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Item Asymmetric total synthesis of TofacitinibAutores: Marican, A.; Simirgiotis, M.J.; Santos, L.S.Abstract: A novel stereoselective synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor, has been achieved starting from (5S)-5-hydroxypiperidin-2-one in 10 steps from 2 with a 9.5% overall yield. The potentiality of this synthetic route is the obtention of tert-butyl-(3S,4R)-3-hydroxy-4-methylpiperidine-1-carboxylate (6b) as a new chiral precursor involved in the synthesis of CP690,550, in a three-step reaction, without epimerizations, rather than the 5 or more steps used in described reactions to achieve this compound from analogues of 6b. (C) 2013 Elsevier Ltd. All rights reserved.Item Short Total Synthesis of (-)-Lupinine and (-)-Epiquinamide by Double Mitsunobu ReactionAutores: Santos, L.S.; Mirabal-Gallardo, Y.; Shankaraiah, N.; Simirgiotis, M.J.Alternative total syntheses of (-)-lupinine (1) and (-)-epiquinamide (2) have been described via the key intermediate 3 obtained from the addition of 2-trialkylsilyloxyfuran 5 to N-acyliminium intermediate derived from 4. The major R, R-isomer 8 obtained from the Mannich reaction was converted into its R, S-isomer through Mitsunobu reaction. Then, a second Mitsunobu reaction of 3 led to cyano 9 and azido 11 derivatives, which were converted into 1 and 2 in 33 and 36% overall yield from 4, respectively. The synthetic route is amenable for the generation of several quinolizidine alkaloids.Item Synthesis of the Indolo[2,3-a]quinolizidine Ring through the Addition of 2-Siloxyfurans to Imines and Intrinsic Reaction Coordinate CalculationsAutores: Mirabal-Gallardo, Y.; Soriano, M.D.P.C.; Caballero, J.; Alzate-Morales, J.; Simirgiotis, M.J.; Santos, L.S.A concise asymmetric diastereoselective strategy for the synthesis of indolo[2,3-a]quinolizidine derivative 1 was developed using diastereoselective addition of 2-siloxyfurans 4 to imine 3 through chiral auxiliary induction. The addition of an ionic liquid as additive in the reaction favored the anti configuration in the major adduct. The stereochemical outcome of the antilsyn (threolerythro) selectivity was rationalized based on transition state and IRC calculations at DFT (B3LYP) and MP2 theories. MP2 calculations was shown to be the method of choice in these systems, which orbital desymmetrizations were observed in the anti transition state of the addition of 4 to 3 and secondary orbital interactions allowed us to rationalize the production of the major anti-adduct 6. Furthermore, the work also suggested that 2-(triisopropylsiloxy)furan (4a) was the nucleophile of choice in this kind of Mannich reaction. Moreover, the strategy features the use of the Mitsunobu reaction to insert an amino group with the correct configuration into amine 2, key intermediate to achieve 1. The synthetic route can also be applied in the total synthesis of promising aza-beta-carboline compounds.
