Presentation on theme: ". RCM strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and pyrrolizidines RCM strategy for the enantiosynthesis."— Presentation transcript:
. RCM strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and pyrrolizidines RCM strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and pyrrolizidines Alessia Colombo, Nicola Landoni, Giordano Lesma, Alessandro Sacchetti and Alessandra Silvani Dipartimento di Chimica Organica e Industriale,Università degli Studi di Milano, via Venezian 21 – 20133 Milano, Italy E-mail: firstname.lastname@example.org, email@example.com@firstname.lastname@example.org 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 THE KEY REACTION: DIHYDROXYLATION WITH OSO 4 THE KEY REACTION: ENZIMATIC DESYMMETRIZATION WITH IONIC LIQUIDS The ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate. (1) With Candida Antarctica lipase and Vinyl acetate as solvent: (2) With Candida Cylindracea lipase using stoichiometric vinyl acetate and 1-butyl-3-methylimidazolium hexafluorophosphate as solvent: EnzymeSolventYieldeeTime CALVinyl acetate62%90%48 h CCL Vinyl acetate + Ionic liquid 80%96%7h HeatingCatalystSolventTemperatureYieldTime Oil bath Microwave Grubbs catalyst 2 nd generation 5% mol Toluene 120°C 180°C 65% 72% 20h 60min. T (°C) 10 60 180 40 THE KEY REACTION: RING CLOSING METATHESIS TS relative energies for Quinolizidine derivatives dr calcd.dr exp. α-Attack 0.0 Kcal/mol 7675 β-Attack 0.7 Kcal/mol 2425 ab d c f e h g j i Reagents and conditions: (a) Vinyl acetate, C.C.L., 1-butyl-3-methylimidazolium hexafluorophosphate, 30°C, (62%), (b) (1) Swern oxidation, (2) t-BuOK, Ph 3 P(Me)Br, (3) KOH, MeOH, (54%), (c) Na 2 CO 3, Acetone/Water, 2:1, Acryloyl chloride, (73%), (d) EDC, DMAP, 3-butenoic acid, (69%), (e) Grubbs catalyst 2 nd generation 5% mol, Toluene, reflux, 20h, (65%), (f) Grubbs catalyst 2 nd generation 5% mol, Toluene, reflux, 20h, (87%), (g) (1) OsO 4, TMAO, (2) 2,2-dimethoxypropane, H +, (3) Chromatographic separation, (47%), (h) (1) OsO 4, TMAO, (2) Chromatographic separation, (64%), (i) (1) BH 3. SMe 2, EtOH (2) Acid resin (H + form), (67%), (j) BH 3 · SMe 2, EtOH, (85%). Time (min.) Second generation Grubbss 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. Second generation Grubbss ruthenium catalyst. TS relative energies for Indolizidine derivatives dr calcd.dr exp. α-Attack 0.0 Kcal/mol 9685 β-Attack 1.98 Kcal/mol 415 PM3 Calc. (Spartan 06, Wavefuction). 5 : 1 3 : 1 Glycosidase catalyze the hydrolysis of the glycosidic linkage to generate two smaller sugars. (1R,2S,5S,8aR)(1S,2R,5S,8aR) (1R,2S,6S,9aR)(1S,2R,6S,9aR) RETROSYNTHETIC STRATEGY From enzymatic desymmetrization Commercially available Swainsonine isolated from Swainsona Canescens Lupinine isolated from Maackia Hupehensis FUTURE DEVELOPMENTS…… Cross Metathesis (CM) Cross Metathesis (CM) Reagents and conditions: (a) BnBr, iPr 2 EtN, CH 2 Cl 2, 55°, 4h, (97%), (b) BOC 2 O, DMAP, CH 3 CN, r.t, 4h, (98%), (c) LiEt 3 BH, THF,-78°C, 3h, (98%), (d) pTSA, MeOH, r.t, 3h, (97%), (e) A: allylltrimethylsilane, BF 3 etherate, Et 2 O, -78°C, r.t, 12h, (75%), 4:1 cis:trans, B: allylMgBr, CuBr·Me 2 S, BF 3 etherate, Et 2 O, -78°C,5h, r.t, 12h (55%), 96:4 trans:cis: C: vinylllithium, CuBr·Me 2 S, BF 3 etherate, Et 2 O, -78°C, 6h, r.t, 12h, (42%), 4:1 trans:cis, (f) TFA, CH 2 Cl 2, r.t, 12h, (A:76% cis, B:86% trans, C:57% trans), (g) acryloilchloride, Na 2 CO 3, acetone, 4h, (A:84%, B:80%, C:81%), (h) Grubbs Catalyst 2 nd Generation 5% mol, toluene, 120°C, 20h, (A:60%, B:67%, C:45%), (i) OsO 4, 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) LiAlH 4,THF, 1.5h, reflux, (A:90%, B:30%, C:40%). Method A Method B Method C e, f a, b, c, d g, h MONOMORINE I Indolizidine 195B isolated from skin of Dendrobates Auratus b Reagents and conditions: (a) allyltrimethylsilane, BF 3 eterate, ET 2 O, -78°, r.t, 12h, (80%), (4:1cis/trans), (i) TFA, CH 2 Cl 2, r.t, 3h, (30% cis), (ii) BOC 2 O, DMAP, TEA, CH 3 CN, r.t, 12h, (98%), (b) MVK, Grubbs-Hoveyda catalyst 5%mol, CH 2 Cl 2, r.t, 12h, (55%). a Castanospermine from seeds of Castanospermum Australe only (6S,7S) only (6R,7R) Nucleophilyc attack on N-acylimminium ion-copper complex Trans Selectivity 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 Australine isolated from Castanospermum Australe i i i l l l 36 : 1 (6S,7S) (6R,7R) (commercially available) (3S,6S,7R,8aR) (3S,6R,7S,8aS) (3S,6R,7S,7aS) Monomerine I isolated from Monomorium pharaonis
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