The Stereoselective Total Synthesis of (6S)‐5,6‐Dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one via Prins Cyclization

The stereoselective total synthesis of an antiproliferative and antifungal α‐pyrone natural product (6S)‐5,6‐dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one is described. The key steps involved are the Prins cyclization, Mitsunobu reaction, and ring‐closing metathesis reaction.     

Olefin Cross‐Metathesis: Studies towards the Total Synthesis of (+)‐Bitungolide F

A stereoselective synthesis of (5S,6S)‐6‐[(2S,5S,7R,8E,10E)‐5‐(benzyloxy)‐7‐{[(tert‐butyl)dimethylsilyl]oxy}‐11‐phenylundeca‐8,10‐dien‐2‐yl]‐5‐ethyl‐5,6‐dihydro‐2H‐pyran‐2‐one (=(+)‐9‐O‐benzyl‐11‐O‐[(tert‐butyl)dimethylsilyl]bitungolide F) is reported. The strategy involves Gilman reaction, olefin cross‐metathesis, and Horner? Wadsworth? Emmons olefination as key steps.     

Absolute Configuration of Two New 6‐Alkylated α‐Pyrones (=2H‐Pyran‐2‐ones) from Ravensara crassifolia

The stem bark CH₂Cl₂ extract of Ravensara crassifolia showed antifungal activity against the phytopathogenic fungus Cladosporium cucumerinum in a bioautographic TLC assay. Activity‐guided fractionation afforded two new α‐pyrones : (6S)‐5,6‐dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one ( 1 ) and (6R)‐6‐[(4R,6R)‐4,6‐dihydroxy‐10‐phenyldec‐1‐enyl]‐5,6‐dihydro‐2H‐pyran‐2‐one ( 2 ). Their structures and absolute configurations were established by NMR spectroscopy, chemical methods, and CD spectroscopy. The antifungal activity against C. cucumerinum was determined for both compounds.     

Synthesis,structure and biological activity of new 6,6‐dimethyl‐2‐oxo‐4‐{2‐[5‐organylsilyl(germyl)]furan(thiophen)‐2‐yl}vinyl‐5,6‐dihydro‐2H‐pyran‐3‐carbonitriles

New 6,6‐dimethyl‐2‐oxo‐4‐{2‐[5‐alkylsilyl(germyl)]furan(thiophen)‐2‐yl}vinyl‐5,6‐dihydro‐2H‐pyran‐3‐carbonitriles (IC₅₀: 1–6 µg ml^?1) have been prepared by the condensation of corresponding silicon‐ and germanium‐containing furyl(thienyl)‐2‐carbaldehydes with 3‐cyano‐4,6,6‐trimethyl‐5,6‐dihydropyran‐2‐one using piperidine acetate as a catalyst. The obtained carbonitriles were identified using NMR (¹H, ¹³C and ²⁹Si) spectroscopy and GC‐MS. The structure of 6,6‐dimethyl‐2‐oxo‐4‐[2‐(5‐trimethylsilyl)thiophen‐2‐yl]‐5,6‐dihydro‐2H‐pyran‐3‐carbonitrile was studied using X‐ray diffractometry. The influences of the heterocycle and the structure of the organoelement substituent on cytotoxicity and on matrix metalloproteinase inhibition have been studied. Copyright © 2015 John Wiley & Sons, Ltd.     

Enantioselective Synthesis of the Natural Product (S)‐Rugulactone

A simple and efficient enantioselective synthesis of (6S)‐5,6‐dihydro‐6‐[(2E)‐4‐oxo‐6‐phenylhex‐2‐en‐1‐yl]‐2H‐pyran‐2‐one (=(S)‐rugulactone) has been accomplished. The synthesis started from commercially available propane‐1,3‐diol and ethyl 3‐phenylpropanoate and involve the Horner? Wadsworth? Emmons (HWE) and Still's modified HWE olefinations, and Sharpless asymmetric epoxidation.     

A Novel and Efficient Synthesis of 3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐ones (=3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐1‐benzopyran‐2‐ones)

An efficient one‐pot synthesis of 3‐[(4,5‐dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐one (=3‐[(4,5‐dihydro‐1H‐pyrrol‐3yl)carbonyl]‐2H‐1‐benzopyran‐2‐one) derivatives 4 by a four‐component reaction of a salicylaldehyde 1 , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one, a benzylamine 2 , and a diaroylacetylene (=1,4‐diarylbut‐2‐yne‐1,4‐dione) 3 in EtOH is reported. This new protocol has the advantages of high yields (Table), and convenient operation. The structures of these coumarin (=2H‐1‐benzopyran‐2‐one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

DFT 1H–1H coupling constants in the conformational analysis and stereoisomeric differentiation of 6‐heptenyl‐2H‐pyran‐2‐ones: configurational reassignment of synargentolide A

Density functional theory (DFT) ¹H–¹H NMR coupling constant calculations, including solvation parameters with the polarizable continuum model B3LYP/DGDZVP basis set together with the experimental values measured by spectral simulation, were used to predict the configuration of hydroxylated 6‐heptenyl‐5,6‐dihydro‐2H‐pyran‐2‐ones 1 , 2 , 4 , and 7 , allowing epimer differentiation. Modeling of these flexible compounds requires the inclusion of solvation models that account for stabilizing interactions derived from intramolecular and intermolecular hydrogen bonds, in contrast with peracetylated derivatives ( 3 , 5 , and 6 ) in which the solvation consideration can be omitted. Using this DFT NMR integrated approach as well as spectral simulation, the configurational reassignment of synargentolide A ( 8 ) was accomplished by calculations in the gas phase among four possible diastereoisomers ( 8–11 ). Calculated ³J_H,H values established its configuration as 6R‐[4′S,5′S,6′S‐(triacetyloxy)‐2E‐heptenyl]‐5,6‐dihydro‐2H‐pyran‐2‐one ( 8 ), in contrast with the incorrect 6R,4′R,5′R,6′R‐diastereoisomer previously proposed by synthesis ( 12 ). Application of this approach increases the probability for successful enantiospecific total syntheses of flexible compounds with multiple chiral centers. Copyright © 2014 John Wiley & Sons, Ltd.     

Strategy to Construct Stair‐Shaped Partially Reduced Naphtho[1,2‐b]pyrano[2,3‐d]oxepines and Dinaphtho[1,2‐b,d]oxepines

A concise and efficient base‐induced synthesis of stair‐shaped, 4‐methylthio‐2‐oxo‐5,6‐dihydro‐2H‐naphtho[1,2‐b]pyran[2,3‐d]oxepine‐3‐carbonitriles ( 3 ) has been delineated by the reaction of 3,4‐dihydronaphtho[1,2‐b]oxepin‐5(2H)‐one ( 1 ) and methyl 2‐cyano‐3,3‐dimethylthioacrylate in DMSO using powdered KOH as a base at room temperature. Amination of 3 has been achieved by reaction with secondary amine in ethanol at reflux temperature to yield 4‐sec‐amino‐2‐oxo‐5,6‐dihydro‐2H‐naphtho[1,2‐b]pyran[2,3‐d]oxepine‐3‐carbonitriles ( 4 ). Reaction of 3 with aryl methyl ketone ( 5 ) in DMSO at room temperature using powdered KOH as a base produced stair‐shaped 5‐aryl‐7,8‐dihydro‐1,4‐dioxa‐2,3‐dioxodinaphtho[1,2‐b,d]oxepine ( 6 ) in good yields. However, reaction of 6‐aryl‐2H‐pyran‐2‐one‐3‐carbonitrile ( 8 ) with 3,4‐dihydronaphtho[1,2‐b]oxepin‐5(2H)‐one ( 1 ) did not give similar product, but in lieu 4‐aryl‐5,6‐dihydronaphtho[1,2‐b]oxepino[4,5‐b]pyran‐2‐ylidene)acetonitrile ( 9 ) was isolated and characterized.     

One‐Pot Synthesis of 1,4‐Dihydro‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic Acid Derivatives by the Reaction of 2‐Isothiocyanatophenyl Ketones with Lithium Enolates of Acetates and Tertiary Acetamides

The one‐pot synthesis of 4‐aryl‐1,4‐dihydro‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic acid derivatives 2 was achieved in good yields by the reaction of aryl(2‐isothiocyanatophenyl)methanones 1 with lithium enolates of acetates and tertiary acetamides. (2E)‐1‐(2‐Isothiocyanatophenyl)‐3‐phenylprop‐2‐en‐1‐one ( 3 ) gave 1,4‐dihydro‐4‐[(1E)‐2‐phenylethenyl]‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic acid derivatives 4 in good yields as well.     

A novel and direct synthetic route to substituted 1,5‐dihydro‐4H‐[1]benzopyrano[4,3‐b]pyridine‐4,5‐diones

The condensation of 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one and substituted 2‐hydroxybenzaldehydes with ammonium acetate gave the title heterocycles. Synthesis of 1,5‐dihydro‐2‐methyl‐4H‐[1]naphtho‐[1′,2′:5,6]pyrano[4,3‐b]‐pyridine‐4,5‐dione is also described. A reaction mechanism is discussed.     

A Novel,One‐Pot Four‐Component Route to 2′‐Thioxo‐2′,3′‐dihydrospiro[indole‐3,6′‐[1,3]thiazin]‐2‐one Derivatives

An efficient route to 2′,3′‐dihydro‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives is described. It involves the reaction of isatine, 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one, and different amines in the presence of CS₂ in dry MeOH at reflux (Scheme 1). The alkyl carbamodithioate, which results from the addition of the amine to CS₂, is added to the α,β‐unsaturated ketone, resulting from the reaction between 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one and isatine, to produce the 3′‐alkyl‐2′,3′‐dihydro‐4′‐phenyl‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives in excellent yields (Scheme 2). Their structures were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses.     

New synthesis and reactivity of 3‐bromoacetyl‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one with binucleophilic amines

3‐(Bromoacetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one was synthesized by the reaction of dehydroacetic acid (DHAA) with bromine in glacial acetic acid. Novel heterocyclic products were synthesized from the reaction of bromo‐DHAA with alkanediamines, phenylhydrazines, ortho‐phenylenediamines, and ortho‐aminobenzenethiol. The obtained new products 3‐(2‐N‐substituted‐acetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐ones, 4‐hydroxy‐3‐[1‐hydroxy‐2‐(2‐phenylhydrazinyl)vinyl]‐6‐methyl‐2H‐pyran‐2‐one, 1‐(2,4‐dinitrophenyl)‐7‐methyl‐2,3‐dihydro‐1H‐pyrano[4,3‐c]pyridazine‐4,5‐dione, 3‐(3,4‐dihydroquinoxalin‐2‐yl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one/3‐(3,4‐dihydroquinoxalin‐2‐yl)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione, 6‐methyl‐3‐(3,4‐dihydroquinoxalin‐2‐yl)‐2H‐pyran‐2,4(3H)‐dione, and (E)‐3‐(2H‐benzo[b][1,4]thiazin‐3(4H)‐ylidene)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione were fully characterized by IR, ¹H and ¹³C NMR, and mass spectra. J. Heterocyclic Chem., 2011.     

New α‐Glucosidase Inhibitors from the Mongolian Medicinal Plant Ferula mongolica

The four new and four known sesquiterpenoid derivatives 1 – 4 and 5 – 8 , respectively, were isolated from the air‐dried roots of Ferula mongolica. The structures of these compounds were determined by spectroscopic methods and found to be rel‐(2R,3R)‐2‐[(3E)‐4,8‐dimethylnona‐3,7‐dienyl]‐3,4‐dihydro‐3,8‐dihydroxy‐2‐methyl‐2H,5H‐pyrano[2,3‐b][1]benzopyran‐5‐one ( 1 ), rel‐(2R,3R)‐2‐[(3E)‐4,8‐dimethylnona‐3,7‐dienyl]‐2,3‐dihydro‐7‐hydroxy‐2,3‐dimethyl‐4H‐furo[2,3‐b][1]benzopyran‐4‐one ( 2 ), rel‐(2R,3R)‐2‐[(3E)‐4,8‐dimethylnona‐3,7‐dienyl]‐2,3‐dihydro‐7‐hydroxy‐2,3‐dimethyl‐4H‐furo[3,2‐c][1]benzopyran‐4‐one ( 3 ), rel‐(2R,3R)‐2‐[(3E)‐4,8‐dimethylnona‐3,7‐dienyl]‐2,3‐dihydro‐7‐methoxy‐2,3‐dimethyl‐4H‐furo[3,2‐c][1]benzopyran‐4‐one ( 4 ), (4E,8E)‐1‐(2‐hydroxy‐4‐methoxyphenyl)‐5,9,13‐trimethyltetradeca‐4,8,12‐trien‐1‐one ( 5 ), the rel‐(2R,3S) diastereoisomer 6 of 2 , the rel‐(2R,3S) diastereoisomer 7 of 4 , and (4E,8E)‐1‐(2,4‐dihydroxyphenyl)‐5,9,13‐trimethyltetradeca‐4,8,12‐trien‐1‐one ( 8 ). These compounds were tested as inhibitors against the enzyme α‐glucosidase. The compounds 1 – 6 and 8 exhibited significant inhibitory activity and, therefore, represent a new class of α‐glucosidase inhibitors.     

Efficient Synthesis of Dialkyl (2Z)‐2‐[(E)‐1‐Aryl‐2‐(3‐arylquinoxalin‐2‐yl)ethenyl]but‐2‐enedioates

The reaction of dialkyl acetylenedicarboxylates 4 with 1‐aryl‐2‐[(3‐arylquinoxalin‐2(1H)‐ylidene)ethanones 3 in the presence of Ph₃P leads to dialkyl (2Z)‐2‐[(E)‐1‐aryl‐2‐(3‐arylquinoxalin‐2‐yl)ethenyl]but‐2‐enedioates 1 in good yields.     

Four Novel Dihydroisocoumarin (=3,4‐Dihydro‐1H‐2‐benzopyran‐1‐one) Glucosides from the Fungus Cephalosporium sp. AL031

Four novel dihydroisocoumarin (=3,4‐dihydro‐1H‐2‐benzopyran‐1‐one) glucosides were isolated from a culture broth of a strain of the fungus Cephalosporium sp. AL031. Their structures were elucidated as (2E,4E)‐5‐[(3S)‐5‐acetyl‐8‐(β‐D ‐glucopyranosyloxy)‐3,4‐dihydro‐6‐hydroxy‐1‐oxo‐1H‐2‐benzopyran‐3‐yl]penta‐2,4‐dienal ( 1 ), (2E,4E)‐5‐[(3S)‐5‐acetyl‐8‐(β‐D ‐glucopyranosyloxy)‐3,4‐dihydro‐6‐methoxy‐1‐oxo‐1H‐2‐benzopyran‐3‐yl]penta‐2,4‐dienal ( 2 ), (3S)‐8‐(β‐D ‐glucopyranosyloxy)‐3‐[(1E,3E,5E)‐hepta‐1,3,5‐trienyl]‐3,4‐dihydro‐6‐hydroxy‐5‐methyl‐1H‐2‐benzopyran‐1‐one ( 3 ), and (3S)‐8‐[(6‐O‐acetyl‐β‐D ‐glucopyranosyl)oxy]‐3‐[(1E,3E,5E)‐hepta‐1,3,5‐trienyl]‐3,4‐dihydro‐6‐methoxy‐5‐methyl‐1H‐2‐benzopyran‐1‐one ( 4 ) by spectroscopic methods, including 2D‐NMR techniques and chemical methods.     

2‐Triazolylpyrimido[1,2,3‐cd]purine‐8,10‐diones via 1,3‐dipolar cycloadditions to 2‐ethynylpyrimido[1,2,3‐cd]purine‐8,10‐dione

This paper presents the synthesis of a series of 5,6‐dihydro‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ring system derivatives with a [1,2,3]triazole ring bonded in position 2. The procedure is based on cycloaddition of substituted alkyl azides to the terminal triple bond of 5,6‐dihydro‐2‐ethynyl‐9‐methyl‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 4 ). This cycloaddition produced two regioisomers ?5,6‐dihydro‐9‐methyl‐2‐(1‐substituted‐1H‐[1,2,3]triazol‐5‐yl)‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 7 ) and 2‐(1‐substituted‐1H‐[1,2,3]triazol‐4‐yl) derivative 8 . The required 2‐ethynyl deriva tive 4 was obtained from the starting 2‐unsubstituted compound 1 by bromination to yield the 2‐bromo derivative 2 , which was converted by Sonogashira reaction to trimethylsilylethyne 3 and finally, the protective trimethylsilyl group was removed by hydrolysis.     

Synthesis of 2‐Aryl‐2,3‐dihydro‐1,8‐naphthyridin‐4(1H)‐ones by Deprotective Cyclization of N‐{3‐[(2E)‐3‐Arylprop‐2‐enoyl]pyridin‐2‐yl}‐2,2‐dimethylpropanamides in Water

A new and convenient method for the preparation of 2‐aryl‐2,3‐dihydro‐1,8‐naphthyridin‐4(1H)‐ones 4 has been developed. Thus, N‐{3‐[(2E)‐3‐arylprop‐2‐enoyl]pyridin‐2‐yl}‐2,2‐dimethylpropanamides 3 are synthesized from commercially available pyridin‐2‐amine using an easily performed three‐step sequence and are subjected to cyclization with deprotection under acidic conditions in H₂O to give the desired products. Similarly, 2‐aryl‐2,3‐dihydro‐1,7‐naphthyridin‐4(1H)‐ones 8 and 2‐aryl‐2,3‐dihydro‐1,6‐naphthyridin‐4(1H)‐ones 12 can be prepared from pyridin‐3‐amine and pyridin‐4‐amine, respectively.     

The conformational analyses of 2‐amino‐N‐[2‐(dimethylphenoxy)ethyl]propan‐1‐ol derivatives in different environments

Four crystal structures of 2‐amino‐N‐(dimethylphenoxyethyl)propan‐1‐ol derivatives, characterized by X‐ray diffraction analysis, are reported. The free base (R,S)‐2‐amino‐N‐[2‐(2,3‐dimethylphenoxy)ethyl]propan‐1‐ol, C₁₃H₂₁NO₂, 1 , crystallizes in the space group P2₁/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium chloride, C₁₃H₂₂NO₂⁺·Cl^?, 2c , crystallizes in the space group P2₁, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2‐picolinic acid, namely, (R,S)‐N‐[2‐(2,3‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium pyridine‐2‐carboxylate, C₁₃H₂₂NO₂⁺·C₆H₄NO₂^?, 1p , and (R)‐N‐[2‐(2,6‐dimethylphenoxy)ethyl]‐1‐hydroxypropan‐2‐aminium pyridine‐2‐carboxylate, C₁₃H₂₂NO₂⁺·C₆H₄NO₂^?, 2p , consists of one cation and one 2‐picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P, while salt 2p crystallizes in the space group P4₁2₁2. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen‐bonded chains, while the structures of the 2‐picolinate salts have hydrogen‐bonded rings as the major features. In both salts with 2‐picolinic acid, the specific R₁²(5) hydrogen‐bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.     

Synthesis of New Pyrano[2′,3′: 5,6]chromeno[4,3‐b]quinolin‐4‐ones via Aza‐DielsAlder Reaction

New pyrano[2′,3′: 5,6]chromeno[4,3‐b]quinolin‐4‐ones have been synthesized by intramolecular aza‐Diels? Alder reaction of the azadienes generated in situ from aryl amines and 8‐formyl‐7‐(prop‐2‐ynyl)2,3‐disubstituted chromones using CuFe₂O₄ nanoparticles as a catalyst in DMSO at 80–90° in good‐to‐excellent yields. Particularly valuable features of this methodology include simple implementation, inexpensive and reusable catalyst, and good yields. The structures were established by spectroscopic data and further confirmed by X‐ray diffraction analysis of one of the products.     

A steroidal phenyldi­hydro‐1,3‐oxazine derivative

The structure of methyl (6R)‐6‐(3′β‐acetoxy‐5′‐androsten‐17′β‐yl)‐2‐phenyl‐5,6‐dihydro‐4H‐[1,3]oxazine, C₃₁H₄₁NO₃, synthesized from an azidopregnene derivative, is reported. The di­hydro‐1,3‐oxazine ring is connected in the β position to the sterane skeleton at C‐17′. An R configuration was found at C‐6.