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Nojirimycin isolated from Streptomices

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Nojirimycin isolated from Streptomices

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  1. . Glycosidases are enzymes that catalyse the hydrolysis of glycosidic bonds in complex carbohydrates and glycoconjugates. They have been identified as an important class of therapeutic targets with applications in the treatment of influenza infection, cancer, AIDS, and diabetes. Since the beginning of the 1960s, a number of polyhydroxylated alkaloids that are potent glycosidase inhibitors have been found in plants and microorganisms. The first natural polyhydroxylated alkaloid to be detected was the piperidine alkaloid nojirimycin, isolated from a Streptomyces filtrate in 1966 by Inouye et al. The high therapeutic potential of these alkaloids, also called azasugars, has prompted considerable efforts towards their structural modifications and towards the design of new stereocontrolled synthetic routes also for unnatural isomers, which might be of interest for SAR studies. In fact, the specificity of natural alkaloids toward their molecular target remains to be optimized and novel synthetic strategies to expand the repertoire of available analogues are needed. We are pursuing a noncarbohydrate based approach to various azabicyclic ring skeletons, starting from chemoenzimatically derived or commercially available chiral synthons and relying on RCM reactions in the key steps. Nojirimycin isolated from Streptomices Glycosidase catalyze the hydrolysis of the glycosidic linkage to generate two smaller sugars. RETROSYNTHETIC STRATEGY From enzymatic desymmetrization RCM strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and pyrrolizidines Alessia Colombo, Nicola Landoni, Giordano Lesma, Alessandro Sacchetti and Alessandra SilvaniDipartimento di Chimica Organica e Industriale,Università degli Studi di Milano, via Venezian 21 – 20133 Milano, Italy E-mail: alessia.colombo@unimi.it , nicola.landoni@unimi.it Commercially available Swainsonine isolated from Swainsona Canescens Lupinine isolated from Maackia Hupehensis e i g c (1R,2S,5S,8aR) (1S,2R,5S,8aR) 5 : 1 a b d j f h (1R,2S,6S,9aR) (1S,2R,6S,9aR) 3 : 1 Reagents and conditions:(a) Vinyl acetate, C.C.L., 1-butyl-3-methylimidazolium hexafluorophosphate, 30°C, (62%), (b) (1) Swern oxidation, (2) t-BuOK, Ph3P(Me)Br, (3) KOH, MeOH, (54%), (c) Na2CO3, Acetone/Water, 2:1, Acryloyl chloride, (73%), (d) EDC, DMAP, 3-butenoic acid, (69%), (e) Grubbs catalyst 2nd generation 5% mol,Toluene, reflux, 20h, (65%), (f) Grubbs catalyst 2nd generation 5% mol, Toluene, reflux, 20h, (87%), (g) (1) OsO4, TMAO, (2) 2,2-dimethoxypropane, H+, (3) Chromatographic separation, (47%), (h) (1) OsO4, TMAO, (2) Chromatographic separation, (64%), (i) (1) BH3.SMe2, EtOH (2) Acid resin (H+ form), (67%), (j) BH3·SMe2, EtOH, (85%). THE KEY REACTION: RING CLOSING METATHESIS THE KEY REACTION: DIHYDROXYLATION WITH OSO4 THE KEY REACTION: ENZIMATIC DESYMMETRIZATION WITH IONIC LIQUIDS Second generation Grubbs’s ruthenium catalyst was very suitable for RCM, when the reaction was performed in toluene at reflux. The use of microwave irradiation in this step allowed to complete the reaction in 1 h compared with the 20 h required under conventional oil bath heating. (1) With Candida Antarctica lipase and Vinyl acetate as solvent: PM3 Calc. (Spartan ’06, Wavefuction). Second generation Grubbs’s ruthenium catalyst. (2) With Candida Cylindracea lipase using stoichiometric vinyl acetate and 1-butyl-3-methylimidazolium hexafluorophosphate as solvent: T (°C) 180 40 60 10 Time (min.) The ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate. g, h l Method A i only (6R,7R) (3S,6S,7R,8aR) a, b, c, d l g, h Method B i e, f 36 : 1 (6S,7S) (6R,7R) (3S,6R,7S,8aS) (commercially available) l Method C g, h Australine isolated from Castanospermum Australe i Nucleophilyc attack on N-acylimminium ion-copper complex (3S,6R,7S,7aS) only (6S,7S) Trans Selectivity Reagents and conditions: (a)BnBr, iPr2EtN, CH2Cl2, 55°, 4h, (97%), (b) BOC2O, DMAP, CH3CN, r.t, 4h, (98%), (c)LiEt3BH, THF,-78°C, 3h, (98%), (d)pTSA, MeOH, r.t, 3h, (97%), (e) A:allylltrimethylsilane, BF3 etherate, Et2O, -78°C, r.t, 12h, (75%), 4:1 cis:trans,B:allylMgBr, CuBr·Me2S, BF3 etherate, Et2O, -78°C ,5h, r.t, 12h (55%), 96:4 trans:cis: C:vinylllithium, CuBr·Me2S, BF3 etherate, Et2O, -78°C, 6h, r.t, 12h, (42%), 4:1 trans:cis,(f) TFA, CH2Cl2,r.t, 12h, (A:76% cis, B:86% trans, C:57% trans), (g)acryloilchloride, Na2CO3, acetone, 4h, (A:84%, B:80%, C:81%), (h)Grubbs Catalyst 2nd Generation 5% mol, toluene, 120°C, 20h, (A:60%, B:67%, C:45%), (i)OsO4, TMAO, Acetone/Water, 3:1, 40°C, 3h, (A: 87% only (6S,7S), B:72% (6S,7S) 1,5%(6R,7R), C:60% only (6S,7S), (l)LiAlH4,THF, 1.5h, reflux, (A:90%, B:30%, C:40%). Highly diastereoselective addition of alkylcopper reagents to the optically active N-acylimminium ions derived from proline; the mechanism involving nucleophilic attack on the less hindered face of the ion. J. Org.Chem.,1995,60, 5011-5015 Castanospermine from seeds of Castanospermum Australe Cross Metathesis (CM) FUTURE DEVELOPMENTS…… a b MONOMORINE I Reagents and conditions: (a) allyltrimethylsilane, BF3eterate, ET2O, -78°, r.t, 12h, (80%), (4:1cis/trans),(i)TFA, CH2Cl2, r.t, 3h, (30% cis),(ii)BOC2O, DMAP, TEA , CH3CN, r.t, 12h, (98%), (b)MVK, Grubbs-Hoveyda catalyst 5%mol, CH2Cl2,r.t, 12h, (55%). Indolizidine 195B isolated from skin of Dendrobates Auratus Monomerine I isolated from Monomorium pharaonis

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