Enzymatic Resolution of Ethyl 3-Hydroxy-3-Phenylpropanoate and Analogs using Hydrolases

Abstracts

This work contributes to the substrate model study of enzymatic hydrolysis of secondary and tertiary beta-hydroxy esters. One secondary and four tertiary beta-hydroxy esters have been employed with PCL, PLE, CRL and AOP enzymes. The best result was observed when PCL was used as an enzyme for the reaction of the secondary ester, ethyl 3-hydroxy-3-phenylpropanoate (1a) (conversion of 50%, ester (R)-1a recovered with 98% e.e. and the acid 1 with 93% e.e. On the other hand, PLE showed the best result for tertiary ethyl 3-hydroxy-3-phenylbutanoate (2a) and ethyl 3-cyclohexyl-3-hydroxy-3-phenylpropanoate (3a), despite the poor selectivity. Ethyl 2-(1-hydroxycyclohexyl)-butanoate (4a) and ethyl 2-(1-hydroxycyclopentyl)-butanoate (5a) were only hydrolyzed by PLE and CRL, but showed no enantioselectivity.

beta-hydroxy ester; enzymatic hydrolysis; hydrolases

Este trabalho contribui com o estudo da relação substrato-modelo em reações de hidrólise de ésteres beta-hidroxilados secundários e terciários. Foram utilizados um beta-hidroxiéster secundário e quatro beta-hidroxiésteres terciários, com as enzimas PCL, PLE, CRL e AOP. O melhor resultado foi obtido quando efetuou-se a reação enzimática do éster secundário 3-hidroxi-3-fenilpropanoato de etila (1a) com a PCL (50% de conversão, éster (R)-1a recuperado com 98% e.e., e o ácido 1 obtido em 93% e.e. Por outro lado, a PLE apresentou o melhor resultado para os ésteres terciários 3-hidroxi-3-fenilbutanoato de etila (2a) e 3-cicloexil-3-hidroxi-3-fenilpropanoato de etila (3a), apesar da baixa seletividade. PLE e CRL também foram avaliadas na resolução enzimática de 2-(1-hidroxicicloexil)-butanoato de etila (4a) e 2-(1-hidroxiciclopentil)-butanoato de etila (5a), entretanto, não apresentaram seletividade.

Article

Enzymatic Resolution of Ethyl 3-Hydroxy-3-Phenylpropanoate and Analogs using Hydrolases

Carlos M. R. Ribeiro^*, Elisa N. Passaroto and Eugênia C. S. Brenelli

Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Campus Valonguinho, 24020-150, Niterói - RJ, Brazil

Este trabalho contribui com o estudo da relação substrato-modelo em reações de hidrólise de ésteres b-hidroxilados secundários e terciários. Foram utilizados um b-hidroxiéster secundário e quatro b-hidroxiésteres terciários, com as enzimas PCL, PLE, CRL e AOP. O melhor resultado foi obtido quando efetuou-se a reação enzimática do éster secundário 3-hidroxi-3-fenilpropanoato de etila (1a) com a PCL (50% de conversão, éster (R)-1a recuperado com 98% e.e., e o ácido 1 obtido em 93% e.e. Por outro lado, a PLE apresentou o melhor resultado para os ésteres terciários 3-hidroxi-3-fenilbutanoato de etila (2a) e 3-cicloexil-3-hidroxi-3-fenilpropanoato de etila (3a), apesar da baixa seletividade. PLE e CRL também foram avaliadas na resolução enzimática de 2-(1-hidroxicicloexil)-butanoato de etila (4a) e 2-(1-hidroxiciclopentil)-butanoato de etila (5a), entretanto, não apresentaram seletividade.

This work contributes to the substrate model study of enzymatic hydrolysis of secondary and tertiary b-hydroxy esters. One secondary and four tertiary b-hydroxy esters have been employed with PCL, PLE, CRL and AOP enzymes. The best result was observed when PCL was used as an enzyme for the reaction of the secondary ester, ethyl 3-hydroxy-3-phenylpropanoate (1a) (conversion of 50%, ester (R)-1a recovered with 98% e.e. and the acid 1 with 93% e.e. On the other hand, PLE showed the best result for tertiary ethyl 3-hydroxy-3-phenylbutanoate (2a) and ethyl 3-cyclohexyl-3-hydroxy-3-phenylpropanoate (3a), despite the poor selectivity. Ethyl 2-(1-hydroxycyclohexyl)-butanoate (4a) and ethyl 2-(1-hydroxycyclopentyl)-butanoate (5a) were only hydrolyzed by PLE and CRL, but showed no enantioselectivity.

Keywords: b-hydroxy ester, enzymatic hydrolysis, hydrolases

Introduction

Enzyme catalysis has been one of the most useful methods for the preparation of enantiomerically pure compounds. Numerous studies have indicated the application of enzymes to prepare synthons for use in asymmetric synthesis and many reviews on this subject have been published recently¹. Enzymes such as Pig liver esterase (PLE), Pseudomonas cepacia lipase (PCL), Candida rugosa lipase (CRL), Burkholderia cepacia lipase (BCL), and Aspergillus oryzae protease (AOP) have been used. Enzymes can be employed in the resolution of alcohols and esters and many examples have been reported in the literature¹. The enzymatic hydrolysis of ethyl 3-hydroxy-3-phenyl-propanoate (1a) or other ester derivatives to the 3-hydroxy-3-phenylpropanoic acid (1) have interested several research groups. Acid 1 is an important intermediate in the synthesis of tomoxetine (I) and fluoxetine (II) hydrochlorides, widely used as antidepressants² (Figure 1).

To this end, PLE³ has been applied and more recently Pseudomonas sp² (Reaction 1). Penicillin G Amidohydrolase⁴ (PGA) and lipase A^4b were also used in the hydrolysis of 1a O-acetyl derivative.

With PLE and at pH 7, a 50% conversion was achieved, yielding ester (R)-1a in 28% (43% e.e.) and (S)-acid 1c in

35% (39% e.e.). Improved enantiomeric excess (58% e.e. for (R)-1a and 46% e.e for (S)-acid 1³ were achieved using 20% aqueous ethanol.

The hydrolysis of 1a in a phosphate buffer solution at pH 7 using lipase PS-30 from Pseudomonas sp (Amano), furnished (S)-acid 1 in 39% conversion and 93% e.e. which was improved to 36% conversion of (R)-1a (98% e.e.), after two consecutive enzymatic hydrolysis².

The hydrolysis of the acetyl ester of 1a using PGA at pH 8 in a phosphate buffer solution led to (R)-1a (36% e.e.)^4a. The hydrolysis of the same derivative using lipase A (Amano) led to ester (S)-1a (95% e.e.)^{4b, 1e}.

These results prompted us to develop a complementary study on the resolution of 1a (prepared as stated in the literature by a classical Aldol reaction)⁵, using the lipases from Pseudomonas cepacia and Candida rugosa, the protease from Aspergilus oryzae, as well as the esterase from Pig liver at pH 8 in a phosphate buffer solution to evaluate the best hydrolysis conditions.

In contrast to secondary alcohol synthesis, relatively few examples of the enzymatic resolution of more substituted systems have been reported⁶. As an extension of this work, the enzymatic resolution of ethyl 3-hydroxy-3-phenylbutanoate (2a) and ethyl 3-cyclohexyl-3-hydroxy-3-phenylpropanoate (3a), as well as ethyl 2-(1-hydroxy-cyclohexyl)-butanoate (4a) and ethyl 2-(1-hydroxycyclo-pentyl)-butanoate (5a) (Figure 2) were studied. These products were also obtained by aldol reactions.

Experimental

The solvents and reagents used were supplied by E. Merck or Aldrich Co. and THF was purified through a process of distillation over LiAlH₄, according to standard laboratory techniques. Melting points were determined on a Fischer-Johns apparatus. Flash chromatography was performed using Kieselgel 60 (230–400 mesh, E. Merck). IR spectra were recorded on films or KBr pellets with a Perkin Elmer 1420 spectrometer. ¹H MNR and ¹³C NMR spectra were obtained in CDCl₃ solutions (Me₄Si as internal standard) with a Varian Unity Plus 300 instrument. Whenever necessary, the e.e. was observed using tris-[3-heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III) derivative (Eu(hfc)₃). Optical rotations were measured in EtOH or CHCl₃ solutions with a Polartronic NH8 Schmidt/Haensch polarimeter at room temperature. The mass spectra were obtained with a VG Autoespec. Pig liver esterase (PLE, E3128, 300 units/mg protein, 15 mg protein/mL suspension), Pseudomonas cepacia lipase (PCL, L9156, 90 units/g solid), Candida rugosa lipase (CRL, type VII, L1754, 835 units/mg solid) and Aspergillus oryzae protease (AOP, type XXIII, P4032, 3,6 units/mg solid) were purchased from Sigma Co.

Preparation of racemic b-hydroxy esters 1a, 2a, 3a, 4a and 5a⁵

General procedure: Under N₂ atmosphere, n-butyllithium (24 mmol) was added to a solution of diisopropylamine (3.7 mL, 26.4 mmol) and THF (15 mL) at –78 ^oC. The solution was stirred for 15 min. The corresponding ethyl ester (22 mmol) was added dropwise to a solution of LDA and the reaction was conducted under stirring for 45 min. After that, benzaldehyde or ketone was added dropwise. The mixture was stirred for 6 h at –78 ^oC, and then treated with NH₄Cl saturated solution and extracted with ethyl acetate. The organic layer was washed with water, saturated with NaCl, and dried over MgSO₄. The solvent was evaporated and the crude product was purified through chromatography on silica gel (n-hexane:ethyl acetate, 95:5).

Ethyl 3-hydroxy-3phenylpropanoate 1a⁹: 95% yield; colorless oil; IR n_max./cm^-1 3450 (OH), 1720 (CO), 1190(CC) (film); ¹H NMR (300 MHz, CDCl₃), d1.27 (3H, t, J 7.2 Hz), 2.70 (1H, dd, J 16.4 and 4.8 Hz), 2.77 (1H, dd, J 16.4 and 8.4 Hz), 3.27 (br s, -OH), 4.18 (2H, q, J 7.2 Hz), 5.13 (1H, dd, J 8.4 and 4.8 Hz), 7.26-7.40 (5H, m); ¹³C NMR (75 MHz, CDCl₃), d14.0, 43.2, 60.8, 70.2, 125.6, 127.7, 128.4, 142.4, 172.3; EI-MS m/z (%) 194 (32), 107 (100), 79 (59).

Ethyl 3-hydroxy-3-phenylbutanoate 2a¹⁰: 80% yield; colorless oil; IR n_max./cm^-1 3480, 1720, 1200 (film); ¹H NMR (300 MHz, CDCl₃), d1.13 (3H, t, J 7.2 Hz), 1.54 (3H, s), 2.79 (1H, d, J 15.9 Hz), 2.98 (1H, d, J 15.9 Hz), 4.06 (2H, q, J 7.2 Hz), 4.41 (br, s, -OH), 7.20-7.47 (5H, m); ¹³C NMR (75 MHz, CDCl₃), d13.8, 30.05, 46.3, 60.6, 72.6, 124.3, 126.7, 128.1, 146.7, 172.6; EI-MS m/z (%) 209 (7), 121 (100), 105 (77).

Ethyl 3-cyclohexyl-3-hydroxy-3-phenylpropanoate 3a¹¹: 75% yield; colorless oil; IR n_max./cm^-1 3480, 1720, 1200 (film); ¹H NMR (300 MHz, CDCl₃), d0.97-1.77 (12H, m), 1.03 (3H, t, J 7.2 Hz), 2.85 (1H, d, J 15.6 Hz), 3.01 (1H, d, J 15.6 Hz), 3.96 (2H, q, J 7.2 Hz), 7.18-7.49 (5H, m); ¹³C NMR (75 MHz, CDCl₃), d13.7, 26.2, 26.9, 42.2, 42.2, 48.6, 60.4, 77.1, 125.7, 126.5, 127.6, 144.9, 173.4; EI-MS m/z (%) 276 (M+), 193 (95), 105 (100).

Ethyl 2-(1-hydroxycyclohexyl)-butanoate 4a¹²: 80% yield; colorless oil; IR n_max./cm^-1 3500, 1715, 1180 (film); ¹H NMR (300 MHz, CDCl₃), d0.90 (3H, t, J 7.2 Hz), 1.25-1.77 (11H, m), 1.29 (3H, t, J 6.9 Hz), 2.34 (1H, dd, J 4.8 and 10.6 Hz), 4.20 (2H, q, J 6.9 Hz); ¹³C NMR (75 MHz, CDCl₃) d12.2, 14.2, 19.4, 21.6, 21.8, 25.6, 34.4, 37.4, 56.2, 60.2, 71.5, 176.4.

Ethyl 2-(1-hydroxycyclopentyl)-butanoate 5a¹³: 77% yield; colorless oil; IR n_max./cm^-1 3450, 1710, 1180 (film); ¹H NMR (300 MHz, CDCl₃) d0.93 (3H, t, J 7.2 Hz), 1.40-1.95 (10H, m), 1.30 (3H, t, J 7.2 Hz), 2.29 (1H, dd, J 3.9 and 11.4 Hz), 2.50 (1H, br s, -OH), 4.20 (2H, q, J 7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) d12.3, 14.2, 21.6, 23.5, 23.7, 37.5, 39.9, 56.1, 60.3, 82.1, 176.5.

Enzymatic hydrolyses

General procedure: racemic esters 1a, 2a, 3a, 4a and 5a (1 mmol) were combined with a phosphate buffer solution (10 mL) (Table 1 and 2) of pH 7 or 8 and with enzyme (units; Table 1 or 2) under vigorous stirring at room temperature. The pH was maintained constant with the continuous addition of 0.25 mol L^-1 aqueous NaOH. After the indicated conversion (Table 1 and 2), the reaction was stopped. The reaction mixture was diluted with aqueous NaHCO₃ and extracted three times with ether. The combined organic layers were dried (MgSO₄) and concentrated in order to obtain 1a, 2a, 3a, 4a or 5a, respectively (the % yield and e.e. are presented in Table 1 and 2). The combined aqueous solution was acidified to pH 1 with 3 mol L^-1 HCl and extracted three times with ether. The extracts were dried (MgSO₄) and concentrated to obtain acid 1, 2, 3, 4 or 5, respectively (the % yield and e.e. are presented in Table 1 and 2).

Esters 1a, 2a, 3a, 4a, and 5a: ¹H and ¹³C NMR, IR, MS data, see above. The e.e. value and the % yield are presented in Table 1 and Table 2. To 1a ester at 50% conversion [a]²⁰_D +44.2 (c 1.01, CHCl₃), literature² [a]²⁰_D +44.0 (c 1.015, CHCl₃), >98% e.e..

3-Hydroxy-3-phenylpropanoic acid 1²: mp 115 ^oC; IR n_max./cm^-1 3450-2500, 1700 (film); ¹H NMR (300 MHz, CDCl₃) d 2.78 (1H, dd, J 16.5 and 3.9 Hz), 2.86 (1H, dd, J 16.5 and 9.0 Hz), 3.80 (br s, -OH), 5.17 (1H, dd, J 9.0 and 3.9 Hz), 7.28-7.41 (5H, m); ¹³C NMR (75 MHz, CDCl₃), d 44.0, 70.3, 125.9, 127.4, 128.4, 144.8, 172.2; EI-MS m/z (%): 166 (54), 107 (100), 79 (83).

3-Hydroxy-3-phenylbutanoic acid 2¹⁰: mp 52 ^oC; IR n_max./cm^-1 3480-2500, 1720 (film); ¹H NMR (300 MHz, CDCl₃) d 1.55 (3H, s), 2.83 (1H, d, J 16.2 Hz), 3.02 (1H, d, J 16.2 Hz), 4.45 (br s, -OH), 7.22-7.44 (5H, m); ¹³C NMR (75 MHz, CDCl₃) d 30.4, 45.8, 72.7, 124.2, 127.0, 128.3, 146.1, 177.2; EI-MS m/z (%): 180 (11), 165 (100), 121 (56), 105 (28).

3-Cyclohexyl-3-hydroxy-3-phenylpropanoic acid 3¹¹: mp 174 ºC; IR n_max./cm^-1 3500-2600, 1680 (film); ¹H NMR (300 MHz, CDCl₃) d 0.88-1.74 (11H, m), 2.90 (1H, d, J 15.9 Hz), 3.06 (1H, d, J 15.9 Hz), 7.20-7.36 (5H, m); ¹³C NMR (75 MHz, CDCl₃) d 26.1, 26.3, 26.4, 26.7, 26.9, 41.5, 48.7, 77.0, 125.5, 126.8, 127.8, 144.3, 177.3; EI-MS m/z (%): 191 (34), 165 (79), 105 (100), 77 (31).

Results and Discussion

The hydrolysis of ester 1a using PCL, PLE, CRL and AOP enzymes were initially studied and the results are presented in Table 1.

The results observed in this work were similar to those obtained by Boaz² and Santaniello³, where the Pseudomonas sp lipase was more active than PLE esterase, in the enzymatic ester 1a hydrolysis. These differences in the activities between these enzymes have been discussed elsewhere^1g.

As expected, the best result was achieved when PCL was used (Table 1). The hydrolysis of 1a at 50% conversion gave the remaining (R)-1a in >98% e.e. and the (S)-acid 1 in 93% e.e. (entry 4, Table 1).

Figure 3 shows the reaction curve for the ester hydrolysis, which demonstrates that the conversion rate decreased drastically after 50% of conversion. Our results showed that the ester hydrolysis could be carried out in a single step without successive reactions, as already mentioned. Similar conclusions were reached for the enzymatic acetylation of the 3-hydroxy-4-alkoxy methylbutanoate, as reported recently by Wunsche et al⁷.

The results obtained from the hydrolysis of ester 1a using PLE at pH 8 (entry 7, Table 1) were similar to those reported by Santaniello et al³. However, at pH 8 a faster hydrolysis reaction was achieved compared with the data reported by Santaniello at pH 7 (40 min versus 4h). The hydrolysis of 1a using AOP was comparable with PLE results, with a significant enhancement in the e.e. towards the recovered ester and the obtained acid (entry 10, Table 1). Compared with the other enzymes, CRL showed little enantioselectivity for the hydrolysis of 1a and a rather extended time of reaction (entry 8, Table 1).

Esters 2a and 3a were hydrolyzed with PLE, PCL and CRL, under the same reaction conditions employed for ester 1a.

PLE at pH 8 provided the best results (Table 2).

When PLE was used in the hydrolysis of 2a and 3a, the recovered esters showed poor selectivity (entry 1 and 4, Table 2). (S)-acid 2 presented a modest e.e. (50%), and acid 3 was racemic. DMSO was used as a cosolvent and the temperature was lowered in order to improve the results for the hydrolysis of 2a. Notwithstanding these modifications the results remained unsatisfactory (entry 2 and 3, Table 2).

CRL (150 mg enzyme and pH 7) promoted the hydrolysis of 2a. However, the products obtained were racemic. After 7 days at room temperature and a conversion of 32%, the yields of recovered ester 2a and acid 2 were 62% and 32%, respectively. Esters 2a and 3a were inert to PCL catalyzed hydrolysis under the same conditions of the 1a hydrolysis.

From the results presented in Tables 1 and 2, a decrease of the enantiomeric excess and an increase in the reaction time may be observed when an hydrogen on C-3 is replaced by methyl and cyclohexyl groups (entry 7, Table 1; entry 1 and 4, Table 2), showing that for larger groups at C-3 the enzyme was not selective. There are useful models for acylated secondary alcohols and a-substituted esters that predict which enantiomer will be faster hydrolyzed^1g,k,n,o,p. The importance of the groups at C-3 concerning enzyme active site are discussed in some papers^1o, and using these models we can infer that bulkier groups at C-3 decrease the enzyme selectivity. The results corroborate the above assumption to the molecular modelling studies of the active site of these enzymes^1p.

PLE and CRL were also used in the hydrolysis of the b-hydroxy esters 4a and 5a. Although these enzymes promoted hydrolyses, only racemic esters and corresponding racemic acids were obtained under these conditions. When PLE (50 units) was employed for the ester hydrolysis of 4a at pH 8 and at room temperature, the yield of recovered ester 4a was 42% and for the corresponding acid was 30% after 9 days at a conversion of 37%. When CRL (150 mg) was used, the reaction time for ester 4a was 5 days at a conversion of 14% (the yield of recovered ester 4a was 11%) and 2 h for ester 5a at a conversion of 15% (the yield of recovered ester 5a was 55%), at pH 7 at room temperature. These results showed that the presence of five and six member rings reduce the enzyme discrimination in these substrates, as observed for 2a and 3a.

The results presented in this paper have added new data to the previously developed works^2-4 and expand the scope of the estimation of the enzymes active sites through molecular modeling studies^1p. The hydrolyses were carried out under different reaction conditions and other enzymes were employed. Four different b-hydroxy esters were also analyzed and the results obtained demonstrated the importance of the group size present at the b carbon during the reaction, as above mentioned. Results confirm that PCL is a better enzyme to hydrolyze secondary b-hydroxy esters than PLE, CRL and AOP. On the other hand PLE, though depicting poor selectivity is more substrate specific. Experiments are in progress in our laboratory to improve the reactions conversions and selectivities.

Acknowledgment

This work was supported by CAPES and PADCT/CNPq.

References

1. (a) Roberts, S. M. Perkin 1 1999, 1; (b) Jones, J. B.; Desantis, G. Acc. Chem. Res. 1999, 32, 99; (c) Stecher, H.; Faber, K. Synthesis 1997, 1; (d) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1995, 51, 3769; (e) Santaniello, E.; Ferrabosh, P.; Grisenti P.; Manzocchi, A. Chem. Rev. (Washington, D. C.) 1992, 92, 1071; (f) Gupta, M. N. Eur. J. Biochem. 1992, 203, 25; (g) Kaslaukas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656; (h) Zhu, L. M.; Tedford, M. C. Tetrahedron 1990, 46, 6587; (i) Chen C. S.; Sih, C. J. Angew. Chem., Int. Ed. 1989, 28, 695; ( j) Whitesides, G. M.; Wong, C. H. Angew. Chem., Int. Ed. 1985, 24, 617; (k) Faber, K. In Biotransformations in Organic Chemistry; Springer-Verlag; Berlin, 1997; (l) Stecher, H.; Faber, K. Synthesis 1997, 1; (m) Azerad, R. Bull. Soc. Chim. Fr. 1995, 132, 17; (n) Lemke, K.; Lemke, M.; Theil, F. J. Org. Chem. 1997, 62, 6268; (o) Itoh, T.; Kuroda, K.; Tomasada, M.; Takagi, Y. J. Org. Chem. 1991, 56, 797; (p) Grabuleda, X.; Jaime, C.; Guerrero, A. Tetrahedron: Asymmetry 1997, 8, 3675

2. Boaz, N. W. J. Org. Chem. 1992, 57, 4289.

3. Santaniello, E.; Ferrabosh, P.; Grisenti, P.; Manzocchi, A.; Trave, S. Gazz. Chim. Ital. 1989, 119, 581.

4. (a) Baldaro, E.; D'Arrigo, P.; Fantoni, P.; Rosell, C. M.; Servi, S.; Tagliani, A.; Terreni, M. Tetrahedron: Asymmetry 1993, 4, 1031; (b) Kumar, A.; Dike S. Y.; Ner, D. H. Bioorg. Med. Chem. Lett. 1991, 1, 383.

5. Keukeleire, D. D.; Saeyens, W. Synth. Commun. 1996, 26, 4397.

6. (a) Feichter, C.; Faber, K.; Griengl, H. Perkin 1 1991, 653; (b) O'Hagen, D.; Zaid, N. A. Chem. Commun. 1992, 947; (c) Brackenridge, I.; McCague, R.; Roberts S. M.; Turner, N. J. Perkin 1 1993, 1093.

7. Wunsche, K.; Schwanenberg, U.; Bornscheur, U. T.; Meyer, H. H. Tetrahedron: Asymmetry 1998, 9, 3825.

8. Mohr, P.; Waespe-Sarcevic, N.; Tamm, C.; Gawronska, K.; Gawronski J. K. Helv. Chim. Acta 1983, 66, 2501.

9. Manzocchi, A.; Casati, R.; Fiecchi, A.; Santaniello, E.; Zhang,Y.; Wu,W. Tetrahedron: Asymmetry 1997, 8, 3575.

10. Kobayashi, M. Chem. Pharm. Bull. 1972, 20, 1898.

11. (a) Schjelderup, L.; Harbitz, O.; Groth, P.; Aasen, A. J. Acta Chem. Scand. B 1987, 41, 356; (b) Obata, S. J. Pharm. Soc. Jpn. 1953, 73, 1295.

12. (a) Duiding, A. S.; Pratt, R. J. J. Am. Chem. Soc. 1953, 75, 3717; (b) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetrahedron 1997, 53, 12469.

13. Rathke, M. R. Org. React. 1975, 22, 423.

Received: June 19, 2000

Published on the web: August 10, 2001

Publication Dates

• Publication in this collection
  15 Apr 2002
• Date of issue
  Dec 2001

History

• Accepted
  10 Aug 2001
• Received
  19 June 2000