Spirocyclic ethers

A variety of spirocyclic ethers were prepared by double RCM of the appropriate polyalkene <01SL357> (Scheme 39). The yields of these processes were generally excellent and modest diastereoselection was observed in some cases. 

The preparation of the unique spirocyclic ether 65 by double RCM was reported <02TL7851> (Scheme 47). 

The alkylation of substituted 2-(phenylsulfonyl)tetrahydropyran anions, such as compound 375 (prepared from the starting material 374), with the iodide 376 bearing an allylsilane moiety, led to the formation of spirocyclic ethers 377 (Scheme 98)551. 

Oxaspirocyclic addition to 1,3-dienes Pd(ll) catalyzed oxidation of the diene 1 with p-benzoquinone in acetone-acetic acid in the presence of a base, Li2COj, results in a spirocyclic ether 2, formed by an overall warw-addition to the diene. Overall cis-addition of the oxygen function can be effected by replacement of Li2CO, by LiCI, which results in the spirocyclic ether 3. 

Young, J-j., Jung, L-j., and Cheng, K-m., 2000, AmberIyst-15-calalyzed Sn2 oxaspirocyclization of secondary allylic alcohols. Application to the total synthesis of spirocyclic ethers Iheaspiiane and theaspirone. 

A stereoselective synthesis of spirocyclic ethers via an intramolecular Piancatelli rearrangement has been reported (Scheme 169). " ... 

Much of the chemistry of Dy(OTf)3 has been focused on transformations in the presence of basic nitrogen groups however, it is not limited to such reactions. It has been shown that Dy(OTf)s catalyzes the intramolecular oxo-Piancatelli rearrangement in toluene to form spirocyclic ethers (eq 8). ... 

Based on the spirocyclic ether structures, several radically polymerizable cyclic monomers have been designed and synthesized. Such monomers are potentially applicable as volume-expandable monomers that can copolymerize with conventional vinyl monomers to suppress the volume shrinkage. 

In a formal synthesis of fasicularin, the critical spirocyclic ketone intermediate 183 was obtained by use of the rearrangement reaction of the silyloxy epoxide 182, derived from the unsaturated alcohol 180. Alkene 180 was epoxidized with DMDO to produce epoxy alcohol 181 as a single diastereoisomer, which was transformed into the trimethyl silyl ether derivative 182. Treatment of 182 with HCU resulted in smooth ring-expansion to produce spiro compound 183, which was subsequently elaborated to the desired natural product (Scheme 8.46) [88]. 

The application of RCM to dihydropyran synthesis includes a route to 2,2-disubstituted derivatives from a-hydroxycarboxylic acids. In a one-pot reaction, the hydroxy esters undergo sequential O-allylation, a Wittig rearrangement and a second O-allylation to form allyl homoallyl ethers 8. A single RCM then yields the 3,6-dihydro-2//-pyran 9. The process is readily adapted not only to variably substituted dihydropyrans but also to 2-dihydrofuranyl and 2-tetrahydrooxepinyl derivatives and to spirocycles e.g. 10 through a double RCM (Scheme 4) <00JCS(P1)2916>. 

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]. 

Although cyclic azoalkanes are well known as biradical precursors [159] they have been used as 1,2- and 1,3-radical cation precursors only recently [160-164]. Apart from the rearrangement products bicyclopentane 161 and cyclopentene 163, the PET-oxidation of bicyclic azoalkane 158 yields mostly unsaturated spirocyclic products [165]. Common sensitizers are triphenyl-pyrylium tetrafluoroborate and 9,10-dicyanoanthracene with biphenyl as a cosensitizer. The ethers 164 and 165 represent trapping products of the proposed 1,2-radical cation 162. Comparison of the PET chemistry of the azoalkane 158 and the corresponding bicyclopentane 161 additionally supports the notion that the non-rearranged diazenyl radical cation 159 is involved (Scheme 31). 

Novel bridged spirolactones have been synthesized via tandem radical cycli-zations of enol ether radical. In Reaction (7.85) the first 5-exo spirocyclization is followed by a 6-endo cyclization to give the bridged derivative as a single diastereoisomer [96]. 

The generality of these observations is supported by the data in Scheme 8. In the case of the reactions of monosubstituted l-(l-alkynyl)cyclopropanols 15, 5-substituted cyclopentenones 17 are obtained with complete selectivity when trans-15 are used as substrates. On the other hand, 4-substituted cyclopentenones 16 are obtained with good to high regioselectivity by employing ferf-butyl-dimethylsilyl ethers of cis-l5 as substrates. Furthermore, 5,5-disubstituted cyclopentenones 20 including a spirocyclic derivative are obtained selectively starting from 2,2-disubstituted l-(l-alkynyl)cyclopropanols 18. 

Beckmann rearrangement of 2,2,5,5-tetramethyltetrahydro-3-furanone oxime (362) afforded 1,3-oxazine 363 in 64% yield (equation 158). 1,4-Oxazines 365 were obtained by acidic deprotection-spirocyclization of oxime ethers 364 (equation 159) . 

The synthesis and stmctnral characterization of a series of spirocyclic organozincates containing two five- or six-membered metallacycles in which zinc is the central spiro atom, is shown in Scheme 1. Compound 8a was prepared via an elegant one-pot synthesis, starting from 1,5-dichloropentane, ZnCl2 and a lithium/sodinm alloy (1% sodinm) in diethyl ether as a solvent (eqnation 4 in Scheme 1). Snbseqnent treatment of a soln-tion of 8a with TMEDA afforded the corresponding TMEDA complex 8b of which the structnre in the solid state was unambiguously established by an X-ray crystal structnre determination. 

The thermal isomerization of a spirocyclic enol ether to the ketone [202] (Eq. 176) is probably a homolytic process. However, it is noted that part of the driving force for the reaction must be the bonding of the ethereal oxygen to a designated donor atom of the cross-conjugated cyclohexadienone moiety. 

The use of propargyl vinyl ethers prompted Toste et al. to develop a stereoselective preparation of 2-hydroxy-3,6-dihydropyrans, suitable for the synthesis of spirocyclic compounds. The reaction was catalyzed by a small amount (1 mol%) of [0(AuPPh3)3]... 

When five- or six-membered ring ethers can readily be formed by intramolecular alkoxymercuration of the initially formed alkenol, cyclic ethers are often the observed product (equation 219).341 This process has recently proven useful in the synthesis of spirocyclic acetals (equation 220).342... 

The cyclofunctionalization of cycloalkenyl systems where the chain containing the nucleophilic functionality is attached at one end of the double bond leads to spirocyclic structures. Cyclizations of cyclic and acyclic enol ethers to generate spiroacetals are shown in equations (66)168 and (67).169 These reactions generate the thermodynamically more stable products based on anomeric and steric factors.170 Spiroacetal products have also been obtained using isoxazolines as the nucleophilic functionality (cf. Table 14).l4lb Studies of steric and stereoelectronic control in selenoetherification reactions which form spirocyclic tetrahydrofurans have been reported.38 An interesting example of stereoelectronic control in the formation of a spirocyclic lactone has been reported in a recent mevinolin synthesis (equation 68).171... 

Scheme 15. Enantioselective synthesis of carbocyclic tertiary ethers and spirocycles through Mo-catalyzed asymmetric olefin metathesis...

A process related to those shown in Scheme 14 involves the asymmetric Mo-catalyzed conversion of tertiary carbocyclic cyclopentenyl ethers to the corre-sponsing cyclohexenyl ethers with enantioselectivity (e.g., 67—>69, Scheme 15) [25]. A remarkable and unusual attribute of this class of transformations is that significantly higher levels of enantioselectivity are observed when ten substrate equivalents of THF are used as an additive. As an example, 69 (Scheme 15) is formed in only 58% ee in the absence of THF (<5% conversion is observed when THF is used as solvent). As also shown in Scheme 15 (70—471), enantioenriched spirocycles may be accessed easily by a similar approach in this case, no additive effect is observed. 

In the course of studies of the insertion of carbenes, generated in the photolysis of spirocyclic diazarines, 528, into OH bonds (equation 314) it has been observed641 that formation of ethers from carbene 527 and ROH(D) is associated with partial rearrangement (equation 315). 

Bridged and spirocyclic bicycloalkenones. The conversion of silyl enol ethers to a,/J-enones by Pd(OAc)2 (8, 378) can result in cyclization to bicyclic systems when applied to silyl enol ethers of cyclohexanones bearing an alkenyl side chain a or y to the carbonyl group. Although the factors favoring cyclization are not fully defined, this cyclization offers a route to a variety of bridged and spirocyclic systems.1... 

Recall that p-toluenesul Innate (tosylate) is a good leaving group in nucleophilic substitution reactions. The nucleophile that displaces tosylate from carbon is the alkoxide ion derived from the hydroxyl group within the molecule. The product is a cyclic ether, and the nature of the union of the two rings is that they are spirocyclic. 

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