Asymmetric synthesis of 2-alkyl-substituted 2-hydroxyglutaric acid γ-lactones

Article abstract of DOI:10.1016/j.tetlet.2006.04.013

3-Alkyl-1,2-cyclopentanediones 1 are transformed into 2-alkyl-2-hydroxyglutaric acid γ-lactones 3 in up to 83% isolated yields and up to 96% ee, affording a simple access to many bioactive compounds, including diacylglycerol lactones (DAG-lactones).

Full text of DOI:10.1016/j.tetlet.2006.04.013

Tetrahedron Letters 47 (2006) 4491–4493
Asymmetric synthesis of 2-alkyl-substituted 2-hydroxyglutaric acid
c-lactones
Anne Paju,a Marit Laos,a Artur Jogi,a Malle Pa¨ri,a Raissa Ja¨a¨laid,b Tonis Pehk,c
˜
˜
Tonis Kangera and Margus Loppa,*
˜
aDepartment of Chemistry, Faculty of Science, Tallinn University of Technology, Ehitajate tee 5, 19086, Tallinn, Estonia
bCompetence Centre for Cancer Research, Akadeemia tee 15, 12618 Tallinn, Estonia
cNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
Received 6 February 2006; revised 30 March 2006; accepted 6 April 2006
Available online 11 May 2006
Abstract—3-Alkyl-1,2-cyclopentanediones 1 are transformed into 2-alkyl-2-hydroxyglutaric acid c-lactones 3 in up to 83% isolated
yields and up to 96% ee, affording a simple access to many bioactive compounds, including diacylglycerol lactones (DAG-lactones).
Ó 2006 Elsevier Ltd. All rights reserved.
Chiral 2-alkyl-5-oxotetrahydrofuran-2-carboxylic acid
(2-alkyl-2-hydroxyglutaric acid c-lactone) units are pres-
ent in the structures of various natural compounds with
potential pharmacological applications.1 Additionally,
monoprotected 5-bis(hydroxymethyl)tetrahydro-2-fura-
nones are convenient templates for diacylglycerol lac-
tones (DAG-lactones), which are found to be more
potent protein kinase C inhibitors than the parent natu-
ral compounds, and can be regarded as promising thera-
peutic agents for treatment of cancer, diabetes, etc.2
28–44% yields.6 We have now developed a simple
and practical method for the synthesis of enantiomeri-
cally enriched 2-alkyl-5-oxotetrahydrofuran-2-carb-
oxylic acids 3, which may serve as a base for various
substituted lactones, including templates for DAG-
lactones and their analogues (Scheme 1).
While oxidizing 3-substituted cyclopentane-1,2-diones
with the Ti(O-i-Pr)4/tartaric ester/t-BuOOH complex in
a 1:1.6:2.5 ratio the main oxidized products appear in a
complex mixture (mixture A), containing 3-hydroxyace-
tals 2, lactones 3, mono-esters 4, dimeric esters 5 (charac-
teristic only for 1d and 1e) and keto acid 6, which
There are several approaches which describe methods
for the synthesis of these chiral tertiary c-lactone struc-
tures, including enzymatic desymmetrization of parent
esters3 and chemical synthesis from natural chiral com-
pounds.1b,4 However, there are only a few examples of
the asymmetric chemical synthesis of related structures,
using a chiral auxiliary,5 chiral reagent1a and chiral
catalyst.1d,2a
required
a
laborious chromatographic separation
(Scheme 2).
The mixture A contained two types of esters, in which 3
and 4 are base sensitive and 5 is acid sensitive. Hence, a
base/acid work-up procedure was applied in order to
We have previously found that 3-alkyl-cyclopentane-
1,2-diones 1, are oxidized with the chiral Ti(O-i-Pr)4/
tartaric ester/t-BuOOH complex resulting in a mixture
of different oxidation products, and amongst them
2-alkyl-5-oxotetrahydrofuran-2-carboxylic acids 3 in
1. Ti(OiPr)4/(+)-DET/tBuOOH
O
HO
1:1.6:2.5
OH
R
O
R
2. NaOH
O
1
3.
HCl
3
O
R= a) -CH3; b) -C2H5; c) -CH2-OBn;
Keywords: Asymmetric oxidation; Tetrahydrofuran carboxylic acid;
DAG-lactone; 2-Hydroxyglutaric acid lactone.
d) -CH2CH2-OMOM e) -CH2CH2-OBn; f) -Bn
*
Corresponding author. Tel.: +372 620 2802; fax: +372 620 2995;
e-mail: lopp@chemnet.ee
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.013

4492
A. Paju et al. / Tetrahedron Letters 47 (2006) 4491–4493
HO
R
O
R'O
O
HO
O
O
O
O
+
R
OH
OiPr
[O]*
O
R
+
+
O
HO
OH
R
OH
R
+
OH
OH
O
O
O
R
R
O
O
OH
OH
OH
1
3
4
6
5
2
O
mixture A
R= a) -CH3; b) -C2H5; c) -CH2-OBn;
d) -CH2CH2-OMOM e) -CH2CH2-OBn; f) -Bn
NaOH
HO
NaO
O
O
H+
R
OH
ONa
R
+ 6
+
5
6
+
O
O
3
7
O
mixture B
mixture C
Scheme 2.
Table 1. Oxidation of 3-alkyl-cyclopentane-1,2-diones 1 with the
Ti(O-i-Pr)4/(+)-tartaric ester/t-BuOOH complex7
simplify it and thus obtain lactone acids 3 by crystalliza-
tion or by simple chromatography. Thus, basic treat-
ment of the mixture A converted lactones 3 and
mono-esters 4 to the same diacid salt 7. Furthermore,
the mono-oxidation product 2, which is always present
after oxidation in mixture A6b was also oxidized with
the excess t-BuOOH in the mixture during basic work-
up and also formed salt 7 (this transformation was con-
firmed in a separate experiment with isolated acetal 2).
As a result, a three component mixture B was formed,
which consisted of salt 7, dimer 5 (in the case of 1d
and 1e, 17% and 13%, respectively), and keto acid 6
(as a decarboxylation product of lactone acid 3). When
mixture B was treated with acid, lactone 3 was formed as
the main product.7 Dimer 5 was hydrolyzed under the
acidic conditions (confirmed in a separate experiment
in the case of 5e, using a mixture of AcOH–i-PrOH–
H2O 4:4:1)8 also resulting in lactone acid 3. Lactone acid
3 and achiral keto acid 6 which are formed after acidifi-
cation of mixture B were easily separable by chromato-
graphy or crystallization. The results obtained are
presented in Table 1.
Entry
Substrate
Isolated lactone acid 39
Keto acid 6
Yield (%)
ee (%)
1
2
3
4
5
6
1aa
1b
1c
75(60b)
72
93(99b)
93
96
94
95
96
6
10
3
—
3
75
1d
1e
1fa
69c
71c
83
6
a Both enantiomers were synthesized.
b From a 50 g scale experiment after recrystallization.
c Together with dimer 5.
plex4a yielding the enantiomeric DAG-lactone template
in one step and with a good yield (76%)10 (Scheme 3).
According to the optical rotation, the absolute configu-
ration of 8c is in accordance with that from our previous
determinations of 2-methyl-5-oxotetrahydrofuran-2-car-
boxylic acid 3a6b and homocitric acid lactone11 from the
asymmetric oxidation; as expected, from diketone 1c
with (+)-diethyl tartrate, lactone acid 3c with R-config-
uration and lactone 8c with S-configuration were
obtained.4b
According to the data obtained, the isolated yield of 2-
alkyl lactone acids 3 was in the range of 69–83%. Also,
the process is highly enantioselective (ee of the isolated
lactone acids 3 is in the range of 93–99%).
The method described opens a simple, straightforward
and highly efficient procedure for synthesizing enantio-
meric 2-alkyl-2-hydroxyglutaric acid c-lactones, DAG-
lactone templates and other compounds of similar
Lactone acid 3c is a convenient precursor of DAG-lac-
tone template 8c.2,3b Thus, benzyloxymethyl lactone
acid 3c was reduced with borane dimethylsulfide com-
HO
HO
O
OBn
R
O
S
BH3SMe2
Ti(OiPr)4/(+)-DET/tBuOOH
OH
-
O
OBn
HO , H+
OBn
O
O
8c
O
1c
3c
Scheme 3.

A. Paju et al. / Tetrahedron Letters 47 (2006) 4491–4493
4493
added and the mixture was again stirred at room temper-
ature for an additional 1 h. The CH2Cl2 layer was
removed and the mixture was acidified with 1 M HCl
solution (pH = 1) and extracted with EtOAc. The com-
bined extracts were dried over MgSO4 and the solvent was
evaporated. The residue was dissolved in CH2Cl2 (20 mL)
and concentrated HCl solution (0.2 mL) was added (in the
case of 3d a catalytic amount of pTsOH was used as the
acid) and the mixture was stirred for 2 h at room
temperature. Then, 10 mL of water was added and the
CH2Cl2 layer was separated. The water layer was extracted
with EtOAc and the combined extracts were dried over
MgSO4. After evaporation of the solvents, the residue was
purified by flash chromatography to give the correspond-
ing c-lactone acids 3.
structure from 3-alkyl-1,2-cyclopentane diones. The
method also has preparative utility.
Acknowledgements
Support from the Estonian Science Foundation (Grant
Nos 5628 and 6778), from the Estonian Ministry of
Education and Science (Grant 0142725s06) and from
the Competence Centre for Cancer Research is
acknowledged.
References and notes
´
8. Kocienski, P. J. In Protecting Groups, 3rd ed.; Thieme:
Stuttgart, NY, 2004; pp 404–405.
9. The synthesized lactone acids have the following physical
characteristics: Compounds 3a, 3b, 3e are identical to
those from Ref. 6b; Compound 3c, 2-[(benzyloxy)methyl]-
5-oxotetrahydrofuran-2-carboxylic acid: 1H NMR (500
MHz, CDCl3): d 9.62 (br s, 1H, OH); 7.35 (m, 2H, m);
7.28–7.32 (m, 3H, o,p); 4.62 (s, 2H, Bn CH2); 3.89 and 3.78
(dd, 2H, J = 10.9 Hz, CH2O), 2.59–2.67 (m, 2H, H-4),
2.35–2.46 (m, 2H, H-3). 13C NMR (125 MHz, CDCl3): d
176.14 (C-5), 174.03 (COOH), 136.97 (s), 128.48 (m),
127.98 (p), 127.73 (o), 85.60 (C-2), 73.86 (Bn CH2), 71.85
1. (a) Tamura, O.; Shiro, T.; Ogasawara, M.; Toyao, A.;
Ishibashi, H. J. Org. Chem. 2005, 70, 4569–4577; (b)
Makino, K.; Shintani, K.; Yamatake, T.; Hara, O.;
Hatano, K.; Hamada, Y. Tetrahedron 2002, 58, 9737–
9740; (c) Masaki, H.; Mizozoe, T.; Esumi, T.; Iwabuchi,
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4804; (d) Janecki, T.; Błaszcyk, E.; Studzian, K.; Rozalski,
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1978, 34, 1449–1452; (b) Lee, J.; Wang, S.; Milne, G. W.
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Tetrahedron Lett. 2006, 47, 213–216; (b) Jang, D.-P.;
Chang, J.-W.; Uang, B.-J. Org. Lett. 2001, 7, 983–985; (c)
Donohoe, T. J.; Stevenson, C. A.; Helliwell, M.; Irshad,
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20
(CH2O), 27.91 (C-4), 27.85 (C-3). ½aꢁD ꢀ10.3 (c 3.34,
CHCl3). Compound 3d, 2-[2-(methoxymethoxy)ethyl]-5-
oxotetrahydrofuran-2-carboxylic acid: 1H NMR (500
MHz, CHCl3): d 8.70 (br s, 1H, OH); 4.57 (s, 2H,
OCH2O); 3.68–3.69 (m, 2H, OCH2CH2); 3.34 (s, 3H,
OCH3); 2.52 and 2.36 (m, 2H, H-4); 2.18 and 1.98 (m, 2H,
OCH2CH2); 2.16 and 2.02 (m, 2H, H-3). 13C NMR
(125 MHz, CDCl3): d 178.86 (C-1), 178.47 (C-5), 96.24
(OCH2O), 75.57 (C-2), 63.58 (CH2O), 55.34 (OCH3),
24
37.88 (OCH2CH2), 33.98 (C-3), 28.39 (C-4). ½aꢁD ꢀ30
(c 3.05, CHCl3). Compound 3f, 2-benzyl-5-oxotetra-
hydrofuran-2-carboxylic acid: 1H NMR (500 MHz,
CDCl3 + DCD3OD): d 7.11–7.20 (m, 5H, o,m,p); 3.26
and 3.03 (2d, 2H, J = 14.6 Hz, Bn CH2); 2.37 and 2.13 (m,
2H, H-3), 2.35 and 1.98 (m, 2H, H-4). 13C NMR
(125 MHz, CDCl3 + DCD3OD): d 176.60 (C-5), 172.95
(COOH), 133.87 (s), 130.25 (o), 128.13 (m), 127.01 (p),
86.27 (C-2), 41.81 (Bn CH2), 29.71 (C-3), 27.84 (C-4).
20
½aꢁD ꢀ5.3 (c 1.97, acetone) and +5.4 (c 2.01, acetone). The
enantiomeric purity of 3c, 3f (directly) and 3d (as
the spirodilactone6b) was determined by chiral HPLC
(Diecel Chiralcel ODH).
6. (a) Paju, A.; Kanger, T.; Pehk, T.; Lopp, M. Tetrahedron
Lett. 2000, 41, 6883–6887; (b) Paju, A.; Kanger, T.; Pehk,
10. The NMR and IR spectra are identical to those from Ref.
4b, however, the chemical shifts for the two proton AB
systems of the a-methylene carbons to the ring should be
exchanged on the basis of J-based selective 1H–13C
polarization transfer experiments. Assignment of 13C
NMR shifts follows: 177.55 (C-2), 137.45 (s), 128.40 (m),
127.78 (p), 127.53 (o), 87.68 (C-5), 73.57 (Bn), 72.35
(CH2OCH2), 65.26 (CH2OH), 29.16 (C-5), 25.57 (C-4).
T.; Lindmaa, R.; Muurisepp, A.-M.; Lopp, M. Tetra-
¨ ¨
hedron: Asymmetry 2003, 14, 1565–1573.
7. A typical synthetic procedure: to a solution of Ti(O-i-Pr)4
˚
(0.3 mL, 1 mmol) and 4 A powdered molecular sieves
(100 mg) in CH2Cl2 (6 mL) at ꢀ20 °C under an argon
atmosphere, (+)-DET (0.27 mL, 1.6 mmol) was added and
the mixture was stirred for 15 min. Then, 3-alkyl-2-
hydroxy-2-cyclopenten-1-one (1 mmol) in CH2Cl2
(2.0 mL) was added and the reaction mixture was stirred
for 30 min. Next t-BuOOH (0.4 mL, 2.5 mmol, 6.25 M
solution in decane) was added and the reaction was kept at
ꢀ20 °C for 68 h. Water (6.0 mL) was added and the
mixture was stirred for 1 h at room temperature, then
1.2 mL of 30% NaOH in saturated NaCl solution12 was
21
21
½aꢁD +9.67 (c 2.4, CHCl3) (lit.4b ½aꢁD +7.73 (c 4.4,
CHCl3)).
11. Paju, A.; Kanger, T.; Pehk, T.; Eek, M.; Lopp, M.
Tetrahedron 2004, 60, 9081–9084.
12. Cao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.