Enzymatic Desymmetrization of Prochiral 2-Substituted-1,3-propanediols: A Practical Chemoenzymatic Synthesis of a Key Precursor of SCH51048, a Broad-Spectrum Orally Active Antifungal Agent

Journal of Organic Chemistry

Volumn 62, Issue 22, 1997, Pages 7736-7743

  Morgan, Brian ^a   Dodds, David R ^a   Zaks, Aleksey ^a   Andrews, David R ^b   Klesse, Ricardo ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Chemical Process R and D   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIFUNGAL AGENT; BACTERIAL ENZYME; PROPANEDIOL DERIVATIVE; SCH 51048; UNCLASSIFIED DRUG;

ARTICLE; CATALYSIS; DRUG ACETYLATION; DRUG HYDROLYSIS; DRUG SYNTHESIS; ENZYMATIC ASSAY; ESTERIFICATION; NONHUMAN;

EID: 0030831509     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo9709920     Document Type: Article

References (22)

1. (a) 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Orlando, Florida, 4-7th October 1994. (Abstract Nos. B16, F181, F183, F185, F187, F193, F195, F197 B179).
2. (b) Blundell, P.; Ganguly, A. K.; Girijavallabhan, V. M. Synlett 1994, 263-265.
3. (c) Saksena, A. K.; Girijavallabhan, V. M.; Lovey, R. G.; Pike, R. E.; Desai, J. A.; Ganguly, A. K.; Hare, R. S.; Loebenberg, D.; Cacciapuoti, A.; Parmegiani, R. M. Biorg. Med. Chem. Lett. 1994, 4, 2023-2028.
4. (d) Lovey, R. G.; Saksena, A. K.; Girijavallabhan, V. M. Tetrahedron Lett. 1994, 35, 6047-6050.
5. (e) Saksena, A. K.; Girijavallabhan, V. M.; Lovey, R. G.; Desai, J. A.; Pike, R. E.; Jao, E.; Wang, H.; Ganguly, A. K.; Loebenberg, D.; Hare, R. S.; Cacciapuoti, A.; Parmegiani, R. M. Biorg. Med. Chem. Lett. 1995, 7, 127-132.
6. (f) A preliminary report of some of this work has appeared previously: Saksena, A. K.; Girijavallabhan, V. M.; Lovey, R. G.; Pike, R. E.; Wang, H.; Ganguly, A. K.; Morgan, B.; Zaks, A.; Puar, M. S. Tetrahedron Lett. 1995, 36, 1787-1790.
7. (g) Saksena, A. K.; Girijavallabhan, V. M.; Pike, R. E.; Wang, H.; Lovey, R. G.; Liu, Y.-T.; Ganguly, A. K.; Morgan, W. B.; Zaks, A. US Patent 5,403,937, April 4, 1995.
8. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976.
9. Blocking the pro-S hydroxyl of triol 6, followed by tosylation, cyclization, deblocking, and tosylation would result in a five-step sequence to cis tosylate 8a. Alternatively, blocking the pro-R hydroxyl would require a seven-step sequence to 8a because of the extra steps to invert the 2R chiral center. Pro-R hydrolysis of the triol diester 10 or 11 would require six steps to 8a.
10. (a) Ramos Tombo, G. M.; Schar, H.-P.; Fernandez i Busquets, X.; Ghisalba, O. Tetrahedron Lett. 1986, 27, 5707-5710.
11. (b) Boland, W.; Frössl, C.; Lorenz, M. Synthesis 1991, 1049-1072.
12. (c) Danieli, B.; Lesma, G.; Passerella, D.; Riva, S. In Adv. Use Synthons Org. Chem. 1993, 1, 143-219.
13. (d) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769-3826.
14. The acylation of 6 and the hydrolysis of 10, 11b varied with enzyme tot and with the nature of the acyl group. Using Sigma PPL Type II, lot no. 23H0294 was more reactive than lot no. 41H0954 under acylation conditions. With both enzyme samples butyrylation (10 equiv of trifluoroethyl butyrate in TBME; 2× enzyme) was faster than acetylation (neat MeOAc; 3× enzyme); however the R,R-monoester was formed in poor de under both conditions. Under hydrolytic conditions (10 mM phosphate buffer; pH 7; 10% THF, 10% MeCN or 50% TBME as cosolvent) lot no. 41H0954 was more reactive than lot no. 23H0294. Hydrolysis of the diacetate 10 yielded the expected R,S-monoacetate 9 with generally poor de. For hydrolysis of the dibutyrate lib under the same conditions, lot no. 23H0294 showed poor reactivity (10% conversion in 10%MeCN/buffer and 4% conversion in 50%TBME/buffer after 6h) but produced the expected R,S-monobutyrate 12b. In contrast, lot no. 41H0954 produced the R,R-monobutyrate under all hydrolytic conditions tested, albeit in poor yield.
15. D -17.8 (c 1, MeOH))
16. Acylation of the pro-S hydroxyl of 13a would result in a five-step sequence to cis tosylate 8a (acylation, iodocyclization, triazole introduction, deacylation, and tosylation), while pro-R acylation would require two extra steps to invert the 2r chiral center. Pro-R hydrolysis of the diester 13a,b would result in a six-step sequence to 8a.
17. Both Novo SP435 and Boehringer-Mannheim Chirazyme L-2 are immobilized forms of Lipase Type B from Candida antarctica.
18. Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1984, 106, 3695-3696.
19. While boronic acids are well known reversible inhibitors of serine proteases (Jones, J. B.; Martichonok, V. J. Am. Chem. Soc. 1996, 118, 950-958 and refs 14,15 therein), we are unaware of reports of borate esters as inhibitors. However, the fact that diacetate 13b continued to be produced while diol 13a apparently remained unconsumed, suggested that the borate ester does not inhibit Novo SP435.
20. 1H NMR and mass spectrometry confirmed the presence of the cyclic borate ester (see Supporting Information).
21. Unlike Novo SP435, Lipase CE catalyzed acetylation showed a pronounced solvent dependence. From a comparison of 10 common solvents, the reaction was fastest in neat vinyl acetate, toluene, or tBME. As for SP435, the Lipase CE acetylation was very slow in isopropenyl acetate at room temperature, but unlike SP435 the reaction was also very slow in MeCN. Furthermore, excess vinyl acetate was required for reasonable reactivity; at 1.5-2.0 equiv of vinyl acetate the reaction was considerably slower.
22. Weber, H. K.; Stecher, H.; Faber, K. Biotechnol. Lett. 1995, 17, 803-808.