Vinylogous Esters Research Articles

Metalation of Biginelli Compounds. A General Unprecedented Route to C-6 Functionalized 4-Aryl-3,4-dihydropyrimidinones

4-Aryl-6-methyl-3,4-dihydro-2(1H)-pyrimidinone esters (DHPMs) readily undergo metalation at the C-6 methyl (vinylogous ester) position on treatment with lithium diisopropylamide at -10 degrees C. The resulting anion intermediates can be treated with electrophilic reagents to afford functionalized DHPMs that have been chemically elaborated mainly at the C-6 position. Di- and trianion formation is also possible at both the vinylogous methyl and NH positions when reactions are performed with excess equivalents of the base.

Reactions of ( Z)-3-aryl-3-chloropropenals with nucleophiles: stereoselective formation of ( E)-vinylogous esters, ( E)-vinylogous amides, and vinamidinium salts

The highly stereoselective conversions of ( Z)-3-aryl-3-chloropropenals to ( E)-3-alkoxy-3-arylpropenals, to ( E)-3-aryl-3-morphorlinopropenals, and to vinamidinium salts are reported. The stereochemical assignments were based on 2D-NMR experiments.

Disarming, non-participating 2- O-protecting groups in manno- and rhamnopyranosylation: scope and limitations of sulfonates, vinylogous esters, phosphates, cyanates, and nitrates

A series of d-mannopyranosyl and l-rhamnopyranosyl thioglycosides protected with electron-withdrawing, non-participating protecting groups on O-2 have been prepared and investigated for their potential as β-glycosyl donors. Both α- and β-thioglycosides were investigated and the latter preferred on the grounds of enhanced stability at room temperature. A 2- O-nitro- l-rhamnosyl fluoride was also prepared and investigated. Moderate β-selectivities were observed with some of these donors. With the more powerfully electron-withdrawing groups reduced donor reactivity leads to a requirement for higher reaction temperatures and reduced selectivities. Decomposition temperatures of the intermediate glycosyl triflates were determined by variable temperature NMR spectroscopy and generally correlate with the disarming propensity of the protecting group system.

Low‐Valent Titanium‐Mediated Cyclopropanation of Vinylogous Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Short Synthesis of New 23‐Vinyl Steroid Derivatives from Sapogenins by the Action of 9‐BBN on Vinylogous Esters

AbstractSome new 16β‐acetoxy‐22,26‐epoxy‐23‐vinylcholest‐22‐ene steroid derivatives have been synthesized from sapogenins via a two‐step sequence involving the reduction of a vinylogous ester moiety by 9‐BBN, a reaction with few precedents and for which a coherent mechanistic interpretation has not been given before now. Some mechanistic insight into this reaction was gained from NMR spectroscopic evidence. A plausible general mechanistic interpretation of the action of 9‐BBN on vinylogous esters is proposed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Total synthesis and biological evaluation of the nakijiquinones.

The Her-2/Neu receptor tyrosine kinase is vastly overexpressed in about 30% of primary breast, ovary, and gastric carcinomas. The nakijiquinones are the only naturally occurring inhibitors of this important oncogene, and structural analogues of the nakijiquinones may display inhibitory properties toward other receptor tyrosine kinases involved in cell signaling and proliferation. Here, we describe the first enantioselective synthesis of the nakijiquinones. Key elements of the synthesis are (i) the reductive alkylation of a Wieland-Miescher-type enone with a tetramethoxyaryl bromide, (ii) the oxidative conversion of the aryl ring into a p-quinoid system, (iii) the regioselective saponification of one of the two vinylogous esters incorporated therein, and (iv) the selective introduction of different amino acids via nucleophilic conversion of the remaining vinylogous ester into the corresponding vinylogous amide. The correct stereochemistry and substitution patterns are completed by conversion of two keto groups into a methyl group and an endocyclic olefin via olefination/reduction and olefination/isomerization sequences, respectively. This synthesis route also gave access to analogues of nakijiquinone C with inverted configuration at C-2 or with an exocyclic instead of an endocyclic double bond. Investigation of the kinase-inhibiting properties of the synthesized derivatives revealed that the C-2 epimer 30 of nakijiquinone C is a potent and selective inhibitor of the KDR receptor, a receptor tyrosine kinase involved in tumor angiogenesis. Molecular modeling studies based on the crystal structure of KDR and a model of the ATP binding site built from a crystal structure of FGF-R revealed an insight into the structural basis for the difference in activity between the natural product nakijiquinone C and the C-2 epimer 30.

Two methods for the preparation of 2-cyclohexenones from resin-bound 1,3-cyclohexanedione

The addition of organolithium or Grignard reagents to vinylogous ester resin 1 followed by mild hydrolysis of product resins 2 provides 3-alkyl-2-cyclohexenones in high purity (>95%). Alternatively, conversion of 1 to vinyl triflate resin 4 followed by palladium-mediated couplings with aryl boronic acids and hydrolysis furnishes 3-aryl-2-cyclohexenones in lower yield, but exceptional purity.

Synthesis of Carbocycles via Intramolecular Conjugate Additions: Total Syntheses of Axane Sesquiterpenoids.

Syntheses of (+/-)-axamide-1 (2) and (+/-)-axisonitrile-1 (1) are described. The syntheses require 12 steps and 13 steps, respectively, from vinylogous ester 8 and feature the diastereoselective cyclization of unsaturated ester 7 to perhydroindan 5. Some interesting reactions of the organometallic derived from [(trimethylsilyl)methyl]magnesium chloride and cerium trichloride are also described.

Titanium-mediated olefinations of cyclobutenedione derivatives

A variety of cyclobutenedione derivatives, including squaric esters, react with dimethyl titanocene to afford the corresponding methylenation products. With certain mixed-substituted substrates the reaction proceeds preferably at a ketonic carbonyl rather than a vinylogous ester.

Intramolecular cyclization reactions of enone radicals

Enone radicals, generated from the corresponding iodo enones, or vinylogous esters and amides, undergo intramolecular cyclization to the tethered trimethylsilyl acetylenic side chain to give the carbo- or heterobicyclic enones.

Stereoselective Michael additions of nitromethane yielding 3R(1S N-substituted aminoethyl)pyrrolidines

The 1,4-addition of nitromethane to vinylogous esters of N-protected amino acids proceeded with good to excellent yields and with good diastereoselectivity.

Metalation of Hantzsch esters and mixed amide esters: a general route to C-2 functionalized 1,4-dihydropyridines

1,4-Dihydropyridine (Hantzsch) diesters 3a-e readily undergo metalation at the C-2 methyl (vinylogous ester) position on treatment with alkyllithium bases. The resulting anion intermediates can be treated with electrophilic reagents to afford 1,4-dihydropyridine products that have been chemically elaborated at the C-2 methyl position. The methodology permits a variety of electrophilic functionalities to be regiospecifically introduced at the C-2 methyl position of 1,4-dihydropyridines. Deuterium distribution studies with mixed dihydropyridine amide esters 20a and 20b having nonequivalent C-2 and C-6 methyl groups indicate specific metalation occurs at the C-2 methyl (vinylogous ester) position.Tri- and tertaanion formaion is also possible at both vinylogous methyl and NH positions when the metalation reactions are performed with excess equivalents of n-BuLi or s-BuLi bases

Hydrogenation of vinylogous esters

Methods for hydrogenation of the vinylogous ester linkage have been investigated. The ideal method appears to be hydrogenation over a palladium on charcoal catalyst, using THF as the solvent. Classical methods such as hydrogenation in hydroxylic solvents and Birch reduction were not successful with fused-ring vinylogous esters.

Cerium Chloride-Catalyzed Addition of Grignard Reagents to Vinylogous Esters: An Improved Route to 3-Substituted Cyclopent-2-en-1-ones

Abstract Addition of Grignard reagents to vinylogous esters in the presence of cerium chloride results in an improved one-pot synthesis of 3-substituted cyclopent-2-en-1-ones

Asymmetric Synthesis of Enantiomerically Pure Phosphonic Analogues of Glutamic Acid and Proline

Michael addition of the metallated camphor derivatives 2 to vinylogous esters and subsequential hydrolysis afforded phosphonic analogues of glutamic acid. The enantiomerically pure lactam 6 was reduced by LiBH 4/BF 3·OEt 2 to phosphoproline 7.

Diastereoselective double michael additions of vinylogous esters and thexyldimethylsilyl triflate-induced cyclizations

Double Michael additions of vinylogous esters of type 1 with crotyl ester generates diastereoselectively bicyclo[2.2.2]octanone 2 with four defined chiral centers via a synclinal transition state. Thexyldimethylsilyl enol ethers of type 5 and 10 undergo smooth cyclization to bicyclo[3.3.1]nonenones 7 and bicylo[3.3.0]octenones 12 by addition of Lewis acids.

ChemInform Abstract: Diastereoselectivity in Conjugate Addition of Alkylcuprates to Vinylogous Ester of N,O‐Diprotected Serinal.

AbstractThe N,O‐diprotected serinal (I) is olefinated with the Wittig reagent (II) to give predominantly the E‐configurated α,β‐unsaturated ester (III).

Diastereoselectivity in conjugate addition of alkylcuprates to vinylogous ester of N O-diprotected serinal.

Various alkylcuprates were added to the Z and E vinylogous esters of N,O-diprotected (D) or (L) serinal 1. Good to excellent yields and asymmetric inductions were observed.

Use of the electrophilic arylation reaction of aryl-lead triacetates in a synthesis of (±)-lycoramine

A formal total synthesis of (±)-lycoramine is reported. The quaternary carbon centre of the alkaloid was produced by a novel electrophilic arylation of the mixture of isomeric vinylogous keto esters (4) and (5) by 2,3-dimethoxyphenyl-lead triacetate. The resulting key intermediate (7c), which was formed in almost quantitative yield, was converted in a straightforward sequence into the formamide (25), from which the alkaloid has been produced previously by a Bischler-Napieralski cyclisation. Functional group protection was only required at one stage in the synthesis.

Di-tert-butylmethylsilyl (DTBMS) trifluoromethanesulfonate. Preparation and synthetic applications of DTBMS esters and enol ethers

DTBMS triflate, readily available from dichloromethylsilane, provides carboxylic esters which resist reduction by hydridoaluminate or acid catalyzed hydrolysis, and vinylogous esters (enol ethers of hydroxymethylene ketones) which resist 1,4-addition of methyllithium.