Enol Ether Moiety Research Articles

7‐(Dimethylamino)tricyclo[5.2.2.01,6]undecene Derivatives from β‐Cyclohexenyl β‐Dimethylamino‐Substituted α,β‐Unsaturated Fischer Carbenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis, reactivity and stereochemistry of new phosphorus heterocycles with 5- or 6-membered rings

Syntheses of novel phosphorus heterocycles containing α-amino or α-hydroxyphosphonic or phosphinic acids motifs are developed. 2,3-dihydro-1,3-oxaphospholes ( 1) and 1,4,2-oxazaphosphinanes ( 2) exhibit a reactive part, respectively the enolether moiety and the P–H bond, which allows various structural modifications: (i) for 1a, by introduction of amino substituents, (ii) for 2a, by hydroxy- or aminoalkylation, by Michael addition or by P-arylation. These reactions present generally a good or even an excellent kinetic diastereoselectivity which can often be predicted by molecular models of the transition states.

7‐(Dimethylamino)tricyclo[5.2.2.01,6]undecene Derivatives from β‐Cyclohexenyl β‐Dimethylamino‐Substituted α,β‐Unsaturated Fischer Carbenes

AbstractWhen heated in pyridine at 80 °C, pentacarbonyl[(2E)‐3‐cyclohexenyl‐3‐(dimethylamino)‐1‐ethoxy‐2‐propen‐1‐ylidene]chromium (1‐Cr) and ‐tungsten (1‐W) complexes undergo 6π‐electrocyclization and subsequent reductive elimination to yield the cyclohexane‐annelated cyclopentadiene 6, which equilibrates by 1,5‐hydrogen shift with its more reactive isomer 7. The latter molecule is efficiently trapped in Diels−Alder reactions with various alkynes 2 and styrenes 8 to give the cyclohexane‐annelated norbornadiene 3 and norbornene derivatives respectively, with high regio‐ and diastereoselectivity in 15−91% yields. The enol ether moiety in compound 3 is particularly easily hydrolyzed, probably due to the through‐space interaction between the two double bond moieties, so that the norbornenone derivatives 4 are isolated in all but one case after chromatographic purification. In this reaction, the tungsten complex 1‐W consistently gave lower yields than 1‐Cr. Arylalkynes with strongly electron‐withdrawing groups and minimal steric congestion are particularly suitable reaction partners for 7. The formation of bis‐cycloadducts 10 from suitable diynes largely depends upon the steric and electronic properties of the corresponding alkynyl‐substituted mono‐cycloaddition products of type 4 or 11. With the fluorenyl‐substituted tricycle 4w in acetonitrile at 25 °C, but not with 4y, dual fluorescence is observed, with a red‐shifted unstructured additional emission band with a dipole moment of 32 D, originating from intramolecular charge transfer. The molecule 2y has an exceptionally large radiative rate constant of 13 × 108 s−1. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Novel galbonolide derivatives as IPC synthase inhibitors: design, synthesis and in vitro antifungal activities

A series of novel galbonolide derivatives having a modified methyl enol ether moiety were prepared in total synthetic procedures and evaluated for their in vitro antifungal activities. The antifungal activity was labile to modification of the enol ether functionality and almost all of the modified compounds lacked the activity except for the analogue with an introduction of a methylthio group at the C-6 position, which retained a modest antifungal potency against Cryptococcus neoformans.

Diels—Alder Reaction of 2‐Nitro Glycals: A New Route to the Synthesis of Benzopyrans.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diels-Alder Reaction of 2-Nitro Glycals: A New Route to the Synthesis of Benzopyrans

Synthesis of different benzopyrans was achieved by Diels-Alder reaction of 2-nitro glycals with Danishefky’s diene, hydrolysis of the enol ether moiety, and subsequent elimination of the nitro and methoxy group.

Structure Determination of Lustromycin, an Antibiotic against Anaerobic Bacteria

Extensive homo and heteronuclear two-dimensional NMR studies revealed lustromycin, an anti-anaerobic antibiotic. Its structure consists of a decaline ring system fused to a 10-membered macrolactone and a 14-membered macrolactone having an enol ether moiety conjugated with a maleic anhydride functionality.

W(CO)5(L)-Catalyzed Construction of Cyclic Carbon Frameworks.

Several novel reactions are developed utilizing the electron-deficient nature of terminal alkyne-W (CO) 5 π-complexes and/or their isomerized vinylidene complexes. Terminal alkynes having a silyl enol ether moiety in the molecule undergo endo-selective cyclization using a catalytic amount of W (CO) 5 (thf). In some cases, both exo-and endo-selective cyclizations are achieved depending on the reaction conditions. Iodinated vinylidene intermediates are generated from the corresponding iodoalkynes and W (CO) 5 (thf), and are employed for the related cyclizations. Electrocyclization of o-ethynylphenyl ketones gives novel benzopyranylidene complexes, which undergo Diels-Alder reaction with electron-rich alkenes to give substituted naphthalenes. Furthermore, the reaction of o-ethynylphenyl ketones and electron-rich alkenes in the presence of a catalytic amount of W (CO) 5 (thf) proceeds through the novel tungsten-containing carbonyl ylides, which react with the electron-rich alkenes in a [3+2] -cycloaddition manner to give polycyclic compounds.

First examples of lithium reagents addition in cyanine dyes series

The reactivity of the cyanine dyes towards nucleophilic reagents is currently being tested. As in the case of phosphine derivatives, carbanions attack the electrophilic C3 carbon of the pentamethine chain to give, with a good yield, new functionalized podands with cyano, keto, amino, amido, or enol-ether moieties.

Synthesis of chiral 1- and 2-( p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-dienes and their behaviour in Diels–Alder cycloadditions

The synthesis of (±)-( E)-1-( p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 1 and ( S S)-2-( p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 2 and their reactions with cyclic dienophiles are described. Cycloaddition of diene 1 with N-methylmaleimide 10 was performed under pressure affording a complex reaction mixture from which two epimers at C-3′, (±)- 11a and (±)- 11b [2,3,3a,4,5,7a-hexahydro-2-methyl-7a-(1-methylsuccinimide-3-yl)-1 H-isoindole-1,3,5-triones], were isolated in equal amounts. Diene (±)- 1 cycloadded to the more reactive 4-methyl-1,2,4-triazoline-3,5-dione 14 at atmospheric pressure and room temperature. However, nothing can be said about the stereochemical outcome of this addition since the loss of the chiral auxiliary via the sulfoxide–sulfenate rearrangement gave the bicyclic α,β-unsaturated ketone 17 (2-methyl-2,3,5,6-tetrahydro-1 H-[1,2,4]triazolo[1,2- a]pyridazine-1,3,6-trione). Diels–Alder cycloaddition of enantiopure diene 2 with 10 occurred under pressure leading to a diastereomeric mixture of adducts where the trimethylsilyl enol ether moiety spontaneously evolved to the ketone function. The major enantiopure product 18a [(3a S,6 S,7a R, R S)-2-methyl-6-( p-tolylsulfinyl)perhydroisoindole-1,3,5-trione] was isolated and characterized. Cycloadditions of both dienes to dienophile 10 appear highly stereoselective.

An Efficient Synthesis of Bicyclo[3.3.0]oct-2-en-4-ones and 2-Azabicyclo[3.3.0]oct-7-en-6-ones via β-Amino-Substituted α,β-Unsaturated Fischer Carbene Complexes

The formal [3+2] cycloaddition of β-amino-substituted α,β-unsaturated Fischer carbenechromium complexes 2, which are easily prepared in a one-pot procedure from terminal alkynes 1 via an initially formed alkynylidene complex by a Michael-type addition of a secondary amine, with a variety of alkynes 3 afford the 1,2,5-trisubstituted 3-alkoxy-5-dialkylamino-1,3-cyclopentadienes 4 with an acetal-protected aldehyde or ketone carbonyl group in either the 5-substituent R1 or the N-substituent R2. Under acidic conditions, both the enol ether moiety in the 5-membered ring as well as the acetals in the side chains are hydrolyzed, and the resulting cyclopentenones 6 with carbonyl-group containing side-chains undergo facile intramolecular aldol reactions to give bicyclo[3.3.0]oct-2-en-4-ones 8 and 8-azabicyclo[3.3.0]oct-2-en-4-ones 12, respectively, in good to very good yields for most cases.

An Efficient Synthesis of Bicyclo[3.3.0]oct-2-en-4-ones and 2-Azabicyclo[3.3.0]oct-7-en-6-ones via β-Amino-Substituted α,β-Unsaturated Fischer Carbene Complexes

The formal [3+2] cycloaddition of β-amino-substituted α,β-unsaturated Fischer carbenechromium complexes 2, which are easily prepared in a one-pot procedure from terminal alkynes 1 via an initially formed alkynylidene complex by a Michael-type addition of a secondary amine, with a variety of alkynes 3 afford the 1,2,5-trisubstituted 3-alkoxy-5-dialkylamino-1,3-cyclopentadienes 4 with an acetal-protected aldehyde or ketone carbonyl group in either the 5-substituent R1 or the N-substituent R2. Under acidic conditions, both the enol ether moiety in the 5-membered ring as well as the acetals in the side chains are hydrolyzed, and the resulting cyclopentenones 6 with carbonyl-group containing side-chains undergo facile intramolecular aldol reactions to give bicyclo[3.3.0]oct-2-en-4-ones 8 and 8-azabicyclo[3.3.0]oct-2-en-4-ones 12, respectively, in good to very good yields for most cases.

Synthesis of enantiopure 2-azabicyclo[3.3.1]nonanes by a radical ring closure

The first synthesis of enantiomerically pure 2-azabicyclo[3.3.1]nonanes by an intramolecular radical reaction of the trichloroacetamido group bearing an ( S)- N-1-phenylethyl substituent with the silyl enol ether moiety in compounds 7 is described. The procedure allows the two enantiomers of the 2-azabicyclo[3.3.1]nonane-3,6-dione, 3 and ent- 3, to be prepared separately. β-Lactam 8 and normorphan 9 are also formed from 7 through an initial radical translocation process in the cyclization step.

Intramolecular Anodic Olefin Coupling Reactions: The Use of Allylsilane Coupling Partners with Allylic Alkoxy Groups.

Intramolecular anodic olefin coupling reactions having an alkoxy substituent on the allylic carbon of an allylsilane moiety have been studied. These substrates were examined as part of an effort to determine the compatibility of the anodic olefin coupling reaction with the presence of very acid-sensitive functional groups and the construction of functionalized five-membered rings. In the initial experiment reported, an enol ether moiety was coupled to a trisubstituted allylsilane to afford a five-membered ring product without loss of the allylic alkoxy group. The reaction was stereoselective and could be used to generate a five-membered ring with three contiguous asymmetric centers. The stereochemical outcome of the reaction was best explained by a "pseudoequatorial" alkoxy group in the transition state; an argument that implied the reaction was under kinetic control. This suggestion was tested with the use of two electrolysis substrates that led to identical products through different transition states. The two substrates led to much different product ratios, proving that the reactions were not controlled by thermodynamics but rather governed by kinetic control. This observation was opposite to the conclusion reached with earlier vinylsilane-based substrates. Finally, the reactions were shown to be compatible with the presence of the alkoxy group even when challenged to form a fused bicyclic ring skeleton and a quaternary carbon. As in the initial case, the reaction to form a quaternary carbon was also highly stereoselective.

Asymmetric synthesis of γ-cyano silyl enol ethers

The selective oxidative cleavage of the SAMP-hydrazone moiety of 4-silyloxy-3-enal hydrazones 6, leading to the corresponding 4-silyloxy-3-alkenenitriles 7, is reported. A clean, good yielding transformation was observed when m-CPBA in CH 2Cl 2 was used as the oxidant, the presence of suspended solid NaHCO 3 being essential in preventing hydrolysis of the silyl enol ether moiety. Use of magnesium monoperoxyphthalate (MMPP) led to over-oxidated products, while hydrogen peroxide, in the presence of catalytic methyltrioxorhenium (MTO), was ineffective. Independent measurements of the enantiomeric excesses for compounds 7 demonstrated the absence of racemization during the process.

Thyrsenols A and B, two unusual polyether squalene derivatives

Two new polyether squalene derivatives, thyrsenol A 2 and thyrsenol B 3, have been isolated from the red alga Laurencia viridis. Their structures, which possess an unusual enol-ether moiety, were determined through the interpretation of 2D-NMR spectral data. The relative stereochemistry is proposed on the basis of ROESY and NOEDIFF data. Their cytotoxic activities were evaluated.

Research and development of beraprost sodium, a new stable PGI2 analogue

A novel prostaglandin I2 (PGI2) analogue, beraprost sodium, is the first launched drug as an orally active PGI2. PGI2 was discovered in 1976, and has attracted much attention as a medicine for cardiovascular diseases such as strokes and heart attacks because of its potent antiplatelet and vasodilating effect. However, PGI2 is extremely unstable for the use as practical medicines. Thus, stable PGI2 analogues have been explored by a large number of researchers in the world. Just after the discovery of PGI2, we started a research on chemically and metabolically stable PGI2 derivatives with longer duration of action and less adverse reaction. We invented a novel class of stable PGI2, 5,6,7-trinor-4,8-inter-m-phenylenePGI2 analogues that have the phenol moiety instead of the enolether moiety of PGI2. Further efforts were devoted to enhance the efficacy of the PGI2 analogues and to eliminate their side effects, and an orally active analogue, beraprost sodium, was obtained. In order to establish the synthetic route of beraprost sodium, various novel processes were invented, including ortho-selective metalation of bromoanisoles by means of Grignard reagents, copper-catalyzed SN2' cyclization to prepare cyclopenta[b]benzofuran, and stereo-selective elongation of the omega-side chain by Prins reaction. Beraprost sodium inhibit platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen and arachidonic acid. It was shown that the drug has a potent antiplatelet effect both in vitro and ex vivo in human and several animal species. In clinical studies, beraprost sodium exerted a marked effect to improve arteriosclerosis obliterans. No serious adverse effects related with the drug have been reported. It was highly evaluated as an orally active PGI2 by pharmaceutical companies overseas as well, and now clinical trials are under way in U.S.A. and Europe.

First Synthesis of Enantiomerically Pure Primary Helical Spirocycles Based on the Repetitive Addition of Lithiated Methoxyallene to Chiral 3(2H)‐Dihydrofuranone Derivatives

AbstractRepetitive additions to chiral 3(2H)‐Dihydrofuranones opened a route to the first enantiomerically pure primary helical spirocyclic compounds. Thus, addition of lithiated methoxyallene 2 to furanone 9 provided adduct 10 with excellent diastereoselectivity. Cyclization with potassium tert‐butoxide in DMSO followed by acid hydrolysis of the resulting enol ether moiety gave spirocyclic furanone 12 in very good overall yield. Repetition of this three‐step sequence converted 12 into 15. For the next series of reactions cerium compound 16 instead of 2 was employed as nucleophile which resulted in reasonable conversion of 15 into adduct 17. By application of the usual methods this compound was transformed into the enantiomerically pure tetracyclic spiro compound 19 in moderate overall yield. Functionalized spiro compounds as described in this paper may serve as enantiomerically pure building blocks in supramolecular chemistry.

2 + 2 + 2]Cycloadditions of Alkynes to Furans and Thiophenes: A Cobalt-Mediated "Enol Ether Walk"

h5-Cyclopentadienylcobalt mediates the [2+2+2]cycloaddn. of two alkyne units to the 2,3-double bond in furans and thiophenes to give the corresponding complexed dihydrobenzoheterocycles, in turn capable of undergoing migration of the enol ether moiety along the periphery of the cyclohexadiene ligand. In some instances the cobalt-mediated alkyne addn. occurs by apparent C-H activation of the heterocyclopentadiene, resulting in the generation of butadienylated products.

Characteristic Reactions of 4‐Siloxy‐2,5‐dihydrooxepines: Desilylation, [2 + 2] and [4 + 2] Cycloadditions

Desilylation of 4-siloxy-2,5-dihydrooxepine 1 with NEt3· HF afforded oxepinone 2. [2 + 2] Cycloadditions of 1 and methyl-substituted derivative 4 to tetracyanoethylene provided bicyclic products 3 and 5, respectively. Hetero Diels-Alder reactions of 2,5-dihydrooxepines 1 and 9 with 1,1,1-trifluoro-2-nitrosopropene furnished the corresponding bicyclic 1,2-oxazines 8 and 10, resp., in reasonable yields. The considerably higher reactivity of the silyl enol ether unit compared with the endocyclic enol ether moiety as revealed by these cycloadditions is discussed.