This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

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Chromone: A Valid Scaffold in Medicinal Chemistry

Chromones as a privileged scaffold in drug discovery: a review.

While tremendous advances have been made in asymmetric synthesis, the resolution of racemates is still the most important industrial approach to the synthesis of chiral compounds. The use of enzymes for the kinetic resolution (KR) of racemic substrates to afford enantiopure compounds in high enantioselectivity and good yield has long been a popular strategy in synthesis. However, transition metal-mediated and more recently organocatalyzed KRs have gained popularity within the synthetic community over the last two decades due to the progress made in the development of chiral catalysts for asymmetric reactions. Many catalytic non-enzymatic procedures have been developed providing high enantioselectivity and yield for both products and recovered starting materials. Indeed, the non-enzymatic KR of racemic compounds based on the use of a chiral catalyst is presently an area of great importance in asymmetric organic synthesis. The goal of this review is to provide an update on the principal developments of catalytic non-enzymatic KR covering the literature since 2004. This review is subdivided into seven sections, according to the different types of compounds that have been resolved through catalytic non-enzymatic KR, such as alcohols, epoxides, amines, alkenes, carbonyl derivatives, sulfur compounds and ferrocenes.



Abbreviations: Ac: acetyl; acac: acetylacetone; AQN: anthraquinone; Ar: aryl; Atm: atmosphere; BINAM: 1,1′-binaphthalenyl-2,2′-diamine; BINAP: 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl; BINEPINE: phenylbinaphthophosphepine; BINOL: 1,1′-bi-2-naphthol; Bmim: 1-butyl-3-methylimidazolium; Bn: benzyl; Boc: tert-butoxycarbonyl; Box: bisoxazoline; BSA: bis(trimethylsilyl)acetamide; Bu: butyl; Bz: benzoyl; c: cyclo; CBS: Corey–Bakshi–Shibata; Cbz: benzyloxycarbonyl; COD: cyclooctadiene; COE: cyclooctene; Cy: cyclohexyl; Dba: (E,E)-dibenzylideneacetone; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC: N,N′-dicyclohexylcarbodiimide; de: diastereomeric excess; DEAD: diethyl azodicarboxylate; Dec: decanyl; DHQD: dihydroquinidine; Difluorphos: 5,5′-bis(diphenylphosphino)-2,2,2′,2′-tetrafluoro-4,4′-bi-1,3-benzodioxole; DIPEA: diisopropylethylamine: DKR: dynamic kinetic resolution; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DNA: deoxyribonucleic acid; DOSP: N-(dodecylbenzenesulfonyl)prolinate; DTBM: di-tert-butylmethoxy; ee: enantiomeric excess; Et: ethyl; equiv.: equivalent; Fu: furyl; Hex: hexyl; HIV: human immunodeficiency virus; HMDS: hexamethyldisilazide; KR: kinetic resolution; L: ligand; LDA: lithium diisopropylamide; MAO: methylaluminoxane; Me: methyl; Ms: mesyl; MTBE: methyl tert-butyl ether; Naph: naphthyl; nbd: norbornadiene; NBS: N-bromosuccinimide; NIS: N-iodosuccinimide; Pent: pentyl; Ph: phenyl; Piv: pivaloyl; PMB: p-methoxybenzoyl; Pr: propyl Py: pyridyl; r.t.: room temperature; s: selectivity factor; Segphos: 5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole; (S,S′,R,R′)-Tangphos: (1S,1S′,2R,2R′)-1,1′-di-tert-butyl-(2,2′)-diphospholane; TBS: tert-butyldimethylsilyl; TBDPS: tert-butyldiphenylsilyl; TCCA: trichloroisocyanuric acid ; TEA: triethylamine; TEMPO: tetramethylpentahydropyridine oxide; THF: tetrahydrofuran; Thio: thiophene; Tf: trifluoromethanesulfonyl; TMS: trimethylsilyl; Tol: tolyl; Ts: 4-toluenesulfonyl (tosyl)

Catalytic Non-Enzymatic Kinetic Resolution

The balance between bone resorption and bone formation is vital for maintenance and regeneration of alveolar bone and supporting structures around teeth and dental implants. Tissue regeneration in the oral cavity is regulated by multiple cell types, signaling mechanisms, and matrix interactions. A goal for periodontal tissue engineering/regenerative medicine is to restore oral soft and hard tissues through cell, scaffold, and/or signaling approaches to functional and aesthetic oral tissues. Bony defects in the oral cavity can vary significantly, ranging from smaller intrabony lesions resulting from periodontal or peri-implant diseases to large osseous defects that extend through the jaws as a result of trauma, tumor resection, or congenital defects. The disparity in size and location of these alveolar defects is compounded further by patient-specific and environmental factors that contribute to the challenges in periodontal regeneration, peri-implant tissue regeneration, and alveolar ridge reconstruction. Efforts have been made over the last few decades to produce reliable and predictable methods to stimulate bone regeneration in alveolar bone defects. Tissue engineering/regenerative medicine provide new avenues to enhance tissue regeneration by introducing bioactive models or constructing patient-specific substitutes. This review presents an overview of therapies (e.g., protein, gene, and cell based) and biomaterials (e.g., resorbable, nonresorbable, and 3-dimensionally printed) used for alveolar bone engineering around teeth and implants and for implant site development, with emphasis on most recent findings and future directions.

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Regenerative Medicine for Periodontal and Peri-implant Diseases

The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their m...

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

Investigations on regio- and stereoselectivities in cycloadditions involving α- (3-pyridyl)-N-phenylnitrone: Development of an efficient route to novel nicotine analogs

Quite unlike the reported facile ene reactions on the periphery of many related heterocyclic systems, similarly disposed moieties on the periphery of the chromen-4-one (=4H-1-benzopyran-4-one) system fail to undergo an ene reaction and display a rather unusual preference for an overall [1,5] shift of the allylic C-atom. Thus, heating xylene solutions of 2-(N-allylanilino)-, 2-(N-crotylanilino)-, and 2-(N-cinnamylamino)-substituted (E)-(oxochromenyl)propenoates 9a–c and 2-[allyl(benzyl)amino]-, 2-[benzyl(crotyl)amino]-, and 2-[benzyl(cinnamyl)amino]-substituted (E)-(oxochromenyl)propenoates 16a–c in a sealed tube at 220–230° leads to a [1,5] shift of the allylic moieties (allyl, crotyl, cinnamyl), which is followed by intramolecular cyclization involving the N-atom and the ester function, to give the 3-allyl-3-crotyl-, and 3-cinnamyl-substituted-1-phenyl- or 1-benzyl-2H-[1]benzopyrano[2,3-b]pyridine-2,5(1H)-diones 10a–c and 17a–c. The anticipated carbonyl–ene reaction in the 2-(N-allylanilino)-, 2-(N-crotylanilino)-, 2-(N-cinnamylanilino)-, 2-[allyl(benzyl)amino]-, 2-[benzyl(crotyl)amino]-, and 2-[benzyl(cinnamyl)amino]-substituted 4-oxochromene-3-carboxaldehydes 8a–c and 15a–c is also not observed, and these molecules remain untransformed under identical conditions. No [1,5] shifts of benzyl, phenyl, or methyl groups are observed, even in the absence of allylic moieties, though facile [1,5]-H shift occurs in 2-(benzylamino)- and 2-(phenylamino)-substituted (E)-(oxochromenyl)propenoates 23a,b, which is followed by a similar intramolecular cyclization leading to the 2H-[1]benzopyrano[2,3-b]pyridine-2,5(1H)-diones 24a,b.

Pericyclic Transformations at the Periphery of Chromen‐4‐one (=4H‐1‐Benzopyran‐4‐one): An Unusual Preference for a 1,5‐Shift of Allylic Moieties over the Ene Reaction

Novel constrained β2,3,3-amino alcohol scaffolds (11a–11e) with varied substitution patterns have been synthesized by reductive cleavage of the N–O bond of isoxazolidines (10a–10e) derived from intramolecular 1,3-dipolar cycloadditions. A number of methods were probed for reductive cleavage, however, better results were obtained with ammonium formate in the presence of Pd/C or Zn as compared to Zn/acetic acid. The obtained scaffolds (11a–11e) can serve as valuable building blocks for peptidomimetics.Key words: β2,3,3-amino alcohol, peptidomimetics, building blocks, isoxazolidines, reductive cleavage, ammonium formate.

Synthesis of constrained aromatic β2,3,3-amino alcohol scaffolds — Precursors of non-proteinogenic phenylalanine for peptidomimetics

Thermal cycloaddition of α-(3-pyridyl)-N-phenylnitrone to a π-bond in norbomadiene not only activates the other double bond towards 1,3-dipolar cycloaddition, it also regulates the regiochemistry of addition leading to regio-and exo-π-facial selective formation of novel 2:1 cycloadducts. A DFT analysis in terms of the global and local reactivity indices affords a rationalization of the obtained results.

Regio- and Exo-p-Facial Selective 1,3-Dipolar Cycloaddition of a-(3-Pyridyl)-N-phenylnitrone to Norbornadiene: Activation of a p-Bond of Norbornadiene and Control of Regiochemistry of Nitrone Cycloaddition by Nitrone Addition to the Other Double Bond

Gurpinder Singh

Papers

Investigations on regio- and stereoselectivities in cycloadditions involving α- (3-pyridyl)-N-phenylnitrone: Development of an efficient route to novel nicotine analogs

Pericyclic Transformations at the Periphery of Chromen‐4‐one (=4H‐1‐Benzopyran‐4‐one): An Unusual Preference for a 1,5‐Shift of Allylic Moieties over the Ene Reaction

Synthesis of constrained aromatic β2,3,3-amino alcohol scaffolds — Precursors of non-proteinogenic phenylalanine for peptidomimetics

Regio- and Exo-p-Facial Selective 1,3-Dipolar Cycloaddition of a-(3-Pyridyl)-N-phenylnitrone to Norbornadiene: Activation of a p-Bond of Norbornadiene and Control of Regiochemistry of Nitrone Cycloaddition by Nitrone Addition to the Other Double Bond

Synthesis and in-vitro cytotoxic evaluation of novel chromano-piperidine fused isoxazolidines: Discovery of a potent lead