Polycyclic enol ethers

Another excellent method for the synthesis of macrolactones by oxidation reaction was reported by Tan et al. [72] via oxidative ring expansion of polycyclic enol ethers and enamines, effectively mediated by NaI04 and catalytic amount of RuClj or RUO2 (Scheme 6.9). 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

C(2)-C(3) fused polycyclic cephalosporins have received considerable attention as new candidates for /3-lactam antibiotics. An access to tricyclic cephalosporins based on metal-promoted alkenylation of 3-trifloxy-A3-cephem and subsequent Diels-Alder reaction has been published <1996TL5967>. Alternatively, the reaction of a cephalosporin triflate with silyl enol ethers and silylketene acetals has been described to afford tri- and tetracyclic cephalosporins <1996TL7549>. A related process is the formation of fused polycyclic cephalosporins 27 and 28 bearing a wide range of functionalities from the reaction of cephalosporin triflates 26 with unsaturated compounds (alkenes and alkynes) and a base (Scheme 5) <1997JOC4998>. These studies have suggested that the reaction proceeds via the intermediacy of a six-membered cyclic allene which undergoes concerted nZs + K2a cycloaddition with alkenes and acetylenes. 

As an extension of this work, Mattay et al. have used this methodology for the construction of unnatural steroid analogues [41]. The polycyclic framework was build-up via a cascade cyclization of the silyl enol ether 32 using DCA as sensitizer (Sch. 19). The two major products 33 were formed with remarkable high trans, //-stereoselectivity. 

A practical synthesis of 1,3-OX AZEPINES VIA PHOTOISOMERIZATION OF HETERO AROMATIC V-OXIDES is illustrated for 3,1-BENZOXAZEPINE. A hydroboration procedure for the synthesis of PERHYDRO-9b-BORAPHENALENE AND PERHYDRO-9b-PHEN-ALENOL illustrates beautifully the power of this methodology in the construction of polycyclic substances. The conversion of LIMONENE TO p-MENTH-8-EN-YL METHYL ETHER demonstrates a regio-and chemoselective method for the PHOTOPROTONATION OF CYCLOALKENES. An efficient method for the conversion of a ketone to an olefin involves REDUCTIVE CLEAVAGE OF VINYL PHOSPHATES. A mild method for the conversion of a ketone into the corresponding trimethylsiloxy enol ether using trimethylsilyl acetate is shownforthe synthesis of (Z)-3-TRIMETHYLSILOXY-2-PENTENE. 

Annulation of furans via electrochemical oxidation at the anode has become an important process for the synthesis of complex polycycles, and was covered in a review <2000T9527>. Furans tethered at the 3-position to electron-rich alkenes, enol ethers, or vinyl sulfides were converted to [6,5] and [7,5]-fused ring systems <1996JOC1578, 2002OL3763, 2004JOG3726, 2005JA8034>, as illustrated in Scheme 20. Analysis of crude reaction mixtures and side... 

The first total synthesis of the marine polycyclic ether toxin (-)-gambierol was accomplished in the laboratory of M. Sasaki. The introduction of the a,(3-unsaturation into the seven-membered H ring of the FGH tricyclic subunit proved to be problematic, because both the conventional selenium-based method and the Nicolaou oxidation with IBX failed. However, when the seven-membered ketone was treated with LiHMDS in the presence of TMSCI and EtsN, the corresponding silyl enol ether was formed, which was oxidized under Saegusa conditions to give the desired cyclic enone in high yield. Because of the small scale of the reaction, a large excess of Pd(OAc)2 was used in acetonitrile so the presence of a co-oxidant was not necessary. 

Photocyclisation of 8-alkoxy-l,2,3,4-tetrahydro-l-naphthalenones and 4-alkoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ones gives naphtho[l, 8-bc]furans and cyclohepta[cd]benzofurans respectively, and conformational and substituent effects of 1,5-biradicals in the cyclisation process are discussed." " The same authors also describe substituent effects on the photocyclisation of ethyl 2-(8-oxo-5,6,7,8-tetrahydro-l-naphthyloxy)acetates and ethyl 2-(5-oxo-6,7,8,9-tet-rahydro-5H-benzocyclohepten-4-yloxy)acetates to give naphtho[l,8-bc]furans and cyclohepta[c,d]benzofurans respectively." Also reported are cyclisations involving photogenerated radical cations of unsaturated silyl enol ethers, fragmentation cyclisations of unsaturated ot-cyclopropyl ketones which occur by photoelectron transfer and give polycyclics, and kinetic and theoretical studies of [2+3] cycloadditions of nitrile ylids. These reactions have been studied mechanistically and their synthetic potential investigated. 

The intramolecular Heck reaction to construct the polycyclic benzofuran skeleton in morphine was reported by Overman [21] in their synthesis of (+)- and (-)-dihydroisocodeine in 1993, and after that, the Heck cyclization has been extensively studied by Cheng [22], Hsin [23, 24], Hudlicky [25] (see Sect. 2.2.3), Trost (see Sect. 2.2.1), and Guillou (see Sect. 2.1.2). In Fukuyama s synthesis, the Heck reaction of 11 works well and successfully provided the A-C-E tricyclic ring system 13 in 87% yield after deprotection of the TBS group in the intermediary enol ether 12. 

Several examples have been reported, where cyclopropyl containing carbenes were used in [4 -H 2], [2 -f 2] and [3 -t- 2] cycloadditions giving monocyclic and polycyclic ring systems. Thus, the chromium cyclopropylethynyl(ethoxy)carbene complex 19 formed a [2-1-2] cycloadduct with silyl enol ethers 20 underwent further conversion with alkynes to form the bicyclo[4.2.0]oc-tadienone skeleton 21. ... 

A TMSOTf-initiated cyclization of the dicarbonyl substrate was invoked to explain the reactivity pattern [79]. Selective complexation of the less hindered carbonyl group activates it toward intramolecular nucleophilic attack by the more hindered carbonyl which leads to an oxocarbenium species. Subsequent attack by the enol ether results in addition to the more hindered carbonyl group. The formation of this cyclic intermediate also explains the high stereochemical induction by existing asymmetric centers in the substrates, as demonstrated by Eq. 52, where the stereochemistry at four centers is controlled. A similar reactivity pattern was observed for the bis-silyl enol ethers of / -diketones. The method is also efficient for the synthesis of oxabicyclo[3.3.1] substrates via 1.5-dicarbonyl compounds, as shown in Eq. 53. Rapid entry into more complex polycyclic annulation products is possible starting from cyclic dicarbonyl electrophiles [80]. 

Dibenzofulvene (100), which is a byproduct of fluorenylmethoxycarbonyl (FMOC) deprotection in peptide synthesis, undergoes Michael addition reactions with carbanions. Conversion of 100 with the silyl enol ether of cyclohexanone (101) and a desilylation reagent furnishes directly the ketone 102, that now can be subjected to the already described acid mediated intramolecular cyclodehydration procedure followed by aromatization. The product is again a polycyclic fluoranthene (103), that can be considered as a naphtho annelated fluor-ene in this sequence (see Scheme 50 [150]). 

A larger number of silyl enol ethers have been studied by kinetic measurements with regard to their synthetic value as dienophiles and their reactivity the readily accessible silyl enol ethers proved to be enol equivalents <92TL8019>. Synthesis of novel heterocyclic clefts such as (153) and (154) can be achieved by (4 -I- 2) cycloaddition reactions of 1,2,4,5-tetrazines (151) with polycyclic diketones... 

The domino [4 + 2]/[3 - - 2] cycloaddition of an enol ether, a nitroalkene and a third alkene is a representative example of a multicomponent reaction in which a polycyclic N-containing system is formed in a single transformation [10, 11]. In this domino reaction, a nitroalkene reacts as a heterodiene with an electron-rich alkene such as an enol ether, in an inverse electron-demand Diels-Alder reaction, to form a cyclic nitronate, which then reacts with another alkene in a 1,3-dipolar cycloaddition to produce a nitroso acetal (Scheme 9.4). 

Fluoroalkyl chromone derivatives can be obtained from the base catalysed reaetion between 2,2-dihydropolyfluoroalkanoates and phenols. Initial loss of HF allows Michael addition of the phenol and subsequent cyclisation of the enol ether yields the heterocycle. m-Substituted phenols give the expected mixture of 5- and 7-substituted chromones, whilst dihydroxy aromatic compounds give polycyclic materials (94JFC263). In a more conventional approach Z-3-(aryloxy)-polyfluoroalkenoic adds, derived from Michael addition of phenols to polyfluoro-2-alkynoic acids, undergo intramolecular Friedel-Crafts acylation to 2-polyfluoro-alkylchromones (94JFC25). 

Unsaturated carbenes (15) generated in the coordination sphere of a Pt(II) salt have been shown to undergo cycloaddition with enol ethers efficiently to yield polycyclic compounds (16) (Scheme 4). ... 

Most examples of the Bradsher cycloaddition reaction have utilized fused polycyclic aromatics as the cationic aza-diene fragment. Falck and co-workers have reported that one can carry out this reaction using monocyclic quaternary aza-aromatics. The application of this methodology was illustrated using the A -(2,4-dinitrophenyl) salt of A, A -diethylnicotin-amide 3 and ethyl nicotinate 4 in conjunction with enol ethers. The reaction proceeded at room temperature to generate adducts 5. This was the result of the exo-addition at the C2-C5 positions of the pyridyl ring. The resultant iminium ion was then trapped by the methanolic solvent. 

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