Direct asymmetric α-hydroxylation of 2-hydroxymethyl ketones

Article abstract of DOI:10.1016/S0040-4020(02)00760-3

A direct α-hydroxylation of racemic 2-hydroxymethyl ketones with the Sharpless epoxidation catalyst resulted in α,β-dihydroxy ketones in high ee (up to 97%) and in moderate to good isolated yield (up to 58%).

Full text of DOI:10.1016/S0040-4020(02)00760-3

Tetrahedron 58 (2002) 7321–7326
Direct asymmetric a-hydroxylation of 2-hydroxymethyl ketones
a
Anne Paju, T o˜ nis Kanger, T o˜ nis Pehk and Margus Lopp
b
c
b,*
a
Institute of Chemistry at Tallinn Technical University, Akadeemia tee 15, Tallinn 12618, Estonia
Department of Chemistry, Tallinn Technical University, Ehitajate tee 5, Tallinn 19086, Estonia
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia
b
c
Received 19 March 2002; revised 5 June 2002; accepted 27 June 2002
Abstract—A direct a-hydroxylation of racemic 2-hydroxymethyl ketones with the Sharpless epoxidation catalyst resulted in a,b-dihydroxy
ketones in high ee (up to 97%) and in moderate to good isolated yield (up to 58%). q 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
We have previously reported that the Sharpless titanium
complex can oxidise cyclobutanones into the corresponding
2
0,21
Chiral a-hydroxy compounds are widely represented among
1
lactones in moderate to good stereoselectivity.
Also,
–4
22
23
biologically active natural products.
Some of those
oxygenated compounds have found important applications
b-hydroxyketones and 3-alkyl-cyclopentane-1,2-diones
oxidise readily with the same complex giving rise to
different enantiomeric a-hydroxy and ring cleavage
oxidation products with excellent enantioselectivity. In the
present study we have investigated in detail the use of the
Sharpless titanium–tartrate catalyst for the direct oxidation
of racemic cyclic and acyclic a-hydroxymethyl ketones.
5
only recently (monosaccharide carba-analogues,
6
components for anti-viral medicines etc.). Therefore,
elaboration of new efficient methods for the synthesis of
chiral a-hydroxy ketones in a non-racemic form is of
importance.
An attractive route to enantiomerically enriched a-hydroxy
ketones is a direct asymmetric oxidation of the parent
carbonyl compounds. A non-asymmetric version of
a-hydroxylation of ketones (as their enolates) is well
2. Results and discussion
2.1. Asymmetric a-hydroxylation of 2-hydroxymethyl
ketones
7
,8
known. The asymmetric generation of a-hydroxy ketones
has been achieved by the chiral auxiliary method, using a
chiral organic or organometallic auxiliary which is bound to
When oxidizing cyclobutanones via a Baeyer–Villiger
reaction with the Sharpless epoxidation catalyst we found
that a-hydroxymethyl cyclobutanone was the most readily
9
the ketone group and by the use of enantiomerically pure
1
0–12
oxaziridines as oxidizing reagents.
In efforts to extend
2
0
the scope of the asymmetric dihydroxylation method,
Sharpless and co-workers found that enol ethers are
excellent substrates for dihydroxylation, giving rise to
oxidised substrate. The oxidation of a-hydroxymethyl
cyclopentanone 1a under the same oxidation conditions,
however, afforded a,b-dihydroxy cyclopentanone 2a in
1
3,14
22
a-hydroxy ketones with high enantiomeric purity.
The
high enantiomeric purity. That preliminary result encour-
aged us to investigate the oxidation of a-hydroxymethyl
alkanones in more detail.
asymmetric generation of a-hydroxy ketones has also been
achieved by oxidation of silyl enol ethers and ketene acetals
using (salen)manganese(III)-complexes together with mild
1
5 – 17
oxidants (NaOCl, N-oxides or iodosylbenzene).
To establish the scope of the reaction, optimal reaction
conditions and the product profile a set of different
b-hydroxy ketones 1 was subjected to oxidation with the
Sharpless complex under various conditions (Table 1).
Recently, some metal-free asymmetric oxidation methods
were reported where the optically active a-hydroxy ketones
have been prepared with moderate to high enantioselectivity
by the oxidation of silyl enol ethers with in situ generated
1
8,19
chiral dioxirane.
First we found that the oxidation conditions that were
optimal for Baeyer–Villiger reaction (cyclobutanone
lactonisation) gave hydroxy ketones 2a and 2b in low
yield (entries 1 and 8). Use of prolonged reaction time
caused only a slight increase in the yield of the product.
Also, a slight improvement in yield was observed when the
quantity of the catalyst was increased (entries 3 and 4).
Keywords: asymmetric oxidation; asymmetric hydroxylation; Sharpless
complex.
*
Corresponding author. Tel.: þ372-6204366; fax: þ372-6524627;
e-mail: lopp@chemnet.ee
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00760-3

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A. Paju et al. / Tetrahedron 58 (2002) 7321–7326
Table 1. Oxidation of cyclic 2-hydroxymethyl ketones under various conditions
Entry
Ketone
Ti(Oi Pr) /DET/TBHP ratio
4
Time
(h)
Hydroxyketone 2
Acid 3 yield
(%)
Recovered 1
(
compared to the substrate)
a
D
b
c
d
Yield
%)
[a]
ee
(%)
Yield
(%)
[a]
D
ee
(%)
(
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1a
1a
1a
1c
1c
1c
1.5/1.8/1.5
1.5/1.8/1.5
1.5/1.8/1.5
2/2.4/1.5
3/3.6/3
2.3/2.8/1.15
3/3.6/1.2
1.5/1.8/1.5
2.4/2.9/1.2
3/3.6/1.2
3/3.6/1.2
3/3.6/1.2
3/3.6/1.2
46
46
160
46
46
46
46
48
46
46
46
92
168
20
15
24
24
15
55
58
11
32
37
29
47
54
þ101
þ94
þ95
þ105
þ96
þ101
þ101
þ53
þ81
þ79
210
210
210
86
5
4
8
7
9
8
8
9
12
12
–
–
–
54
56
35
35
37
15
3
56
33
23
49
30
21
0
0
0
0
0
0
e
0
87
85
86
86
75
97
97
95
93
91
þ21
þ40
þ32
þ5
10
24
21
15
29
35
10
11
12
13
þ10
þ13
a
b
c
d
e
Measured in 96% ethanol.
Determined using R-(2)-a-methoxyphenylacetic acid mono esters of the primary alchols by HPLC (12a, 12c) and by NMR spectroscopy (12b) (Scheme 3).
Measured in CH Cl
Determined by HPLC from the R-(2)-a-methoxyphenylacetic acid esters.
þ)-DIPT (diisopropyl tartrate) was used instead of (þ)-DET.
2
2
.
(
Nevertheless, in all cases a considerable amount of the
substrate remained unreacted. Addition of more oxidant to
the system (larger excess of tBuOOH (TBHP)) diminished
the yield (entry 5). The reaction rate just accelerated when
the amount of the oxidant was decreased (entries 6 and 7).
The best yield was obtained with a ratio of the
ketone 1c also results in the corresponding hydroxyketone
2c with high enantioselectivity (entries 11–13). A finding
that open chain ketones which have much more flexible
structure than the cyclic compounds are also oxidised under
the same reaction conditions in high enantioselectivity is
quite remarkable. Such a result hints at the possibility of
formation of a cis-enolate similar to the corresponding
enolates of the cyclic substrates.
substrate/Ti(Oi Pr) /(þ)-diethyl tartrate (DET)/TBHP
4
1
/3/3.6/1.2 (entry 7).
Reaction conditions had little or no effect on the enantio-
selectivity. On the other hand, the selectivity of
a-hydroxylation depended considerably on the substrate.
The highest ee value was obtained in the case of
cyclopentanone 1a (entries 9 and 10), while the oxidation
of cyclohexanone derivative 1b proceeded with slightly
lower enantioselectivity. The same tendency has also been
observed in the epoxidation of allylic alcohols in the case of
Longer reaction times resulted in a higher chemical yield of
the product with a slight decrease in the enantiomeric purity
of the a-hydroxyketone (entries 12 and 13). The ee of the
unreacted starting ketone 1c also increased steadily in time.
The total sum of the recovered and transformed product
slightly decreases with prolonged reaction time (78% versus
75%). This result indicates that formation of a certain
amount of the other by-products (,22–25%) occurs and
these were not isolated from the reaction mixture.
2
4
cyclohexenols. Analogously to the oxidation of cyclo-
2
0
butanones, the use of (þ)-DIPT instead of (þ)-DET
effected the oxidation in a similar way diminishing both the
product yield and enantioselectivity. Thus, cyclohexanone
An attractive model for rationalizing a possible mechanism
of a-hydroxylation can be drawn by assuming that the
reaction proceeds in a similar fashion to the Sharpless
asymmetric epoxidation via an allylic intermediate, which
forms from the substrates under the influence of the
titanium–tartrate complex (Scheme 1, path a). It is very
likely the case when cyclohexanone ketone 1b is used as a
substrate. Indeed, the recovered starting compound did not
reveal optical activity (entries 1–6) hinting at the possible
formation of an allylic enolate from the racemic starting
ketone prior to oxidation (continuous in situ racemization of
the substrate). In that case the reaction is directed by the
enantioface selection of the achiral substrate by the chiral
1
b was oxidised with (þ)-DIPT to a lower extent than with
(
þ)-DET resulting in a lower yield of hydroxyketone 2b
under identical reaction conditions (entry 2; compare with
entry 1). The a-hydroxylation reaction was accompanied by
the formation of a certain amount of achiral ketoacids 3. As
can be seen from Table 1, entry 5 an excess of TBHP
diminishes the yield of ketone diol 2b. At the same time, any
substantial increase in the amount of the oxidative cleavage
product 3b was not observed.
Oxidation of the a-branched aliphatic a-hydroxymethyl

A. Paju et al. / Tetrahedron 58 (2002) 7321–7326
7323
Scheme 1. Possible mechanistic pathways for the asymmetric oxidation of b-hydroxy ketones.
Figure 1. Unreactive substrates under the Sharpless oxidation conditions.
complex rather than by the kinetic resolution. In the case of
the substrates 1a and 1c the recovered starting ketone
revealed optical activity. The ee of the recovered substrate
depends on the reaction time (which is characteristic of a
kinetic resolution, entries 8, 9 and 11–13). However, the
determined enantiomeric purity of the recovered starting
compound was at least two times less than expected from
the reaction selectivity (s<140; estimated from the
enantiomeric purity 95% ee of the product at 50%
conversion). The result may be explained by assuming
that enantioselection also exists in the enolate formation
step. It means that the ketone/enolate equilibrium should be
shifted towards the ketone, reducing the influence of the
kinetic resolution. The other option may be the following:
the enolate formation is not taking place prior to oxidation
2.2. Determination of the enantiomeric excess and the
absolute configuration of the products
The enantiomeric purity of the a,b-dihydroxy ketones was
determined by HPLC from the diastereomeric ratio of
their mono-R-(2)-a-methoxyphenylacetic acid esters
1
(Scheme 3). The obtained ratio was confirmed by the H
1
3
and C NMR data and was used as a measure of ee of the
diols.
2.2.1. NMR spectra of R-(2)-a-methoxyphenylacetic
1
13
acid esters. The H and
C NMR spectra of the
diastereomeric mono-R-(2)-a-methoxyphenylacetic acid
primary alcohol esters of diols 2a–c differ considerably
1
13
from each other—nearly all H and C nuclei give different
chemical shifts for the corresponding atoms (Section 4).
These differences can in principle be used for the assign-
ment of absolute configuration of the parent chiral alcohols.
That method is generally accepted for the determination of
(
path b) and the complexation with the ketone oxygen
occurs without enol formation or the enolate is formed
enantioselectively from one enantiomer only.
2
5,26
The presence of the b-hydroxy group and branching of the
substrate at the a-position are essential to achieve
a-hydroxylation. Thus, a-branched ketones such as
absolute configurations of secondary alcohols.
For chiral primary alcohols the differences that are caused
by the anisotropy effects of phenyl ring are usually too small
to be observed and, therefore, 9-anthrylmethoxyacetic acid
as a more powerful source of aromatic shielding effects has
2
-methylcyclopentanone 4 and 2-methylcyclohexanone 5
Fig. 1) were not oxidised under the ordinary reaction
(
conditions.
2
7
been usually introduced.
Our attempts to extend the scope of the asymmetric
a-hydroxylation to other b-hydroxy-substituted cyclic
carbonyl compounds (Fig. 1, compounds 6–9) failed—
these compounds did not oxidise under the usual oxidation
conditions (the relative stereochemistry of the substrates 8
and 9 did not influence the result: both diastereomers were
inactive).
In the present case the phenyl ring induced differences are
still remarkable and the largest effect is observed on the
protons a-to the carbonyl group. In all major diastereo-
isomers of compounds 12 these signals are shifted up to
The a-hydroxy cyclopentanone 10 (Scheme 2) undergoes
non-asymmetric oxidation and was completely converted
(no starting ketone left) to the achiral oxidative cleavage
product 11 (isolated in 63% yield) under the usual oxidation
conditions.
Scheme 2. Titanium–tartrate catalysed oxidation of 2-hydroxycyclopenta-
none.

7324
A. Paju et al. / Tetrahedron 58 (2002) 7321–7326
Scheme 3. R-Methoxyphenylacetic acid monoesters of ketodiols 2.
0
.37 ppm towards higher field. Despite a large number of
performed using DC-Alufolien Kieselgel 60 F254 (Merck).
Merck Silica gel 60 (0.063–0.200 mm) or Chemapol silica
gel L 40/100 was used for column chromatography. HPLC
was performed on a LKB liquid chromatograph equipped
with a UV spectrometric detector (2158 Uvicord SD,
254 nm) and a column Waters Spherisorb 3 mm Silica
(4.6£100 mm). All reactions that were sensitive to oxygen
or moisture were conducted under argon atmosphere in
oven-dried glassware. Commercial reagents were generally
used as received. CH Cl was distilled from CaH and
bonds between the phenyl ring and the above-mentioned
protons we made an attempt to explain the observed
differences on the basis of the widely accepted model of
preferred conformation of a-methoxyphenylacetic acid
ester. According to that model the ether and carbonyl
oxygen atoms and the carbinol hydrogen atoms should be in
a coplanar conformation. The preferred conformation of the
remaining part of the molecules was assigned by using
calculations according to Merck MM, AM1, PM3 and ab
initio HF/6-31G methods using 2c as a model compound.
All these calculations suggest that the most stable
conformation is such where the carbonyl and 3-hydroxyl
oxygen atoms are nearly eclipsed, and the terminal hydroxyl
group is trans-oriented to the 3-methyl group. Only that
conformation where the pro-S carbinol Ha hydrogen–
carbon bond (see Scheme 3) is coplanar with the CO bond
results in a remarkable anisotropy effects of the phenyl ring
on the alcohol part of the molecule. These effects depend on
the absolute configuration of alcohol. From that model we
can suggest the 3S configuration of the stereogenic centre
because that configuration should give larger shielding
effect on a-protons. This result is in accordance with the
absolute configuration predicted by the Sharpless oxidation
face selection rule.
2
2
2
p
28
˚
stored over 3 A molecular sieve pellets. THF and ether were
distilled from LiAlH before use. Petroleum ether (40–65)
was distilled before use as the chromatography solvent.
4
The substrates 1a and 1b were prepared according to the
2
9
reported procedure (from commercially available ethyl
2-oxocyclopentanecarboxylate and from methyl 2-oxo-
3
0
cyclohexanecarboxylate respectively); 1c, 4 and 5 were
purchased from Aldrich. Compound 6 was made from 1,3-
cyclopentanediol by Jones mono-oxidation; compound 7
was made from cis,cis-1,3,5-cyclohexanetriol (Aldrich) by
protecting it with phenyl boronic acid followed by Jones
oxidation and deprotection; compound 8 was made from
2-methylcyclopentane-1,3-dione by convering it to
ethyleneglycol diacetal, followed by selective deprotection
of one of the protecting groups and reduction with NaBH4;
cis- and trans-isomers were separated on silica gel,
deprotected and used in the subsequent oxidation separ-
ately; compound 9 was prepared and the diastereomers
separated analogously to compound 8.
3. Conclusions
The proposed novel a-hydroxylation method provides a
valuable way to obtain important enantiomeric 2,3-keto-
diols, that are frequently found in the structural units of
several biologically active natural products. The method
produces chiral a,b-dihydroxy ketones in a straightforward
manner from cyclic and acyclic b-hydroxy ketones with
high enantioselectivity (86–97% ee) and in satisfactory
isolated yield (37–58%). However, the method is limited to
a-hydroxymethyl substituted ketones.
4.1. General procedure for the asymmetric oxidation of
a-hydroxymethyl ketones
To a solution of Ti(Oi Pr) (0.89 mL, 3 mmol) in CH Cl
2
4
2
(6 mL), (þ)-DET (0.6 mL, 3.6 mmol) was added at 2208C
and the mixture was stirred for 15 min. After addition of a
substrate (1 mmol) in CH Cl (2 mL) the mixture was
2 2
stirred for 30 min. Then TBHP (0.35 mL, 1.2 mmol, 3.4 M
solution in toluene) was added and the mixture was kept at
2208C for 46 h. The reaction was quenched by stirring with
a solution of citric acid monohydrate (630 mg, 3 mmol in a
mixture of 10% acetone in ether, 30 mL) at room
temperature for 1 h. The reaction mixture was filtered
through a path of Celite, the Celite layer was washed with
acetone and methanol. The solutes were concentrated and
the residue was purified on silica gel.
4
. Experimental
1
13
H and C NMR spectra were determined in CDCl
1
3
solution on a Bruker AMX-500 spectrometer. Residual H
1
signal from of CDCl (d 7.27 ppm) was used for H and d
3
1
3
7
7.0 ppm for C as internal references. IR spectra were
recorded on a Hitachi 270-30 Infrared Spectrophotometer.
Mass spectra were measured on a Hitachi M80B spec-
trometer using EI (70 eV) and CI (isobutane) mode. Optical
rotations were obtained using a Polamat A polarimeter or a
Kr u¨ ss Optronic GmbH Polarimeter P 3002. TLC was
4.1.1. 2-Hydroxy-2-hydroxymethyl-cyclopentanone (2a)
and 6-hydroxy-5-oxohexanoic acid (3a). Cyclopentanone
1a was oxidised according to the general procedure and

A. Paju et al. / Tetrahedron 58 (2002) 7321–7326
7325
purified by column chromatography (petroleum ether/
acetone 10/2–10/5) affording the compounds 2a (48 mg,
s, 1-H), 1.29 (3H s, 3-CH ); d (125 MHz, CDCl ) 210.96
3 C 3
(C-2), 79.82 (C-3), 67.78 (C-4), 23.82 (C-1), 21.20 (3-CH );
3
þ
75 (100), 57 (98.5), 43 (58.4%); HRMS (EI): [M2H CO] ,
þ
3
7%) and 3a (18 mg, 12%). 2a: colourless oil; R (petroleum
f
m/z (CI) 119 (41, MH ); m/z (EI) 88 (16.8, [M2H CO] ),
2
1
9
þ
ether/acetone 10/4) 0.16; ee 97%; [a] ¼þ79 (c 3.02,
D
2
ethanol); n
1
(liquid film) 3370, 2960, 2880, 1740, 1455,
found 88.0516. C H O requires 88.0524.
4 8 2
max
400, 1165, 1060 cm21; d (500 MHz, CDCl ) 3.67 (1H d,
H 3
J¼11.9 Hz, CH OH), 3.62 (1H d, J¼11.9 Hz, CH OH),
4.1.4. 5-Oxopentanoic acid (11). Cyclopentanone 10 was
oxidised according to the general procedure and purified by
column chromatography (petroleum ether/acetone 10/2)
affording the compound 11 (73 mg, 63%) as a colourless oil;
Rf (petroleum ether/acetone 10/3) 0.22; nmax (liquid film)
2
2
3
.18 (1H bs, OH); 2.38 (2H t, J¼8.1 Hz, 5-H), 2.07 (2H m,
3
CDCl ) 219.55 (C-1), 78.78 (C-2), 64.95 (CH OH), 35.29
-H), 1.93 (1H m, 4-H), 1.87 (1H m, 4-H); d (125 MHz,
C
3
2
þ
9.7, [M2H O] ), 100 (6.3), 84 (25.8), 74 (89.6), 56
(
(
(
C-5), 32.43 (C-3), 17.23 (C-4); m/z (EI) 130 (1.1, M ), 112
þ
100%); HRMS (EI): M , found 130.0669. C H O
21
3100, 2950, 2730, 1720, 1415, 1245, 1165, 1078 cm ; dH
2
þ
(500 MHz, CDCl ) 9.77 (1H d, J¼0.9 Hz, 5-H), 2.56 (2H td,
6
10
3
3
þ
requires 130.0629; (M2H O) , found 112.0538. C H O
2
J¼7.3, 0.9 Hz, 4-H), 2.42 (2H t, J¼7.3 Hz, 2-H), 1.95 (2H
quin, J¼7.3 Hz, 3-H); d (125 MHz, CDCl ) 201.58 (C-5),
179.10 (C-1), 42.66 (C-4), 32.79 (C-2), 16.89 (C-3); m/z
6 8
2
requires 112.0524. 3a: white solid, mp 45–468C; Rf
petroleum ether/acetone 10/4) 0.11; dH (500 MHz,
C
3
(
þ
þ
CDCl ) 4.27 (2H s, 6-H), 2.53 (2H t, J¼7.1 Hz, 4-H),
(CI) 117 (100, MH ); m/z (EI)115 (0.3, [M2H] ), 98 (5.4),
þ
3
2
d (125 MHz, CDCl ) 208.90 (C-5), 178.19 (C-1), 68.03
.43 (2H t, J¼7.1 Hz, 2-H), 1.98 (2H quin, J¼7.1 Hz, 3-H);
88 (18.3), 60 (100%); HRMS (EI): [M2H] , found
115.0382. C H O requires 115.0394.
C
3
5 7 3
(
(
(
C-6), 36.99 (C-4), 32.72 (C-2), 18.30 (C-3); m/z (CI) 147
100, MH ); m/z (EI) 129 (3.2, [M2OH] ), 115 (74.9), 97
þ
7.1), 87 (72.9%); HRMS (EI): [M2OH] , found 129.0554.
þ
4.2. Preparation of primary (R )-(2)-a-methoxyphenyl-
acetic acid mono esters
þ
C H O requires 129.0551.
6 9 3
Preparation of compounds (12). To a mixture of (R )-(2)-
MPA (21.6 mg, 0.13 mmol) and DCC (26.8 mg, 0.13 mmol)
in dry THF (0.6 mL) a,b-dihydroxyketone (0.1 mmol) in
THF (0.5 mL) and DMAP (6.7 mg) were added. After
stirring at rt for 2.5 h the mixture was diluted with ether
(5 mL) and water (1 mL) was added. Then additional
amount of ether (25 mL) was added and the mixture was
washed with 1 M HCl solution, with saturated NaHCO3
solution, brine, dried (Na SO ) and concentrated. Flash
4
.1.2. 2-Hydroxy-2-hydroxymethyl-cyclohexanone (2b)
and 7-hydroxy-6-oxoheptanoic acid (3b). Cyclohexanone
b was oxidised according to the general procedure and
1
purified by column chromatography (petroleum ether/
acetone 10/3–10/5) affording the compounds 2b (84 mg,
5
8%) and 3b (13 mg, 8%). 2b: colourless oil; R (petroleum
f
1
9
ether/acetone 10/4) 0.26; ee: 86%; [a ] ¼þ101 (c 4.76,
D
ethanol); n
1
(liquid film) 3420, 2950, 2870, 1718, 1458,
max
2
4
248, 1122, 1050 cm21; d (500 MHz, CDCl ) 4.31 (1H bs,
chromatography on silica gel (petroleum ether/EtOAc 10/3)
gave the primary R-MPA mono-esters of the corresponding
dihydroxy ketone.
H
3
OH), 3.96 (1H d, J¼11.7 Hz, 7-H), 3.66 (1H d, J¼11.7 Hz,
-H), 2.77 (1H bs, OH), 2.55–2.53 (2H m, 6-H), 2.16 (1H
m, 3-H ), 2.09 (1H m, 5-H ), 1.81 (1H m, 4-H ), 1.68 (1H m,
7
e
e
e
5
CDCl ) 212.59 (C-1), 80.01 (C-2), 66.71 (C-7), 38.27 (C-6),
-H ), 1.67 (1H m, 4-H ), 1.60 (1H m, 3-H ); d (125 MHz,
4.2.1. Compound 12a major isomer. dH (500 MHz,
CDCl ) 7.41–7.35 (5H m, Ph), 4.77 (1H s, CHOCH ),
a
a
a
C
3
3
3
3
M ), 126 (12.5, [M2H O] ), 114 (47.3), 100 (20.4), 85
7.40 (C-3), 27.70 (C-5), 22.38 (C-4); m/z (EI) 144 (4.5,
4.32 (1H d, J¼11.5 Hz, 6-H), 4.08 (1H d, J¼11.5 Hz, 6-H),
þ
100), 67 (48.8%); HRMS (EI): M , found 144.0831.
þ
3.42 (3H s, OCH ), 2.27–2.25 (2H m, 5-H), 1.94 (1H m,
3
2
þ
(
C H O requires 144.0785; (M2H O) , found 126.0677.
4-H), 1.89–1.87 (2H m, 3-H), 1.73 (1H m, 4-H); dC
(125 MHz, CDCl ) 216.41 (C-1), 170.45 (COO), 135.82
þ
C H O requires 126.0680. 3b: white solid; mp 97–988C;
7
12
3
2
3
(s-Ph), 128.87 ( p-Ph), 128.64 (m-Ph), 127.18 (o-Ph), 82.28
(CHO), 77.34 (C-2), 66.18 (C-6), 57.42 (OCH ), 34.95
7
10 2
Rf (petroleum ether/acetone 10/4) 0.12; dH (500 MHz,
CDCl ) 4.26 (2H s, 7-H), 2.46 (2H t, J¼7.1 Hz, 5-H), 2.40
3
(C-5), 32.84 (C-3), 16.91 (C-4); HPLC (hexane/i-PrOH
97/3, flow rate 0.7 mL/min) t 10.09 min.
3
(
d (125 MHz, CDCl ) 209.19 (C-6), 178.04 (C-1), 68.07
2H t, J¼7.1 Hz, 2-H), 1.72 (2H m, 4-H), 1.68 (2H m, 3-H);
R
C
3
(
m/z (CI) 161 (27, MH ), m/z (EI) 160 (0.1, M ), 143 (1.1,
C-7), 37.89 (C-5), 33.39 (C-2), 24.05 (C-3), 22.85 (C-4);
4.2.2. Compound 12a minor isomer. dH (500 MHz,
CDCl ) 7.41–7.35 (5H m, Ph), 4.79 (1H s, CHOCH ),
þ
þ
M2OH] ), 129 (36.2), 111 (29.5), 101 (32.5%); HRMS
3
3
þ
EI): [M2OH] , found 143.0718. C H O requires
[
(
4.34 (1H d, J¼11.6 Hz, 6-H), 4.06 (1H d, J¼11.6 Hz, 6-H),
þ
3.40 (3H s, OCH ), 2.35 (1H m, 5-H), 2.31 (1H m, 5-H),
3
7
11
3
1
43.0707.
1.96 (1H m, 4-H), 1.89–1.87 (2H m, 3-H), 1.71 (1H m,
4-H); d (125 MHz, CDCl ) 216.44 (C-1), 170.54 (COO),
C 3
4
.1.3. 3,4-Dihydroxy-3-methyl-2-butanone (2c). 4-
135.89 (s-Ph), 128.88 ( p-Ph), 128.68 (m-Ph), 127.17 (o-Ph),
82.19 (CHO), 77.67 (C-2), 66.29 (C-6), 57.41 (OCH3),
34.73 (C-5), 32.86 (C-3), 16.89 (C-4); HPLC (hexane/
Hydroxy-3-methyl-2-butanone 1c was oxidised according
to the general procedure and purified by column chroma-
tography (petroleum ether/acetone 10/3) affording 2c
i-PrOH 97/3, flow rate 0.7 mL/min) t 10.54 min.
R
(
64 mg, 54%) as a colourless oil; Rf (petroleum
2
0
D
ether/acetone 10/3) 0.19; ee 91%; [a ] ¼210 (c 4.12,
4.2.3. Compound 12b major isomer. dH (500 MHz,
CDCl ) 7.37 (2H m, o-Ph), 7.36 (2H m, m-Ph), 7.34 (1H
2
0
ethanol); [a ] ¼þ4 (c 4.20, CH Cl ); n
(liquid film)
420, 2980, 2940, 2880, 1710, 1452, 1360, 1125,
D
2
2
max
3
3
1
m, p-Ph), 4.76 (1H s, CHOCH ), 4.57 (1H d, J¼11.7 Hz,
3
045 cm2
1
;
dH (500 MHz, CDCl3) 3.85 (1H d,
7-H), 4.18 (1H d, J¼11.7 Hz, 7-H), 4.09 (1H s, OH), 3.40
J¼11.7 Hz, 4-H); 3.64 (1H d, J¼11.7 Hz, 4-H); 2.28 (3H
(3H s, OCH ), 2.31 (1H m, 6-H), 2.17 (1H m, 6-H), 2.13 (1H
3

7326
A. Paju et al. / Tetrahedron 58 (2002) 7321–7326
m, 3-H), 2.02 (1H m, 5-H), 1.77 (1H m, 4-H), 1.62 (1H m,
-H), 1.60 (1H m, 3-H), 1.58 (1H m, 5-H); d (125 MHz,
CDCl ) d 210.23 (C-1), 170.51 (COO), 135.87 (s-Ph),
3. Seepersand, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41,
4291–4293.
4
C
4. Chen, X.; Schauder, S.; Potier, N.; VanDorsselaer, A.; Pelczer,
I.; Bassler, L. B.; Hugson, M. F. Nature 2002, 415, 545–549.
5. Bianco, A.; Celona, D.; Di Rita, S.; Guiso, M.; Melchioni, C.;
Umani, F. Eur. J. Org. Chem. 2001, 4061–4066.
3
1
7
28.78 ( p-Ph), 128.61 (m-Ph), 127.01 (o-Ph), 82.01 (CHO),
7.88 (C-2), 68.39 (C-7), 57.38 (OCH ), 38.20 (C-3), 37.89
3
(
C-6), 27.58 (C-5), 22.52 (C-4).
6
. Gurjar, M. K.; Maheshwar, K. J. Org. Chem. 2001, 66,
7552–7554.
4.2.4. Compound 12b minor isomer. dH (500 MHz,
CDCl ) 7.41 (2H m, o-Ph), 7.37 (2H m, m-Ph), 7.35 (1H
7. Schultz, M.; Kluge, R.; Sch u¨ shler, M.; Hoffmann, G.
Tetrahedron 1995, 51, 3175–3180.
3
m, p-Ph), 4.76 (1H s, CHOCH ), 4.60 (1H d, J¼11.7 Hz,
3
7
(
-H), 4.16 (1H d, J¼11.7 Hz, 7-H), 3.93 (1H s, OH), 3.38
3H s, OCH ), 2.54 (2H m, 6-H), 2.13 (1H m, 3-H), 2.09 (1H
3
8. Vedejs, E.; Larsen, S. Org. Synth. 1985, 64, 127–137.
9. Enders, D.; Bhushan, V. Tetrahedron Lett. 1988, 29,
2437–2440.
m, 5-H), 1.77 (1H m, 4-H), 1.64 (1H m, 4-H), 1.64 (1H m,
-H), 1.61 (1H m, 3-H); d (125 MHz, CDCl ) d 210.52
5
10. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am.
Chem. Soc. 1990, 112, 6679–6690.
C
3
(
(
(
C-1), 170.51 (COO), 135.81 (s-Ph), 128.88 ( p-Ph), 128.65
m-Ph), 127.12 (o-Ph), 82.01 (CHO), 77.95 (C-2), 68.18
C-7), 57.31 (OCH ), 37.84 (C-3), 38.23 (C-6), 27.52 (C-5),
11. Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919–934.
12. Gala, D.; DiBenedetto, D. J.; Mergelsberg, J.; Kugelman, M.
Tetrahedron Lett. 1996, 37, 8117–8120.
3
2
2.42 (C-4).
1
3. Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem.
1992, 57, 5067–5068.
4.2.5. Compound 12c major isomer. dH (500 MHz,
CDCl ) 7.41–7.33 (5H m, Ph); 4.75 (1H s, CHOCH ),
14. Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463–8464.
15. Adam, W.; Fell, R. T.; Mock-Knoblauch, C.; Saha-M o¨ ller,
C. R. Tetrahedron Lett. 1996, 37, 6531–6534.
3
3
4
3
.34 (1H d, J¼11.7 Hz, 4-H), 4.17 (1H d, J¼11.7 Hz, 4-H),
.92 (1H s, OH), 3.40 (3H s, OCH ), 1.86 (3H s, 1-H), 1.27
3
(
3H s, 3-CH ); d (125 MHz, CDCl ) 208.76 (C-2), 170.23
3 C 3
(
1
COO); 135.98 (s-Ph), 128.89 ( p-Ph), 128.69 (m-Ph),
27.09 (o-Ph), 82.09 (CHO), 77.59 (C-3), 68.95 (C-4),
16. Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-M o¨ ller, C. R.
J. Am. Chem. Soc. 1998, 120, 708–714.
5
i-PrOH 97/3, flow rate 0.7 mL/min) t 10.15 min.
7.38 (OCH ), 23.45 (C-1), 21.65 (3-CH ). HPLC (hexane/
17. Fukuda, T.; Katsuki, T. Tetrahedron Lett. 1996, 37,
4389–4392.
3
3
R
1
8. Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39,
7819–7822.
4
.2.6. Compound 12c minor isomer. dH (500 MHz,
CDCl ) 7.41–7.33 (5H m, Ph); 4.75 (1H s, CHOCH ),
19. Adam, W.; Fell, R. T.; Saha-M o¨ ller, C. R.; Zhao, C.-G.
Tetrahedron: Asymmetry 1998, 9, 397–401.
3
3
4
3
.32 (1H d, J¼11.7 Hz, 4-H), 4.22 (1H d, J¼11.7 Hz, 4-H),
.65 (1H s, OH), 3.39 (3H s, OCH ), 2.13 (3H s, 1-H), 1.29
3
20. Lopp, M.; Paju, A.; Kanger, T.; Pehk, T. Tetrahedron Lett.
1996, 37, 7583–7586.
(
3H s, 3-CH ); d (125 MHz, CDCl ) 209.16 (C-2), 170.31
3 C 3
(
1
COO); 135.87 (s-Ph), 128.92 ( p-Ph), 128.69 (m-Ph),
27.09 (o-Ph), 82.33 (CHO), 77.76 (C-3), 68.79 (C-4),
21. Kanger, T.; Kriis, K.; Paju, A.; Pehk, T.; Lopp, M.
Tetrahedron: Asymmetry 1998, 9, 4475–4482.
22. Lopp, M.; Paju, A.; Kanger, T.; Pehk, T. Tetrahedron Lett.
1997, 38, 5051–5054.
5
i-PrOH 97/3, flow rate 0.7 mL/min) t 9.71 min.
7.35 (OCH ), 24.02 (C-1), 21.50 (3-CH ). HPLC (hexane/
3
3
R
2
2
2
2
2
3. Paju, A.; Kanger, T.; Pehk, T.; Lopp, M. Tetrahedron Lett.
000, 41, 6883–6887.
2
4. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237–6240.
5. Pehk, T.; Lippmaa, E.; Lopp, M.; Paju, A.; Borer, B. C.;
Taylor, R. J. K. Tetrahedron: Asymmetry 1993, 4, 1527–1532.
6. Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry
Acknowledgments
Support from the Estonian Science Foundation (Grants Nos
5133, 3781 and 4976) and from the Estonian Ministry of
Education (Grant 0350312) is acknowledged.
2001, 12, 2915–2925.
7. Ferreiro, M. J.; Latypov, Sh. K.; Quinoa, E.; Riguera, R.
Tetrahedron: Asymmetry 1996, 7, 2195–2198.
28. Spartan 5.0; Wavefunction Inc.
References
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1
30. Krapcho, A. P.; Diamanti, J.; Cayen, C.; Bingman, R. Organic
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2
1