Short asymmetric synthesis of phenanthroindolizidines through chiral homoallylic sulfinamine

An efficient stereocontrolled preparation of chiral phenanthroindolizidines is detailed. The synthesis relies on the stereoselective indium-mediated allylation of 2-(phenanthren-9-yl)acetaldehyde derivatives with chiral tert-butylsulfinamide. Chemoselective transformations from the corresponding homoallylic sulfinamine allow the synthesis of the phenanthroindolizidines in only three synthetic operations, without any detectable racemization. Following this procedure, the synthesis of natural (−)-tylophorine was successfully accomplished.We thank the Spanish Ministerio de Ciencia e Innovación for their financial support (CTQ2011-24165). C. A.-T. thanks the ISO for a grant

A general protocol to afford enantioenriched linear homoprenylic amines

The reaction of a readily obtained chiral branched homoprenylamonium salt with a range of aldehydes, including aliphatic substrates, affords the corresponding linear isomers in good yields and enantioselectivities.We thank the Spanish Ministerio de Ciencia e Innovación for their financial support (CTQ2011-24165). I. B. acknowledges the Generalitat Valenciana for a predoctoral fellowship (ACIF/2011/159)

Regio- and Stereoselective Aminopentadienylation of Carbonyl Compounds

A simple and robust protocol is detailed for the preparation of enantioenriched α-substituted (1,4-pentadien-3-yl)amine derivatives. The methodology involves the addition of an in situ formed pentadienyl indium reagent to chiral tert-butylsulfinimines, previously formed in the same pot. The addition takes place with excellent γ-regio- and diastereoselectivity for a wide range of carbonyl compounds, including α-unsubstituted aldehydes and methyl alkyl ketones. The catalytic hydrogenation of the sulfinamines obtained provides a convenient access to chiral α-substituted (3-pentyl)amines. The hydroboration–oxidation of the α-(1,4-pentadien-3-yl)amine derivatives, followed by a cyclization under Mitsunobu conditions, takes place with an excellent diastereoselectivity governed by the chiral sulfinyl group.We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24165) for financial support. I.B. acknowledges the Generalitat Valenciana for a predoctoral fellowship (ACIF/2011/159). E.B. acknowledges the Council of Higher Education- Turkey for a postdoctoral fellowship (16.10.12-B.09.6.YÖK.0.71.01-207.02-12285)

Diastereoselective Allylation of Carbonyl Compounds and Imines: Application to the Synthesis of Natural Products

We thank the Spanish Ministerio de Ciencia e Innovación (Grant Nos. CTQ2007-65218 and Consolider Ingenio 2010-CSD-2007-00006 and CTQ2011-24165), the Generalitat Valenciana (Grant No. PROMETEO/2009/039 and FEDER), and the University of Alicante for generous and continuous financial support

A radical addition/cyclization of diverse ethers to 2-isocyanobiaryls under mildly basic aqueous conditions

Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogenative addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution (BHAS).We thank the Ministerio de Economia y Competitividad (CTQ2015-66624-P) and the University of Alicante (VIGROB-173) for financial support. C. A.-T. thanks the ISO for a grant

Oxidative Coupling of 4-Hydroxycoumarins with Quinoxalin-2(1H)-ones Induced by Visible Light under Aerobic Conditions

Direct and selective C(sp2)-H/C(sp2)-H cross-dehydrogenative coupling has become a promising strategy to increase molecular complexity with a high atom economy. This study describes an efficient and straightforward protocol for the regioselective C3-H/C3-H cross-coupling of 4-hydroxycoumarin derivatives with quinoxalin-2(1H)-ones, including late-stage modification of natural drugs, promoted by visible light under aerobic conditions at room temperature. With this approach, a wide range of hybrid drug-like molecules were prepared, using air as the terminal oxidant. Remarkably, the C4 OH group at the coumarin ring is essential for the reaction and has been used as a handle for diverse functionalizations of the final products. Moreover, sunlight can promote the reaction under very mild and sustainable conditions, even on a gram scale. Qualitative and semi-quantitative tools were used to demonstrate the greenness advance of this methodology over previously reported ones. Several experiments were conducted to propose a plausible mechanism for this transformation.This work was financially supported by the Spanish Ministerio de Ciencia e Innovación (grant no. CTQ2017-88171-P), Generalitat Valenciana (SEJIGENT/2021/005, granted to I. B.), and the University of Alicante (GRE20-03-A granted to I. B.)

Natural Tetraponerines: A General Synthesis and Antiproliferative Activity

A stereocontrolled general methodology to access all natural tetraponerines from (+)-T1 to (+)-T8 is detailed. Two consecutive indium-mediated aminoallylations with the appropriate enantiomer of chiral N-tert-butylsulfinamide and a thermodynamic control at the aminal stereocenter allow the formation of each natural tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal in the first aminoallylation leads to the formation of 5–6–5 tetraponerines, while 5-bromopentanal is required to build the scaffold of 6–6–5 tetraponerines. A cross-metathesis reaction of the second aminoallylation product with cis-3-hexene is used to elongate the side chain up to 5 carbons so as to prepare the tetraponerines T5 to T8. The anticancer activity of these heavier tetraponerines against four different carcinoma human cell lines is examined, observing a promising cytotoxic activity of (+)-T7 against breast carcinoma cell line MCF-7.We thank the Spanish Ministerio de Ciencia e Innovación for their financial support (CTQ2011-24165). I.B. acknowledges the Generalitat Valenciana for a predoctoral fellowship (ACIF/2011/159)

Alkanes in Minisci-Type Reaction under Photocatalytic Conditions with Hydrogen Evolution

We report herein a protocol for the selective activation of C(sp3)–H bonds based on the interplay of two readily available organic catalysts and their successful implementation in cross-coupling azaarenes with alkanes. This Minisci-like reaction is promoted by visible light at room temperature and is free from chemical oxidants, metals, and chlorinated solvents. A wide range of substrates are compatible, including some bioactive molecules. Mechanistic studies support a dual catalytic cycle with H2 evolution.This work was financially supported by the Generalitat Valenciana (SEJIGENT/2021/005 and IDIFEDER/2021/13) and the University of Alicante (GRE20-03-A granted to I. B.)

Electrochemically site-selective alkoxylation of twisted 2-arylbenzoic acids via spirolactonization

The Electrochemical Cross-Dehydrogenative Coupling (ECDC) of twisted biphenyl-2-carboxylic acids with aliphatic alcohols provides 4′-alkoxyspirolactones which isomerize, under mild basic conditions, to give 4′-alkoxy-2-phenylbenzoic acids. This site-selective alkoxylation was readily adapted to 1 mmol scale and is environmentally friendly, as no terminal oxidants are needed and H2 is the only residue. The suitability of diphenic acid derivatives in this two-step protocol is noteworthy, especially for axially chiral substrates that can be functionalized with retention of the configuration and of the enantiomeric purity. We have proposed a plausible mechanism based on experimental pieces of evidence that support the single-electron oxidation of the carboxylate, formed by deprotonation of the biphenyl-2-carboxylic acids with 2,6-lutidine, and DFT calculations that suggest a very fast spirocyclization of the intermediate σ-aroyloxyl radical. Competing pathways to benzocoumarins were also examined by computational studies.This work was generously supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICIU; grant no. CTQ2017-88171-P) and the University of Alicante (grant no. VIGROB-285/19). I. B. acknowledges the Spanish MICIU for a Juan de la Cierva-incorporación grant (no. IJCI-2017-33706)

Salicylic Acid‐Catalyzed Arylation of Enol Acetates with Anilines

α‐Aryl ketones are both structure moieties commonly found in bioactive compounds and versatile synthetic intermediates for the preparation of drug‐like molecules. An operationally simple and scalable protocol has been developed to prepare α‐aryl ketones from readily available aromatic amines and enol acetates (or silyl enol ethers). This metal‐free methodology features the use of salicylic acid as a convenient catalyst to promote the formation of aryl radicals from in‐situ generated aryl diazonium salts, without demanding thermal or photochemical activation. The mild reaction conditions used are compatible with anilines substituted with diverse functionalities. Structural elaboration of some prepared α‐aryl ketones was accomplished to illustrate their usefulness as building blocks.This work was generously supported by the Spanish Ministerio de Economía y Competitividad (MINECO; grant no. CTQ2017-88171-P), the Generalitat Valenciana (GV; grant no. AICO/2017/007), and the Institute of Organic Synthesis (ISO)