Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases

A straightforward chemoenzymatic synthesis of luli- conazole has been developed. The key step involved the preparation of the enantiomerically pure beta-halohydrin (1S)-2-chloro- 1-(2,4-dichlorophenyl)-1-ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435\uae. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the halohydrin was obtained with high selectivity (ee > 99%, E > 200) after just 15 min, at 45 \ub0C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)-beta-halohydrin was sub- jected to a mesylation reaction; the mesylated derivative re- acted with 1-cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee

Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization

Racemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym\uae 435). In all cases, the kinetic resolution was highly selective (E > 200) leading to the corresponding (S)-\u3b2-halohydrin with ee > 99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the \u3b2-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the \u3b2-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the \u3b2-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for \u3b2-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects

Chemoenzymatic synthesis of (S)-Pindolol using lipases

A straightforward chemoenzymatic synthesis of (S)-Pindolol has been developed. The key step involved the enzymatic kinetic resolution of rac-2-acetoxy-1-(1H-indol-4-yloxy)-3-chloropropane with lipase from Pseudomonas fluorescens via hydrolytic process to obtain enantiomerically enriched halohydrin (2S)-1-(1H-indol-4-yloxy)-3-chloro-2-propanol (96% ee) and (2R)-2-acetoxy-1-(1H-indol-4-yloxy)-3-chloropropane (97% ee). The latter was subjected to a hydrolysis reaction catalyzed by Candida rugosa leading to (2R)-1-(1H-indol-4-yloxy)-3-chloro-2-propanol (97% ee), followed by a reaction with isopropylamine, producing (S)-Pindolol (97% ee) in quantitative yield

The Stemona Alkaloids

The Stemonaceae (order Dioscoreales) is a small, monocotyledonous family with three small genera: Croomia (Southeastern North America and Japan), Stemona (Southeast Asia through Malaysia to North Australia), and Stichoneuron (Southeast Asia, including the Malay Peninsula) (1). Herbal extracts from various plants belonging to the Stemonaceae family have been used for the treatment of respiratory diseases and as antihelmintics in China and other East Asian countries for thousands of years. Amongst them, three species of the Stemona genus (S. tuberosa, S. japonica, and S. sessilifolia), which comprises about 25 species and represents the largest genus of the Stemonaceae family, have been officially listed in the 2000 Edition of the Chinese Pharmacopoeia as antitussive traditional Chinese medicinal herbs (2). Since the roots of several species are widely used as insecticides and for medicinal purposes, they are sold in local markets and herb shops. As an example, the dried roots of S. japonica, S. sessilifolia, or S. tuberosa (known as "Bai Bu" in traditional Chinese medicine, "Bach Bo" in Vietnam, or "Non Tai Yak" and "Pong Mot Ngam" in Thailand) contain several alkaloids, such as tuberostemonine, stenine, isostemonamine, stemonine, and protostemonine, and are used to suppress excitation of the respiratory center and inhibit the coughing reflex (3-5). The active principles are claimed to exert antituberculous, antibacterial, antifungal, and antihelminthic effects. "Bai Bu" displays a pesticide effect against Pediculus capitus, and the alcohol based extract is used as an insecticide and household spraying agent (6). However, because of the similarity of the fleshy tuberous roots, the same vernacular names are often used for different species, and even for representatives from other plant families. Caution is therefore recommended in order to properly classify plant material for studies or practical applications in agriculture and medicine (3-5). Despite their long history in traditional medicine, phytochemical studies on the Stemonaceae family have been limited to 14 species. Notwithstanding, these studies have provided structurally unique alkaloids which have sparked interest regarding their chemical and biological properties. Most of the Stemona alkaloids are structurally characterized by the presence of a pyrrolo[1,2-a]azepine (also known as perhydroazaazulene or 4-azaazulene) or, as revealed recently, a pyrido[1,2-a]azepine nucleus (Fig. 1). The Stemona alkaloids represent a class of polycyclic alkaloids with relatively complex structures which emerged from the structural elucidation of its first representative, tuberostemonine (Fig. 2) in the 1960s (7). Götz and Strunz reviewed this class of alkaloids in 1975 covering the structural elucidation of tuberostemonine, stenine, oxotuberostemonine, stemonine, protostemonine, stemofoline, and tuberostemonine A (7). Additionally, the physical data of 11 representatives of this family possessing unknown structures were also described. The field was reviewed again in 2000 covering literature data up to 1998 (8). The pyrrolo[1,2-a]azepine ring system is also present in alkaloid 275A which has been isolated from the skin of a Colombian poison frog, Dendrobates lehmanni (9). A limited number of Stemona alkaloids either lack or have a hidden pyrrolo[1,2-a]azepine architecture which can only be revealed on cleavage or formation of C-C bonds. This review focuses on the structural classification, isolation and structural elucidation, biological activity, and total synthesis of the Stemona alkaloids reported so far in the literature. Although dihydrophenanthrenes and stilbenoids, particularly several phenylbenzofurans, have been isolated from Stemona species (S. collinsae and Stemona cf. pierrei) and are of interest in their own right, these compounds are not included in the present review (10,11). © 2005 Elsevier Inc. All rights reserved.6277173Duyfjes, B.E.E., (1991) Blumea, 36, p. 239Chung, H.-S., Hon, P.-M., Lin, G., But, P.P.-H., Dong, H., (2003) Planta Med., 69, p. 914Shiengthong, D., Donavanik, T., Uaprasert, V., Roengsumran, S., Massey-Westropp, R.A., (1974) Tetrahedon Lett., 23, p. 2015Taguchi, H., Kanchanapee, P., Amatayakul, T., (1977) Chem. Pharm. Bull., 25, p. 1026Huang, K.C., (1999) The Pharmacology of Chinese Herbs. 2nd Edition, p. 274. , CRC Press, Boca Raton, FloridaPilli, R.A., F. de Oliveira, M.C., (2000) Nat. Prod. Rep., 17, p. 117Garraffo, H.M., Jain, P., Spande, T.F., Daly, J.W., Jones, T.H., Smith, L.J., Zottig, V.E., (2001) J. Nat. Prod., 64, p. 421Pacher, T., Seger, C., Engelmeier, K., Vajrodaya, S., Hofer, O., Greger, H., (2002) J. Nat. Prod., 65, p. 820Kostecki, K., Engelmeier, D., Pacher, T., Hofer, O., Vajrodaya, S., Greger, H., (2004) Phytochemistry, 65, p. 99Lin, W.-H., Ye, Y., Xu, R.-S., (1992) J. Nat. Prod., 55, p. 571Ye, Y., Qin, G.-W., Xu, R.-S., (1994) J. Nat. Prod., 57, p. 665Ye, Y., Qin, G.-W., Xu, R.-S., (1994) Phytochemistry, 37, p. 1201Ye, Y., Qin, G.-W., Xu, R.-S., (1994) Phytochemistry, 37, p. 1205Lin, W.-H., Xu, R.-S., Zhong, Q.-X., (1991) Acta Chim. Sinica, 49, p. 927Lin, W.-H., Xu, R.-S., Zhong, Q.-X., (1991) Acta Chim. Sinica, 49, p. 1034Uyeo, S., Irie, H., Harada, H., (1967) Chem. Pharm. Bull., 15, p. 768Kakuta, D., Hitotsuyanagi, Y., Matsuura, N., Fukaya, H., Takeya, K., (2003) Tetrahedron, 59, p. 7779Pham, H.-D., Yu, B.-W., Chau, V.-M., Ye, Y., Qin, G.-W., (2002) J. Asian Nat. Prod. Res., 4, p. 81Götz, M., Bogri, T., Gray, A.H., Strunz, G.M., (1968) Tetrahedron, 24, p. 2631Brem, B., Seger, C., Pacher, T., Hofer, O., Vajrodaya, S., Greger, H., (2002) J. Agric. Food Chem., 50, p. 6383Jiang, R.-W., Hon, P.-M., But, P.P.-H., Chung, H.-S., Lin, G., Ye, W.-C., Mak, T.C.W., (2002) Tetrahedron, 58, p. 6705Qin, G.-W., Xu, R.-S., (1998) Med. Res. Rev., 18, p. 375Dao, C.N., Luger, P., Ky, P.T., Kim, V.N., Dung, N.X., (1994) Acta Cryst. C., 50, p. 1612Edwards, O.E., Feniak, G., Handa, A.K., (1962) Can. J. Chem., 40, p. 455Ky, P.T., Kim, V.N., Dung, N.X., (1992) Chem. Abstr., 117, pp. 108076cWipf, P., Kim, Y., Goldstein, D.M., (1995) J. Am. Chem. Soc., 117, p. 11106Morimoto, Y., Iwahashi, M., Nishida, K., Hayashi, Y., Shirahama, H., (1996) Angew. Chem., Int. Ed. Engl., 35, p. 904Sakata, K., Aoki, K., Chang, C.-F., Sakurai, A., Tamura, S., Murakoshi, S., (1978) Agric. Biol. Chem., 42, p. 457Ye, Y., Xu, R.S., (1992) Chin. Chem. Lett., 3, p. 511Lin, W., Ye, Y., Xu, R., (1992) Chem. Abstr., 116, pp. 148183wKaltenegger, E., Brem, B., Mereiter, K., Kalchhauser, H., Kählig, H., Hofer, O., Vajrodaya, S., Greger, H., (2003) Phytochemistry, 63, p. 803Lin, W.H., Wang, L., Qiao, L., Cai, M.S., (1993) Chin. Chem. Lett., 4, p. 1067Lin, W.H., Ma, L., Cai, M.S., Barnes, R.A., (1994) Phytochemistry, 36, p. 1333Cheng, D., Guo, J., Chu, T.T., Roder, E., (1988) J. Nat. Prod., 51, p. 202Kuo, C., Chu, T.T., (1979) Chem. Abstr., 90, pp. 164717vJia, G., (1981) Acta Chim. Sinica, 39, p. 865Kohno, Y., Narasaka, K., (1996) Bull. Chem. Soc. Jpn., 69, p. 2063Irie, H., Ohno, K., Osaki, K., Taga, T., Uyeo, S., (1973) Chem. Pharm. Bull., 21, p. 451Noro, T., Fukushima, S., Ueno, A., Miyase, T., Iitaka, Y., Saiki, Y., (1979) Chem. Pharm. Bull., 27, p. 1495Lin, W.-H., Cai, M.-S., Ying, B.-P., Feng, R., (1993) Acta Pharm. Sinica, 28, p. 202Xu, R.-S., Lu, Y.-J., Chu, J.-H., Iwashita, T., Naoki, H., Naya, Y., Nakanishi, K., (1982) Tetrahedron, 38, p. 2667Lin, W.-H., Ye, Y., Xu, R.-S., (1991) Chin. Chem. Lett., 2, p. 369Cong, X., Zhao, H., Guillaume, D., Xu, G., Lu, Y., Zheng, Q., (1995) Phytochemistry, 40, p. 615Iizuka, H., Irie, H., Masaki, N., Osaki, K., Uyeo, S., (1973) J. Chem. Soc., Chem. Commun., 4, p. 125Lin, W.-H., Yin, B.-P., Tang, Z.-J., Xu, R.-S., (1990) Acta Chim. Sinica, 48, p. 811Jiwajinda, S., Hirai, N., Watanabe, K., Santisopasri, V., Chuengsamarnyart, N., Koshimizu, K., Ohigashi, H., (2001) Phytochemistry, 56, p. 693Mungkornasawakul, P., Pyne, S.G., Jatisatienr, A., Lie, W., Ung, A.T., Issakul, K., Sawatwanich, A., Jatisatienr, C., (2004) J. Nat. Prod., 67, p. 1740Mungkornasawakul, P., Pyne, S.G., Jatisatienr, A., Supyen, D., Lie, W., Ung, A.T., Skelton, B.W., White, A.H., (2003) J. Nat. Prod., 66, p. 980Mungkornasawakul, P., Pyne, S.G., Jatisatienr, A., Supyen, D., Jatisatienr, C., Lie, W., Ung, A.T., White, A.H., (2004) J. Nat. Prod., 67, p. 675Lin, W.-H., Xu, R.-S., Wang, R.-J., Mak, T.C.W., (1991) J. Crystallogr. Spec. Res., 21, p. 189Ke, C.Q., He, Z.S., Yang, Y.P., Ye, Y., (2003) Chin. Chem. Lett., 14, p. 173Chen, C.Y., Hart, D.J., (1990) J. Org. Chem., 55, p. 6236Chen, C.Y., Hart, D.J., (1993) J. Org. Chem., 58, p. 3840Morimoto, Y., Iwahashi, M., Kinoshita, T., Nishida, K., (2001) Chem. Eur. J., 7, p. 4107Ginn, J.D., Padwa, A., (2002) Org. Lett., 4, p. 1515Golden, J.E., Aubé, J., (2002) Angew. Chem. Int. Ed., 41, p. 4316Wipf, P., Rector, S.R., Takahashi, H., (2002) J. Am. Chem. Soc., 124, p. 14848Williams, D.R., Reddy, J.P., Amato, G.S., (1994) Tetrahedron Lett., 35, p. 6417Kinoshita, A., Mori, M., (1996) J. Org. Chem., 61, p. 8356Kinoshita, A., Mori, M., (1997) Heterocycles, 46, p. 287Jacobi, P.A., Lee, K., (1997) J. Am. Chem. Soc., 119, p. 3409Jacobi, P.A., Lee, K., (2000) J. Am. Chem. Soc., 122, p. 4295Gurjar, M.K., Reddy, D.S., (2002) Tetrahedron Lett., 43, p. 295Williams, D.R., Shamim, K., Reddy, J.P., Amato, G.S., Shaw, S.M., (2003) Org. Lett., 5, p. 3361Williams, D.R., Brown, D.L., Benbow, J.W., (1989) J. Am. Chem Soc., 111, p. 1923Martin, S.F., Barr, K.J., (1996) J. Am. Chem. Soc., 118, p. 3299Martin, S.F., Barr, K.J., Smith, D.W., Bur, S.K., (1999) J. Am. Chem. Soc., 121, p. 6990Williams, D.R., Fromhold, M.G., Earley, J.D., (2001) Org. Lett., 3, p. 2721Kende, A.S., Hernando, J.I.M., Milbank, J.B.J., (2001) Org. Lett., 3, p. 2505Kende, A.S., Hernando, J.I.M., Milbank, J.B.J., (2002) Tetrahedron, 58, p. 61Kende, A.S., Smalley, Jr., T.L., Huang, H., (1999) J. Am. Chem. Soc., 121, p. 7431Brüggemann, M., McDonald, A.I., Overman, L.E., Rosen, M.D., Schwink, L., Scott, J.P., (2003) J. Am. Chem. Soc., 125, p. 15284Shinozaki, H., Ishida, M., (1985) Brain Res., 334, p. 33Rinner, B., Siegl, V., Pürstner, P., Efferth, T., Brem, B., Greger, H., Pfragner, R., (2004) Anticancer Res., 24, p. 49

Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization

11siRacemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym® 435). In all cases, the kinetic resolution was highly selective (E>200) leading to the corresponding (S)-β-halohydrin with ee>99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the β-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the β-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the β-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for β-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects.partially_openopenThiago de Sousa Fonseca, Kimberly Benedetti Vega, Marcos Reinaldo da Silva, Maria da Conceição Ferreira de Oliveira, Telma Leda Gomes de Lemosa, Martina Letizia Contenteb, Francesco Molinari, Marco Cespugli, Sara Fortuna, Lucia Gardossi, Marcos Carlos de Mattos,de Sousa Fonseca, Thiago; Benedetti Vega, Kimberly; Reinaldo da Silva, Marcos; da Conceição Ferreira de Oliveira, Maria; Leda Gomes de Lemosa, Telma; Letizia Contenteb, Martina; Molinari, Francesco; Cespugli, Marco; Fortuna, Sara; Gardossi, Lucia; Carlos de Mattos, Marco