Pyrones VII. An Efficient Preparation and the Selective Reduction of Methyl 2,6-Dimethyl-4H-Pyran-4-one-3-Carboxylate

The syntheses of 4H-pyran-4-one-3-carboxylic acids and derivatives which have been previously reported (for example, starting with ketene¹, diketene², or dehydroacetic acid³) normally proceed only in low yield, often requiring rigorous control of the reaction conditions. We have shown that the reaction of dehydroacetic acid (1) with “magic methyl” (methyl fluorosulfonate) produces methyl 2,6-dimethyl-4H-pyran-4-one-3-carboxylate (4) in high yield (85%) under mild conditions.     

An Efficient Synthesis of (±)-Cuparene from 4,4-Dimethyl-2-Cyclohexen-1-One

An efficient synthesis of (±)-cuparene 1 from 4,4-dimethyl-2-cyclohexen-1-one 2 involves 1,4-addition by use of organozinc reagent, ozonolysis and Dieckmann condensation as the key steps.     

Studies towards the synthesis of ertugliflozin from l-Arabinose

A new method for the diastereoselective synthesis of enantiomerically pure ertugliflozin was developed. The crucial step involves an aldol condensation between 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone and (4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolane-4-carbaldehyde, which was prepared from known 2-C-trityloxymethyl-2,3-O-isopropylidene-l-erythrose (easily accessible in three steps from l-arabinose) by standard reduction/oxidation and protection/deprotection manipulations. Dihydroxylation of the aldol condensation product and further global deprotection led to the formation of the target molecule.     

Aldol condensation versus conjugate addition: intramolecular cyclization using a combination of Lewis acid and 1,2-diol

The reactivity of 3-substituted 4-methyl-4-(3-oxobutyl)-2-cyclohexen-1-ones (1) in the presence of a combination of a Lewis acid and a 1,2-diol was studied. The results suggest several factors that influence 6-membered ring formation, including two types of intramolecular aldol reaction and intramolecular 1,4-addition, due to the C3-substituent, Lewis acid, and the presence of diol. In this study, novel methodology to prepare two types of decalin skeleton could be developed.     

Synthesis of the C1-C16 fragment of spirastrellolide A

Synthesis of the C1-C16 fragment of spirastrellolide A is described here featuring Sharpless asymmetric epoxidation, an acid promoted O-1,4-addition, and Mukaiyama 1,3-anti-aldol.     

Condensation of 2-naphthylamine or N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexane-3-carboxylate

Condensation of 2-naphthylamine with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate afforded depending on the reaction conditions methyl 9,9-dimethyl-11-oxo-8,9,10,12-tetrahydro-7H-benzo[a]acridine-10-carboxylate or 4-alkoxymethyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??Hspirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylate. The condensation of N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate provided with the quantitative yield the corresponding methyl 4-benzyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??H-spirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylates.     

Addition conjuguée dans le thf-hmpt d'arylacétonitriles lithies aux cyclohexèn-2 ones substituées: intervention des facteurs stériques et électroniques

The reaction of lithiated arylacetonitriles 2a-c with 2-cyclohexenones 3-9 in THF-HMPA (80:20 v/v) at ?70° leads in all cases but one to δ-ketoalkylnitriles, resulting from 1,4-addition. The only case where some 1,2-addition takes place is the reaction of 2a with 4,4-dimethyl 2-cyclohexenone 7. The formation of allylic alcoholates, products of 1,2-addition, is shown to be reversible in this solvent mixture. However, in several cases, kinetic control of 1,4-addition is demonstrated. The rate of formation of 1,4-addition products depends upon the arylacetonitrile substituents: 2a >2b >2c (i.e. the higher lying the nucleophile HOMO the faster the reaction). It is also sensitive to the cyclohexenone substituents; although methyl on C-2 and gem-dimethyl on C-5 or t-butyl on C-4 have small influence on the reaction rate, methyl on C-3 or gem dimethyl on C-4 induce a noticeable rate decrease. The addition, of 2b on 4-t-butyl 2-cyclohexenone 8 leads, at the early stage, to a predominating isomer 15b, to which the trans diaxial configuration of the substituents has been attributed by 250 MHz ¹H NMR. A single transition state model, reagent-like, where the nucleophile approaches the C-C bond by the less hindered face of the 2-cyclohexenone in a 1,2-diplanar conformation, the CN substituent being directed towards the C=0 group, accounts for all the substituent effects and the stereoselectivity observed.     

Isolation and identification of three urinary metabolites of retinoic acid in the rat.

After the intraperitoneal administration of high doses of ¹⁴C- and ³H-labelled retinoic acid ( 1 ) to rats three major urinary metabolites have been isolated in microgram amounts by use of column, thin-layer and high-pressure liquid chromatography. Their structures were elucidated by mass spectroscopy and Fourier transform ¹H-NMR. spectroscopy as 2 (5-methyl-5-[2-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)vinyl]-2-tetrahydrofuranone), 3 (5-[2-(6-hydroxymethyl-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl)vinyl]-5-methyl-2-tetrahydrofuranone) and 4 (6-(6-hydroxymethyl-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl)-4-methyl-4-hexenoic acid). In these metabolites the tetraene side chain of 1 is shortened and the cyclohexene ring oxidized. The radioactivity of 2 and 3 accounted for about 10% (0.9% of the dose) each, metabolite 4 for about 6% (0.5% of the dose) of the total urinary radioactivity.     

Substituent directed regioselective synthesis of 2-oxonicotonic acids and methyl nicotinates

An innovative synthesis of aryl tethered 1,2-dihydro-2-oxopyridine-3-carboxylic acids has been developed through nucleophile induced ring transformation of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates using either cyanamide or arylamidine in excellent yields. Further, the reaction of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates with formamidine acetate under analogous reaction conditions did not follow the same course of reaction and produced methyl nicotinate, regioselectively, in good yield. Decarboxylation of a 6-aryl-4-methylsulfanyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid has been achieved by heating in PPA. The 4-methylsulfanyl substituent in 3 has also been oxidized to the corresponding methylsulfonyl group with m-chloroperbenzoic acid.     

Chemistry of pyrones related to dehydroacetic acid. Functionalization at C-5 and at the methyl group at C-6. An attempted synthesis of a thromboxane B2 analogue

New derivatives of dehydroacetic acid and triacetic acid lactone functionalized at both C-5 and at the methyl group at C-6 have been synthesized as intermediates for the preparation of thromboxane B₂ analogues. 6-Mercaptomethyl-4-methoxy-2-pyrone and some derived thioethers have been also prepared. New thioether derivatives of O-alkyloximes of dehydroacetic acid have been synthesized and tested for herbicidal activity.     

A novel free C-12 higher carbon sugar: asymmetric synthesis and reactivity with nucleophiles

A novel C-12 higher carbon sugar, (1R)-(1,4:3,6-dianhydro-d-mannitol-2-yl)-1,4:3,6-dianhydro-d-fructose, was firstly synthesized via a convenient aldol reaction of 1,4:3,6-dianhydro-d-fructose without any protection and activation of functional groups. The reactivity of the novel higher sugar with nucleophiles was also studied, through which a series of oxazolidines and other derivatives of the higher sugar were available. The study showed that the higher sugar possesses a highly reactive carbonyl group and a good stereo controlling ability in the reaction.     

Synthesis of Urinary Metabolites of Retinoic Acid

Urinary metabolites 5-methyl-5-[2-(2,6,6-trimethyl -3-oxo-1-cyclohexen-1-yl)-vinyl]-2-tetrahydrofuranone (1) and 5-[2-(6-hydroxymethyl-2, 6-dimethyl-3-oxo-1- cyclohexen-1-yl)vinyl]-5-methyl-2-tetrahydrofuranone (2) of retinoic acid have been synthesized from 4-[2,2,6-trimethyl-3-(tetrahydro-2 H -pyran-2-yl)oxy-1-cyclohexen-1-yl]-3-buten-2-one (4) and methyl 2-(3,3-ethylenedioxy-1-butenyl)-1, 3-dimethyl-4-oxo-2-cyclohexene-1-carboxylate (5) .     

Novel synthesis of the pyrrolo[2,1-c][1,4]benzodiazocine ring system via a Dieckmann condensation

A novel four-step synthesis to the pyrrolo[2,1-c][1,4]benzodiazocine ring system is described. 1H-Pyrrole-2-carbaldehyde was alkylated with ethyl or methyl bromoacetate and the resulting ethyl or methyl (2-formyl-1H-pyrrol-1-yl)acetates oxidised with potassium permanganate to the corresponding 1-[(2-ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acids. The latter was converted into their acid chlorides by reaction with thionyl chloride and without isolation transformed into the respective methyl 2-({[1-(2-ethoxy or methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates by reaction with methyl anthranilate. Dieckmann condensation of methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoate provided the pyrrolo[2,1-c][1,4]benzodiazocine.     

Regioselective addition of organomagnesium reagents to N-silyl activated nicotinic acid esters—a convenient method for the synthesis of 4,4-disubstituted 1,4-dihydronicotinates

The addition of RMgX or R₂Mg to nicotinic acid esters, activated with triisopropylsilyl triflate, was investigated. The regioselectivity of this reaction, where 4-unsubstituted and 4-substituted pyridine derivatives were employed as starting materials, was examined. Depending on the structure of the organomagnesium reagent varying ratios of 1,2-, 1,4-, and 1,6-regioisomers were obtained but in any case the 1,4-addition products were clearly predominating. Desilylation of the isomeric pure addition products with LiOH provided stable 4,4-disubstituted dihydropyridines, which could be easily N-alkylated with alkylhalides in high yield. Furthermore, it was shown that the silyl protecting group of the obtained dihydropyridines can be easily replaced by an acyl group.     

Synthesis and cytotoxic properties of derivatives of the tert-butyl ester of 7-alkylidene-3-methyl-3-cepheme-4-carboxylic acid

Sulfones of the tert-butyl esters of 7-arylmethylene-and 7-(2-furyl)methylene-3-methyl-3-cepheme-4-carboxylic acid were obtained by the condensation of the tert-butyl ester of 3-methyl-7-oxo-3-cepheme-4-carboxylic acid with arylmethylene-and 2-furylidenetriphenylphosphoranes and subsequent oxidation of the intermediate products by meta-chloroperbenzoic acid. The combination of the tert-butyl esters of 7E-bromomethylene-and 7,7-dibromomethylene-3-methyl-1,1-dioxo-3-cepheme-4-carboxylic acids with trimethylsilylacetylene under conditions of the Sonogashira reaction gave the tert-butyl esters of 3-methyl-1,1-dioxo-7E-(3-trimethylsilyl-2-propynylidene)-3-cepheme-4-carboxylic acid and 3-methyl-1,1-dioxo-7-[1,5-bis(trimethylsilyl)-1,4-pentadiyn-3-ylidene]-3-cepheme-4-carboxylic acid. The Vilsmeier reagent was used to incorporate the dimethylaminomethylene group at C-2 of the 7Z-and 7E-isomers of the tert-butyl ester of 7-(4-chlorophenyl)methylene-3-methyl-1,1-dioxo-3-cepheme-4-carboxylic acid. The cytotoxic properties of the derivatives of the tert-butyl ester of 7-alkylidene-3-methyl-3-cepheme-4-carboxylic acid in regard to cancer and normal cells in vitro depends on the structure and 7Z-or 7E-isomerism of the substituent in the 7-alkylidene group as well as the presence of a dimethylaminomethylene group at C-2 of the 3-cepheme system.     

Highly diastereoselective alkylation of vicinal dianions of chiral succinic acid derivatives: a new general strategy to (R)-β-arylmethyl-γ-butyrolactones

The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione react with arylmethyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral α-arylmethylated succinic acid derivatives; the (R)-products are converted into (R)-β-arylmethyl-γ-butyrolactones and (R)-α-arylmethyl-γ-butyrolactones.     

Diacetoxylation of conjugated dienes with thallium(III) acetate in acetic acid

The reaction of conjugated dienes such as 1,3-butadiene, isoprene, 2,3-dimethyl-1,3-butadiene, 2,5-dimethyl-2,4-hexadiene, 1,3-cyclopentadiene, and 1,3-cyclohexadiene, with thallium(III)acetate in acetic acid at 10–65° for 0.5–15 hr affords an isomeric mixture of the corresponding diacetoxyalkenes (1,2- and 1,4-addition products) in 10–92% yields. The 1,2-addition products are predominantly formed in all cases examined except the case of 1,3-cyclopentadiene. The reaction is assumed to proceed through acetoxythallation and dethallation steps, the latter step being accompanied and/or followed by an attack of acetoxyl group. An initial attack of thallium moiety is proposed to occur mainly at C-1 and C-2 carbons in the cases of linear terminal dienes and cyclic dienes, respectively.     

Degradation of deoxycholic acid by Pseudomonas Sp. NCIB 10590

The microbial degradation of deoxycholic acid 1 by Pseudomonas NCIB 10590 has been studied and two major products have been isolated and identified as 12β-hydroxyandrosta-1,4-dien-3,17-dione 2 and 12α-hydroxypregna-1,4-dien-3-one-20-carboxylic acid 9. Three minor products were isolated and evidence is given for the following structures: 12α-hydroxyandrosta-1,4-dien-3,17-dione 4, 12β-hydroxyandrosta-4-en-3,17-dione 7 and 12?, 17?-dihydroxyandrosta-1,4-dien-3-one 8.     

丁酸氯维地平降解杂质的合成

以4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸(2-氰基乙基)（甲基）酯(5)为起始原料,合成了丁酸氯维地平的5种降解杂质：4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯(A), 4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3-吡啶羧酸甲酯(B), 4-(2,3-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸单甲酯(C), 4-(2,3-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸（丁酰氧基甲基）（甲基）酯(D)和4-(2,3-二氯苯基)-2,6-二甲基-3-吡啶羧酸甲酯(E)。其中A由5水解制得;B由A脱羧制得;C由5氧化后再经水解制得;D由C和丁酸氯甲酯缩合制得;E由C脱羧制得,化合物结构经¹H NMR和MS（ESI）确证。     

Asymmetric 1,4-addition of organoboronic acids to α,β-unsaturated ketones and 1,2-addition to aldehydes catalyzed by a palladium complex with a ferrocene-based phosphine ligand

A combination of palladium with ferrocene-based phosphine ligand with a carbon–bromine bond was found to be a good catalyst for the 1,4-addition of arylboronic acids to α,β-unsaturated ketones and the 1,2-addition to aldehydes. Using Pd(dba)₂ and (S,R_p)-[1-(2-bromoferrocenyl)ethyl]diphenylphosphine (S,R_p)-1, 3-phenylcyclohexanone was obtained from the reaction of 2-cyclohexen-1-one with phenylboronic acid in the presence of K₂CO₃ in toluene at room temperature after 3 h in 92% yield with 76% ee. In the 1,2-addition of 4-methylphenylboronic acid to benzaldehyde, 96% of (4-methylphenyl)phenylmethanol was afforded after 24 h, while the enantiomeric excess was only 6%.