromatic moiety have
O
O
P
O
O
O
(AlkO)2PO
C3H7
(R)
C3H7
(R)
O
(R)
C3H7
H2O
CF3COOH
Ph
Ph
Ph
O
H
OH
Ph
O
H
H
6a,f-(R)
CF3C(O)O
(S,R)-7a,f
O
O
O(O)CCF3
C3H7
O
O
P
O
C3H7
(R)
(ArO)2PO
(S) C3H7
H2O
O
(R)
CF3COOH
Ph
O
H
H
Ph
O
OH
6a,f-(S)
H
(S,R)-7b,g,h
Scheme 9. Proposed courses of the hydrolysis of acyclic enol phosphate epoxides 7.

1486
E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
been easily epoxidized with high enantioselectivity using simple
organic catalyst, a fructose derived ketone 2 and Oxone as the oxi-
4.2.2. Phosphoric acid 2H-chromen-4-yl ester diethyl ester 5b
25
Yellow oil (78%); Rf 0.5, (50% EtOAc/hexane); 1H NMR
dant. The corresponding enantioselective
a
-hydroxy cyclic ketones
(200 MHz, CDCl3) d 7.27 (dd, 1H, J 7.6, 1.5 Hz, CH), 7.14 (dt, 1H, J
7.6, 1.5 Hz, CH), 6.87 (dt, 1H, J 7.6, 1.0 Hz, CH), 6.76 (dd, 1H, J 8.1,
1.0 Hz, CH), 5.59 (dt, 1H, J 4.0, 1.5 Hz, C@CH), 4.87 (dd, 2H, J 4.0,
2.0 Hz, CH2), 4.19 (dd, 4H, J 7.0 Hz, OCH2CH3), 1.33 (t, 6H, J
7.0 Hz, OCH2CH3), 13C NMR (50 MHz, CDCl3) d 161.1 (d, J 7.2 Hz),
152.0, 130.6, 127.1, 123.4, 122.7, 115.6, 70.4, 64.1, 64.0, 13.7,
13.6; 31P NMR (81 MHz, CDCl3) d ꢁ6.15; IR (film, cmꢁ1) 3078,
2985, 2911, 1609, 1478, 1465, 1237, 1218, 1034, 982, 762; m/z
(EI) 284 (25), 255 (21), 227 (16), 146 (100), 120 (69); HRMS calc
for C13H17O5P [M+] 284.0813; found for 284.0805;
were obtained in good yields. This epoxidation of acyclic enol
phosphates affords enantiomerically enriched enol phosphate
epoxides. The acidic hydrolysis of these epoxideslends to both
enantiomers of acyclic
a-hydroxy ketones, depending on AlkO or
ArO groups on the phosphorus atom. The synthetic scope of both
asymmetric oxidations: the osmium catalyzed AD reactions and
epoxidation reactions using an organic catalyst is extended by con-
version of (Z) and (E)-enol phosphates into the pool of versatile
substrates.
4.3. General procedure for the Sharpless AD reactions of acyclic
enol phosphates 4a–e and cyclic enol phosphate 5a with AD-
4. Experimental
4.1. General
mix-b and AD-mix-a (Table 1)
A mixture of AD-mix-b or AD-mix-
a
(1.4 g) and MeSO2NH2
1H, 13C, and 31P NMR spectra were recorded on a Bruker AC 200
Spectrometer at 200.13, 50.32, and 81.02 MHz, respectively (using
CDCl3 as a solvent) unless otherwise noted. IR spectra were mea-
sured on an Ati Mattson Infinity FTIR 60. MS spectra (EI, CI, and
HRMS) were recorded on a Finnigan MAT 95 spectrometer. Optical
rotation values were measured in a 100 mm cell on Perkin Elmer
241 MC under Na lamp radiation. The enantiomer ratios were
determined by HPLC analysis on the commercially available col-
umn Chiracel OD under the conditions specified. Flash chromatog-
raphy separations were performed on silica gel columns (Merck,
Kieselgel 70–230 mesh) with the indicated eluent. Chemicals, sol-
(95 mg, 1 mmol) in t-BuOH-H2O (5 mL/5 mL) was stirred at room
temperature until the mixture became nearly homogeneous. Then
it was cooled to 0 °C and to this mixture, the appropriate enol
phosphate (1 mmol) was added at once. The heterogeneous mix-
ture was stirred vigorously at 0 °C for 16 h (ice bath). Then the
reaction was quenched at 0 °C by the addition of sodium sulfite
(1 g) and the mixture was stirred for 1 h. After the addition of
CH2Cl2 (30 mL) and separation of the layers, the aqueous layer
was extracted with CH2Cl2 (40 mL). The organic extracts were
dried (MgSO4) and evaporated to give a crude product, which
was purified by flash chromatography (silica gel, gradient of
vents, AD-mix-a, and AD-mix-b were obtained from commercial
sources and distilled or dried according to standard methods.
EtOAc/hexane) to give the pure acyclic a-hydroxy ketones 6a,c–e,
which were characterized by 1H NMR.14b The enantiomeric excess
was determined by HPLC with a Chiracel OD-H column. All runs
were carried out at room temperature. The absolute configurations
of products 6a,c–e, and 9a were determined by the comparison of
the sign of the specific rotation with the literature data: 6a,26 6c,27
6d,26 6e,26 9a28 and additionally by comparison of HPLC data.14
4.2. Synthesis of materials
Enol phosphates 4a–f,h, 5a,c,d were prepared according to the
literature.14b Racemic epoxides 7a,b,f–h, 8a,c,d and racemic
a
-hy-
droxy ketones 6a–f, 9a,c,d were prepared as described.14b The
products, enantiomerically enriched -hydroxy ketones 6 and 9
a
4.3.1. 2-Hydroxy-1-phenyl-1-propan-1-ones(S)-(ꢁ)- and (R)-(+)-
6a (Table 1, entry 1)
were characterized by comparison of their data with those of
known samples14b or by their spectroscopic data.
(S)-(ꢁ)-6a, colorless liquid, HPLC conditions: 5% i-PrOH in hex-
ane, 0.4 mL/min; tR [min] 16.3 (S), tR [min] 17.6 (R); ½a D20
¼ ꢁ96:4 (c
ꢂ
0.7, CHCl3), lit. (S)-(ꢁ)-6a: ½a D20
ꢂ
¼ ꢁ80:9 (c 2.0, CHCl3), ee = 95%;26a
4.2.1. Phosphoric acid bis-(4-chloro-phenyl) ester 1-phenyl-
pent-1-enyl ester 4g. General procedure
(R)-(+)-6a, 5% i-PrOH in hexane, 0.4 mL/min; tR [min] 20.7 (S), tR
[min] 22.7 (R);
½
a 2D0
ꢂ
¼ þ55:4 (c 0.1, CHCl3), lit. (R)-(+)-6a:
To a solution of freshly prepared LDA (9 mmol) in THF (100 mL)
at ꢁ78 °C was added butyl phenyl ketone (1.2 g, 7.6 mmol) in THF
(20 mL) and the mixture was stirred under an Ar atmosphere for
1.5 h. Next, a solution of di-(4-chloro-phenyl)-phosphorochlori-
date (3 g, 9 mmol) in THF (20 mL) was added dropwise at the same
temperature. The mixture was stirred and allowed to warm slowly
to room temperature. After 2 h of stirring at ambient temperature,
the solvent was evaporated, the residue was dissolved in ether,
washed with saturated NH4Cl and water, and dried (MgSO4). Evap-
oration of the solvent afforded the crude reaction mixture, which
was analyzed by 1H and 31P NMR spectroscopy. Pure enol phos-
phate was obtained by column chromatography with petroleum
ether/EtOAc (6:4) as a single isomer, yellow oil (1.8 g, 50%); Rf
0.75, (50% EtOAc/hexane); 1H NMR (200 MHz, CDCl3) d 7.45–7.32
(m, 5H, Ph), 7.25 (dt, 4H, J 6, 3 Hz, 4-ClC6H4), 7.02 (d, 4H, J
8.1 Hz, 4-ClC6H4), 5.62 (dt, 1H, J 7, 1.5 Hz, C@CH), 2.22 (dq, 2H, J
7.5, 2.6 Hz, CH2), 1.43 (sext, 2H, J 7.5 Hz, CH2), 0.88 (t, 3H J
7.5 Hz, CH3); 13C NMR (50 MHz, CDCl3) d 148.9, 145.9 (d, J
9.6 Hz), 134.9 (d, J 9.8 Hz), 130.9, 129.9, 129.7, 128.5, 128.3,
125.5, 121.3 (d, J 4.8 Hz) 118.6 (d, J 6.6 Hz), 28,1, 22.2, 13.8; 31P
NMR (81 MHz, CDCl3) d ꢁ17.1; IR (KBr, cmꢁ1) 3095, 2960, 2931,
2870, 1588, 1486, 1301, 1196, 1092, 957, 830; HRMS calculated
for C23H21Cl2O4P [M+] 462.0554; found for 462.0549.
½
a 2D0
ꢂ
¼ þ82:2 (c 2.0, CHCl3), ee = 96%.26c
4.3.2. 2-Hydroxy-1-phenyl-1-propan-1-ones(S)-(ꢁ) and (R)-(+)-
6a (Table 1, entry 2)
(S)-(ꢁ)-6a, HPLC conditions: 4% i-PrOH in hexane, 0.5 mL/min;
tR [min] 14.4 (S), tR [min] 15.8 (R); ½a D20
¼ ꢁ82:5 (c 0.6, CHCl3);
ꢂ
(R)-(+)-6a, 4% i-PrOH in hexane, 0.5 mL/min; tR [min] 17.8 (S), tR
[min] 19.5 (R); ½a D20
¼ þ55 (c 0.35, CHCl3).
ꢂ
4.3.3. 2-Hydroxy-1-(4-methoxyphenyl)-1-propan-1-ones(S)-(ꢁ)-
and (R)-(+)-6c (Table 1, entry 3)
(S)-(ꢁ)-6c, colorless liquid, HPLC conditions: 0.7% i-PrOH in
hexane, 0.5 mL/min; tR [min] 43.2 (S); ½a D20
¼ ꢁ79 (c 0.7, CHCl3),
ꢂ
lit. (S)-(ꢁ)-6c: ½a D20
ꢂ
¼ ꢁ33:4 (c 1.0, MeOH);27 (R)-(+)-6c, 0.7% i-
PrOH in hexane, 0.5 mL/min; tR [min] 47.7 (R); ½a D20
¼ þ59 (c 0.5,
ꢂ
CHCl3).
4.3.4. 2-Hydroxy-1-phenyl-1-butan-1-ones(S)-(ꢁ)- and (R)-(+)-
6d (Table 1, entry 4)
(S)-(ꢁ)-6d, colorless liquid, HPLC conditions: 4% i-PrOH in hex-
ane, 0.5 mL/min; tR [min] 11.8 (S), tR [min] 14.5 (R); ½a D20
¼ ꢁ34:4 (c
ꢂ
0.7, CHCl3), lit. (S)-(ꢁ)-6d:
½
a 2D0
ꢂ
¼ ꢁ30:8 (c 2.24, CHCl3),

E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
1487
ee = 95%;26a (R)-(+)-6d, 4% i-PrOH in hexane, 0.5 mL/min; tR [min]
and water (20 mL), dried (Na2SO4), and evaporated. The crude mix-
ture, analyzed by 1H and 31P NMR, was found to contain
-hydroxy
chromanone 9b together with the ketone 2. Careful separation of
12.0 (S), tR [min] 13.9 (R); ½a D20
ꢂ
¼ þ31:2 (c 0.7, CHCl3), lit. (R)-(+)-
a
6d: ½a 2D0
ꢂ
¼ þ40:5 (c 0.3, CHCl3), ee = 81%.14b
this mixture by flash chromatography (Hexane/EtOAc 9/1) afforded
4.3.5. 2-Hydroxy-1,2-diphenyl-ethanone(R)-(ꢁ)-6e (Table 1,
entry 5)
pure 9b as a white solid (98 mg, 60% yield); ½a D20
¼ þ82 (c 0.85,
ꢂ
CHCl3), Rf (50% EtOAC/hexane) 0.7; mp 58.5 °C; the enantiomeric
excess was determined by HPLC, (Chiracel OD-H): (R)-(+)-9b, ee
92%, HPLC conditions: (Table 2, entry 2), 0.7% i-PrOH in hexane,
0.5 mL/min; tR [min] 34.3(R), tR [min] 40.4 (S).; lit. (R)-(+)-9b:
(R)-(ꢁ)-6e, white solid, mp 140 °C, HPLC conditions: 5% i-PrOH
in hexane, 0.4 mL/min; tR [min] 36.6 (R); ½a D20
¼ ꢁ142 (c 0.7,
ꢂ
CHCl3), lit. (S)-(+)-4d: ½a D20
ꢂ
¼ þ114:9 (c 1.5, acetone), ee = 95%.26
½
a 2D0
ꢂ
¼ þ71:25 (CHCl3), ee = 83%.17
4.3.6. 2-Hydroxy-3,4-dihydro-2H-naphthalen-1-one(R)-(+)-9a
(Table 1, entry 6)
4.5.2. (R)-(+)-2-Hydroxy-3,4-dihydro-2H-naphthalen-1-one
9a14b,28 (Table 2, entry 1)
(R)-(+)-9a, colorless liquid, HPLC conditions: 0.3% i-PrOH in
hexane, 0.5 mL/min; tR [min] 36.3 (R), tR [min] 41.0 (S);
Epoxide 8a was prepared according to the general epoxidation
procedure (method A) from phosphoric acid 3,4-dihydro-naphtha-
len-1-yl ester diethyl ester 5a and dioxirane 3 to provide crude
compound 8a.14b 1H NMR (200 MHz, CDCl3) d 7.77–7.72 (m, 1H,
Ar), 7.28 (d, 2H, J 4.4 Hz, Ar), 7.11 (t, 1H, J 4.4 Hz, Ar), 4.53 (dd,
1H, J 5.5, 1.6 Hz, POCOC(H)), 4.20 (quint, 4H, J 7.0, OCH2CH3),
2.72–2.61 (m, 2H, CH2), 2.40–2.30 (m, 1H, CH2), 1.98–1.70 (dd,
1H, J 13.0, 6.2, CH2), 1.38 (d, 6H, J 7.0, OCH2CH3); 31P NMR
½
a 2D0
ꢂ
¼ þ11 (c 0.7, CHCl3).
4.3.7. 2-Hydroxy-3,4-dihydro-2H-naphthalen-1-ones(R)-(+)-
and (S)-(ꢁ)-9a (Table 1, entry 7)
(R)-(+)-9a, HPLC conditions: 0.3% i-PrOH in hexane, 0.5 mL/min;
tR [min] 28.1 (R), tR [min] 29.9 (S); (S)-(ꢁ)-9a 0.3% i-PrOH in hex-
ane, 0.4 mL/min; tR [min] 52.3(R), tR [min] 60.8 (S); ½a D20
¼ ꢁ11:2
ꢂ
(c 0.3, CHCl3); lit. (S)-(ꢁ)-9a: ½a D20
ꢂ
¼ ꢁ8:6 (c 1.0, CH2Cl2), ee = 99%.28
(81 MHz, CDCl3) d 6.09. Epoxide 8a was hydrolyzed with
CF3C(O)OH in Et2O/H2O solution at 0 °C14b to the title compound
9a. The enantiomeric excess was determined by HPLC (Chiracel
OD-H), (R)-(+)-9a entry 1;0.3% i-PrOH in hexane, 0.4 mL/min; tR
4.4. Procedure for Sharpless AD reactions with cyclic enol
phosphate 5b. Preparation of (S)-3-hydroxy-2,3-dihydro-4H-
chromen-4-one 9b.17
[min] 50.9 (R), tR [min] 60.9 (S); ½a D20
¼ þ14:7 (c 0.6, CHCl3).
ꢂ
A mixture of AD-mix-b (2.8 g), MeSO2NH2 (130 mg, 1.5 mmol),
and Na2S2O8 (375 mg, 1.5 mmol) was dissolved in CH3CN (10 mL)
and water (10 mL) and stirred at 0 °C for 15 min. To this slurry
was added the enol phosphate of chromanone 5b (284 mg,
1 mmol) and the mixture was stirred overnight at 0 °C. Next
methyl t-butyl ether (10 mL) and brine (8 mL) were added. After
separation, the aqueous layer was extracted with MTBE (10 mL),
washed with water, and the combined organic layers were dried
with Na2SO4. After evaporation of the solvent, the yellow oil was
purified by flash chromatography (silica gel, gradient of EtOAc/
hexane) to give product 9b as a white crystalline solid; 49 mg,
4.5.3. (S)-(ꢁ)-2,3-Dihydro-3-hydroxy-1H-phenanthren-4-one
9c14b (Table 2, entry 4)
Epoxide 8c was prepared according to the general epoxidation
procedure (method A) from phosphoric acid 1,2-dihydro-phenan-
thren-4-yl ester diethyl ester 5c and dioxirane 3 to provide crude
compound 8c; 1H NMR (200 MHz, CDCl3) d 8.36 (d, 1H, J 8.0, Ar),
7.74–7.60 (m, 2H, Ar), 7.47–7.33 (m, 2H, Ar), 7.18–7.14 (m, 1H,
Ar), 4.05 (quint, 4H, J 7.1, OCH2CH3), 3.55 (dq, 1H, J 8.4, 2 Hz, PO-
COC(H)), 3.26–3.19 (m, 1H), 2.84–2.42 (m, 3H), 1.38 (d, 6H, J 7.1,
OCH2CH3); 31P NMR (81 MHz, CDCl3) d ꢁ5.8. Epoxide 8c was
hydrolyzed with CF3C(O)OH in Et2O/H2O solution at 0 °C14b to
the title compound 9c (yellow oil). The enantiomeric excess was
determined by HPLC (Chiracel OD-H), (S)-(ꢁ)-9c, entry 4; 5% i-
PrOH in hexane, 0.4 mL/min; tR [min] 21.6 (S), tR [min] 26.3 (R);
30%; ½a 2D0
¼ ꢁ8:8 (c 0.7, CHCl3), Rf (50% EtOAC/hexane) 0.7; mp
ꢂ
57–59 °C; 1H NMR (200 MHz, CDCl3) d 7.88 (1H, dd, J 7.8, 1.5 Hz,
Ar), 7.52 (1H, dt, J 7.8, 1.5 Hz, Ar), 7.06 (1H, t, J 7.6 Hz, Ar), 6.98
(1H, d, J 8.3 Hz, Ar), 4.71–4.57 (2H, AB part of ABX, CH2), 4.20–
4.05 (1H, X part of ABX, CH), 2.5 (1H, br s, OH); m/z (CI, isobutane)
165 (100, MH+); Enantiomeric excess was determined by HPLC,
Chiracel OD-H: (S)-(ꢁ)-9b, ee 12%, (Table 1, entry 8), HPLC condi-
tions: 0.7% i-PrOH in hexane, 0.5 mL/min; tR [min] 34.6(R), tR
½
a 2D0
ꢂ
¼ ꢁ20 (c 0.8, CHCl3); lit. (R)-(+)-9c: ½a D20
¼ þ17:5 (c 0.4,
ꢂ
CHCl3), ee = 81%14b
4.5.4. (S)-(ꢁ)-2-Hydroxy-2-methyl 1-indanone 93b,14b, (Table 2,
entry 5)
Epoxide 8d was prepared according to the general epoxidation
procedure (method A) from phosphoric acid diethyl ester 2-
methyl-3H-inden-1-yl ester 5d and dioxirane 3 to provide crude
compound 8d. 1H NMR (200 MHz, CDCl3) d 7.75–7.71 (m, 1H,
Ph), 7.27–7.22 (m, 2H, Ph), 7.19–7.13 (m, 1H, Ph), 4.21 (d sextet,
[min] 39.9 (S), lit. (S)-(ꢁ)-9b: ½a D20
ꢂ
¼ ꢁ57 (c 2.0, CHCl3), ee = 100%31
4.5. General epoxidation procedure. Method A (under non-
catalytic conditions)
4.5.1. Preparation of (R)-(+)-3-hydroxy-2,3-dihydro-4H-
chromen-4-one 9b17,31 from 5b
4H, J 7.1, 1.2 Hz, OCH2CH3), 2.94 (AB, 2H, J 18.1 Hz, PO-
COC(CH3)CH2), 1.76 (s, 3H, CH3), 1.34 (t, 6H, J = 7.1 Hz, OCH2CH3);
31P NMR (81 MHz, CDCl3) d ꢁ4.5. Epoxide 8d was hydrolyzed with
CF3C(O)OH in Et2O/H2O solution at 0 °C14b to the title compound
9d (white solid, mp 46 °C). The enantiomeric excess was deter-
mined by HPLC (Chiracel OD-H), (S)-(ꢁ)-9d, entry 5; 1.6% i-PrOH
in hexane, 0.4 mL/min; tR [min] 29.1.(S), tR [min] 32.9 (R);
Aqueous Na2(EDTA) (1 ꢃ 10ꢁ4 M, 10 mL) and a catalytic amount
of Bu4N+OHꢁ were added to a solution of enol phosphate 5b
(284 mg, 1 mmol) in acetonitrile (15 mL) with stirring at 0 °C. A
mixture of Oxone (3 g, 5 mmol) and K2CO3 (2.1 g, 15 mmol) was
mixed, and a small amount of this mixture was added to the reac-
tion mixture to bring the pH to ꢄ8, after which ketone 2 (770 mg,
3 mmol) was added portionwise over 1 h. Simultaneously, the rest
of the Oxone and bicarbonate mixture was added over 50 min.
After completion of the addition of both components, the reaction
mixture was stirred for 1 h at 0 °C. Next, it was diluted with water
(35 mL) and the organic layer was separated. The residue was ex-
tracted with hexanes (3 ꢃ 20 mL) and next with diethyl ether
(2 ꢃ 20 mL). This organic layer was washed with brine (10 mL)
½
a 2D0
ꢂ
¼ ꢁ3:7 (c 0.4, CHCl3); lit. (S)-(ꢁ)-9d: ½a D20
¼ ꢁ22:7 (c 1.62,
ꢂ
CHCl3), ee = 85%.3b
4.5.5. (R)-(+)-2-Hydroxy-1-phenyl-1-propan-1-one 6a14b,26
(Table 2, entry 6)
Epoxide 7a was prepared according to the general epoxidation
procedure (method A) from phosphoric acid diethyl ester 1-phe-
nyl-propenyl ester 4a and dioxirane 3 to provide crude compound

1488
E. Krawczyk et al. / Tetrahedron: Asymmetry 23 (2012) 1480–1489
7a 1H NMR (200 MHz, CDCl3) d 7.50–7.42 (m, 2H, Ph), 7.38–7.30
(m, 3H, Ph), 4.05, 4.06 (d sextet, 4H, J 7.2, 1.2 Hz,, OCH2CH3), 3.01
(dq, 1H, J 5.3,1.8 Hz, POCOC(H), 1.66 (d, 3H, J 5.3 Hz, CH3), 1.24,
1.14 (2t, 6H, J 7.2 Hz, OCH2CH3); 31P NMR (81 MHz, CDCl3) d
ꢁ3.9. Epoxide 7a was hydrolyzed with CF3C(O)OH in Et2O/H2O
solution at 0 °C14b to the title compound 6a. The enantiomeric ex-
cess was determined by HPLC (Chiracel OD-H), (R)-(+)-6a, entry 6:
5% i-PrOH in hexane, 0.4 mL/min; tR [min] 18.8 (S), tR [min] 21.1
7.1 Hz, CH2), 0.92 (t, 3H J 7.0 Hz, CH3); 31P NMR (81 MHz, CDCl3)
d ꢁ14.8. Epoxide 7h was hydrolyzed with CF3C(O)OH in Et2O/
H2O solution at 0 °C14b to the title compound 6f. The enantiomeric
excess of 6f was determined by HPLC (Chiracel OD-H), 3% i-PrOH in
hexane, 0.3 mL/min; tR [min] 19.3 (S), tR [min] 25.8 (R);
½
a 2D0
ꢂ
¼ ꢁ14:1 (c 0.34, CHCl3); lit.14b (R)-(+)-6f: ½a 2D0
¼ þ17:3 (c
ꢂ
1.3, CHCl3), ee = 68% from 4h.
(R); ½a 2D0
ꢂ
¼ þ73:3 (c 0.4, CHCl3).
4.6. General epoxidation procedure Method B (under catalytic
conditions). Preparation of (R)-(+)-3-hydroxy-2,3-dihydro-4H-
chromen-4-one 9b from 5b
4.5.6. (S)-(ꢁ)-2-Hydroxy-1-phenyl-1-propan-1-one 6a14b,26
(Table 2, entry 7)
Epoxide 7b was prepared according to the general epoxidation
procedure (method A) from phosphoric acid diphenyl ester 1-phe-
nyl-propenyl ester 4b and dioxirane 3 to provide crude compound
7b. 1H NMR (200 MHz, CDCl3) d 7.54–7.06 (m, 15H, Ph, OPh), 3.09
(dq, 1H, J 5.3,1.8 Hz, POCOC(H), 1.62 (d, 3H, J 5.3 Hz, CH3); 31P NMR
The mixture of buffer (0.05 M Na2B4O7 10 H2O in 4 ꢃ 10ꢁ4
aqueous Na2(EDTA), 10 mL), enol phosphate 5b (284 mg, 1 mmol),
Bu4N+OHꢁ (cat.), and ketone 2 in acetonitrile (15 mL) was cooled to
0 °C with stirring. Next, a solution of Oxone (0.85 g, 1.38 mmol) in
aqueous Na2(EDTA) (4 ꢃ 10ꢁ4 M, 8 mL) and a solution of K2CO3
(0.8 g, 5.8 mmol) in water (7 mL) were placed in two separate fun-
nels. These solutions were added dropwise for 1.5 h to the reaction
mixture (pH ꢄ10) after which the reaction was quenched by the
addition of hexane and water. The mixture was extracted with
hexane (2 ꢃ 10 mL) and then with diethyl ether (2 ꢃ 20 mL),
washed with brine, and dried over Na2SO4. After evaporation of
the solvents, the crude mixture was analyzed by 1H and 31P
NMR. Separation of the mixture by flash chromatography (Hex-
M
(81 MHz, CDCl3)
d
ꢁ15.1. Epoxide 7b was hydrolyzed with
CF3C(O)OH in Et2O/H2O solution at 0 °C14b to the title compound
6a. The enantiomeric excess was determined by HPLC (Chiracel
OD-H), (S)-(ꢁ)-6a, entry 7: 4% i-PrOH in hexane, 0.4 mL/min; tR
[min] 17.3 (S), tR [min] 19.3 (R); ½a D20
¼ ꢁ55:2. (c 1, CHCl3).
ꢂ
4.5.7. (R)-(+)-2-Hydroxy-1-phenyl-1-pentan-1-one 6f
29,30(Table 2, entry 8)
Epoxide 7f was prepared according to the general epoxidation
procedure (method A) from phosphoric acid diisopropyl ester 1-
phenyl-pent-1-enyl ester 4f and dioxirane 3 to provide crude com-
pound 7f, 1H NMR (200 MHz, CDCl3) d 7.50–7.45 (m, 3H, Ph), 7.36–
7.28 (m, 2H, Ph), 4.62 (m, 2H, OCH(CH3)2), 2.85 (br t, 1H, J 6.0 Hz,
(POCOC(H)), 1.82–1.74 (m, 2H, CH2), 1.53–1.46 (m, 2H, CH2), 1.26
(br t, 6H, J 6.0 Hz, OCH(CH3)2Hz), 0.93 (t, 3H, J 7.0 Hz, CH3); 31P
NMR (81 MHz, CDCl3) d ꢁ6.2. Epoxide 7f was hydrolyzed with
CF3C(O)OH in Et2O/H2O solution at 0 °C14b to the title compound
6f (colorless liquid). The enantiomeric excess of 6f was determined
by HPLC (Chiracel OD-H), 3% i-PrOH in hexane, 0.3 mL/min; tR
ane/EtOAc 9/1) gave
a
-hydroxy chromanone 9b as a white solid
(65 mg, 40% yield). ½a D20
ꢂ ¼ þ30 (c 0.2, CHCl3), Rf (50% EtOAC/hex-
ane) 0.7; mp 58–60 °C; Enantiomeric excess was determined by
HPLC, Chiracel OD-H: (R)-(+)-9b, ee 83%, HPLC conditions: (Table 2,
entry 3) 0.7% i-PrOH in hexane, 0.5 mL/min; tR [min] 33.9(R), tR
[min] 40.1 (S).
Acknowledgments
Financial support by the Ministry of Science and Higher Educa-
tion of Poland (Grant No. N204 517839; 2010–2013) is gratefully
acknowledged. The authors thank Professor P. Kiełbasinski for
[min] 19.0 (S), tR [min] 25.5 (R); ½a D20
ꢂ
¼ þ11:0. (c 0.2, CHCl3); lit.14b
´
(R)-(+)-6f: ½a 2D0
ꢂ
¼ þ17:3 (c 1.3, CHCl3), ee = 68% from 4h; lit.31 (R)-
helpful discussion.
acetate derivative of 6f ½a D20
¼ ꢁ2:3 (c 0.5, acetone).
ꢂ
References
4.5.8. (S)-(ꢁ)-2-Hydroxy-1-phenyl-1-pentan-1-one 6f29,30
(Table 2, entry 9)
1. (a)Total Synthesis of Natural Products: The Chiron Approach; Hanessian, S.,
Epoxide 7g was prepared according to the general epoxidation
procedure (method A) from phosphoric acid bis-(4-chloro-phenyl)
ester 1-phenyl-pent-1-enyl ester 4g and dioxirane 3 to provide
crude compound 7g 1H NMR (200 MHz, CDCl3) d 7.35–7.31 (m,
5H, Ph), 7.22–7.19 (m, 4H, 4-ClC6H4), 6.95 (d, 4H, J 8.6 Hz, 4-
ClC6H4), 3.30 (br s, 1H, (POCOC(H)), 2.08 (dq, 2H, J 7.6, 2.5 Hz,
CH2), 1.43 (dd, 2H, J 7.1, 2.5 Hz, CH2), 0.77 (t, 3H J 7.1 Hz, CH3);
31P NMR (81 MHz, CDCl3) d ꢁ15.9. Epoxide 7g was hydrolyzed with
CF3C(O)OH in Et2O/H2O solution at 0 °C14b to the title compound
6f. The enantiomeric excess of 6f was determined by HPLC (Chira-
cel OD-H), 3% i-PrOH in hexane, 0.3 mL/min; tR [min] 19.7 (S), tR
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[min] 27.3 (R); ½a D20
ꢂ
¼ ꢁ10:2. (c 0.14, CHCl3); lit.14b (S)-(ꢁ)-6f:
½
a 2D0
ꢂ
¼ ꢁ19:9 (c 2.4, CHCl3), ee = 88% from 4f; lit.30 (S)-acetate
derivative of 6f ½a D20
ꢂ
¼ þ1:9 (c 0.8, acetone).
4.5.9. (S)-(ꢁ)-2-Hydroxy-1-phenyl-1-pentan-1-one 6f29,30
(Table 2, entry 10)
Epoxide 7h was prepared according to the general epoxidation
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6.87–6.73 (m, 4H, 4-MeOC6H4), 3.6 (s, 6H, MeO), 2.94 (dt, 1H, J 6.0,
1.9 Hz, (POCOC(H)), 1.80 (q, 2H, J 7.1 Hz, CH2), 1.52 (br t, 2H, J
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