1,721,160 research outputs found
Highly Diastereoselective DABCO-catalyzed Synthesis of Spirooxindole-based 4-methyleneazetidines via Formal [2+2] Annulation Reaction
No full textThe strained four-membered ring system of azetidines occurs as a structural motif in several natural products and pharmaceutical agents.1 Despite the interest in azetidin-2-ones, in general azetidines have received much less attention compared to their lower and higher homologues, and their application in drug discovery programs is not so common, with only a few spirocyclic azetidine scaffolds proposed as new potential lead compounds.2
Our long-standing interest in the asymmetric synthesis of 3,3-disubstituted oxindoles derivatives,3 combined with the growing interest in hybrid drugs as therapeutic agents, inspired us to connect the two pharmacologically relevant moieties in a spiro arrangement.
Relying on our previous experience with isatin-derived ketimines,3b we considered the formal [2+2] annulation reactions of such compounds with allenoates as a practical and direct strategy to obtain highly functionalized chiral spirooxindole-based 4-methyleneazetidines with a high level of atom-economy. Since Shi's pioneer work,4 additional examples of such [2+2] annulations were reported, both on electron-deficient aldimines and ketimines.5 However, to the best of our knowledge, no diastereoselective strategies employing chiral imines have been described for the preparation of methyleneazetidines.
Herein we demonstrate the suitability of chiral, isatin-derived tert-butanesulfinyl ketimines for reaction with allenoates, applying this reaction to the synthesis of unprecedented, enantiopure spirooxindole-based 4-methyleneazetidines. Some post-transformation reactions were also performed to increase the number of useful compounds and to show the versatility of these scaffolds. Further research aimed to establish these compounds as possible lead compounds for drug discovery programs is currently underway.
References:
1 A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008, 108, 3988-4035.
2 M. Lüthy, M. C. Wheldon, C. Haji-Cheteh, M. Atobe, P. S. Bond, P. O’Brien, R. E. Hubbard, I. J. S. Fairlamb, Bioorg. Med. Chem. 2015, 23, 2680-2694.
3 (a) M. Stucchi, G. Lesma, F. Meneghetti, G. Rainoldi, A. Sacchetti, A. Silvani, J. Org. Chem. 2016, 81, 1877-1884. (b) G. Lesma, F. Meneghetti, A. Sacchetti, M. Stucchi, A. Silvani, Belstein J. Org. Chem. 2014, 10, 1383-1389. (c) A. Sacchetti, A. Silvani, F. G. Gatti, G. Lesma, T. Pilati, B. Trucchi, Org. Biomol. Chem. 2011, 9, 5515-5522. (d) G. Lesma, N. Landoni, A. Sacchetti, A. Silvani, Tetrahedron, 2010, 66, 4474-4478. (e) G. Lesma, N. Landoni, T. Pilati, A. Sacchetti, A. Silvani, J. Org. Chem. 2009, 74, 4537-4541.
4 G. L. Zhao, J. W. Huang, M. Shi, Org. Lett. 2003, 5, 4737-4739.
5 (a) L. J. Yang, S. Li, S. Wang, J. Nie, J. A. Ma, J. Org. Chem. 2014, 79, 3547-3558. (b) J. B. Denis, G. Masson, P. Retailleau, J. Zhu, Angew. Chem. Int. Ed. 2011, 50, 5356-5360. (c) B. S. Santos, A. L. Cardoso, A. Matos Beja, M. Ramos Silva, J. A. Paixão, F. Palacios, T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2010, 17, 3249-3256
Organocatalytic Vinylogous Mannich Reaction of Silyloxy Furan with Isatin-derived Benzhydryl-Ketimines
No full textOptically active -amino--unsaturated carbonyl compounds, particularly those bearing the -butenolide skeleton, are receiving attention due to their broad application in the synthesis of biologically active compounds. The vinylogous Mannich-type reaction of imines with a dienolate equivalent, such as trimethylsiloxyfuran (TMSOF), is a useful mean to prepare -butenolide derivatives bearing an amine functionality. Metal complexes and organocatalysts promote efficiently asymmetric vinylogous Mannich (AVM) reactions of aldimines, affording optically active -amino--unsaturated carbonyl compounds in high yields and enantiomeric excesses. Application of the AVM reaction to ketimines is more challenging, due to the lower reactivity of ketimines compared with aldimines and to the steric challenge inherent in the stereocontrolled formation of a quaternary stereocenter consecutive with a bulky tertiary one.
As part of our interest in the asymmetric synthesis of 3,3-disubstituted oxindole derivatives and related spiro-compounds, herein we report the BINOL-derived phosphoric acid-catalyzed asymmetric synthesis of quaternary 3-aminooxindole butenolides via a AVM reaction, consisting in the enantioselective addition of TMSOF to isatin-derived ketimines.
We began our investigation using the unprecedented N-diphenylmethyl ketimine 1a (R1 = Bn, R2 = H, Scheme). Reaction of 1a with TMSOF, initially carried out in THF at room temperature, in the presence of the protic cosolvent MeOH, afforded the corresponding 3-aminooxindole butenolide 3a in 84% yield. From subsequent reaction conditions screening, the temperature proved to be a key parameter for the asymmetric induction. Carrying out the reaction at - 40 oC, with catalyst 2a, both anti and syn diastereoisomers could be recovered in almost equal quantities (80% overall yield), showing excellent enantioselectivities (ee anti up to 90%, ee syn up to 92%).
The substrate scope of the AVM reaction has then been surveyed, by evaluating differently N-substituted isatins and the presence of substituents at 5- or 6-position of the isatin nucleus, as well as the potentiality of post-transformation reactions. The assignment of the absolute and relative configuration is currently underway on selected compounds, as well as computational studies aimed to explain the stereochemical outcome of this organocatalyzed process.
(a) Lesma, G.; Meneghetti, F.; Sacchetti, A.; Stucchi, M.; Silvani, A. Belstein J. Org. Chem. 2014, 10, 1383-1389. (b) Sacchetti, A.; Silvani, A.; Gatti, F. G.; Lesma, G.; Pilati, T.; Trucchi, B. Org. Biomol. Chem. 2011, 9, 5515-5522. (c) Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron 2010, 66, 4474-4478. (d) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 4537-4541
Convenient and expeditious synthesis of some indoloquinolizine alkaloids
No full textThe ambident reactivity of the imine-enamines (1) and (2) towards 1,3-dihalogenopropanes leads to an expeditious and efficient synthesis of some indoloquinolizines
Efficient synthesis of 1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-α] quinolizine: A key precursor to eburnane alkaloids
No full textThe title compound has been conveniently synthesized from the imine (3) by cyclisation with acrylic acid followed by reduction
The configuration of (+)-evodiamine: A long-standing problem in the chemistry of indole alkaloids
No full textThe absolute configuration (S) of the long-known indole alkaloid (+)-evodiamine (1) has been established by correlation with (S)-tryptophan via (7S,13bS)-carboxyevodiamine (2)
A new spirocyclic proline-based lactam as efficient type II' b-turn inducing peptidomimetic
No full textA new proline-based spirotricyclic lactam is reported as an efficient type II′ β-turn inducing peptidomimetic. After investigations of the reverse turn properties by computational techniques, the scaffold has been synthesized by a straightforward sequence relying on a key RCM reaction for the construction of the spirocyclic lactams ring. For its conformational properties, the scaffold can be considered a privileged structure to be employed as a mimic of the β-turn motif of the potent antibiotic Gramicidin S
A new tryptophan derived alkaloid from Evodia rutaecarpa (Juss.) Benth. et Hook
No full textThe first tryptophan-derived indolopyridoquinazoline alkaloid has been isolated from the fruits of Evodia rutaecarpa (Jussieu) Bentham et Hook. Its structure is deduced on the basis of spectral data and enantioselective synthesis. The compound has been assigned the absolute configuration (7 S,13b S)-7-carboxy-8,13,13b,14-tetrahydro-14-methylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5(7 H)-one
Indoloquinolizidine alkaloids. A highly stereoselective synthesis of (±)-deplancheine using a dienetricarbonyliron(0) complex
No full textAn efficient synthesis of (±)-deplancheine (1) is presented. Key steps include a tandem excited-state oxidation-cyclisation of the η4-diene complex (7), and a stereoselective double bond shift [(11) → (12)] induced by Fe2(CO)9
New chiral diamino ligands as sparteine analogues. Application to the palladium-catalyzed kinetic oxidative resolution of 1-phenyl ethanol
No full textNovel chiral 9-keto-bispidines were investigated as ligands in the palladium-catalyzed kinetic oxidative resolution (KOR) of 1-phenyl ethanol. The ligands were easily prepared by means of a two-step synthetic sequence starting from commercially available products
Pyrroloisoquinoline-based tetrapeptide analogues mimicking reverse-turn secondary structures
No full text(Chemical Equation Presented) New pyrroloisoquinoline-based tetrapeptides were synthesized in enantiomerically pure form, and their conformational features were studied by NMR, IR, and molecular-modeling techniques. The presence of a reverse turn was observed in both structures, with the C1 stereochemistry playing a central role in determining stable conformations. In particular, all of the analyses led to the conclusion that a type II′ β-turn is mostly stabilized in tetrapeptide mimic 3a, while a typical inverse γ-turn geometry is revealed for the diastereoisomer 3b
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