Asymmetric oxidation of 1,2-cyclopentanediones

Article abstract of DOI:10.1016/S0040-4039(00)01106-0

Cyclic 3-alkyl-1,2-cyclopentanediones undergo a direct asymmetric oxidation with the DET/Ti(OiPr)₄/ tBuOOH oxidative system, resulting in enantiomeric α-hydroxy compounds and ring-cleaved hydroxylated acids (lactones) up to 95% ee. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01106-0

Tetrahedron Letters 41 (2000) 6883±6887
Asymmetric oxidation of 1,2-cyclopentanediones
Anne Paju,a Tonis Kanger,b Tonis Pehkc and Margus Loppa,*
aDepartment of Chemistry, Tallinn Technical University, Ehitajate tee 5, 19086 Tallinn, Estonia
bInstitute of Chemistry at Tallinn Technical University, Akadeemia tee 15, 12618 Tallinn, Estonia
cNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
Received 4 May 2000; accepted 29 June 2000
Abstract
Cyclic 3-alkyl-1,2-cyclopentanediones undergo a direct asymmetric oxidation with the DET/Ti(OiPr)4/
tBuOOH oxidative system, resulting in enantiomeric a-hydroxy compounds and ring-cleaved hydroxylated
acids (lactones) up to 95% ee. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric reaction; oxidation; hydroxylation; lactones.
The titanium tetraisopropoxide/diethyl tartrate/tert-butyl hydroperoxide (Ti(OiPr)4/DET/
tBuOOH) catalyst system developed by Sharpless et al.1 has been widely used in the asymmetric
oxidation of allylic alcohols1 and sul®des.2 Recently, we found that several ketones are also oxi-
dized under the conditions of the Sharpless oxidation: cyclobutanones undergo asymmetric
Baeyer±Villiger oxidation,3 resulting in enantiomerically enriched lactones,4 and b-hydroxy-
ketones undergo asymmetric a-hydroxylation,5 resulting in a,b-dihydroxy ketones6 in high
enantiomeric purity. On the basis of these results, it may be assumed that the unique properties of
the Ti/DET complex could be used more extensively in asymmetric synthesis.
We investigated the oxidation of di€erent 3-alkyl-cyclopentane-1,2-diones7 1 using Sharpless
oxidation conditions and found that they undergo a direct asymmetric oxidation, resulting in
enantiomerically enriched products (Scheme 1). The results obtained are presented in Table 1.
Scheme 1.
* Corresponding author. E-mail: lopp@chemnet.ee
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01106-0

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Table 1
Oxidation of cyclopentanediones under Sharpless oxidation conditionsa
The formation of two major types of oxidation product was observed: primary hydroxylation
products 2 and derivatives of more oxygenated, ring-cleaved, hydroxylation products 3 (isolated
as lactones 4). The enantiomeric purity of both types of the products is high in the case of 3-
alkylsubstituted substrates 1a and 1b, while in the case of the hydroxyethyl substrates 1c and 1c0
the enantiomeric purity of the products is moderate. In the case of the silyl protected substrate
1c0, the ee is considerably higher than in the case of the unprotected OH compound 1c. The latter
may result in a complex where two chiral ligands are attached. This may cause opposite face
selection and reduce the total enantioselectivity. Also, the deprotection of 1c0 that occurs during
the course of the oxidation may reduce the enantioselectivity.
We assume th0at at ®rst the a-hydroxylation reaction results in hemiacetals 2a, 2b and 2c, or
enols 2a0 and 2b , correspondingly.8 In the case of the hydroxyethyl substrates (1c and 1c0), the
primary oxidation products form bicylic intramolecular acetals 2c. All these hydroxylated dike-
tones 2a and 2b may be oxidized further, resulting in the ring cleavage products, i.e. the deriva-
tives of the aliphatic diacids 3 (isolated as lactones and esters 4a and 4b, respectively) (Scheme 2).
In the same way, the bicyclic acetal 2c oxidizes further, resulting in the lactones 4c and spiro-

6885
Scheme 2.
dilactone 4c00. In the case of the substrate 1c0, the hydrolysis was performed in a methanolic
mixture and a methyl ester 4c0 was also formed, together with the spiro-dilactone 4c00 (Scheme 3).
We assume that the Ti catalyst forms, at ®rst, in enolate complex 5 with substrate 1. This
complex is responsible for the asymmetric induction and directs the facial selection. Then, the
intermediate epoxide 6 undergoes methanolysis, resulting in formation of the acetal 2 (Scheme 4).
The structures of all the reaction products obtained were established on the basis of NMR studies
1
1
(2D H±1H and H±13C COSY correlation was applied when necessary).9 To determine the
absolute con®guration of compound 2a0, the di-(R)-MPA ester 8 from compound 2a0 and the
corresponding diastereomeric ester mixtures from racemic 2a0 were made. The 13C NMR spectra
of the diastereomeric mixture rac-8 and 8 (Scheme 5) gave regular and well-de®ned e€ects derived
from the second aromatic nucleus (the ester of the tertiary alcohol), shifting the C-1 (0.30 ppm),
C-4 (0.32 ppm) and H-4 (0.18 and 0.17 ppm) signals in opposite directions. On the basis of these
values, the absolute con®guration of 2a0 was determined assuming that the same regularities are
observed as are known for secondary alcohols10 (in the present case the position of the carbinol
proton is replaced by the methyl group). Thus, the R con®guration is proposed for 2a0 on the
basis of all 1H and 13C chemical shifts11 and their analysis, as described in the literature.10
Scheme 3.
Scheme 4.

6886
Scheme 5.
Acknowledgements
Support from the Estonian Science Foundation (Grant Nos. 3834, 3781 and 3164) is
acknowledged.
References
1. Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
NewYork, 1991; Vol. 7, Chapter 3.2, pp. 389±436. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765±5780.
2. Pitchen, P.; Dunach, E.; Desmukh, M. N.; Kagan, H. B. J. Am. Chem. Soc. 1984, 106, 8188±8193. Furia, F. D.;
Modena, G.; Seraglia, R. Synthesis 1984, 325±326.
3. For some other possibilities for asymmetric Baeyer±Villiger oxidation of cycloalkanones, see: Bolm, C.;
Schlinglo€, G.; Weickhardt, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 1848±1849. Bolm, C.; Schlinglo€, G.
J. Chem. Soc., Chem. Commun. 1995, 1247±1248. Sugimura, T.; Fujiwara, Y.; Tai, A. Tetrahedron Lett. 1997, 38,
6019±6022. Bolm, C.; Schlinglo€, G.; Bienewald, F. J. Mol. Catal. A: Chemical 1997, 117, 347±350. Bolm, C.;
Luong, T. K. K.; Schlinglo€, G. Synlett 1997, 1151±1152. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737±
750.
4. Lopp, M.; Paju, A.; Kanger, T.; Pehk, T. Tetrahedron Lett. 1996, 37, 7583±7586. Kanger, T.; Kriis, K.; Paju, A.;
Pehk, T.; Lopp, M. Tetrahedron: Asymmetry 1998, 9, 4475±4482.
5. For enantiomeric a-hydroxyketones, see: Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919±934 and references
cited therein. Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067±5068. Fukuda, T.;
Katsuki, T. Tetrahedron Lett. 1996, 37, 4389±4392. Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Moller, C. R.
J. Am. Chem. Soc. 1998, 120, 708±714.
6. Lopp, M.; Paju, A.; Kanger, T.; Pehk, T. Tetrahedron Lett. 1997, 38, 5051±5054.
7. Compounds 1a and 1b were obtained from Aldrich; 1c and 1c0 were prepared from 2-cyclopentene-1-acetic acid.
8. Diketone 2a00 was also seen in 13C NMR spectra (depending on the solvent used).
9. The structures of obtained compounds were con®rmed by their fully assigned 500.17 MHz 1H and 125.7 MHz 13
C
NMR spectra. Compound 2a: 1H NMR (CDCl3) ꢀ 1.95 and 2.02 (H-4, m), 2.38 (H-5, m), 3.19 (2-OMe, s), 1.32 (3-
Me, s), 2.43 and 4.31 (OH at C-2 and C-3); 13C NMR ꢀ 213.12 (C-1), 98.37 (C-2), 76.67 (C-3), 30.30 (C-4), 31.20
(C-5), 50.36 (2-OMe), 19.73 (3-Me). Compound 2a0 (DMSO-d6), enol form: 6.32 (H-3, t, 3.2 Hz), 2.37 and 2.42 (H-
4, dd, Jgem=17.3 Hz), 1.16 (5-Me, s); 13C NMR ꢀ 204.69 (C-1), 150.89 (C-2), 127.08 (C-3), 39.43 (C-4), 71.90 (C-
5), 25.06 (5-Me). Compound 2a00 (DMSO-d6), keto form: H NMR ꢀ 2.10 (H-4, m), 2.41 and 2.45 (H-5, m), 1.27
1
(3-Me, s); 13C NMR ꢀ 200.84 (C-1), 204.41 (C-2), 71.73 (C-3), 30.75 (C-4), 32.73 (C-5), 21.37 (3-Me), di€erent
from the starting compound 1, which exists predominantly (>97%) in the enol form in chloroform or in DMSO
solution; both forms of 2a0 and 2a00 are seen without any indication of exchange in room temperature NMR
1
spectra. Compound 2b (as 3-ethyl-2,3-dihydroxy-2-methoxycyclopentanone): H NMR (CDCl3) ꢀ 1.94 (H-4, m),
2.41 (H-5, m), 3.18 (2-OMe, s), 1.68 (3-Et CH2, m), 0.98 (3-Et Me, t 7.5); 13C NMR ꢀ 213.54 (C-1), 98.78 (C-2),
77.00 (C-3), 28.38 (C-4), 31.24 (C-5), 50.26 (2-OMe), 6.73 and 25.75 (3-Et). Compound 2b0 (as 5-ethyl-2,5-

6887
dihydroxy-cyclopent-2-en-1-one): 1H NMR (CDCl3) ꢀ 6.57 (H-3, t, 3.2 Hz), 2.53 and 2,63 (H-4, both dd, Jgem=17.6
Hz), 0.91 (5-Et methyl, t, 7.5 Hz), 1.65 and 1.70 (CH2 of Et, q 7.5, d 13.7), 6.2 and 2.8 (2- and 5-OH, bs); 13C
NMR ꢀ 205.27 (C-1), 150.42 (C-2), 129.63 (C-3), 36.29 (C-4), 75.95 (C-5), 31.15 and 7.66 (5-Et). Compound 2c (as
1
1,5-dihydroxy-2-oxabicyclo[3.3.0]octan-8-one): H NMR (CDCl3+CD3OD) ꢀ 3.80 and 4.05 (H-3, m), 2.05 (H-4,
m), 1.87 and 1.92 (H-6, m), 2.34 and 2.36 (H-7, m); 13C NMR ꢀ 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). Compound 4a (as 2-methyl-5-oxotetrahydrofuran-2-carboxylic acid): 1H
NMR (CDCl3) ꢀ 1.70 (CH3, s), 2.20 (H-3, t 9.9, d 13.4), 2.60 (H-3, d 3.8, d 9.8, d 13.4), 2.63 and 2.72 (H-4, m),
10.4 (COOH); 13C NMR ꢀ 83.50 (C-2), 32.87 (C-3), 28.29 (C-4), 176.71 (C-5), 23.37 (2-Me), 176.31 (2-COOH).
Compound 4b (as 2-ethyl-5-oxotetrahydrofuran-2-carboxylic acid): 1H NMR (CDCl3) ꢀ 1.02 (CH3, t 7.5), 1.89 and
2.12 (CH2 of Et, q 7.5, d 14.3), 2.23 (H-3, t 9.8, d 13.5), 2.53 (H-3, d 3.9, d 9.8, d 13.5), 2.57 and 2.63 (H-4, m), 9.90
(COOH); 13C NMR ꢀ 86.97 (C-2), 30.97 (C-3), 28.08 (C-4), 176.39 (C-5), 8.03 and 30.33 (2-Et), 176.11 (2-COOH).
Compound 4c (as 3-(3-hydroxy-2-oxotetrahydrofuran-3-yl)propanoic acid): 1H NMR (CDCl3) ꢀ 2.30 and 2.34 (H-
2, m), 1.75 and 1.91 (H-3, m), 2.09 and 2.11 (H-40, m), 4.06 and 4.19 (H-50, m); 13C NMR ꢀ 175.52 (C-1), 27.57 (C-
2), 30.35 (C-3), 178.44 (C-20), 73.13 (C-30), 34.74 (C-40), 65.06 (C-50). Compound 4c0 (as methyl-3-(3-hydroxy-2-
oxotetrahydrofuran-3-yl)propanoate): 1H NMR (CDCl3) ꢀ 2.59 and 2.61 (H-2, m), 2.03 and 2.15 (H-3, m), 2.26 and
2.38 (H-40, m), 4.25 and 4.41 (H-50, m), 3.70 (OMe, s); 13C NMR ꢀ 174.25 (C-1), 28.13 (C-2), 30.85 (C-3), 178.09
(C-20), 73.82 (C-30), 35.27 (C-40), 65.15 (C-50), 52.08 (OMe). Compound 4c00 (as 1,7-dioxaspiro[4.4]nonane-2,6-
dione): 1H NMR (CDCl3) ꢀ 2.64 and 2.93 (H-3, m), 2.29 and 2.59 (H-4, m), 4.39 and 4.47 (H-8, m), 2.42 and 2.69
(H-9, m); 13C NMR ꢀ 174.04 (C-2), 27.86 (C-3), 29.25 (C-4), 82.05 (C-5), 174.83 (C-6), 65.45 (C-8), 34.15 (C-9).
10. Pehk, T.; Lippmaa, E.; Lopp, M.; Paju, A.; Borer, B. C.; Taylor, R. J. K. Tetrahedron: Asymmetry 1993, 4, 1527±
1532.
1
1
11. 500.17 MHz H and 125.7 MHz 13C NMR spectra (CDCl3). Compound R-8: H NMR ꢀ 7.24 (H-3, t 3.2), 2.65
and 2.89 (H-4, dd, Jgem=18.1), 4.78 and 4.97 (H-100 and H-20, s), 3.45 and 3.49 (OMe, s), 7.35±7.50 (o, m, p); 13C
NMR ꢀ 195.67 (C-1), 146.21 (C-2), 139.71 (C-3), 37.57 (C-4), 78.59 (C-5), 167.64 and 169.73 (C-10 and C-200), 82.12
and 82.26 (C-100 and C-20), 57.54 and 57.70 (C-OMe), 135.19 and 135.54 (s0 and s00), 127.15 and 127.38 (o0 and o00),
128.65 and 128.78 (m and m0), 128.83 and 129.06 (p and p0). Compound S-8: 1H NMR ꢀ 7.07 (H-3, t 3.2), 2.54 and
2.71 (H-4, dd, Jgem=18.1), 4.49 and 5.00 (H-100 and H-20, s), 3.41 and 3.49 (OMe, s), 7.35±7.50 (o, m, p); 13C NMR
ꢀ 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 (C-10 and C-200), 81.82 and
81.98 (C-100 and C-20), 57.50 and 57.67 (C-OMe), 135.21 and 135.70 (s0 and s00), 127.22 and 127.40 (o0 and o00),
128.72 and 128.82 (m and m0), 128.90 and 129.11 (p and p0).