Metallation reactions. XXXIV. Synthesis of 2‐(1‐hydroxy‐1‐arylethyl)‐1,3‐benzoxathiol‐3‐oxide derivatives

The reaction of benzoxathiole‐3‐oxide with lithiumdiisopropylamide in tetrahydrofuran gave an anion, which was reacted with various aryl‐methyl‐ketones to give 2‐(1‐hydroxy‐1‐arylethyl)‐1,3‐benzoxathiol‐3‐oxide derivatives. The reaction was carried out in different temperature conditions: at ‐88 °C the trans addition stereoisomers to the sulfoxide oxygen atom were the main products.     

Stereoselective Synthesis of cis‐2,5‐Disubstituted Pyrrolidines via Copper‐Catalyzed Cyclization of Alkenes

An efficient methodology for the stereoselective synthesis of cis‐2,5‐disubstituted pyrrolidines using copper catalyst was developed. The corresponding cis‐2,5‐disubstituted pyrrolidines could be obtained in reasonable yields and with good stereoselectivities in the presence of 4,4′‐di‐tert‐butyl‐2,2′‐bipyridine as ligand and 1‐methyl‐2‐pyrrolidinone as solvent.     

2,5‐Disubstituted Pyrazolo[4,3‐c]cinnolin‐3‐ones

Complementary strategies to 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones are reported herein, providing late stage substituent introduction at either the 2‐ or the 5‐position. Treating a readily prepared 4‐thiocinnoline ester with substituted hydrazines afforded late stage access to the 2‐position, while late stage substituent introduction at the 5‐position was achieved via two different strategies: alkylation of 4‐hydrazonopyrazol‐3‐ones, followed by a ring‐closing intramolecular S_NAr tactic and direct reaction of 5‐(2‐fluorophenyl)‐2,4‐dihydro‐3H‐pyrazol‐3‐ones with aryl diazonium salts, followed by cyclization. The strategies described herein provide practical and general methods to prepare 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones.     

A Regio‐ and Stereoselective ω‐Transaminase/Monoamine Oxidase Cascade for the Synthesis of Chiral 2,5‐Disubstituted Pyrrolidines

Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one‐pot ω‐transaminase (TA)/monoamine oxidase (MAO‐N) cascade process for the synthesis of chiral 2,5‐disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio‐ and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio‐ and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks.     

Synthesis of Multifunctionalized 1,2,3,4‐Tetrahydropyridines, 2,3‐Dihydropyridin‐4(1H)‐ones,and Pyridines from Tandem Reactions Initiated by [5+1] Cycloaddition of N‐Formylmethyl‐Substituted Enamides to Isocyanides: Mechanistic Insight and Synthetic Application

Tandem reactions for the efficient synthesis of multifunctionalized 1,2,3,4‐tetrahydropyridines, 2,3‐dihydropyridin‐4(1H)‐ones, and pyridine derivatives have been developed and reaction mechanisms have been investigated. Synthetic cascades are initiated by the Zn(OTf)₂‐mediated [5+1] cycloaddition of N‐formylmethyl‐substituted tertiary enamides to isocyanides, thus leading to the versatile heterocyclic enamino imine intermediates. Interception of the intermediates by diastereoselective reduction of imine functionality with Me₄NBH(OAc)₃ afforded 1,6‐disubstituted trans‐3‐hydroxy‐4‐arylamino‐ or ‐alkylamino‐1,2,3,4‐tetrahydropyridines, whereas acylation of the imino group followed by acidic hydrolysis produced 1,6‐disubstituted 3‐acyloxy‐2,3‐dihydropyridin‐4(1H)‐ones. Aerobic oxidation led to the aromatization followed by intermolecular acyl‐group transfer from the pyridinium nitrogen to the 3‐hydroxy moiety, thereby yielding substituted 3‐acyloxy‐4‐aminopyridines. Synthetic potentials of the resulting products have been demonstrated by expedient and highly stereoselective synthesis of cis,cis‐4,5‐dihydroxy‐2‐phenylpiperidine and trans,trans‐4‐amino‐5‐hydroxy‐2‐phenylpiperidine compounds, which are important in medicinal chemistry, through simple and practical reduction reactions.     

Regioselective Ring‐Opening of Amino Acid‐Derived Chiral Aziridines: an Easy Access to cis‐2,5‐Disubstituted Chiral Piperazines

An efficient four‐step synthetic strategy for cis‐2,5‐disubstituted chiral piperazines derived from amino‐acid‐based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF₃ ⋅ OEt₂)‐mediated ring‐opening of less‐reactive N‐Ts chiral aziridines by α‐amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)‐piperazinomycin.     

Enantioselective Organocatalytic Diels–Alder Trapping of Photochemically Generated Hydroxy‐o‐Quinodimethanes

The photoenolization/Diels–Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light‐triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy‐o‐quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels–Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity‐defining event.     

Stereoselective Synthesis and Physicochemical Properties of Liquid‐Crystal Compounds Possessing a trans‐2,5‐Disubstituted Tetrahydropyran Ring with Negative Dielectric Anisotropy

Three stereoselective syntheses and the physicochemical properties of trans,trans‐5‐(4‐ethoxy‐2,3‐difluorophenyl)‐2‐(4‐propylcyclohexyl)tetrahydropyran, which is an important liquid‐crystal compound with a large negative dielectric anisotropy (Δε=?7.3), are described. The key step in the construction of the trans‐2,5‐disubstituted tetrahydropyran ring in the first approach involved a benzylic cation mediated intramolecular olefin cyclization of a 2‐allyloxy‐1‐arylethanol derivative. The second method included the Et₂Zn‐induced 1,2‐aryl shift of a bromohydrin obtained from a hetero‐Diels–Alder reaction, followed by stereoselective bromination. The third approach utilized the hetero‐Diels–Alder reaction of trans‐4‐propylcyclohexanecarboxaldehyde and a 2‐aryl‐3‐(trimethylsilyl)oxy‐1,3‐butadiene, followed by stereoselective protonation. From results obtained by using a quantum chemical calculation method, the reason why the target compound shows a large negative Δε value is discussed.     

Iron‐Promoted Practical One‐Pot Synthesis of 2,5‐Disubstituted Oxazoles

A practical one‐pot protocol for the synthesis of 2,5‐disubstituted oxazoles from 1‐aryl‐2‐nitroethanones was reported. In the presence of iron/AcOH in acetonitrile, the reaction of 1‐aryl‐2‐nitroethanones with trimethyl orthoacetate or trimethyl orthobenzoate delivered the corresponding 2,5‐disubstituted oxazoles in moderate to good yields.     

Enantiodivergent Synthesis of (+)‐ and (−)‐Pyrrolidine 197B: Synthesis of trans‐2,5‐Disubstituted Pyrrolidines by Intramolecular Hydroamination

A highly efficient, diastereoselective, iron(III)‐catalyzed intramolecular hydroamination/cyclization reaction involving α‐substituted amino alkenes is described. Thus, enantiopure trans‐2,5‐disubstituted pyrrolidines and trans‐5‐substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l ‐α‐amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)‐ and (?)‐pyrrolidine 197B alkaloids from l ‐glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation.     

Enzyme‐catalyzed ring‐opening polymerization of 3(S)‐isopropylmorpholine‐2,5‐dione

The enzymatic ring‐opening polymerization of a 6‐membered cyclic depsipeptide, 3(S)‐isopropylmorpholine‐2,5‐dione in the bulk, was investigated by using lipases as catalysts at 100 and 130°C. Unchanged monomer was recovered in the absence of the enzyme or using an inactivated enzyme, indicating that the present polymerization proceeds through enzymatic catalysis. Poly(3‐isopropylmorpholine‐2,5‐dione) has a carboxylic acid group at one end and a hydroxy group at the other end.     

Synthesis,lipophilicity and structure of 2,5‐disubstituted 1, 3, 5‐dithiazine derivatives

A series of 2,5‐disubstituted 1,3,5‐dithiazine derivatives were synthesized as potential analogues of the potent dopamine uptake inhibitor GBR 12909. The lipophilic character of the 1,3,5‐dithiazine derivatives were experimentally (log P) and computationally (clog P) determined. The in vitro binding affinities of the 2,5‐disubstituted 1,3,5‐dithiazine derivatives at the dopamine transporter were determined to be much less potent than the binding affinity of GBR 12909 due to steric and electronic effects inherent to the 1,3,5‐dithiazine ring system. The X‐ray crystal structure of 2‐(2‐[bis(4‐fluorophenyl)methoxy]ethyl)‐5‐(3‐phenylpropyl)‐1,3,5‐dithiazine (7) revealed that the 5‐(3‐phenylpropyl) group is in a pseudo‐axial orientation and syn to the 2‐ethoxybenzhydryl moiety.     

Conjugate Umpolung of β,β‐Disubstituted Enals by Dual Catalysis with an N‐Heterocyclic Carbene and a Brønsted Acid: Facile Construction of Contiguous Quaternary Stereocenters

A sterically hindered homoenolate has been generated by the NHC‐catalyzed conjugate umpolung of β,β‐disubstituted enals and successfully employed in a facile stereoselective annulation with isatins. The strategy provides efficient access to spirocyclic oxindoles bearing two highly congested contiguous quaternary carbon centers. The use of a Brønsted acid cocatalyst was found to be crucial for guaranteeing both excellent reactivity and high stereoselectivity.     

Synthesis of Acetyl and Iodo Derivatives of 4‐Hydroxy‐6‐phenyl‐6H‐pyrano[3,2‐c]pyridine‐2,5‐diones and 4‐Hydroxy‐1‐phenylpyridin‐2(1H)‐ones

A simple and efficient method has been described for the synthesis of acetyl and iodo derivatives of 4‐hydroxy‐6‐phenyl‐6H‐pyrano[3,2‐c ]pyridine‐2,5‐diones 1 and 4‐hydroxy‐1‐phenylpyridin‐2(1H )‐ones 5 . Compounds 1 with phenyl and alkyl substituent at C(7) and C(8), respectively, can be easily acetylated by refluxing in a mixture of acetic acid and polyphosphoric acid to give 3‐acetyl‐4‐hydroxy‐6‐phenyl‐6H‐pyrano[3,2‐c ]pyridine‐2,5‐diones 2 in excellent yields. Compounds 1 and 5 can be iodinated with iodine and anhydrous sodium carbonate in boiling dioxane to give 4‐hydroxy‐3‐iodo‐6‐phenyl‐6H‐pyrano[3,2‐c ]pyridine‐2,5‐diones 3 and 4‐hydroxy‐3‐iodo‐1‐phenylpyridin‐2(1H )‐ones 6 , respectively, in good yields. The structures were confirmed using infrared, nuclear magnetic resonance , and elemental analysis.     

Stereoselective Solvent‐Free Synthesis of 4‐Hydroxy‐1,3‐thiazinane‐2‐thiones

An efficient solvent‐free one‐pot stereoselective synthesis of 4‐hydroxy‐1,3‐thiazinane‐2‐thione derivatives from the reaction of primary amines and carbon disulfide in the presence of α,β‐unsaturated aldehydes has been reported. The 4‐hydroxy‐1,3‐thiazinane‐2‐thione derivatives were easily converted to the related dehydrated or acetylated products.     

Synthesis of (E)‐1,1‐Diethoxy‐3‐(3‐hydroxy‐3‐arylfuro[2,3‐b]quinoxalin‐2(3H)‐ylidene)propan‐2‐ones via Acid‐Catalyzed,Stereoselective 5‐Exo‐Dig Cyclization

A number of 3‐(4,4,5,5‐tetraethoxy‐1‐hydroxy‐1‐arylpent‐2‐ynyl)quinoxalin‐2(1H)‐ones, obtained by reacting the lithium acetylide of 3,3,4,4‐tetraethoxybut‐1‐yne (TEB) with 3‐aroylquinoxalin‐2(1H)‐ones, appeared to undergo stereoselective cyclization in the 5‐exo‐Dig manner when heated at reflux in acidic, aqueous THF. In each case, the products were the corresponding (E)‐1,1‐diethoxy‐3‐(3‐hydroxy‐3‐arylfuro[2,3‐b]quinoxalin‐2(3H)‐ylidene)propan‐2‐ones and 1,1‐diethoxy‐3‐hydroxy‐3‐(3‐arylfuro[2,3‐b]quinoxalin‐2‐yl)propan‐2‐one, which were isolated in an approximate ratio of 2:1 in high total yield. Irrespective of the structure of the aryl group, both compounds were stable solids when kept in a refridgerator (3 °C), but when the latter product was dissolved in chloroform and stored at room temperature, it rearranged smoothly and quantitatively to the former compound within a few days.     

Kinetic and thermodynamic control in the cyclization via thiiranium ions. Stereoselective synthesis of a 2,3,5‐trisubstituted tetrahydropyran ring

The stereoselective rearrangement of tetrahydrofuran or tetrahydropyran rings having a phenylsulfanyl group in an exo position, via the intermediate thiiranium ions, is reported. The 5‐ or 6‐exo‐tet cyclization of hydroxy sulfides gave the kinetic products while the 6‐endo‐tet or 5‐endo‐tet gave the thermodynamic products. The rearrangement of the 5‐exo product to the 6‐endo‐ one is an interesting way for the stereoselective synthesis of substituted tetrahydropyrans.     

Total Synthesis of (±)‐Corymine

The first total synthesis of the hexacyclic indole alkaloid (±)‐corymine is described. Starting from the readily available N‐protected tryptamine, the title compound was achieved in 21 steps in 3.4 % overall yield. Key steps of the synthesis include: a) the addition of a malonate to a 3‐bromooxindole to afford 3,3‐disubstituted oxindole, b) the formation of a 12‐membered cyclic enol ether by intramolecular O‐propargylation, immediately followed by propargyl Claisen rearrangement to provide the α‐allenyl ketone stereospecifically, c) DMDO oxidation to install a hydroxy group in a highly stereoselective manner, and d) the SmI₂‐mediated reductive C−O bond cleavage to remove the α‐keto carboxyl group.     

One‐pot Synthesis of 2,5‐Disubstituted‐1,3,4‐oxadiazoles Based on the Reaction of N,N‐Dimethyl Amides with Acid Hydrazides

Convenient and efficient one pot method for the synthesis of 2,5‐disubstituted‐1,3,4‐oxadiazoles based on the reaction of N,N‐dimethyl amides with acid hydrazides has been developed. The methodology is applied to a wide range of difference aryl hydrazide and difference N,N‐dimethyl amides to 2,5‐disubstituted‐1,3,4‐oxadiazoles yield the in good to excellent yields. It will be possible wide useful application in synthesis.     

Enantioselective Preparation of Arenes with β‐Stereogenic Centers: Confronting the 1,1‐Disubstituted Olefin Problem Using CuH/Pd Cooperative Catalysis

Arenes with β‐stereogenic centers are important substructures in pharmaceuticals and natural products. We have developed an asymmetric anti‐Markovnikov hydroarylation of 1,1‐disubstituted olefins by dual palladium and copper hydride catalysis as a convenient and general approach to access these substructures. This efficient one‐step process addresses several limitations of the traditional stepwise approaches. The use of cesium benzoate as a base and a common phosphine ligand for both the Cu‐ and Pd‐catalyzed processes were important discoveries that allow these challenging olefin substrates to be efficiently transformed. A variety of aryl bromide coupling partners, including numerous heterocycles, were coupled with 1,1‐disubstituted alkenes to generate arenes with β‐stereogenic centers.