Bicyclic enol ether

Photooxygenation of bicyclic enol ether 617 at —78°C affords intermediate 1,2-dioxetane 618, which reacts with a premixed acetaldehyde without acidic additives or... 

Formula 366) gives a bicyclic enol ether (Formula 367) which is hydrolyzed to Formula 368 (161,162). The sequence of Formulas 366-368 represents a potentially general synthesis of bicyclic cyclobutanone derivatives. A clever synthesis of m-3-cyclobutene-l,2-dicarboxylic acid anhydride (Formula 369) has been accomplished by irradiation of muconic anhydride (Formula 370) in ether (163). 

R = CH3 or Ac) bearing a 3-kctam moiety. The use of microwave irradiation on 2-azetidinone-tethered bis(allene) retains the reactivity pattern, but suppresses the keto—enol isomerization while maintaining the same regioselectivity of the cyclization step affording exclusive formation of the bicyclic enol ether 98 in reasonable yields (Scheme 27). 

A Swiss group has reported on a new fragmentation mode of bicyclic enol ethers, when macrocyclic lactones are obtained vicinal a-hydroperoxytetra-hydropyranyl ethers (33) annelated to cyclododecane, prepared via the corresponding cyclododecanone enol ethers, are smoothly converted homolytically into a mixture of macrocyclic lactones. This fragmentation has been developed to provide an economically feasible synthesis of exaltolide (34). 

This methodology was initially applied to a synthesis of (—)-alloyohimbane (82) (Scheme 3.13) (29). Readily available levoglucosenone (75), a product of cellulose pyrolysis, was the starting material. Diels-Alder reaction of 75 with 1,3-butadiene afforded adduct 76 which underwent Wolff-Kishner elimination and subsequent acylation to provide the bicyclic enol ether 77. Hydrolysis followed by oxidation and saponification afforded hydroxymethyl lactone 78 which was then condensed with tryptamine to yield the amide diol 79. Periodate cleavage of the diol was followed by conversion to chloride 80 which was cyclized to afford lactam 81. Subsequent Bischler-Napieralski cyclization followed by hydrogenation of the olefin moiety afforded the target ( )-alloyohimbane (82). 

The silyl enol ethers 209 and 212 are considered to be sources of carbanions. and their transmetallation with Pd(OAc)2 forms the Pd enolate 210. or o.w-tt-allylpalladium, which undergoes the intramolecular alkene insertion and. 1-elimination to give 3-methylcyclopentenone (211) and a bicyclic system 213[199], Five- and six-membered rings can be prepared by this reaction[200]. Use of benzoquinone makes the reaction catalytic. The reaction has been used for syntheses of skeletons of natural products, such as the phyllocladine intermediate 214[201], capnellene[202], the stemodin intermediate 215[203] and hir-sutene [204]. 

Cyclopropyl ketones 95 also react with enol ether 100 in presence of 5 mol% of [Au(NTf2)(lPr)] in a [4+2] cycloaddition reaction to afford the bicycle[3.2.0] heptane skeleton 101 (Scheme 5.26) [26]. 

Twofold Michael additions have been utilized by the groups of Spitzner [2] and Hagiwara [3] to construct substituted bicyclo[2.2.2]octane frameworks. In Hagiwara s approach towards valeriananoid A (2-6) [4], treatment of trimethylsily-enol ether 2-2, prepared from the corresponding oxophorone 2-1, and methyl acrylate (2-3) with diethylaluminum chloride at room temperature (r.t.) afforded the bicyclic compound 2-4 (Scheme 2.2). Its subsequent acetalization allowed the selective protection of the less-hindered ketone moiety to provide 2-5, which could be further transformed into valeriananoid A (2-6). 

In 1996, the first successful combination of an enzymatic with a nonenzymatic transformation within a domino process was reported by Waldmann and coworkers [6]. These authors described a reaction in which functionalized bicy-clo[2.2.2]octenediones were produced by a tyrosinase (from Agaricus bisporus) -catalyzed oxidation of para-substituted phenols, followed by a Diels-Alder reaction with an alkene or enol ether as dienophile. Hence, treatment of phenols such as 8-1 and an electron-rich alkene 8-4 in chloroform with tyrosinase in the presence of oxygen led to the bicyclic cycloadducts 8-5 and 8-6 in moderate to good yield (Scheme 8.1). It can be assumed that, in the first step, the phenol 8-1 is hydroxylated by tyrosinase, generating the catechol intermediate 8-2, which is then again oxidized enzy-... 

The reaction of acyclic ADC compounds with monoenes has already been discussed in Sections III,B and IV,B. In certain cases the major reaction pathway involves addition of the ADC compound as a 47r component, to the monoene to give 1,3,4-oxadiazines (Scheme 1). 1,3,4-Oxadiazines are the major or sole products from the reactions of ADC compounds with indene,80 and 4-nitrophenyl vinyl ether,90 and from the reaction of azodibenzoyl with enamines and enol ethers.91 93 Norbornadiene also gives a 1,3,4-oxadiazine (42) with ADC compounds.82 However, benzonorbornadiene behaves differently, and the major product from the reaction with PTAD has the structure 119.205 Other bicyclic monoenes react similarly.206 1,3,4-... 

Schreiber and his coworkers have published extensively over the past decade on the use of this photocycloaddition for the synthesis of complex molecules730 81. Schreiber was the first to recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic conditions to afford threo aldol products of 1,4-dicarbonyl compounds (175 to 176) (Scheme 40). The c -bicyclic system also offers excellent stereocontrol in the addition of various electrophilic reagents (E—X) to the enol ether of these photoadducts on its convex face (175 to 177). This strategy has been exploited in the synthesis of a variety of architecturally novel natural products. 

Finally, production of tricyclic array 153 (Scheme 24) required cyclization of bicyclic ester 151 in which additional oxygenation was present in the olefinic appendage. The successful conversion to enol ether 152 demonstrated further the power of the method and led to the JKF fragment 153 [34b]. 

The products are ds-fused. They are hydrolyzed by TsOH in aqueous THF to lactols, which can be oxidized by Fetizon s reagent to lactones or converted to dials by DBU. The enol ether group of the adduct can be selectively oxidized by Cl-QH4CO3H or OsO to provide bicyclic tetrahydrofurans. 

Enol ethers 268a-c reacted with N-tosy]-4-vinylidene-l,3-oxazolidin-2-ones to give bicyclic tetrahydropyridine derivatives 269a-c (Table 12.12). Methyl /Tmcthoxyacry-late afforded 269c without formation of the [2 + 2] adduct. 

Similarly, tandem hydroformylation/aldol sequences can be applied to the formation of bicyclic and spirocyclic compounds. Thus silyl enol ethers of 3-vinyl and 3-allyl cycloalkanones give ring anellated products (Scheme 33) [86,87]. 

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

Enyne 7a having a silyloxy group on the alkyne gives cyclic compound 8a having a vinyl silyloxy moiety, which is converted into methyl ketone 9a by desilylation. In a similar manner, enyne 7b affords bicyclic methyl ketone 9b in 68% yield after deprotection of the silyl group. However, ynoate 7c and yne-phosphonate 7d do not give cyclized compounds. Ene-ynoate 12, which is obtained by treatment of enol ether 11 with BuLi affords cyclic enol ether 13 in good to moderate yields " (Scheme 4). 

Auto-tandem hydroformylation-cyclization, catalyzed by [RhCl(cod)]2, enables expansion of the organic skeleton of unsaturated silyl enol ethers (Scheme 10). Linear aldehydes generated in the hydroformylation step subsequently undergo Rh-catalyzed, intramolecular Mukaiyama aldol addition. Bicyclic ketones are also accessible from cyclic silyl enol ethers. 

Irradiation of a-tropolone methyl ether (Formula 8a) first gives the valence tautomer 9a, then the rearranged bicyclic product 18a, and finally the ester 19a (12). The reactions occur in sequence, and each stage requires light (the final transformation of Formula 18 to Formula 19 can also be achieved by acid). The initial reaction has ample precedent (11). The final transformation simply involves addition of water to the enol ether followed by a reverse aldol reaction. 

Most cyclizations of 3-allenic alcohols have produced six-membered ring products via a 6-endo process (equation 85).168 205 The exception is found with terminally unsubstituted allenes as shown in equation (86).205d The bicyclic acetal results from a 5-exo cyclization to an enol ether, which undergoes a second cyclization to form the acetal. 

Bicyclic ketones, also, have been prepared intramolecularly from silyl enol ethers. Six-membered rings are formed more easily in these reactions than in the reactions forming monocyclic products, described earlier.38... 

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