Ming‐Phos/Gold(I)‐Catalyzed Stereodivergent Synthesis of Highly Substituted Furo[3,4‐d][1,2]oxazines†

A gold(I)‐catalyzed asymmetric intermolecular tandem [3+3]‐cyclization reaction of 2‐(1‐alkynyl)‐2‐ alken‐1‐ones with nitrones has been developed by using Ming‐Phos as a chiral ligand. This method enables access to the stereodivergent synthesis of highly substituted furo[3,4‐d][1,2]oxazines in excellent efficiency and stereoselectivity (up to 99% yield, 99% ee, >20 : 1 dr).     

Palladium(0)‐Catalyzed Intermolecular Arylative Dearomatization of β‐Naphthols

The first Pd⁰‐catalyzed intermolecular arylative dearomatization of β‐naphthols with aryl halides is described. It was found that Q‐Phos could facilitate the palladium‐catalyzed cross‐coupling‐type dearomatization of β‐naphthols, while avoiding O‐arylation, to construct 2‐naphthalenones in excellent yields and with high chemoselectivity.     

A New Type of Chiral Sulfinamide Monophosphine Ligands: Stereodivergent Synthesis and Application in Enantioselective Gold(I)‐Catalyzed Cycloaddition Reactions

A simple, new type of chiral sulfinamide monophosphines, the so‐called Ming‐Phos ligands, is reported; these ligands could be easily prepared from inexpensive and commercially available starting materials. The Ming‐Phos ligands performed well in the enantioselective gold‐catalyzed cycloaddition reaction of 2‐(1‐alkynyl)‐alk‐2‐en‐1‐ones with nitrones. Both enantiomers of the products could be obtained in good yields and with excellent diastereo‐ and enantioselectivity through transformations that were catalyzed by gold complexes derived from two diastereomers of Ming‐Phos ligand M5 (Ar=1‐naphthyl).     

Single‐Flask Multicomponent Palladium‐Catalyzed α,γ‐Coupling of Ketone Enolates: Facile Preparation of Complex Carbon Scaffolds

A three‐component palladium‐catalyzed reaction sequence has been developed in which γ‐substituted α,β‐unsaturated products are obtained in a single flask by an α‐alkenylation with either a subsequent γ‐alkenylation or γ‐arylation of a ketone enolate. Coupling of a variety of electronically and structurally different components was achieved in the presence of a Pd/Q‐Phos catalyst (2 mol %), usually at 22 °C with yields of up to 85 %. Most importantly, access to these products is obtained in one simple operation in place of employing multiple reactions.     

Synthesis of multi‐functionalized carbonyl compounds by palladium–catalysed γ‐substitution of MBH adducts with activated amides

Catalytic allylic γ‐substitution with Morita‐Baylis‐Hillman (MBH) adducts for creating a new family of unsymmetrical dicarbonyl compounds was presented in this work, in which a variety of allylated amide products were achieved in good yields and high regioselectivity with excellent linear‐to‐branched ratios. Especially, it was found that the Pd/HZNU‐Phos complex exhibited remarkably high activity (with a TON up to 16800) in this transformation between dicarbonyl amides and MBH adducts. In addition, the possibly multisite interaction between multifunctional Pd/HZNU‐Phos catalyst system and substrates might responsible for its exceptionally high efficiency in this reaction.     

Cu‐free Sonogashira Type Cross‐Coupling of 6‐Halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl) Quinazolin‐4(3H)‐ones as Potential Antimicrobial Agents

C(sp)–C(sp2) bond formation via Sonogashira cross‐coupling reactions on 6‐halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl)quinazolin‐4(3H )‐ones with appropriate alkynes was explored. Optimization of reaction conditions with various catalysts, ligands, bases, and solvents was conducted. The combination of PdCl₂(MeCN)₂ with X‐Phos proved to be the best metal–ligand system for this conversion in the presence of triethylamine (Et₃N) in tetrahydrofuran at room temperature for iodosubstrates, at 80°C for the bromosubstrates in 8 h, and also for the chlorosubstrates in 16 h. We also demonstrated synthesis of a successful diversity‐oriented synthesis library of highly functionalized quinazolinones via Cu‐free Sonogashira coupling of diverse aryl halides and azido‐alkyne (“click”) ligation reactions with substituted azides. The library exhibited significant antimicrobial activity when screened against several microorganisms.     

Photoinduced and thermal reactions of α‐cyano‐β‐bromomethylcinnamide with 1‐benzyl‐1,4‐dihydronicotinamide

The photoinduced reaction of a mixture of (Z)‐α‐cyano‐β‐bromomethylcinnamide (1) and (E)‐α‐cyano‐β‐bromomethylcinnamide (2) with 1‐benzyl‐1, 4‐dihydronicotinamide produces a mixture of the (E)‐ and (Z)‐ isomers of α‐cyano‐β‐methylcinnamide (3 and 4). Using spin‐trapping technique for monitoring reactive intermediate, it is shown that the reaction proceeds via electron transfer‐debromination‐H abstraction mechanism. The thermal reaction of the same substrate with BNAH at 60°C in the dark gives three products: the (E)‐ and (Z)‐isomers of α‐cyano‐β‐methylcinnamide and a dehydrodimeric product; 2, 7‐dicyano‐3, 6‐diphenylocta‐2, 4, 6‐trien‐1, 8‐dioic amide (7). Based on product analysis, scavenger experiment and cyclic voltammetry, an electron transfer‐debromination‐disproportionation mechanism is proposed.     

Oxidative Fragmentations of the 5α‐ and 5β‐Hydroxy‐B‐norcholestan‐ 3β‐yl Acetates

Oxidations of 5α‐hydroxy‐B‐norcholestan‐3β‐yl acetate ( 8 ) with Pb(OAc)₄ under thermal or photolytic conditions or in the presence of iodine afforded only complex mixtures of compounds. However, the HgO/I₂ version of the hypoiodite reaction gave as the primary products the stereoisomeric (Z)‐ and (E)‐1(10)‐unsaturated 5,10‐seco B‐nor‐derivatives 10 and 11 , and the stereoisomeric (5R,10R)‐ and (5S,10S)‐acetals 14 and 15 (Scheme 4). Further reaction of these compounds under conditions of their formation afforded, in addition, the A‐nor 1,5‐cyclization products 13 and 16 (from 10 ) and 12 (from 11 ) (see also Scheme 6) and the 6‐iodo‐5,6‐secolactones 17 and 19 (from 14 and 15 , resp.) and 4‐iodo‐4,5‐secolactone 18 (from 15 ) (see also Scheme 7). Oxidations of 5β‐hydroxy‐B‐norcholestan‐3β‐yl acetate ( 9 ) with both hypoiodite‐forming reagents (Pb(OAc)₄/I₂ and HgO/I₂) proceeded similarly to the HgO/I₂ reaction of the corresponding 5α‐hydroxy analogue 8 . Photolytic Pb(OAc)₄ oxidation of 9 afforded, in addition to the (Z)‐ and (E)‐5,10‐seco 1(10)‐unsaturated ketones 10 and 11 , their isomeric 5,10‐seco 10(19)‐unsaturated ketone 22 , the acetal 5‐acetate 21 , and 5β,19‐epoxy derivative 23 (Scheme 9). Exceptionally, in the thermal Pb(OAc)₄ oxidation of 9 , the 5,10‐seco ketones 10, 11 , and 22 were not formed, the only reaction being the stereoselective formation of the 5,10‐ethers with the β‐oriented epoxy bridge, i.e. the (10R)‐enol ether 20 and (5S,10R)‐acetal 5‐acetate 21 (Scheme 8). Possible mechanistic interpretations of the above transformations are discussed.     

Reactions of 3‐methylamino‐5‐phenylthiophene with α,β‐unsaturated esters and α,β‐unsaturated nitriles

Treatment of 3‐methylamino‐5‐phenylthiophene with α,β‐unsaturated esters, i.e., methyl acrylate, (E)‐methyl crotonate, diethyl fumarate, diethyl maleate and ethyl propiolate, in tetrahydrofuran for several days at reflux gave 1‐methyl‐3,4‐dihydrothieno[2,3‐e]pyridin‐2‐ones 4 and/or 1‐methylthieno[2,3‐e]pyridin‐2‐ones 5 , depending on the structure of the esters. On the other hand, the same reactions with α,β‐unsaturated nitriles such as acrylonitrile and tetracyanoethene, gave the corresponding thiophenes 7 and 10 bearing 2‐cyanoethyl and 1,2,2‐tricyanoethenyl groups at C‐2, respectively. The reaction with (Z)‐1,2‐dicyanoethene under the same conditions produced the corresponding thiophene 9 bearing the 1,2‐dicyanoethenyl group and 1,2‐dicyano‐5‐methylaminobiphenyl.     

Synthesis of Substituted α‐(Hydroxymethyl)‐β‐iodoacrylates via MgI2‐Promoted Stereoselective Aldol Coupling

The efficient and highly stereoselective syntheses of a variety of (Z)‐configured, substituted α‐(hydroxymethyl) ‐ β‐iodo‐acrylates from prop‐2‐ynoate and various aldehydes was achieved. The synthetic protocol involves a simple one‐pot coupling reaction under mild conditions, promoted by MgI₂, which serves both as a Lewis acid and iodine source for a Baylis? Hillman‐type reaction. All adducts were generated in good‐to‐excellent yields, the (Z)‐isomers being formed in high selectivity (>98%). The conversion of methyl prop‐2‐ynoate into an active ‘β‐iodo allenolate’ intermediate, which then nucleophilically attacks an aldehyde, is proposed as a plausible reaction mechanism.     

Reaction of β‐Bromo‐β,γ‐unsaturated Pyrroline Nitroxide Aldehydes and Nitriles with Aromatic N,S‐Binucleophiles

Reactions of β‐bromo‐β,γ‐unsaturated pyrroline nitroxide aldehyde ( 1 ) or nitrile ( 4 ) or their diamagnetic forms ( 5, 6 ) with 2‐aminothiophenol or 2‐mercaptobenzimidazole were evaluated. The reaction could be reproduced more easily with the application of O‐acetyl derivatives of nitroxides to generate 2‐substituted‐benzothiazole, pyrrolo[3,4‐b ]benzo[1,5]tiazepine scaffolds with 2‐aminothiophenol and benzimidazo[2,1‐b ]pyrrolo[3,4‐e ]‐[1,3]thiazine scaffold with 2‐mercaptobenzimidazole.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Synthesis of new optically active α,α′,β‐trisubstituted‐β‐lactones as monomers for stereoregular biopolyesters

Various optically active (4R)‐alkyloxycarbonyl‐3,3‐dialkyl‐2‐oxetanones as monomers were synthesized from L‐(S)‐malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by ¹H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2586–2597     

Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.     

Synthesis of β‐Arylacyl/β‐Heteroarylacyl‐β‐alkylidene Malonates and Their Application in Substituted Pyridone Synthesis

A novel approach has been developed for the synthesis of β‐arylacyl/β‐heteroarylacyl‐β‐alkylidine malonates in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β‐chloroalkylidene malonates. The reaction involves conjugate (Michael) addition of Stork enamine on β‐chloroalkylidene malonates and elimination of chloride ion. These Michael adducts were utilized as intermediates for the synthesis of highly substituted 1,4‐dialkyl‐2‐oxo‐6‐aryl/hetreoaryl‐1,2‐dihydro‐pyridine‐3‐carboxylic acid ethyl esters via 5 + 1 ring annulation protocol.     

Synthesis of dihydrofuro[2,3‐b]pyridines by the reaction of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles with α,β‐unsaturated carbonyl compounds

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles 1a‐d with α,β‐unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a‐d , 3a‐d and 4a‐d. Compounds 2a‐d and 3a‐c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a‐alkoxyhexahydrofuro[2,3‐b]pyridines 5a‐d, 6a‐d, 7a‐c and 8a‐c . Treatment of 5a‐d, 6a‐d, 7a‐c and 8a‐c with potassium tert‐butoxide produced the corresponding dihydrofuro[2,3‐b]pyridines 9a‐d and 10a‐c . The reaction of 4a‐c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro‐furo[2,3‐b]pyridines 11a‐c .     

Reactions of 4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines with α,β‐unsaturated carbonyl compounds

The reaction of 5,7‐diphenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine ( 1 ) with α,β‐unsaturated carbonyl compounds 2a‐f led to the formation of the alkylated heterocycles 3a‐f (Figure 1). However, the reaction of 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine ( 5 ) with 2a‐c yielded under the same conditions the triazolo[5,1‐b]quinazolines 6a‐c (Figure 3). In this case, the alkylation is followed by a cyclocondensation. The structure elucidation of the products is based on ir, ms, ¹H and ¹³C nmr measurements and on an X‐ray diffraction study.     

Reactions of α,β‐Unsaturated Thioamides with Diazo Compounds

Several reactions of the α,β‐unsaturated thioamide 8 with diazo compounds 1a – 1d were investigated. The reactions with CH₂N₂ ( 1a ), diazocyclohexane ( 1b ), and phenyldiazomethane ( 1c ) proceeded via a 1,3‐dipolar cycloaddition of the diazo dipole at the C?C bond to give the corresponding 4,5‐dihydro‐1H‐pyrazole‐3‐carbothioamides 12a – 12c , i.e., the regioisomer which arose from the bond formation between the N‐terminus of the diazo compound and the C(α)‐atom of 8 . In the reaction of 1a with 8 , the initially formed cycloadduct, the 4,5‐dihydro‐3H‐pyrazole‐3‐carbothioamide 11a , was obtained after a short reaction time. In the case of 1c , two tautomers 12c and 12c ′ were formed, which, by derivatization with 2‐chlorobenzoyl chloride 14 , led to the crystalline products 15 and 15 ′. Their structures were established by X‐ray crystallography. From the reaction of 8 and ethyl diazoacetate ( 1d ), the opposite regioisomer 13 was formed. The monosubstituted thioamide 16 reacted with 1a to give the unstable 4,5‐dihydro‐1H‐pyrazole‐3‐carbothioamide 17 .