Regioselective Cyclization Research Articles

Strong base- or acid-mediated chemoselectivity shifts in the synthesis of 2H-chromene or coumarin derivatives from common Baylis-Hillman adducts

Reaction of tert-butyl 3-(2-hydroxyphenyl)-2-methylenepropanoate esters with aqueous KOH provides convenient and chemoselective one-pot access to 2H-chromene-3-carboxylic acids, the overall transformation involving tandem conjugate addition, hydrolysis and elimination steps. The methodology complements the chemoselective, acid-catalysed route to 3-substituted coumarins from the same substrates by switching the regioselectivity of cyclisation.

Product Formation by the Promiscuous Lanthipeptide Synthetase ProcM is under Kinetic Control.

Lanthipeptides are natural products that belong to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs). They contain characteristic lanthionine (Lan) or methyllanthionine (MeLan) structures that contribute to their diverse biological activities. Despite its structurally diverse set of 30 substrates, the highly substrate-tolerant lanthipeptide synthetase ProcM is shown to display high selectivity for formation of a single product from selected substrates. Mutation of the active site zinc ligands to alanine or the unique zinc ligand Cys971 to histidine resulted in a decrease of the cyclization rate, especially for the second cyclization of the substrates ProcA1.1, ProcA2.8, and ProcA3.3. Surprisingly, for ProcA3.3 these mutations also altered the regioselectivity of cyclization resulting in a new major product. ProcM was not able to correct the ring topology of incorrectly cyclized intermediates and products, suggesting that thermodynamic control is not operational. Collectively, the data in this study suggest that the high regioselectivity of product formation is governed by the selectivity of the initially formed ring.

Construction of a hemifullerene skeleton: a regioselective intramolecular oxidative cyclization.

A two-step synthesis of a strained π bowl, with hemifullerene skeleton from sumanene, was achieved in a high yield. The first step is a base-promoted condensation reaction with a benzophenone compound, bis(3,5-dimethylphenyl)methanone. The second step is the regioselective intramolecular oxidative cyclization, which is a key reaction for the hemifullerene skeleton synthesis. This regioselective cyclization is likely to be under thermodynamic control. This strategy will allow facile synthesis of various highly strained π bowls.

Construction of a Hemifullerene Skeleton: A Regioselective Intramolecular Oxidative Cyclization

AbstractA two‐step synthesis of a strained π bowl, with hemifullerene skeleton from sumanene, was achieved in a high yield. The first step is a base‐promoted condensation reaction with a benzophenone compound, bis(3,5‐dimethylphenyl)methanone. The second step is the regioselective intramolecular oxidative cyclization, which is a key reaction for the hemifullerene skeleton synthesis. This regioselective cyclization is likely to be under thermodynamic control. This strategy will allow facile synthesis of various highly strained π bowls.

ChemInform Abstract: Synthesis of 7‐Arylquinolinones and 6‐Arylindoles from 3‐Aminobiphenyls Through Regioselective Cyclization Reactions.

Abstract 7-Arylquinolinones were obtained in two steps from 3-aminobiphenyls through conversion into cinnamic amides. The highly regioselective cyclization under elimination of anisole proceeded in the presence of phosphoric acid and phosphorous pentoxide. 6-Arylindoles were accessible, although in lower yields, from 3-aminobiphenyls via 3-(biphenylamino)acrylates and palladium-catalyzed cyclization reactions.

Synthesis of benzo-fused spiropiperidines through a regioselective free radical-mediated cyclization as key step: a suitable alternative towards the lead σ-1 receptor ligand L-687384

The synthesis of four novel benzo-fused spiropiperidines and the lead σ-1 receptor ligand L-687384 through a xanthate-mediated free radical spirocyclization as key step is described. Furthermore, the key free radical-based cyclization was computationally studied by means of the density functional theory approach at the UB3LYP/6-311+G(d) level to understand the regioselectivity because there are three possible closure pathways and only the benzo-fused spiropiperidines (ipso products) were experimentally found.

β-Cyclodextrin in water: highly facile biomimetic one pot deprotection of phenolic THP/MOM/Ac/Ts ethers and concomitant regioselective cyclization of chalcone epoxides and 2′-aminochalcones

A “green” and mild catalytic method for the deprotection of THP/MOM/Ac/Ts ethers and the concomitant cyclizations of epoxy chalcone to 2-hydroxyindanone or 2′-aminochalcone to aza-flavanone are reported.

An Efficient Synthesis of Aurone Derivatives by the Tributylphosphine-catalyzed Regioselective Cyclization of o-Alkynoylphenols

Abstract An organocatalytic regioselective synthesis of aurones from o-alkynoylphenols was achieved. A catalytic amount of tributylphosphine selectively induced the 5-exo cyclization of o-alkynoylphenols under ambient conditions leading to aurone derivatives in high to excellent yields.

One-Pot Regioselective Synthesis of 5-Amino-3-Benzyl-7H-[1,3]Thiazolo[3,2-A]Pyrimidin-7-Ones via Sonogashira Coupling Reaction

GRAPHICAL ABSTRACT

Synthesis of 7-arylquinolinones and 6-arylindoles from 3-aminobiphenyls through regioselective cyclization reactions

7-Arylquinolinones were obtained in two steps from 3-aminobiphenyls through conversion into cinnamic amides. The highly regioselective cyclization under elimination of anisole proceeded in the presence of phosphoric acid and phosphorous pentoxide. 6-Arylindoles were accessible, although in lower yields, from 3-aminobiphenyls via 3-(biphenylamino)acrylates and palladium-catalyzed cyclization reactions.

Substrate-Dependent Mechanisms for the Gold(I)-Catalyzed Cycloisomerization of Silyl-Tethered Enynes: A Computational Study

The gold(I)-catalyzed alkenyl-, allyl-, and arylsilylation reactions of silyl-tethered enynes discovered by Murakami et al. provide efficient methods for the facile constructions of 1-silaindene derivatives. A comprehensive mechanistic DFT study of these reactions was carried out to better understand the experimental outcomes, and divergent and substrate-dependent mechanisms for the formations of 1-silaindene derivatives were uncovered based on the computational results. From cationic gold(I) π-alkyne complexes, the endo-dig cyclization pathway may lead possibly to both C2- and C3-group-substituted (group = alkenyl, allyl, or aryl) 1-silaindene products, and the regioselectivity will be finally determined by the 1,2-group migration of the gold carbenoid intermediate. On the other hand, the exo-dig cyclization pathway leads only to C3-group-substituted (group = alkenyl, allyl, or aryl) 1-silaindene, in which a notable promoting effect of the bistriflimide counterion on the rearrangement of the silyl cation intermediate was disclosed. The results reported herein provide insights into aspects of regioselective cyclization, silyl-involved skeletal rearrangements, chemoselective 1,2-migration in gold carbenoids, and the dramatic counterion effect in the reactions concerned.

Bismuth-catalyzed synthesis of polycyclic aromatic hydrocarbons (PAHs) with a phenanthrene backbone via cyclization and aromatization of 2-(2-arylphenyl)vinyl ethers.

The reaction of 2-(2-arylphenyl)vinyl ethers in the presence of a catalytic amount of bismuth(III) triflate gave substituted phenanthrenes in excellent yields under mild reaction conditions. The reaction was also applied to the construction of other polycyclic aromatic hydrocarbons (PAHs), such as chrysene, helicene, and pyrene having a phenanthrene backbone, via regioselective cyclization. This method has the advantages of easy availability of the cyclization precursors, operational simplicity, and high reaction efficiency.

ChemInform Abstract: Synthesis of Densely Functionalized 5‐Halogen‐1,3‐oxazin‐2‐ones by Halogen‐Mediated Regioselective Cyclization of N‐Cbz‐Protected Propargylic Amines: A Combined Experimental and Theoretical Study.

AbstractThe halocyclization reaction of chiral propargylic amines (I) proceeds with complete regioselectivity, taking place through a 6‐endo‐dig process regardless of the nature of the halogen and of the substituents in the starting material.

An Expedient Synthesis of Linden Ether

We here describe a comprehensive study on the preparation of the intensive flavor 3,9-epoxy-p-mentha-1,4(8)-diene (1). Key steps of the presented synthesis are the selective addition of MeLi to the keto-ester 7, the regioselective cyclization of the obtained triol to give the ethers 4 and 8 and the selective dehydration of ether 4 through the use of POCI3 and pyridine. It is worth noting that the presented synthesis represents the first expedient and reliable entry to ether 1. Being present in linden honey, 1 is also known as linden ether and it has been regarded as a potential marker for the authentication of the linden honey origin. Therefore, ether 1 can be used as a useful reference standard for the analysis of the natural flavors, as we demonstrated by means of its identification in a sample ofunifloral linden honey.

ChemInform Abstract: Facile Synthesis of Thiochromeno[2,3‐b]indol‐11(6H)‐ones and Pyrido[3′,2′:5,6]thiopyrano[2,3‐b]indol‐5(10H)‐ones.

AbstractA facile synthesis of the title compounds is achieved via regioselective cyclization of substrates (I) with 2‐chloronicotinoyl chloride or 2‐fluorobenzoyl chlorides, respectively.

Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy

A scalable and convergent synthesis of a BTK (Bruton’s tyrosine kinase) inhibitor has been developed. Synthetic routes to key intermediates were explored for the scale-up campaign, especially the process for 6-dimethylaminodihydroisoquinolinone, which was prepared via a regioselective cyclization of an isocyanate, mediated by AlCl3. Improved routes to key building blocks were demonstrated by expedient multikilogram productions. The target compound was assembled through a Pd-catalyzed amidation reaction followed by a Suzuki–Miyaura cross-coupling reaction.

ChemInform Abstract: Synthesis of Chromones Through LiOtBu/Air‐Mediated Oxidation and Regioselective Cyclization of o‐Hdroxyphenyl Propargyl Carbinols.

AbstractThe cascade oxidative cyclization reaction for the synthesis of chromones proceeds in the presence of LiO‐tBu as a mediator and air as an oxidant without the assistance of a transition metal.

Highly Regioselective Synthesis of Substituted Isoindolinones via Ruthenium-Catalyzed Alkyne Cyclotrimerizations.

(Cyclooctadiene)(pentamethylcyclopentadiene)ruthenium chloride [Cp*RuCl(cod)] has been used to catalyze the regioselective cyclization of amide-tethered diynes with monosubstituted alkynes to give polysubstituted isoindolinones. Notably, the presence of a trimethylsilyl group on the diyne generally led to complete control over the regioselectivity of the alkyne cyclotrimerization. The cyclization reaction worked well in a sustainable non-chlorinated solvent and was tolerant of moisture. The optimized conditions were effective with a diverse range of alkynes and diynes. The 7-silylisoindolinone products could be halogenated, protodesilylated or ring opened to access a range of usefully functionalized products.

Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives

With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

ChemInform Abstract: A Regioselective Synthesis of 1‐Haloisoquinolines via Ruthenium‐Catalyzed Cyclization of O‐Methylbenzohydroximoyl Halides with Alkynes.

A ruthenium-catalyzed highly regioselective cyclization of substituted N-methoxy benzimidoyl halides with alkynes in the presence of CsOAc (25 mol%) to give substituted 1-halo and 1-alkoxy substituted isoquinolines in good to excellent yields is described.