Asymmetric total synthesis of Tofacitinib

Marican, A (Marican, Adolfo); Santos, LS (Santos, Leonardo S). Univ Talca, Lab Asymmetr Synth, Chem Inst Nat Resources, Talca, ChileAbstract: 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

Antioxidant capacity, polyphenolic content and tandem HPLC-DAD-ESI/MS profiling of phenolic compounds from the South American berries Luma apiculata and L. chequen

Schmeda-Hirschmann, G (Schmeda-Hirschmann, Guillermo). Univ Talca, Lab Quim Prod Nat, Inst Quim Recursos Nat, Talca, ChileAbstract: Native Myrtaceae fruits were gathered by South American Amerindians as a food source. At present, there is still some regional consume of the small berries from trees belonging to genus Luma that occurs in southern Chile and Argentina. The aerial parts and berries from Luma apiculata and Luma chequen were investigated for phenolic constituents and antioxidant capacity. A high performance electrospray ionisation mass spectrometry method was developed for the rapid identification of phenolics in polar extracts from both species. Thirty-one phenolic compounds were detected and 27 were identified or tentatively characterised based on photodiode array UV-vis spectra (DAD), ESI-MS-MS spectrometric data and spiking experiments with authentic standards. Twelve phenolic compounds were detected in L apiculata fruits and 12 in the aerial parts while L. chequen yielded 10 compounds in fruits and 16 in aerial parts, respectively. From the compounds occurring in both Luma species, seven were identified as tannins or their monomers, 15 were flavonol derivatives and five were anthocyanins. The whole berry and aerial parts extracts presented high antioxidant capacity in the DPPH assay (IC50 of 10.41 +/- 0.02 and 2.44 +/- 0.03 mu g/mL for L. apiculata, 12.89 +/- 0.05 and 3.22 +/- 0.05 for L chequen, respectively), which can be related to the diverse range of phenolics detected. The antioxidant capacity together with the high polyphenolic contents and compounds identified can support at least in part, their use as botanical drugs. From the compounds identified in both species, 3-O-(6 ''-O-galloyl)-hexose derivatives of myricetin, quercetin, laricitrin and isorhamnetin are reported for the first time for the genus Luma. (C) 2013 Elsevier Ltd. All rights reserved

Supramolecular Host-Guest Asymmetric Induction In Organic Synthesis

Reprint Address: Santos, LS (reprint author), Talca Univ, Lab Asymmetr Synth, Chem Inst Nat Resources, POB 747, Talca, Chile.In past decades, the pharmacopoeia was dominated by racemates, but since the emergence of new technologies in the 1990s that allowed the preparation of pure enantiomers in significant quantities, the awareness and interest in the stereochemistry of drug actions have increased. In this short review, the implementation of several hosts, guests, building blocks and methods in host-guest supramolecular chemistry was outlined with an emphasis on the synthetic aspects, catalyst libraries and molecular recognition. Solid-state host-guest interactions, intra- and intermolecular host-guest photoreactions in solution and in the solid state, molecular and supramolecular self-assembly and molecular recognition between host and guests, and some specific and important reactions, such as aldol and Michael reactions, were reviewed

Direct characterisation of phenolic antioxidants in infusions from four Mapuche medicinal plants by liquid chromatography with diode array detection (HPLC-DAD) and electrospray ionisation tandem mass spectrometry (HPLC-ESI-MS)

Schmeda-Hirschmann, G (reprint author), Univ Talca, Lab Quim Prod Nat, Inst Quim Recursos Nat, Casilla 747, Talca, Chile.A simple, fast and direct method was developed for the qualitative analysis of phenolic constituents from infusions of Mapuche medicinal plants. Teas made of Linum chamissonis Schiede, Quinchamalium chilensis Mol., Adesmia emarginata Clos. and Escallonia illinita K. Presl. were analysed by high-performance liquid chromatography with diode array detector (HPLC-DAD) and electrospray mass spectrometry (ESI-MS). This technique allowed for the first time the tentative identification of 16 phenolic compounds in E. illinita, 27 in Q. chilensis, 10 in L chamissonis and 19 in A. emarginata. The compounds were mainly phenolic acids, flavonoid glycosides, anthocyanins and tannins. The total phenolic and flavonoid content of the infusions was assessed as well as the free radical scavenging capacity measured by the bleaching of a solution of the 2,2-diphenyl-1-picrylhydrazyl (DPPH(-)) radical. From the four species, Q. chilensis exhibited the strongest antioxidant activity with highest total phenolic and flavonoid content. (C) 2011 Elsevier Ltd. All rights reserve

Short Total Synthesis of (-)-Lupinine and (-)-Epiquinamide by Double Mitsunobu Reaction

Santos, LS (Silva Santos, Leonardo. Univ Talca, Chem Inst Nat Resources, Lab Asymmetr Synth, Talca, ChileAlternative 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

Synthesis of the Indolo[2,3-a]quinolizidine Ring through the Addition of 2-Siloxyfurans to Imines and Intrinsic Reaction Coordinate Calculations

Santos, LS (reprint author), Talca Univ, Chem Inst Nat Resources, Lab Asymmetr Synth, POB 747, Talca, ChileA 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