Asymmetric oxidation of 3-alkyl-1,2-cyclopentanediones. Part 1: 3-Hydroxylation of 3-alkyl-1,2-cyclopentanediones

Article abstract of DOI:10.1016/S0957-4166(02)00589-X

3-Alkyl-1,2-cyclopentanediones undergo asymmetric 3-hydroxylation with the Sharpless Ti-complex resulting in enantiomeric 3-hydroxy carbonyl compounds with ee up to 95% in yields of 22-40%.

Full text of DOI:10.1016/S0957-4166(02)00589-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2439–2448
Asymmetric oxidation of 3-alkyl-1,2-cyclopentanediones. Part 1:
3-Hydroxylation of 3-alkyl-1,2-cyclopentanediones
Anne Paju,a To˜nis Kanger,a To˜nis Pehk,b Aleksander-Mati Mu¨u¨riseppa and Margus Loppa,*
aDepartment of Chemistry, Faculty of Natural Sciences, Tallinn Technical University, Ehitajate tee 5, Tallinn 19086, Estonia
bNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia
Received 3 September 2002; accepted 26 September 2002
Abstract—3-Alkyl-1,2-cyclopentanediones undergo asymmetric 3-hydroxylation with the Sharpless Ti-complex resulting in enan-
tiomeric 3-hydroxy carbonyl compounds with ee up to 95% in yields of 22–40%. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
sponding lactones with moderate to good stereoselectiv-
ity (asymmetric Baeyer–Villiger oxidation)24,25 and
hydroxylates 2-hydroxymethyl ketones (asymmetric a-
hydroxylation) to yield a,b-dihydroxy ketones with
high enantiomeric purity.26,27
Chiral a-hydroxy carbonyl compounds are widely
spread among natural products (sugars, a-hydroxy
acids, etc.). Some analogues of those oxygenated com-
pounds have interesting biological properties and are
used in a number of medical preparations (e.g.
monosaccharide carba-analogues as components for
anti-viral medicines,1–10 hydroxycyclopentenones as
anti-cancer drugs,11 etc.)
Recently, we found that the Sharpless complex also
oxidizes different cyclic 3-alkyl-1,2-diones at the posi-
tion adjacent to the 2-carbonyl group, resulting in
3-hydroxylated products with excellent enantioselectiv-
ity.28 In this study, the results from a detailed investiga-
tion of 3-hydroxylation of the cyclic 3-alkyl-1,2-diones
1a–e are presented.†
An attractive route to enantiomerically enriched a-
hydroxy ketones is the direct asymmetric oxidation of
the parent carbonyl compounds. A non-asymmetric
version of a-hydroxylation of ketones (as their Ti-eno-
lates using tert-BuOOH) is known in the literature.12
The asymmetric a-hydroxylation of ketones has been
achieved by the oxidation of enol ethers and/or enolates
using (salen)manganese(III)-complexes together with
mild oxidants (NaOCl, N-oxides or iodosylbenzene)13–
15 enantiomerically pure oxaziridines16–18 and dioxi-
ranes.19,20 Sharpless and co-workers found that enol
ethers are excellent substrates for dihydroxylation, giv-
ing rise to a-hydroxy ketones with high enantiomeric
purity.21,22
2. Results and discussion
2.1. Substrates
Cyclopentane-1,2-diones are readily available com-
pounds. We obtained the substrates 3-methylcyclopen-
tane-1,2-dione 1a and 3-ethylcyclopentane-1,2-dione 1b
from Aldrich.
The synthesis of substrates 1c–e is straightforward,
from 2-cyclopentene-1-acetic acid 2 by converting the
double bond into a 1,2-diol followed by mild oxidation
to give the dione functionality. The sequence of reac-
tions is presented in Scheme 1.
We have previously reported that the Sharpless catalyst
system (Ti(OiPr)4/diethyl tartrate (DET)/tert-BuOOH
(TBHP))23 oxidizes cyclobutanones to afford the corre-
The cyclohexane derivatives 1f29and 1g30 were synthe-
sized according to the known procedures. Compound
1h was purchased from Aldrich.
* Corresponding author. E-mail: lopp@chemnet.ee
† The ring-cleavage reaction will be discussed in a separate paper.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00589-X

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A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
Scheme 1. Synthesis of cyclopentanediones 1c–e. Reagents and conditions: (a) MeOH, HCl, 24 h, rt; (b) LiAlH4, 0°C, 1 h, 84%
from 2; (c) TBDMSCl, imidazole, DMF, 20 h, rt, 87%; (d) KMnO4, NaOH, tBuOH, 20 min, 0°C, 67%; (e) (ClCO)2, DMSO,
CH2Cl2, Et3N, −60°C, 1 h, 48%; (f) HCl/H2O, THF, 88%; (g) BnCl, NaH, DMF, overnight, rt, 86%.
Table 1. 3-Hydroxylation of 3-methyl-1,2-cyclopentane-
dione 1a at different Sharpless complex compositionsa
2.2. 3-Hydroxylation of 3-methyl-1,2-cyclopentanedione
The 3-hydroxylation reaction was investigated in detail,
using 3-methyl-1,2-cyclopentanedione 1a as a model
compound. The formation of two major types of oxida-
tion product was observed: The 3-hydroxylation prod-
ucts 6 and 7 and ring cleaved 3-hydroxylated products,
derivatives of the diacid 828 (Scheme 2).
No. Molar ratio
Ti(OiPr)4/(+)-DET/TBHP
Yield 6a (%)b
Ee (%)c
1
2
3
4
5
6
7
8
0.5/1.0/1.5
0.8/1.6/1.5
1.0/1.5/1.2
1.0/1.6/1.5
1.5/1.8/1.5
2/2.4/1.5
2/2.4/2
28
37
37
40
37
32
30
25
94.7
95.5
94.8
94.3
92.4
89.6
88.8
87.7
The 3-hydroxylation products exist in the reaction mix-
ture in different forms (as free hydroxy diones 6 and/or
as acetals 7), depending on the conditions used for the
reaction quench and the work-up procedure. When, in
the case of 1a, the reaction was completed by quench-
ing with methanol, the 3-hydroxylated product
appeared in the form of acetal 7a (a single
diastereomer). After purification on silica gel a certain
amount of the enol 6a was always formed. We found
that methyl acetal 7a undergoes reacetalization in iso-
propanol, resulting in the crystalline isopropyl acetal
9a. Acetal 9a hydrolyses in water to the relatively stable
hydrate 10a. Under anhydrous conditions (e.g. chro-
matography on silica gel), acetals 7a and 9a form
3-hydroxy-1,2-diketone 6a (enol form) (Scheme 3).
3/3.6/2
a Temp.: −20°C, reaction time: 42 h.
b Isolated yields after column chromatography.
c Determined by HPLC on chiral column (Daicel Chiralcel ODH)
from the corresponding isopropyl acetals 9a (a single diastereomer,
de 100%; the relative configuration established by NMR).
As can be seen from Table 1, the 3-hydroxylation
reaction does not require an excess of the catalyst. The
best enantioselectivity was observed when 0.8–1.5
equiv. of Ti (based on the substrate) were used at the
Ti/DET ratio from 1:1.2 to 1:2.0 (entries 2–5). The
optimal ratio is similar to that used in the Sharpless
oxidation of allylic alcohols31 and lower than that used
in a-hydroxylation of 2-hydroxymethyl ketones.26,27
The highest isolated yield (40%) of 3-hydroxylation
product was obtained at the ratio of Ti(OiPr)4/(+)-
DET/TBHP 1/1.6/1.5. The oxidation of other sub-
strates was performed at this reagent composition.
Higher Ti/substrate ratios lead to a reduction in both
It is well known that asymmetric oxidation by the
Sharpless complex is sensitive to the reagent/substrate
ratio.31 In order to find the optimal conditions for
predominant formation of the 3-hydroxylation prod-
ucts we investigated the oxidation of the model com-
pound at different reagent compositions. The results
are presented in Table 1.
Scheme 2. Asymmetric 3-hydroxylation of 3-alkyl-1,2-cyclopentanediones 1a–e.

A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
2441
Scheme 3. Reacetalization, hydration and enolization of hydroxylated diketone.
the selectivity and yield of the hydroxylation reaction
(entries 6–8).
methanol) a crystalline isopropyl acetal 9c as the primary
hydroxylation product. It means that acetalization with
the participation of isopropyl alcohol (released in the
course of formation of the Sharpless complex DET+
Ti(OiPr)4) occurs. However, during purification of 9c on
silica gel, partial deacetalization occurs, affording a
mixture of hydrate 10c, and enol/diketone 6c (as one
fraction; the equilibrium of enol/diketone was well
observed in NMR). The primary 3-oxidation product in
the case of substrate 1e was isolated as the stable
intramolecular acetal 7e (the same product was also
obtained when deprotecting the benzyl derivative 9c; see
Scheme 4).
2.3. 3-Hydroxylation of 3-ethyl-, 3-hydroxyethyl-, and
3-benzyloxyethyl-1,2-cyclopentanediones
The substrates 1b–e were also subjected to oxidation using
the optimal conditions found for the model compound
1a. The results from the 3-hydroxylation reactions of
substrates 1b–e are presented in Table 2.
In the case of 1b, in the course of quenching the reaction
with methanol, the initially formed methyl acetal 7b
undergoes deacetalization affording the mixture of enol
6b and hydrate 10b. The acetals and hydroxydiones are
easily separable by chromatography over silica gel.
However, hydrate 10b usually elutes on silica gel together
with deacetalized compounds. The acetals are relatively
unstable and transform on standing into the deacetalized
products. Thus, 3-hydroxydiketone 6b was separated in
its enol form as a stable crystalline solid. The oxidation
of 1c gave (after quenching the reaction and adding citric
acid in the ether–acetone mixture without using
Scheme 4. Palladium-catalyzed hydrogenolysis of the benzyl
group in acetal 9c; formation of 7e.
Table 2. Asymmetric 3-hydroxylation of 3-substituted-cyclopentane-1,2-dionesa
No.
Cyclic dione 1
a-Hydroxylated product (sum of products, %)
Ee (%)b
Sum of ring cleavage products 8e (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1ef
6a, 7a (40)
6b, 7b, 10b (22)
6c, 9c, 10c (31)
7e (3)
7e (25)
7e (25)
94.3
\95c
\98d
62
\95
30
31
44
34
41
58
48
a Reagents and conditions: Ti(OiPr)4/(+)-DET/TBHP ratio 1:1.6:1.5; −20°C, 42 h; the reaction was quenched by adding citric acid in
CH2Cl2–MeOH (9:1) in the case of 1b and 1d, or by adding acetone–ether (9:1) in the case of 1c and 1e.
b Determined by HPLC using a chiral column (Daicel Chiralcel ODH).
c Methyl acetal 7b was converted to the corresponding isopropyl acetal 9b prior to chiral chromatography.
d Isopropyl acetal 9c was converted into an intramolecular acetal 7e (Scheme 4) prior chiral chromatography.
e The oxidative cleavage products are presented in Ref. 28.
f 2 equiv. of the complex in respect of the substrate were used.

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A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
2.5. A model of the 3-hydroxylation reaction
In the case of the silyl protected substrate 1d, only 3%
of the intramolecular acetal 7e with moderate ee was
isolated after chromatographic separation on silica gel.
It is possible that the protecting group is cleaved during
the oxidation process, resulting in a complex mixture
that does not give a predominant product on oxidation.
The high enantioselectivity of the process may be ratio-
nalized by using a simplified model of the Sharpless
intermediate complex.35 It can be assumed that in the
course of the oxidation, the Ti-catalyst forms first an
enolate-type complex with the substrate in planar con-
formation (alternatively, the complexation of Ti to
ketone group may be considered). The face of the
oxidation is directed by the structure of the complex.
According to the Ti-enolate model (Scheme 7) we can
distinguish ‘favoured’ and ‘unfavoured’ conformations
of the substrate–catalyst complex. The formation of a
planar conformation of the enolized substrate in the
complex supports the high enantioselectivity of the
oxidation.
2.4. Oxidation of 3-methyl-1,2-cyclohexanediones and
2-methylcyclopentane-1,3-dione
In order to establish the scope of the reaction, 3-
methyl-1,2-cyclohexanediones 1f and 1g were oxidized
using the optimal conditions found for the cyclopen-
tane derivative 1a. Surprisingly enough, the oxidation
reaction proceeded very slowly and did not lead to the
formation of any expected a-hydroxy compounds 6f
and 6g. Instead, only the ring contraction products 12f
and 12g, respectively, were detected in small amounts
(5–9%, 140 h, −20°C) (Scheme 5).
This result implies the existence of the intermediate 11
that undergoes ring contraction (observed in the case of
a-hydroxy ketones32 and a,b-epoxy ketones,33,34 in our
case, the rearrangement of the a-hydroxy-a,b-epoxy
ketone occurs).
It is noteworthy that the enantioselectivity of the oxida-
tion is significantly dependant on the substrate/complex
ratio in the case of the free-OH substrate 1e. The ee of
product 7e is high when the ratio is 1/1 (Table 2, entry
5; the same enantioselectivity as observed in the oxida-
tion of other cyclopentanediones 1a–c) and relatively
low when 2 equiv. of the complex were used in the
oxidation (Table 2, entry 6). This result indicates that in
the latter case a complex with two chiral catalyst
molecules attached to the substrate is formed (one
attached to the enol moiety and the other to the
primary alcohol moiety). Indeed, as the substrate 1e
exists predominantly in the enol form, the hydroxyethyl
substituent may be regarded as a homoallylic alcohol.
It is possible that the Ti-complex is formed preferen-
tially (first) with the enol function when 1 equiv. of the
We also made attempts to oxidize a cyclic 1,3-dione
(2-methyl-1,3-cyclopentanedione, 1h) under the usual
reaction conditions. However, after a long incubation
time (186 h), we were able to isolate 8% of 4,5-dioxo-
hexanoic acid 13 as the only reaction product together
with 82% of the unreacted starting diketone 1h (Scheme
6).
Scheme 5. Oxidation of 3-methyl-1,2-cyclohexanediones.
Scheme 6. Titanium tartrate-catalyzed oxidation of 1,3-cyclopentanedione.

A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
2443
Scheme 7. Enantioface selection. Formation of favoured and unfavoured intermediate complexes of the opposite face selection.
catalyst is used, affording a complex in planar ‘favoured’
conformation (which supports the high enantioselectivity
of the oxidation). When the second molecule of catalyst
is added, a homoallylic Ti-complex is also formed. It is
known from the Sharpless asymmetric epoxidation of
homoallylic alcohols that the oxidation of homoallylic
structures proceeds with moderate selectivity and with
the opposite facial selectivity as compared to that of
allylic alcohols.36 This means that in our case each of the
complexes may have an opposite facial preference and as
a result, lower enantioselectivity is obtained.
all atoms, and in the analyzed sample of 6a esters, only
the single diastereoisomeric monoester 14a and diester
15a were observed.
The NMR spectra from MPA esters of secondary alco-
hols can be used for the determination of their absolute
configurations.37,38 Compound 14a is a vinyl as well as
a tertiary alcohol. Comparison of differential effects in
1H and 13C chemical shifts of diastereoisomeric vinyl
esters 14a separated by 2 bonds from the stereogenic
centre did not reveal any regularities, which can be
interpreted as phenyl ring anisotropy effects. Formation
of the second MPA ester 15a at the stereogenic carbon
atom gives a more defined picture: Both H-4 protons as
well as C-4 of the (R)-MPA ester 15a are shifted to a low
field (1H by 0.11 and 0.18 ppm, 13C by 0.32 ppm). At the
same time, C-1 is shifted to a high field by 0.29 ppm.
However, there are no known NMR rules for the
assignment of absolute configurations from the differen-
tial shieldings of MPA esters of chiral tertiary alcohols.
The use of a conformational model for secondary alco-
hols by replacing the carbinol proton with a methyl
group28 is not sufficiently justified. The only report
known to us is connected with the use of Mosher esters
2.6. Determination of the ee and the absolute configuration
of the products
In addition to the chiral HPLC analysis for determina-
tion of the enantiomeric purity of 6a, the 2-mono- and
2,5-di-(R)-MPA ester derivatives were prepared, and
1
their H and 13C NMR spectra were compared to those
from the corresponding diastereomeric ester mixtures
formed from ( )-7a (Scheme 8).
Both pairs of diastereoisomeric esters from the racemic
diol gave different 1H and 13C chemical shifts for nearly
Scheme 8. (R)-Methoxyphenylacetic acid diesters from rac-7a.

2444
A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
for the configurational assignment of enantiomeric ter-
tiary pinanols by the use of MM2 calculations.39 Our
conformational calculations using MM (Merck and
Sybyl force fields) and semi-empirical (AM1 and PM3
models) on the (R)-MPA esters of (R)-15a and (S)-15a
with the Spartan 5.0 program40 indicate that the con-
former with trans-orientation of carbonyl and methyl
carbons is the most stable (Scheme 9).
M80B spectrometer using the EI (70 eV) mode and
HRMS mode. Optical rotations were obtained using a
Polamat A polarimeter or A. Kru¨ss Optronic GmbH
polarimeter P 3002. TLC was performed using DC-Alu-
folien Kieselgel 60 F254 (Merck) or Silufol® UV 254
silica gel plates. Merck Silica gel 60 (0.063–0.200 mm)
or Chemapol silica gel L 40/100 was used for column
chromatography. All reactions sensitive to oxygen or
moisture were conducted under argon atmosphere in
oven-dried glassware. Commercial reagents were gener-
ally used as received. CH2Cl2 was distilled from CaH2
,
and stored over 3 A molecular sieve pellets. THF and
ether were distilled from LiAlH4 before use, DMF and
Et3N from CaH2.
3.2. Substrates
3.2.1. 2-Hydroxy-3-(2-tert-butyldimethylsilyloxyethyl)-
cyclopent-2-en-1-one, 1d and 2-hydroxy-3-(2-hydroxy-
ethyl)cyclopent-2-en-1-one, 1e. 2-Cyclopentene-1-acetic
acid 2 (1.26 g, 10 mmol) was dissolved in MeOH (10
mL), followed by conc. HCl (0.1 mL). After stirring at
rt for 24 h the mixture was diluted with ether (150 mL),
washed with satd NaHCO3 solution, brine and dried
(MgSO4). The extract was then concentrated to ꢀ5 mL
and added at 0°C to a suspension of LiAlH4 (380 mg,
10 mmol) in dry ether (10 mL). The mixture was stirred
at 0°C for 1 h and water (1.9 mL) was added dropwise.
After stirring at rt for 0.5 h and filtration with ether,
the filtrate was dried (MgSO4) and ether evaporated.
The residue was purified by flash chromatography (sil-
ica gel, petroleum ether/acetone 10:1) giving 0.94 g
(84%) of 2-cyclopentene-1-ethanol 3.
Scheme 9. The most stable conformations of (R)-MPA esters
of the R and S enantiomers of 6a ((R)-15a and (S)-15a)
calculated by Merck FF.
The conformations obtained were used to calculate z
and z parameters of the Johnson–Bovey model for the
estimation of phenyl ring anisotropy effects.41 These
calculations result in S configuration for 15a (com-
pound (S)-15a) and consequently for 6a also. Taking
into account the fact that the oxidative ring cleavage
should not affect the stereochemistry at the tertiary
carbon formed by hydroxylation, the absolute configu-
ration of the compound 6a was also determined by
converting 7a to the known lactone 8a (Scheme 10).
The ring cleavage was accomplished by using peracetic
acid. The sign of the specific rotation of the obtained 8a
was found to be (−) ([h]2D2=−15.2; c 1.78, water), which
corresponds to (S)-(−)-2-hydroxypentane-1,5-dienoic
acid 2,5-lactone ([h]2D3=−16.2; c 1.86, water).42 This
means that the absolute configuration of 6a is S, and
according to the specific rotation value its ee is at least
93%.
The solution of 3 (0.94 g, 8.39 mmol), TBDMSCl (1.9
g, 12.58 mmol) and imidazole (1.14 g, 16.78 mmol) in
dry DMF (37 mL) was stirred at rt for 20 h. Ether (200
mL) was then added, the mixture was washed with
water, with 5% NaHCO3 solution, water, brine, dried
(Na2SO4) and ether evaporated. The residue was
purified by flash chromatography (silica gel, petroleum
ether/acetone 100:1) to give silyl-protected 2-cyclopen-
tene-1-ethanol (1.642 g, 87%).
3. Experimental
3.1. Materials and methods
To a stirred solution of cyclopentene–1-ethanol (1.642
g, 7.26 mmol) in tert-BuOH (44 mL) and water (30
mL), cooled in an ice bath, was added over a 20-min
period a cooled solution of KMnO4 (1.264 g, 8 mmol)
and NaOH (0.436 g, 10.9 mmol) in water (50 mL).
After completion of the addition, the solution was
stirred at 0°C for 20 min, and then Na2SO3 (0.365 g, 2.9
mmol) in water (8 mL) was added. The reaction mix-
ture was filtered and the filtrate was extracted three
1H and 13C NMR spectra were determined in deuter-
ated solvents on a Bruker AMX-500 spectrometer. The
solvent peaks CHCl3 (l 7.26 ppm), CH3OH (l 3.30
1
ppm), (CH3)2SO (l 2.50 ppm) for H and CDCl3 (l
77.0 ppm), CD3OD (l 49.0 ppm) (CD3)2SO (l 39.50
ppm) for 13C were used as internal references. IR
spectra were recorded on a Hitachi 270-30 spectropho-
tometer. Mass spectra were measured on a Hitachi
Scheme 10. Determination of the absolute configuration of 6a.

A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
2445
times with EtOAc. The combined extracts were washed
3.3. Oxidation of 3-alkyl-1.2-cyclopentanediones
with water, brine, dried (Na2SO4) and the solvents
evaporated. Flash chromatography (silica gel,
petroleum ether/acetone 10:1) yielded the diol 4 (1.262
g, 67%).
3.3.1. Typical procedure for asymmetric 3-hydroxylation
of 3-alkyl-1.2-cyclopentanediones. To a solution of
,
Ti(OiPr)4 (0.3 mL, 1 mmol) and 4 A powdered molecu-
lar sieves (100 mg) in CH2Cl2 (6 mL) (+)-DET (0.27
mL, 1.6 mmol) were added and the mixture was stirred
for 15 min at −20°C. After addition of cyclopentane-
dione (1 mmol) in CH2Cl2 (2 mL) the mixture was
stirred for 30 min. Then TBHP (0.44 mL, 1.5 mmol, 3.4
M solution in toluene) was added and the mixture was
kept at −20°C for 42 h. The reaction was quenched by
stirring with a solution of citric acid monohydrate (210
mg, 1 mmol in a mixture of 10% MeOH in CH2Cl2) at
rt for 1 h. The reaction mixture was filtered through a
path of Celite and purified by column chromatography
on silica gel.
To a solution of oxalyl chloride (1.27 mL, 14.55 mmol)
in CH2Cl2 (33 mL) DMSO (2.25 mL, 31.8 mmol) in
CH2Cl2 (7 mL) was dropwise added at −60°C. The
mixture was stirred for 10 min, followed by addition of
diol 4 (1.262 g, 4.85 mmol) in CH2Cl2 (10 mL). After
stirring at −60°C for 1 h, Et3N (6.75 mL, 48.5 mmol)
was added at −60°C. The reaction mixture was then
allowed to warm to rt, poured into a cold 1N HCl
solution (100 mL) and extracted twice with CH2Cl2.
The extract was washed with brine, dried (Na2SO4) and
concentrated. The residue was chromatographed (silica
gel, petroleum ether/EtOAc 10:1 to 10:1.5) to give 594
mg (48%) of 1d as a white solid.
3.3.2. 2,5-Dihydroxy-5-methylcyclopent-2-en-1-one, 6a,
and 2,3-dihydroxy-2-methoxy-3-methylcyclopentanone,
7a. Diketone 1a was oxidized according to the typical
procedure and purified by column chromatography
(CH2Cl2/MeOH 60:1 to 20:1) to afford 6a as a colour-
less oil (19 mg, 15%); ee 94%; [h]1D8=−49 (c 0.71,
CH2Cl2). Unlike the starting 1a, which exists predomi-
nantly (>97%) in enol form in chloroform or in DMSO
solution, both forms of 6a can be distinguished in
NMR spectra without any indication of exchange at rt;
1H NMR (500 MHz, DMSO-d6) from the ꢀ2:1 mix-
ture of enol and keto forms: enol l, ppm: 1.16 (s, 3H,
5-Me), 2.37 and 2.42 (dd, J=3.2, Jgem=17.3 Hz, 2H,
H-4), 6.32 (t, J=3.2 Hz, 1H, H-3), ketone l 1.27 (s, 3H,
3-Me); 2.10 (m, 2H, H-4), 2.41 and 2.45 (m, 2H, H-5);
13C NMR (125 MHz, CDCl3) enol l 204.69 (C-1),
150.89 (C-2), 127.08 (C-3), 39.43 (C-4), 71.90 (C-5),
25.06 (5-Me), ketone l 200.84 (C-1), 204.41 (C-2), 71.73
(C-3), 30.75 (C-4), 32.73 (C-5), 21.37 (3-Me); IR (film,
cm−1): 3332, 2980, 2932, 1714, 1648, 1628, 1394, 1280,
1210, 1078, 1024; EIMS (m/z, %): 128 (M+, 11.8), 100
(4.1), 86 (4.9), 72 (12.4), 58 (26.6), 57 (28.3), 55 (21.6),
43 (100); HRMS calcd for C6H8O3: 128.0473; found:
128.0482. Compound 7a: Separated as a reddish oil (40
mg, 25%); ee 94%; [h]1D8=+35 (c 1.12, CH2Cl2); 1H
NMR (500 MHz, CDCl3): l 1.32 (s, 3H, 3-Me), 1.95
and 2.02 (m, 2H, H-4), 2.38 (m, 2H, H-5), 2.43 (bs, 1H,
OH), 3.19 (s, 3H, 2-OMe), 4.31 (bs, 1H, OH); 13C
NMR (125 MHz, CDCl3): l 213.12 (C-1), 98.37 (C-2),
76.67 (C-3), 30.30 (C-4), 31.20 (C-5), 19.73 (3-Me),
50.36 (2-OMe); IR (film, cm−1): 3464, 2972, 2946, 2840,
1756, 1454, 1378, 1264 1196, 1100, 1072; EIMS (m/z,
%): 160 (M+, 0.8), 128 (14.1), 104 (78.5), 100 (11), 89
(9.4), 87 (9.4), 72 (28.4), 71 (11.1), 58 (57.7), 55 (44.1),
43 (100).
To a solution of 1d (272 mg, 1.06 mmol) in THF (6
mL) 1.5N HCl solution (2.4 mL) was added. After
stirring at rt for 2 h the mixture was diluted with water
(20 mL) and extracted 12 times with dry EtOAc. The
combined extracts were dried (Na2SO4) and concen-
trated. The residue was purified by flash chromatogra-
phy (silica gel, petroleum ether/acetone 10:5) yielding
1
132 mg (88%) of 1e as a white solid; H NMR (500
MHz, CDCl3+DCD3OD): l 2.24 (m, 2H, H-5), 2.33 (m,
2H, H-4), 2.46 (t, J=6.0 Hz, 2H, H-1%), 3.69 (t, J=6.0
Hz, 2H, H-2%); 13C NMR (125 MHz, CDCl3+
DCD3OD): l 204.01 (C-1), 149.69 (C-2), 145.73 (C-3),
25.71 (C-4), 31.96 (C-5), 32.26 (C-1%), 59.13 (C-2%).
3.2.2. 2-Hydroxy-3-(2-benzyloxyethyl)-2-cyclopenten-1-
one, 1c. To a solution of 2-cyclopentene-1-ethanol 3
(0.906 g, 8.1 mmol) in DMF (12 mL) NaH (467 mg,
12.2 mmol, 60–65% in mineral oil) was added at 0°C.
After the reaction subsided, benzyl chloride (1.7 mL,
14.6 mmol) was added. The reaction was stirred
overnight, then quenched with water (5 mL) and
extracted three times with CH2Cl2. The combined
extracts were washed with water, brine, dried (Na2SO4)
and the solvents evaporated. The residue was purified
by flash chromatography (silica gel, petroleum ether/
acetone 100:1) affording benzyl ether 5 (1.38 g, 86%).
This compound was dihydroxylated with KMnO4, fol-
lowed by Swern oxidation according to the procedures
for synthesis of 1c. Chromatography (silica gel,
petroleum ether/EtOAc 10:2 to 10:2.5) gave diketone 1c
as a white solid (708 mg, 31% from 2-(2-benzy-
loxyethyl)-1-cyclopentene); 1H NMR (500 MHz,
CDCl3): l 2.40 (m, 2H, H-5), 2.47 (m, 2H, H-4), 2.71 (t,
J=6.2 Hz, 2H, H-1%), 3.74 (t, J=6.2 Hz, 2H, H-2%),
4.52 (s, 2H, Bn-CH2), 6.80 (s, 1H, OH), 7.30–7.35 (m,
5H, Bn-Ph); 13C NMR (125 MHz, CDCl3): l 203.06
(C-1), 149.67 (C-2), 144.18 (C-3), 25.89 (C-4), 32.01
(C-5), 29.47 (C-1%), 67.44 (C-2%), 73.02 (Bn-CH2), 137.50
(Bn-Ph s), 127.75 (Bn-Ph o), 128.40 (Bn-Ph m), 127.78
(Bn-Ph p); EIMS (m/z, %): 232 (M+, 4.4), 201 (4.3), 141
(10.6), 126 (41.6), 91 (100).
3.3.3.
2,3-Dihydroxy-2-isopropoxy-3-methylcyclopen-
tanone, 9a. Methyl acetal 7a (38 mg, 0.24 mmol) was
dissolved in iPrOH (1.5 mL) and allowed to stand at rt
for 5 days. The mixture was concentrated and purified
by flash chromatography (silica gel, petroleum ether/
iPrOH 10:1) to afford 9a as white crystals (22 mg,
49%); mp 58–61°C; ee 95%; [h]2D1=+75 (c 1.22, iPrOH);
1H NMR (500 MHz, CDCl3): l 0.98 and 1.15 (2d,
J=6.2Hz, 6H, 2-iPr Me), 1.31 (s, 3H, 3-Me), 1.92 and

2446
A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
2.04 (m, 2H, H-4), 2.39 (m, 2H, H-5), 3.91 (sept.,
J=6.2 Hz, 1H, 2-iPr CHO), 4.10 (bs, OH); 13C NMR
(125 MHz, CDCl3): l 214.58 (C-1), 98.08 (C-2), 76.80
(C-3), 30.02 (C-4), 31.27 (C-5), 65.96, 23.14 and 24.56
(2-iPrO), 19.69 (3-Me); EIMS (m/z, %): 160 (0.9), 146
(1.2), 132 (11.2), 128 (3.8), 100 (6.1), 99 (7.0), 90 (62.7),
72 (10.7), 58 (19.6), 43 (100); HRMS calcd for
C9H16O4:188.1047; found: 188.1087.
mg, 17%); ee >98%; [h]2D0=+38 (c 1.05, CHCl3); 1H
NMR (500 MHz, CDCl3): l 1.88 (ddd, J=3.8, 7.6, 13.2
Hz, 1H, H-4), 2.03 (dt, J=13.2, 9.7 Hz, 1H, H-4),
2.37–2.39 (m, 2H, H-5), 1.78 (ddd, J=3.5, 5.6, 14.9 Hz,
1H, H-3%), 2.27 (ddd, J=4.4, 9.1, 14.9 Hz, 1H, H-3%),
3.74 (ddd, J=4.4, 5.6, 9.8 Hz, 1H, H-3¦), 3.80 (ddd,
J=3.5, 9.1, 9.8 Hz, 1H, H-3¦), 0.96 and 1.04 (both d,
J=6.2 Hz, i-Pr CH3), 4.06 (sept., J=6.2 Hz, i-Pr CH),
4.51 and 4.57 (d, J=11.5 Hz, 2H, Bn CH2), 7.30–7.35
(m, 5H, Bn-Ph), 3.92 and 4.93 (bs, OH); 13C NMR (125
MHz, CDCl3): l 212.37 (C-1), 97.94 (C-2), 78.25 (C-3),
30.30 (C-4), 31.47 (C-5), 32.50 (C-3%), 66.31 (C-3¦),
23.10, 24.54, 65.84 (i-PrO), 73.40 (Bn CH2), 137.02
(Bn-Ph s), 127.95 (Bn-Ph o), 128.51 (Bn-Ph m), 128.00
(Bn-Ph p); EIMS (m/z, %): 308 (M+, 1.0), 291 (14.8),
252 (9.71), 249 (33.9), 231 (9.0), 181 (11.9), 142 (14.5),
141 (23.0), 91 (100); HRMS calcd for C7H10O3 (M−
OBn−OiPr)+: 142.0629; found: 142.0647.
3.3.4. 3-Methyl-2,2,3-trihydroxycyclopentanone, 10a.
Isopropyl acetal 9a (22 mg, 0.117 mmol) was dissolved
in water (1 mL) and iPrOH was removed under
reduced pressure to afford 17 mg of hydrate 10a (100%
yield), which crystallized on standing. ee 95%; [h]2D2=+
1
40 (c 0.92, acetone); H NMR (500 MHz, DMSO-d6): l
1.14 (s, 3H, 3-Me); 1.71 (ddd, J=3.9, 8.7, 12.6 Hz, 1H,
H-4), 1.81 (ddd, J=8.7, 9.6, 12.6 Hz, 1H, H-4), 2.13
(dt, J=19.0, 8.7 Hz, 1H, H-5), 2.18 (ddd, J=3.9, 9.6,
19.0 Hz, 1H, H-5), 13C NMR (125 MHz, DMSO-d6): l
213.75 (C-1), 95.80 (C-2), 75.64 (C-3), 31.24 (C-4),
31.08 (C-5), 20.05 (3-Me); EIMS (m/z, %): 146 (M+,
0.3), 128 (17.5), 112 (7.0), 100 (29.7), 90 (48.1), 72
(51.2), 58 (100), 43 (79.4).
Compounds 6c (enol form), 6c (dione form) and 10c
were isolated as a mixture: Compound 6c (enol form):
1H NMR (500 MHz, CDCl3): l 6.45 (t, J=3.2 Hz, 1H,
H-3), 2.59 (dd, J=3.1, 17.6 Hz, 1H, H-4), 2.69 (dd,
J=3.4, 17.6 Hz, 1H, H-4), 1.92 (m, 1H, H-5%), 2.06 (m,
1H, H-5%), 3.65 (m, 1H, H-5¦), 3.80 (m, 1H, H-5¦); 13C
NMR (125 MHz, CDCl3): l 204.08 (C-1), 149.89 (C-2),
127.79 (C-3), 38.05 (C-4), 75.45 (C-5), 37.18 (C-5%),
66.38 (C-5¦), 73.47 (Bn CH2), 137.47 (Bn-Ph s), 127.74
(Bn-Ph o), 128.44 (Bn-Ph m), 127.77 (Bn-Ph p); Com-
3.3.5. 5-Ethyl-2,5-dihydroxycyclopent-2-en-1-one, 6b, 3-
ethyl-2,3-dihydroxy-2-methoxycyclopentanone, 7b, and
3-ethyl-2,2,3-trihydroxycyclopentanone, 10b. Diketone
1b was oxidized according to the typical procedure and
purified by column chromatography (CH2Cl2/MeOH
80:1 to 30:1) to afford 6b as a colourless oil which
crystallized on standing (11 mg, 8%); ee >95%; [h]2D1=−
1
pound 6c (dione form): H NMR (500 MHz, CDCl3): l
2.03 (m, 1H, H-3%), 2.18 (m, 1H, H-3%), 2.29 (m, 2H,
H-4), 2.50 (m, 1H, H-5), 2.70 (m, 1H, H-5), 3.63 (m,
1H, H-3¦), 3.78 (m, 1H, H-3¦); 13C NMR (125 MHz,
CDCl3): l 202.42 (C-1), 202.49 (C-2), 76.04 (C-3), 30.00
(C-4), 33.19 (C-5), 36.43 (C-3%), 65.72 (C-3¦), 73.24 (Bn
CH2), 136.82 (Bn-Ph s), 127.87 (Bn-Ph o), 128.49 (Bn-
1
146 (c 0.73, CH2Cl2); H NMR (500 MHz, CDCl3): l
0.91 (t, J=7.5 Hz, 3H, H-5¦), 1.65 and 1.70 (qd, J=7.5,
13.7 Hz, 2H, H-5%), 2.53 (dd, J=3.1, 17.7 Hz, 1H, H-4),
2.63 (dd, J=3.3, 17.7 Hz, 1H, H-4), 2.8 (bs, 1H, OH),
6.2 (bs, 1H, OH), 6.57 (t, J=3.2 Hz, 1H, H-3); 13C
NMR (125 MHz, CDCl3): l 205.27 (C-1), 150.42 (C-2),
129.63 (C-3), 36.29 (C-4), 75.95 (C-5), 31.15 (C-5%), 7.66
(C-5¦); IR (film, cm−1): 3356, 2976, 2932, 1712, 1650,
1628, 1396, 1268, 1204, 1056, 1030; EIMS (m/z, %): 142
(M+, 18.5), 113 (10.3), 86 (12.0), 72 (10.9), 57 (100);
HRMS calcd for C7H10O3: 142.0629; found: 142.0622.
Compound 7b: Separated as a reddish oil (25 mg, 14%
yield, in NMR spectra also 6b and 10b are observed);
1H NMR (500 MHz, CDCl3): l 0.98 (t, J=7.5 Hz, 3H,
H-3¦), 1.67–1.69 (m, 2H, H-3%), 1.95 (m, 2H, H-4), 2.41
(m, 2H, H-5), 3.18 (s, 3H, 2-OMe); 13C NMR (125
MHz, CDCl3): l 213.54 (C-1), 98.78 (C-2), 77.00 (C-3),
28.38 (C-4), 31.24 (C-5), 50.26 (2-OMe), 25.75 (C-3%),
6.73 (C-3¦). Compound 10b: 1H NMR (500 MHz,
CDCl3): l 1.00 (t, J=7.5 Hz, 3H, H-3¦), 1.67–1.69 (m,
2H, H-3%), 1.96 (m, 2H, H-4), 2.38 (m, 2H, H-5); 13C
NMR (125 MHz, CDCl3): l 215.07 (C-1), 96.05 (C-2),
78.84 (C-3), 28.29 (C-4), 31.04 (C-5), 25.54 (C-3%), 6.87
(C-3¦).
1
Ph m), 127.85 (Bn-Ph p); Compound 10c: H NMR
(500 MHz, CDCl3): l 1.98 (m, 1H, H-3%), 2.18 (m, 1H,
H-3%), 2.01 (m, 2H, H-4), 2.46 (m, 1H, H-5), 2.49 (m,
1H, H-5), 3.73 (m, 1H, H-3¦), 3.81 (m, 1H, H-3¦); 13C
NMR (125 MHz, CDCl3): l 213.19 (C-1), 95.49 (C-2),
78.23 (C-3), 30.24 (C-4), 31.28 (C-5), 33.98 (C-5%), 65.98
(C-5¦), 73.47 (Bn CH2), 136.76 (Bn-Ph s), 128.05 (Bn-
Ph o), 128.60 (Bn-Ph m), 127.74 (Bn-Ph p).
3.3.7. 1,5-Dihydroxy-2-oxabicyclo[3.3.0]octane-8-one, 7e.
Diketone 1e was oxidized according to the typical
procedure and purified by column chromatography
(petroleum ether/acetone 10:3) affording 7e as white
crystals (40 mg, 25%); mp 98–101°C; ee >95%; [h]2D0=−
26 (c 1.17, acetone); 1H NMR (500 MHz, CDCl3+
CD3OD): l 1.87 and 1.92 (m, 2H, H-6), 2.05 (m, 2H,
H-4), 2.34 and 2.36 (m, 2H, H-7), 3.80 and 4.05 (m, 2H,
H-3), 4.06 (bs, 2H, OH); 13C NMR (125 MHz, CDCl3+
CD3OD): l 101.06 (C-1), 67.03 (C-3), 36.40 (C-4), 82.88
(C-5), 29.49 (C-6), 33.43 (C-7), 210.83 (C-8); EIMS
(m/z, %): 158 (M+, 0.2), 130 (7.5), 102 (68.6), 86 (3.7),
71 (3.9), 57 (23.7), 56 (100); HRMS calcd for (M−CO)+
C6H10O3: 130.0629; found: 130.0621.
3.3.6. 5-[(2-Benzyloxy)ethyl]-2,5-dihydroxy-2-cyclopen-
ten-1-one, 6c, 3-[(2-benzyloxy)ethyl]-2,3-dihydroxy-2-iso-
propoxycyclopentanone, 9c, and 3-[2-(benzyloxy)ethyl]-
2,2,3-trihydroxycyclopentanone, 10c. Diketone 1c was
oxidized according to the typical procedure and
purified by column chromatography (petroleum ether/
acetone 10:1.5 to 10:4) to afford 9c as a white solid (52
3.3.8. Isopropyl 1,2-dihydroxy-2-methylcyclopentane-1-
carboxylate, 12f. Diketone 1f was oxidized according to
the typical procedure for 140 h and purified by column

A. Paju et al. / Tetrahedron: Asymmetry 13 (2002) 2439–2448
2447
chromatography (petroleum ether/ethyl acetate 10:2),
affording 12f as a yellow oil (10 mg, 5%); H NMR
82.12 and 82.27 (CHO), 57.54 and 57.70 (OMe), 135.19
1
and 135.54 (Ph s), 127.15 and 127.38 (Ph o), 128.65 and
1
(500 MHz, CDCl3): l 1.14 (s, 3H, 2-Me), 1.29 and 1.30
(2d, J=6.2 Hz, 6H, iPr Me), 1.70 and 1.92 (m, 2H,
H-4), 1.85 and 1.94 (m, 2H, H-5), 1.98 and 2.18 (m, 2H,
H-3), 2.84 and 3.72 (bs, OH), 5.11 (sept., J=6.2 Hz,
1H, iPr CH); 13C NMR (125 MHz, CDCl3): l 84.31
(C-1), 80.72 (C-2), 37.50 (C-3), 19.52 (C-4), 34.03 (C-5),
22.69 (2-Me), 174.82 (COO), 70.05 (iPr CH), 21.58 and
21.74 (iPr Me).
128.78 (Ph m), 128.83 and 129.06 (Ph p). (R)-15a: H
NMR (500 MHz, CDCl3): l 1.58 (s, 3H, 5-Me), 2.54
(dd, J=3.4, 18.2 Hz, 1H, H-4), 2.71 (dd, J=2.8, 18.2
Hz, 1H, H-4), 3.41 and 3.49 (s, 3H, OMe), 4.79 and
5.00 (s, 1H, CHO), 7.07 (t, J=3 Hz, 1H, H-3), 7.35–
7.50 (Ph o, m, p); 13C NMR (125 MHz, CDCl3): l
195.96 (C-1), 146.47 (C-2), 140.21 (C-3), 37.21 (C-4),
78.62 (C-5), 167.75 and 169.45 (COO), 81.82 and 81.98
(CHO), 57.50 and 57.67 (OMe), 135.21 and 135.70 (Ph
s), 127.22 and 127.40 (Ph o), 128.72 and 128.82 (Ph m),
128.90 and 129.11 (Ph p). The assignment of R and S
isomers reported in Ref. 28 should be reversed.
3.3.9. Isopropyl 1,2-dihydroxy-2,4,4-trimethylcyclopen-
tane-1-carboxylate, 12g. Diketone 1g was oxidized
according to the typical procedure for 140 h and
purified by column chromatography (petroleum ether/
ethyl acetate 10:1.5) affording 12g as a colourless oil (21
3.5. (S)-(−)-2-Hydroxypentane-1,5-dienoic acid 2,5-
lactone, (S)-8a
1
mg, 9%); H NMR (500 MHz, CDCl3): l 1.13 and 1.24
(s, 6H, 4-Me), 1.15 (s, 3H, 2-Me), 1.31 and 1.32 (2d,
J=6.1 Hz, 6H, iPr Me), 1.81 and 1.87 (both d, J=13.4
Hz, 2H, H-3), 1.86 and 2.31 (both d, J=14.3 Hz, 2H,
H-5), 2.81 and 3.76 (s, OH), 5.12 (sept., J=6.1 Hz, 1H,
iPr CH); 13C NMR (125 MHz, CDCl3): l 85.36 (C-1),
81.79 (C-2), 52.45 (C-3), 34.63 (C-4), 48.98 (C-5), 23.74
(2-Me), 31.50 and 32.97 (4-Me), 174.57 (COO), 70.19
(iPr CH), 21.66 and 21.79 (iPr Me).
A mixture of 7a (32 mg, 0.2 mmol) and hydrogen
peroxide (30% solution in water, 0.2 mL) in acetic acid
(3 mL) was stirred at rt for 2.5 h. Then Na2SO3 (200
mg) in water (2 mL) was added and the solvents were
removed at reduced pressure. The residue was dissolved
in water (10 mL), extracted with EtOAc (4×15 mL),
dried (MgSO4) and solvents evaporated. Flash chro-
matography (petroleum ether/acetone 10:3 to 10:4) gave
lactone-acid 8a as a white solid (18 mg, 63%); [h]2D3=
3.3.10. 4,5-Dioxohexanoic acid, 13. Diketone 1h was
oxidized according to the typical procedure for 186 h
and purified by column chromatography (petroleum
ether/iPrOH 20:1) affording 13 as a yellow solid (11
1
−15.2 (c 1.78, water); H NMR (500 MHz, CDCl3): l
1.69 (s, 3H, 2-Me), 2.20 (dt, J=13.3, 9.8 Hz, 1H, H-3),
2.60 (ddd, J=3.7, 9.8, 13.3 Hz, 1H, H-3), 2.63 (ddd,
J=3.7, 9.8, 18.0 Hz, 1H, H-4), 2.71 (dt, J=18.0, 9.8
Hz, 1H, H-4), 8.02 (bs, 1H, COOH); 13C NMR (125
MHz, CDCl3): l 83.55 (C-2), 32.90 (C-3), 28.32 (C-4),
176.27 (C-5), 23.44 (2-Me), 176.25 (2-COOH).
1
mg, 8%); H NMR (500 MHz, CDCl3): l 2.36 (s, 3H,
H-6), 2.71 (t, J=6.1 Hz, 2H, H-2), 3.04 (t, J=6.1 Hz,
2H, H-3); 13C NMR (125 MHz, CDCl3): l 177.83
(C-1), 27.45 (C-2), 30.56 (C-3), 196.80 (C-4 or C-5),
197.07 (C-5 or C-4), 23.55 (C-6); EIMS (m/z, %): 127
(M−OH)+, (0.9), 101 (23.2), 73 (8.8), 55 (17.7), 43 (100);
HRMS calcd for (M−OH)+ C6H7O3: 127.0394; found:
127.0378.
Acknowledgements
3.4. Preparation of (R)-(−)-a-methoxyphenylacetic acid
Support from Estonian Science Foundation (Grant
No.’s 5133, 3781 and 4976) and from Estonian Ministry
of Education (Grant 0350312) is acknowledged.
diesters, 15a
A mixture of 7a (12.4 mg, 0.078 mmol), (R)-(−)-MPA
(51.5 mg, 0.31 mmol), DCC (64 mg, 0.31 mmol) and
DMAP (13 mg) in THF (1.5 mL) was stirred at rt for
2 h. Then the mixture was diluted with ether (5 mL)
and water (1 mL) was added. An additional quantity of
ether (25 mL) was added, and the mixture was washed
sequentially with 1 M HCl solution, satd NaHCO3
solution, brine, dried (Na2SO4) and the solvents
removed. Flash chromatography (Chemapol silica gel L
40/100, benzene/acetone 30:1) afforded (S)-15a (32 mg,
97%).
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