Asymmetric synthesis of tertiary 2-substituted 5-oxotetrahyrofuran-2- carboxylic acids

Article abstract of DOI:10.3987/COM-13-S(S)28

3-Substituted 1,2-cyclopentanediones 1 were transformed to 2-substituted 5-oxotetrahydrofuran-2-carboxylic acids 2 using a catalytic process with 0.2-0.3 equivalent of Ti(OiPr)₄/tartaric ester/tBuOOH complex in up to 72% isolated yield and up to 94% ee. Different functional groups in the 3-alkyl substituent of 1 like, hydroxy, ether, Boc-amino and ester groups are tolerated.

Full text of DOI:10.3987/COM-13-S(S)28

HETEROCYCLES, Vol. 88, No. 2, 2014
981
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 981 - 995. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 7th June, 2013, Accepted, 19th September, 2013, Published online, 30th September, 2013
DOI: 10.3987/COM-13-S(S)28
ASYMMETRIC SYNTHESIS OF TERTIARY 2-SUBSTITUTED
5-OXOTETRAHYROFURAN-2-CARBOXYLIC ACIDS
a
a
a
a
a
Anne Paju, Karolin Oja, Katharina Matkevitš, Priit Lumi, Ivar Järving,
b
a
Tõnis Pehk, and Margus Lopp *
a
Department of Chemistry, Faculty of Science, Tallinn University of Technology,
Akadeemia tee 15, 12618, Tallinn, Estonia; *lopp@chemnet.ee
b
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618
Tallinn, Estonia
Abstract – 3-Substituted 1,2-cyclopentanediones 1 were transformed to
2
-substituted 5-oxotetrahydrofuran-2-carboxylic acids 2 using a catalytic process
with 0.2-0.3 equivalent of Ti(OiPr) /tartaric ester/tBuOOH complex in up to 72%
4
isolated yield and up to 94% ee. Different functional groups in the 3-alkyl
substituent of 1 like, hydroxy, ether, Boc-amino and ester groups are tolerated.
Boc-aminomethyl substituents lead to -amino acid analogues and
Boc-aminoethyl substituent to -amino acid analogues as well as spiro-lactone-
lactams. A direct, two-step procedure for homocitric acid synthesis is described.
INTRODUCTION
Chiral 2-substituted 5-oxotetrahydrofuran-2-carboxylic acids are common structural units in various
1
2
3
4
bioactive natural compounds like lycoperdic acid, aspernolides, monatins, methylisocitrate,
5
6
3
sartorymensins, and other compounds with potential pharmacological and other applications. The
5
,6f,14
particular biomedicinal interest may have spiro-lactone-lactam structures.
A very simple method for diastereoselective In catalyzed synthesis of tertiary lactone structures has been
7
described by Kumar. There are several methods describing the synthesis of chiral tertiary -lactone
8
structures, including enzymatic desymmetrization of parent esters for the synthesis of tertiary butenolides
9
and protein kinase C ligands. In many cases chemical synthesis from natural chiral compounds is used,
1
0
(
e.g for the synthesis of lycoperdic acid). There are a few examples of the asymmetric chemical
synthesis of related structures by using the chiral auxiliaries in the synthesis of crobarbatic acid and its
1
1
12
6c
6g,13
homologues, and other chiral -butyrolactones. Also, chiral reagents or catalysts
have been
used.

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HETEROCYCLES, Vol. 88, No. 2, 2014
We have previously developed a method for the synthesis of enantiomerically enriched
1
5
2
3
-alkyl-5-oxotetrahydrofuran-2-carboxylic acids 2
by using the asymmetric oxidation of
/tartaric ester/tBuOOH
-alkyl-1,2-cyclopentanediones 1 with a stoichiometric amount of Ti(OiPr)
4
1
6
complex (Scheme 1).
HO
O
O
[
O]
O
O
OH
R
R
+
H O, H
O
2
R
O
2
1
Scheme 1. General scheme for synthesis 2-alkyl-5-oxotetrahydrofuran-2-carboxylic acids 2
Herein we describe our attempts to develop a catalytic version of the asymmetric oxidation process and
broaden of the scope of the reaction by using functionalized substituents in substrate 1, in order to obtain
chiral synthons for natural compound synthesis. Using this strategy, homocitric acid lactone and
spiro-lactone-lactam were synthesized.
RESULTS AND DISCUSSION
The starting 3-substituted-1,2-cyclopentanediones 1 are easily accessible compounds: the preparation of
1
18
1
1
compound 1a (a R = Bn) has been described by us earlier; diketones 1b (b R = Me) and 1c (c R = Et)
are commercially available. Other compounds were prepared from 3-substituted cyclopentenes by
17
dihydroxylation, followed by Swern oxidation of the resulted diols by using our common protocols
2
(
Scheme 2). In many cases the most convenient starting compound for 3-substituted cyclopentenes 4 (R
1
1
=
H) was cyclopenten-3-acetic acid 5 (for compounds 1d-1h; d R = CH
2
CH
2
OH; e R = CH
2
CH
2
OBn; f
1
1
1
1
2
R = CH
2
NHBoc; g R = CH
2
CH
2
NHBoc; h R = CH
2
CO
2
tAm). Compound 1i (R = Bn, R =
OSiMe
2
tBu) was prepared from commercially available cis-4-cyclopentene-1,3-diol 6 by mono-acylation,
protection of the OH group and Grignard replacement of the acetate, followed again by a standard
reaction sequence cited above.
Scheme 2. Retrosynthetic sequence for 3-substituted 1,2-cyclopentanediones 1

HETEROCYCLES, Vol. 88, No. 2, 2014
983
We have previously shown that the oxidation of 1,2-cyclopentanediones 1 consists of three steps:
epoxidation (-hydroxylation), in situ Baeyer-Villiger reaction of the resulted intermediate and acylation
1
9
(
Scheme 3). The products that may be isolated are hydroxy diketones from intermediates 7,
dioxygenated products - diacids and diacid esters 9, and after hydrolysis and acylation lactone carboxylic
acids 2.
Scheme 3. The formal reaction cascade
Ti species participate in all steps of the cascade, catalyzing not only the oxidation but also the epoxide
re-arrangement and acylation reactions. It is obvious that titanium is complexed to both, the products and
the reagent. It is straightforward from Scheme 3 that a prerequisite for a catalytic reaction is the existence
of equilibrium between Ti that is complexed with reaction products 8 and the substrate 1, allowing the
Ti-catalyst to enter the next catalytic cycle.
We made mixtures of the substrate 1a (Figure 1, D) with Ti(OiPr)
ratios and recorded the NMR spectra of the resulted solutions. The experimental NMR data show that
Ti(OiPr) forms with substrate 1a with a ratio of 1:2 in single clearly distinguishable complex, the
4 2 2
in CH Cl at different substrate/Ti
4
spectrum of which is presented in Figure 1, A. Adding of the oxidation reagent, tBuOOH to the complex
not only initiates the oxidation reaction, but also changes the initial complex, releasing free substrate 1a
to the reaction medium (Figure 1, B and C). These results may indicate that the complexes of Ti with
tBuOOH and the reaction products are more stable than these with substrate 1a.
Having this discouraging information, we made an attempt to perform the oxidation of
3
-benzyl-1,2-cyclopentanedione 1a with tBuOOH in the presence of various amounts of Ti(OiPr)4,
keeping the ratio of Ti to (+)-diethyl tartrate constant in 1:1.6 . The reaction was quenched with basic

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HETEROCYCLES, Vol. 88, No. 2, 2014
water to hydrolyze the formed esters to diacids, and then subjected to acidic treatment to lactonize the
hydroxy diacids. The obtained results are presented in Table 1.
13
4
Figure 1. C NMR spectra of the substrate 1a, its complex with Ti(OiPr) and tBuOOH
Table 1. Catalytic conditions for the oxidation of 3-benzylcyclopentane-1,2-dione 1a
Entry
Ti(OiPr)
eq)
4
(+)-DET
(eq)
tBuOOH
Yield
(%)
ee
(%)
(
(eq)
a
1
2
3
4
5
1
1.6
2.5
83
78
42
71
72
96
93
25
91
93
a
0.5
0.5
0.3
0.3
0.8
2.5
b
0.1
2.5
a
0.48
0.48
2.5
b
2.5
b
6
7
0.2
0.1
0.32
0.16
2.5
69
26
91
68
a
2.5
a
tBuOOH contains ~4% of water
anhydrous tBuOOH was used
b

HETEROCYCLES, Vol. 88, No. 2, 2014
985
The data reveal that by reducing the amount of Ti (together with (+)-diethyl tartrate) to 0.5 equivalents
towards substrate 1a from the initial 1:1 amount, a slight reduction of the yield and stereoselectivity
occurs (Table 1, Entries 1 and 2). Further reduction of the Ti/substrate ratio to 0.3 caused some additional
reduction in the yield and stereoselectivity (Table 1, Entries 4, 5). Even at 0.2 ratio 69% yield and 91% ee
were obtained. Also, we observed that anhydrous reaction conditions are preferable for the
non-stoichiometric process, affording slightly better selectivity 91% vrs 93% (Table 1, Entries 4 and 5).
Reduction of the substrate Ti/1a ratio from 1 to 0.2 causes 5% reduction in the stereoselectivity and 14%
in the yield. Keeping in mind that reduction of the catalyst fivefold may considerably simplify separation
of the products, this result may be acceptable for some industrial purposes.
It is clearly seen that 0.1 eq of Ti is not sufficient for an efficient and selective process, causing already a
considerable loss in the yield and stereoselectivity. Also, it is not possible to change the ratio of Ti/tartaric
ester by reducing the amount of the chiral ligand because of drastic reduction in stereoselectivity and
yield (Table 1, Entry 3).
We applied the found conditions (0.3 equivalents of Ti(OiPr)
4
and 0.48 equivalents of chiral ligand
(
+)-DET towards substrate) for oxidation of differently substituted substrates 1. The formed lactone
carboxylic acids were isolated and their stereoisomeric purities were determined by means of chiral
HPLC. The obtained results are presented in Table 2, together with a reference of the corresponding
values for a stoichiometric process.
The asymmetric oxidation method of 3-substituted 1,2-diones with Ti/tartaric ester/tBuOOH complex is
quite universal: different functional groups like alkyl, benzyl, hydroxyl, ether, Boc-amino and ester
groups are tolerated. In most cases the stoichiometric process affords the isolated yield of lactone acid ~
70% or higher. The most remarkable feature of the process is its toleration of strong electron donating
groups like Boc-aminoalkyl and ester groups. In both cases high selectivity with satisfactory yield was
obtained (Table 2, Entries 8-10). The aminomethyl lactone acid 1f has once before been detected and
2
0
characterized by MS. According to the best of our knowledge, aminoethyl lactone acid as well as its
Boc-derivative have not been synthesized before.
The catalytic process with 0.3 Ti/substrate ratio affords slightly lower yields and selectivity than the
stoichiometric process. However, in all cases the yields and the enantiomeric purities of the products are
satisfactory also for the catalytic process (yield ~60% or higher and ee ~90%).
The racemic substrate 1i reveals very high stereoselectivity for the oxidation of the enol double bond for
both enantiomers: the resulted diastereomers had high enantiomeric purities. It means that the configuration
of the protected OH group did not influence the stereoselectivity of oxidation: both enantiomers reacted
with similar rate and the observed ratio of diastereomers was 1:1.

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HETEROCYCLES, Vol. 88, No. 2, 2014
Table 2. Synthesis of substituted lactone carboxylic acids 2 from 3-substituted cyclopentane-1,2-diones 1
No
Lactone acid 2
Stoichiometric
1
Yield %
Catalytic
ee %
Catalytic
a
b
a
b
Stoichiometric
6
c
1
2
3
4
5
6
7
8
9
a
a
a
83
62
72
63
68
69
nd
96
93
91
92
94
nd
c
6c
92
d
nd
nd
b
c
d
e
f
75
72
94
93
e
g
g
80
75
69
38
66
58
95
90
94
6
c
71
47
95
98
92
g
h
i
69
nd
98
92
1
1
0
1
nd
94
f
f
54
52
95/97
95/95
a
Ratio of substrate/ Ti(OiPr)
Ratio of substrate/ Ti(OiPr)
4
/(+) DET/ tBuOOH 1:1:1.6;2.5; reaction time 48 h
4
/(+) DET/ tBuOOH 1:0.3:0.5:2.5; reaction time 48 h
b
c
Reaction time 2 h
d
Reaction time 4 h
e
f
17b
Spirodilactone was obtained
2
diastereomers at 1:1 ratio
tBuOOH contained 4% of water
g
The direct cascade oxidation of 3-substituted 1,2-cyclopentanediones opens an attractive approach for the
short and direct synthesis of different chiral compounds of interest. Earlier we have used a stoichiometric
oxidation process for the synthesis of a natural compound homocitric acid by using
2
1
hydroxyethyl-substituted diketone 1d or acetic ester substituted diketone 1h. Now we have applied an
improved protocol that enables the obtaining of homocitric acid in a two-step process using catalytical
reaction conditions. Thus, diketone 1h was subjected to asymmetric oxidation by using a standard catalytic

HETEROCYCLES, Vol. 88, No. 2, 2014
987
4
procedure with 0.3 equivalents of Ti(OiPr) , to afford lactone acid 1h in 58% yield and 94% ee (Table 2,
Entry 10). After acidic hydrolysis of the t-amyl ester with conc. HCl, homocitric acid was obtained in 88%
yield.
Lactone acids 2f and 2g are prospective candidates for the synthesis of analogues of - and -amino acid
analogues, correspondingly. We transformed lactone acid 2g to spiro--lactone--lactam 10 by
lactamization of 2g, followed by removal of the Boc-group, in 59% overall yield (Scheme 4).
H
O
HO
O
N
O
NHBoc
HCl
toluene
CH Cl
o
1
00 C
2
2
O
O
O
NHBoc
1
0
O
O
O
2
g
Scheme 4. Spiro--lactone--lactam 10 from lactone acid 2g
The obtained structure may serve as a new chiral synthon for further transformations. This type of skeleton
is known in many bioactive compounds.
EXPERIMENTAL
General
1
13
H and C spectra were recorded in deuterated solvents on a Bruker AMX-500 or Avance II 400
spectrometer. Deuterated solvent peaks were used as references. 2D FT methods were used for the full
1
13
assignment of H and C chemical shifts. Mass spectra were measured on a Shimadzu GCMS – QP 2010
spectrometer using EI (70 eV). IR spectra were recorded on a Perkin-Elmer Spectrum BX FTIR
spectrometer. Elemental analyses were performed on a Perkin-Elmer 2400 Analyzer. Optical rotations were
measured using a Krüss Optronic GmbH polarimeter P 3002 or Anton Paar GWB polarimeter MCP 500.
High resolution mass spectra were obtained on an Accurate-Mass Q-TOF LC/MS instrument Agilent
Technologies 6450 UHD by using AJ-ESI ionization. TLC was performed using DC-Alufolien Kieselgel
6
0 F254 (Merck) silica gel plates. For column chromatography silica gel KSK 40-100 μm and 100-160 μm
was used. All reactions sensitive to oxygen or moisture were conducted under argon atmosphere in
oven-dried glassware. Commercial reagents were generally used as received. THF was distilled from
4 2 2 2
LiAlH before use. CH Cl was distilled from CaH and stored over 3Ǻ molecular sieve pellets. DMF and
tAmOH was distilled from CaH
2
.
(
2-Cyclopent-2-enylmethyl)carbamic acid tert-butyl ester 4f

988
HETEROCYCLES, Vol. 88, No. 2, 2014
2
2
For the synthesis of compound 4f one-pot Curtius rearrangement was used. To a solution of
cyclopent-2-enylacetic acid 5 (1.134 g, 9 mmol), NaN (2.046 g, 33 mmol), TBAB (435 mg, 1.35 mmol)
3
and zinc triflate (108 mg, 0.297 mmol) in THF (90 mL) at 45 °C di-tert-butyl dicarbonate (2.364 g, 9.9
mmol) was added. The reaction mixture was stirred at 45 °C for 20 h. The mixture was cooled to room
temperature and 20% aqueous solution of NaNO
0 min at room temperature the layers were separated and the aqueous phase was extracted with EtOAc
2x50 mL). The combined extracts were washed with saturated NH Cl (2x40 mL), with saturated aqueous
NaHCO (50 mL), with brine (50 mL) and dried (Na SO ). The solvents were removed under reduced
2
(75 mL) and EtOAc (80 mL) was added. After stirring for
2
(
4
3
2
4
pressure and the residue was purified by flash chromatography (silica gel, petroleum ether/ EtOAc 25:1 to
1
1
0:1) giving 4f as a white solid (1.225 g, 69%); mp 46-48 °C; H NMR (500 MHz, CDCl
3
): δ 5.82 (qd,
J=3x2.2 and 5.6 Hz, 1H, H-3), 5.62 (qd, J=3x2.2 and 5.6 Hz, 1H, H-2), 4.57 (bs, 1H, NH), 3.17 and 3.06 (m,
2
1
H, H-6), 2.87 (m, 1H, H-1), 2.37 and 2.31 (m, 2H, H-4), 2.01 (tdd, J=2x8.8, 5.2 and 13.6 Hz, 1H, H-4),
1
3
3
.51 (tdd, J=2x5.9, 9.2 and 13.6 Hz, 1H, H-4), 1.44 (s, 9H, H-9); C NMR (125 MHz, CDCl ): δ 156.13
(
(
C-7), 132.75 (C-2), 131.85 (C-3), 79.01 (C-8), 46.00 (C-6), 44.81 (C-1), 32.02 (C-3), 28.39 (C-9), 26.93
-1
C-4); IR (KBr, cm ): 3339, 3959, 2983, 2865, 1682, 1538, 1437, 1391, 1365, 1276, 1253, 1174, 1141,
1
2
081, 989; MS (m/z): 198, 182, 141, 130, 124, 97, 80, 67, 57 (base); HRMS: Calcd for C11H19NO Na
+
[
M+Na] 220.1308, found 220.1317.
(
2-Cyclopent-2-enylethyl)carbamic acid tert-butyl ester 4g
1
7a
2 2 3
To a solution of 2-cyclopent-2-enyl-ethanol (2.24 g, 20mmol) in CH Cl (100 mL), Et N (3.9 mL, 28
mmol) and methanesulfonyl chloride (1.856 mL, 24 mmol) at 0 °C were added and the mixture was stirred
for 3.5 h at 0 °C. Water (200 mL) and 1N HCl solution (4 mL) were then added and the aqueous phase was
2 2
extracted with CH Cl (1x80 mL and 1x60 mL). The combined extracts were washed with brine (80 mL),
dried on Na SO , the solvent was removed under reduced pressure and the residue was purified by flash
2
4
chromatography (silica gel, petroleum ether/ EtOAc 5:1) giving 3.61 g (95%) of methanesulfonic acid
-cyclopent-2-enylethyl ester. The mixture of obtained ester (1.71 g, 9 mmol) and NaN (1.024 g, 15.75
2
3
mmol) in DMF (13.5 mL) was stirred for 2 h at 50 °C and for 1.5 h at 70 °C. After cooling water (80 mL)
was added and the mixture extracted with petroleum ether (80 mL), the extract was dried over Na SO . The
2
4
solvent was removed under reduced pressure to yield a crude azide (1.138 g). For the conversion of azide
2
3
functionality to Boc protected amine a literature procedure was used. To the azide (1.138 g, 8.3 mmol) in
the mixture of THF (40 mL) and water (40 mL), triphenylphosphine (4.364 g, 16.6 mmol) was added and
the mixture was stirred for 2.5 h at room temperature. Then, the reaction was cooled to 0 °C, Et
3
N (1.83 mL,
1
3.3 mmol) and di-tert-butyl dicarbonate (2.69 g, 12.7 mmol) were added dropwise. After stirring for 5.5 h
2
at room temperature, water (40 mL) and Et O (40 mL) were added, the layers were separated and the
2
aqueous phase was extracted with Et O (2x40 mL). The combined extracts were washed with brine (40 mL),

HETEROCYCLES, Vol. 88, No. 2, 2014
989
2 4
dried (Na SO ) and the solvent was removed. The residue was dissolved in pentane (25 mL), the precipitate
was removed by filtration and the filtrate was concentrated. Flash chromatography (silica gel, petroleum
ether/acetone 100:1 to 25:1) afforded 4g as a colorless oil (1.446 g, 76% from methanesulfonic acid
2
-cyclopent-2-enylethyl ester), which physical and spectroscopic properties correspond to the data given in
2
4
literature.
Cyclopent-2-enylacetic acid 1,1-dimethylpropyl ester 4h
Cyclopent-2-enylacetic acid methyl ester was synthesized according to literature procedure from
2
6
2
7
cyclopent-2-enylacetic acid 5. For the synthesis of compound 4h transesterification process was used. To
a solution of cyclopent-2-enylacetic acid methyl ester (1.54 g, 10 mmol) in tAmOH (5.45 mL), Li-pieces (7
mg, 1 mmol) was added and the mixture was heated at 130 °C for 1.5 h. Then the temperature was raised to
1
40 °C and MeOH/tAmOH azeotropic mixture (1 mL) was removed. The reaction was cooled, tAmOH (1
mL) was added and the mixture was again heated at 130 °C for 1.5 h, followed by removal of azeotrope.
This procedure was repeated four times. Finally, the volatiles were removed at 140-150 °C and the reaction
mixture was cooled. Water (5 mL) was added and extracted with petroleum ether (3x6 mL), the extracts
were washed with water (5 mL), dried (MgSO
petroleum ether/Et
CDCl
4
) and concentrated. Flash chromatography (silica gel,
1
2
O 60:1 to 50:1) afforded 4h as a colourless oil (1.2 g, 61%); H NMR (500 MHz,
3
): δ 5.73 (qd, J=3x2.2 and 5.6 Hz, 1H, H-3), 5.65 (qd, J=3x2.2 and 5.6 Hz, 1H, H-2), 3.04 (m, 1H,
H-1), 2.34 and 2.28 (m, 2H, H-4), 2.29 (dd, J=6.8 and 14.7 Hz, 1H, H-6), 2.19 (dd, J=8.1 and 14.7 Hz, 1H,
H-6), 2.10 (m, 1H, H-5), 1.76 (q, J=7.5 Hz, 2H, H-10), 1.45 (m, 1H, H-5), 1.41 (s, 6H, H-9), 0.87 (t, J=7.5
1
3
3
Hz, 3H, H-11); C NMR (125 MHz, CDCl ): δ 172.21 (C-7), 133.90 (C-2), 131.12 (C-3), 82.47 (C-8),
-
1
4
3
7
2.24 (C-1), 41.73 (C-6), 33.44 (C-10), 31.80 (C-4), 29.53 (C-5), 25.53 (C-9), 8.16 (C-11); IR (neat, cm ):
053, 2975, 2852, 1730, 1462, 1368, 1265, 1145, 1061, 948, 836, 724; MS (m/z): 181, 167, 126, 109, 108,
9, 71, 70, 67 (base), 66, 55, 43, 41, 39.
General procedure for the synthesis of 1,2-cyclopentanediones 1f-i
2-Cyclopent-2-enylmethyl)carbamic acid tert-butyl ester 4f (2.23 g, 11.3 mmol) was dissolved in a
tBuOH/H O mixture 3:1 (38 mL), fiber bound OsO catalyst (7.5% OsO , 38 mg, 0.0113 mmol) and NMO
50 wt. % solution in water, 3.1 mL, 14.7 mmol) were added. The reaction mixture was stirred at 60 °C for
(
2
4
4
(
8
days (1-4 days for the other alkenes), the catalyst was filtered off, rinsed with EtOAc (3x10 mL) and
(40 mL) was added. The aqueous layer was extracted with EtOAc (2x50
mL and 1x30 mL), the combined extracts were washed with brine (40 mL), dried (Na SO ) and the solvents
2 2 3
aqueous solution of 10% Na S O
2
4
were removed under reduced pressure. Purification of the residue by flash chromatography (silica gel,
petroleum ether/acetone 10:2 to 10:4) afforded 1.855 g, (71%) of the diol 3f. The same procedure was used
for diols 3g-i. Thus, diols 3g (2.153 g, 91%), 3h (1.05 g, 84%) and 3i (2.493 g, 92%) were obtained from

990
HETEROCYCLES, Vol. 88, No. 2, 2014
2
8
alkenes 4g (2.015 g, 9.5 mmol), 4h (1.05 g, 5.4 mmol) and 4i (2.419 g, 8.4 mmol), respectively. The diols
were oxidized as followed: to a solution of DMSO (1.81 mL, 23 mmol) in CH Cl (108 mL), TFAA (3.25
mL, 19 mmol) was added dropwise at -60 °C. The mixture was stirred for 10 min followed by the addition
of the above diol (1.855 g, 8 mmol) in a DMSO/ CH Cl mixture 1:2 (8 mL). After stirring for 1.5 h at
60 °C, Et N (7.4 mL, 53 mmol) was added at -60 °C and the mixture was stirred for 1.5 h at that
temperature. Then the reaction mixture was warmed to ca. 5 °C, poured into a cold 1N HCl solution (220
mL) and the aqueous layer was extracted with CH Cl (2x80 mL). The combined extracts were washed with
water (200 mL), dried (Na SO ) and the solvent was evaporated. The residue was dissolved in CH Cl (80
mL), K CO (373 mg, 2.7 mmol) was added and the mixture was stirred for 21 h at room temperature. Then,
N HCl solution (45 mL) was added, stirred for 10 min and the aqueous layer was extracted with CH Cl
2x40 mL). The combined extracts were washed with water (50 mL), dried (MgSO ) and the solvent was
evaporated. The residue was purified by flash chromatography (silica gel, petroleum ether/ EtOAc 10:5 to
0:6) giving the target compound.
2
2
2
2
-
3
2
2
2
4
2
2
2
3
1
2
2
(
4
1
(
2-Hydroxy-3-oxocyclopent-1-enylmethyl)carbamic acid tert-butyl ester 1f
1
Obtained as a white solid (1.458 g, 80%); mp 134-136 °C; H NMR (500 MHz, CDCl
3
): δ 7.30 (bs, 1H,
OH), 5.29 (bs, 1H, NH), 4.07 (bd J=6.0Hz, 2H, H-6), 2.47 (m, 2H, H-5, 2.42 (m, 2H, H-4), 1.43 (s, 9H,
1
3
3
H-9); C NMR (125 MHz, CDCl ): δ 203.76 (C-3), 156.54 (C-7), 149.47 (C-2), 142.99 (C-1), 80.07
-
1
(
C-8), 38.71 (C-6), 31.91 (C-4), 28.23 (C-9), 23.92 (C-5); IR (KBr, cm ): 3365, 3337, 2988, 1703, 1684,
1
5
664, 1523, 1410, 1398, 1368,1283, 1251, 1192, 1164, 1111; MS (m/z): 171, 154, 127, 111, 110, 84, 82,
7 (base). Anal. Calcd for C11 N: C, 58.14; H, 7.54; N, 6.16. Found: C, 58.10; H, 7.59; N, 6.15.
17 4
H O
[2-(2-Hydroxy-3-oxocyclopent-1-enyl)ethyl]carbamic acid tert-butyl ester 1g
Diketone 1g was obtained from diol 3g (1.114 g, 4.55 mmol) as a white solid (0.722 g, 66%), which
25
physical and spectroscopic properties correspond to the data given in literature.
2-Hydroxy-3-oxocyclopent-1-enyl)acetic acid 1,1-dimethylpropyl ester 1h
(
Diketone 1h was obtained from diol 3h (1.48 g, 6.43 mmol) as a white solid (0.766 g, 53%), mp
1
7
1-72 °C; H NMR (500 MHz, CDCl
3
): δ 6.85 (s, 1H, OH), 3.38 (s, 2H, CH
CH ), 1.42 (s, 6H, (CH ), 0.86 (t, J=7.3Hz, 3H, CH
): δ 203.16 (C-3), 168.80 (COO), 150.04 (C-2), 138.61 (C-1), 84.24 (OC(Me)
CO), 33.36 (CH CH ), 32.01 (C-4), 25.36 (OC(Me) and C-5), 8.09 (CH CH ).; IR (KBr,
2
CO), 2.53 (m, 2H, H-5), 2.43
1
3
(
m, 2H, H-4), 1.75 (q, J=7.3Hz, 2H, CH
NMR (125 MHz, CDCl
5.42 (CH
2
3
3
)
2
2
CH
3
). C
),
3
2
3
2
2
3
2
3
2
-1
cm ): 3316, 2979, 2938, 2885, 1727, 1700, 1665, 1465, 1415, 1386, 1346, 1193, 1150, 1007, 844, 696;
+
MS (m/z): 226, 156, 139, 111, 71, 55, 43 (base); HRMS: Calcd for C H O Na [M+Na] 249.1097,
1
2
18
4
found 249.1101.
-Benzyl-4-(tert-butyldimethylsilanyloxy)-2-hydroxycyclopent-2-enone 1i
3

HETEROCYCLES, Vol. 88, No. 2, 2014
991
1
Dikeone 1i was obtained from diol 3i (2.075 g, 6.4 mmol) as a white solid (1.532g, 75%) , mp 92-96 C, H
NMR (400 MHz, CDCl
3
):  7.36 – 7.15 (m, 5H, Bn),  6.22 (s, 1H, OH),  4.67 (m, 1H, H-4),  3.76 (dd, J
),  2.74 and 2,27 (both dd, J = 19.5 Hz, 2H, 5-H),  0.90 (s, 9H, tBu),  0.03
), C NMR (101 MHz, CDCl ) δ 200.19 (C-1), 149.56 (C-2), 145.17 (C-3), 137.80 (sBn),
29.13 (o-Bn), 128.71 (m-Bn), 126.66 (p-Bn), 66.97 (C-4), 43.35 (C-5), 31.18 (Bn-CH ), 25.87 (tBu CH ),
).; IR (KBr, cm ): 3248, 3084, 1711, 1671, 1601, 1454, 1256, 1112,
072, 835, 778, 757, 696; MS (m/z, %):186, 158 (base), 129, 115, 105, 91, 77, 66, 51, 41; Anal. Calcd for
=
186.1, 14.4 Hz, 2H, Bn-CH
2
1
3
(
s, 6H, 2 CH
3
3
1
1
1
2
3
-1
3 3
8.10 (tBu C), -4.30 (CH ), -4.85 (CH
C H O Si: C, 67.88; H, 8.23. Found: C, 67.76; H, 8.30.
1
8
26
3
General procedure for catalytic asymmetric oxidation of 1,2-cyclopentanediones 1a-i
2 2
To a solution of Ti(OiPr) (0.18 mL, 0.6 mmol) and 4Å powdered molecular sieves (200 mg) in CH Cl (5
4
mL), (+)-DET (0.164 mL, 0.48 mmol) was added at -20 °C and the mixture was stirred for 15 min. Then,
cyclopentanedione (2 mmol) in CH Cl (3.0 mL) was added and the reaction mixture was stirred for 30
2
2
min. Next tBuOOH (0.85 mL, 5 mmol, 5.85M solution in decane) was added and the reaction was kept at
20 C for 48 h. Water (6.0 mL) was added and the mixture was stirred for 1 h at room temperature, then 1.8
mL of 30% aqueous NaOH in saturated aqueous NaCl solution was added and the mixture was again
stirred at room temperature for an additional 1 h. The CH Cl layer was removed and the mixture was
acidified with 1M HCl solution (pH=1-2) and extracted with EtOAc. The combined extracts were dried
over MgSO and the solvent was evaporated. The residue was dissolved in CH Cl (40 mL) and
-
2
2
4
2
2
concentrated HCl solution (0.4 mL) was added (in the case of 2h a catalytic amount of pTsOH was used as
the acid and for 2f, 2g, 2i thermal cyclization in toluene was used) and the mixture was stirred for 2 h at
room temperature. Then, 20 mL of water was added and the CH
was extracted with EtOAc and the combined extracts were dried over MgSO
solvents, the residue was purified by flash chromatography to give the corresponding -lactone acids 2.
2
Cl
2
layer was separated. The water layer
4
. After evaporation of the
15b,15c,16b
Lactone acid 1a-e correspond to the data given in literature.
(
2R)-2-(tert-Butoxycarbonylaminomethyl)-5-oxotetrahydrofuran-2-carboxylic acid 2f
2
2
Lactone acid 2f was obtained as a white solid (196 mg, 38%); mp 138-139 C; []D +9.3 (c 2.3,
1
CHCl
3
-MeOH 1:1); ee 92%; H NMR (500 MHz, CDCl
3
+CD
3
OD):  3.61 and 3.56 (2d, J = 14.6 Hz, 2H,
H-6), 2.64 (td, J = 2x9.7 and 18.1 Hz, 1H, H-4,), 2.54 (ddd, J = 4.0, 9.9 and 18,1 Hz, 1H, H-4), 2.36 (ddd,
13
J = 4.0, 9.7 and 13.5 Hz, 1H, H-3), 2.27 (ddd, J = 9.7, 9.9 and 13.5 Hz, 1H, H-3), 1.38 (s, 9H, H-9); C
NMR (125 MHz, CDCl +CD OD): δ 177.07 (C-5), 172.34 (COOH), 156.85 (C-7), 86.07 (C-2), 80.28
C-8), 44.69 (C-6), 28.29 (C-9), 28.26 (C-3), 28.21 (C-4); IR (KBr, cm ): 3386, 2984, 2939, 2613, 1797,
3
3
-
1
(
1
785, 1748, 1656, 1537, 1464, 1392, 1290, 1260, 1185, 1161, 1098956, 922. 854, 774; HRMS: Calcd. for

992
HETEROCYCLES, Vol. 88, No. 2, 2014
-
C
11
H16NO
6
[M-H] 258.0983, found 258.0990.
2R)-2-(2-tert-Butoxycarbonylaminoethyl)-5-oxotetrahydrofuran-2-carboxylic acid 2g
Cyclopentanedione 1g (237 mg, 0.98 mmol) was oxidized according to general procedure to give 2g as a
(
2
D
5
1
white solid (177 mg, 66%); mp 139-141 °C; []
CDCl ):  6.99 (bt, J = 5.7 Hz, 1H, NH), 3.29 and 3.18 (2m, 2H, H-7), 2.70 and 1.69 (2m, 2H, H-6), 2.53
and 2.52 (2m, 2H, H-4), 2.49 and 2.15 (2m, 2H, H-3), 1.43 (s, 9H, H-10); C NMR (125 MHz, CDCl ): δ
-14.0 (c 2.51, MeOH); ee 92%; H NMR (500 MHz,
3
1
3
3
1
75.93 (C-5), 174.93 (COOH), 158.33 (C-8), 83.66 (C-2), 81.61 (C-9), 36.91(C-7), 36.70 (C-6), 32.99
-1
(
C-3), 27.98 (C-10), 27.72 (C-4); IR (KBr, cm ): 3406, 2982, 2591, 1784, 1526, 1370, 1254, 1174, 1197,
-
1
029, 901, 865, 780; HRMS: Calcd. for C12
H18NO
6
[M-H] 272.1140, found 272.1142.
(
2R)-2-(1,1-Dimethylpropoxycarbonylmethyl)-5-oxotetrahydrofuran-2-carboxylic acid 2h
2
5
Lactone acid 2h was obtained as a white solid (301 mg, 58%); mp 38-40 C; []D -18.3 (c 4.74, CHCl3);
1
ee 94%; H NMR (400 MHz, CDCl
3
2
):  9.91 (br s, 1H, OH), 3.11 and 2.86 (2d, 2H, J = 16.8 Hz, CH CO),
2
.76-2.53 (m, 3H, H-4, H-3), 2.36-2.28 (m, 1H, H-3), 1.75 (q, J = 7.5 Hz, 2H, CH CH ), 1.39 (s, 6H,
2 3
1
3
(
CH
3
)
2
), 0.85 (t, J = 7.5 Hz, CH
67.81 (CH CO), 85.33 (OC(CH
CH ), 25.50 (CH
2
CH
3
); C NMR (101 MHz, CDCl
3
) δ 175.84 (C-5), 175.56 (COOH),
CH ), 31.41 (C-3), 27.82
1
2
3
)
2
), 82.91 (C-2), 42.84 (CH
2
CO), 33.33 (CH
2
3
-
1
(
C-4), 25.52 (CH
2
3
2
CH
3
), 8.25 (CH
3
CH
2
); IR (KBr, cm ): 3445, 2981, 2945, 2886, 2595,
-
1
786, 1730, 1464, 1388, 1371, 1187, 1152, 1069, 947, 842; HRMS: Calcd. for C12
H
17
O
6
[M-H] 257.1031,
found 257.1040.
(
(
2S,3R)-2-Benzyl-3-(tert-butyldimethylsilanyloxy)-5-oxotetrahydrofuran-2-carboxylic acid 2i and
2S,3S)-2-Benzyl-3-(tert-butyldimethylsilanyloxy)-5-oxotetrahydrofuran-2-carboxylic acid 2i’
Cyclopentanedione 1i (414 mg, 1.3 mmol) was oxidized according to the general procedure to give 2i and
2
5
1
2
i’ as white solids in 1:1 ratio (238 mg, 52%). 2i: mp 99-102 C; []D -23.5 (c 2.07, CHCl ); ee 95%; H
3
3
NMR (400 MHz, CDCl ) δ 7.44-7.10 (m, 5H, Bn), 4.52-4.34 (m, 1H, H-3), 3.28 (dd, J = 81.6, 14.5 Hz, 2H,
Bn-CH ), 2.46 and 2.25 (2dd, J = 24.2 Hz, 2H, H-4), 0.87 (s, 9H, t-Bu), 0.09 (d, J = 23.5 Hz, 6H, 2 Si-CH ).
2
3
1
3
C NMR (101 MHz, CDCl
3
) δ 174.36 (C-5), 170.51 (COOH), 133.99 (p-Bn), 130.54 (m-Bn), 128.67
(
(
o-Bn), 127.49 (s-Bn), 91.04 (C-2), 72.44 (C-3), 40.12 (Bn-CH
2
), 38.03 (C-4), 25.44 (t-Bu CH
). IR (KBr, cm ): 3034, 2860, 1498, 1262, 1082, 781. Anal. Calcd
Si: C, 61.69; H, 7.48. Found: C, 61.65; H, 7.52.
3
), 17.79
-1
3 3
t-Bu C), -4.74 (Si-CH ), -5.20 (Si-CH
for C18
H
26
O
5
2
5
1
2
5
0
i’: mp 110-113 C; []
D
-13.3 (c 0.72, CHCl
3
); ee 95%; H NMR (400 MHz, CDCl
)), 2.81 and 2.39 (2dd, J = 19.1Hz, 2H, H-4),
.96 (s, 9H), 0.20 (d, J = 15.4 Hz, 6H, 2 Si-CH ). C NMR (101 MHz, CDCl ) δ 175.13 (C-5), 171.66
3
) δ 7.41 – 7.13 (m,
H, Bn), 4.77-4.63 (m, 1H, H-3), 3.43 – 3.08 (m, 2H, Bn-CH
2
1
3
3
3
(COOH), 134.73 (p-Bn), 130.08 (m-Bn), 127.83 (o-Bn), 126.67 (s-Bn), 91.58 (C-2), 72.96 (C-3), 38.44
-1
(
2 3 3 3
C-4), 37.52 (Bn-CH ), 25.22 (t-Bu CH ), 17.74 (t-Bu C), -5.39 (Si-CH ), -5.50 (Si-CH ). IR (KBr, cm ):

HETEROCYCLES, Vol. 88, No. 2, 2014
993
+
3
483, 1770, 1705, 1497, 1254, 1085, 833, 706; HRMS: Calcd. for C18
27 5
H O Si [M+H] 351.1622, found
3
51.1631.
(
R)-1-Oxa-7-azaspiro[4.4]nonane-2,6-dione 10
2R)-2-(tert-Butoxycarbonylamino-methyl)-5-oxotetrahydrofuran-2-carboxylic acid 2g (76 mg, 0.26
(
mmol) was dissolved in toluene and boiled at reflux for 9 h. After cooling, the toluene was removed under
reduced pressure and the residue was purified by flash chromatography (silica gel, petroleum ether/acetone
1
0:2) giving Boc-protected spirolactam (46 mg). To the solution of obtained protected compound (46 mg,
.18 mmol) in CH Cl (10 mL) concentrated HCl solution (0.1 mL) was added and the mixture was stirred
0
2
2
for 23 hours at room temperature. Then, 6 mL of water was added and the water layer was extracted several
portions with CH Cl , dried (Na SO ) and concentrated. Flash chromatography (silica gel, petroleum
ether/ acetone 10:5 to 10:6) gave 10 as a white solid (24 mg, 59%) from lactone acid 2g; mp 158-160 C;
2
2
2
4
2
2
1
[
]D +124.2 (c 2.63, CHCl ); ee 92%; H NMR (400 MHz, CDCl ):  7.26 (br s, 1H, NH), 3.53-3,47 (m,
3
3
1H, H-8), 3.39-3.33 (m, 1H, H-8), 2.97-2.88 (m, 1H, H-3) ,2.61-2.50 (m, 3H, H-3, H-4, H-9), 2.28-2.11 (m,
1
3
2
3
H, H-9, H-4); C NMR (101 MHz, CDCl ) δ 176.11 (C-2), 174.83 (C-6), 84.81 (C-5), 38.84 (C-8), 33.45
-1
(
C-9), 29.82 (C-4), 28.74 (C-3); IR (KBr, cm ): 3253, 2966, 1776, 1717, 1672, 1459, 1437, 1301, 1257,
1197, 1179, 1138, 1113, 1076, 1053, 1012, 982, 912, 769, 690; MS (m/z): 155, 137, 127, 113, 110, 100, 98,
+
8
7 3
4, 70, 56 (base), 55; HRMS: Calcd. for C H10NO [M+H] 156.0655, found, 156.0651.
ACKNOWLEDGEMENTS
The authors are grateful to Prof. Victor Sniečkus for helpful discussions, suggestions and encouragement
during a long period of time. The authors thank the Estonian Ministry of Education and Research (Grants
No. 0140060s12 and ESF8880) and EU European Regional Development Fund (3.2.0101.08-0017) for
financial support.
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