Vinylic Ether Substrates

The methods described thus far represent only a small subset of the available methodologies for the formation of C-furanosides and C-pyranosides. Other methods shown to be useful include cyclizations of halo olefins and ene-ynes. As shown in Scheme 7.6.1, Lee, et al.,29 prepared halo olefins from suitable alcohols and acetylenic esters. Subsequent application of free radical conditions thus effected cyclizations. All reactions proceeded in yields exceeding 95%. Furthermore, where the formation of diastereomers was an issue, selective cis formation was observed. Thus the ease of preparation of the vinyl ether substrates required for these cyclization reactions makes this methodology an extremely useful addition to the technology surrounding the preparation of C-glycosides. 

A solution of 2.0 mmol of an allyl vinyl ether substrate in 15mL of 1.2-dichloroethane is treated with 4.4 mL (4.4 mmol) of 1.0 M trimethylaluminum in hexane at 25 "C (60 C) for 15 min (2 h). The resulting mixture is diluted with 15 mL of Et20, and poured into 20 mL of 1 M HC1. The ethereal extracts are washed with two 20-mL portions of brine, dried over anhyd Na2S04, and concentrated. The crude product is purified by column chromatography(silica gel, hexane/EtOAc). 

Sigmatropic rearrangement of allyl vinyl ether substrates usually requires heating at around 200 . Allyl phenyl ether rearranges at room temperature in the presence of Lewis acid reagents, which have, however, turned out to be ineffective with aliphatic ethers. The concept of "combined acid-base attack previously mentioned (18,19) has motivated several successful experiments as shown in Schemes 10 through 12 (20). 

There are a number of examples of 6-endo radical cyclization of vinylic ether substrates. For example, Thomas reported synthesis of the tetrahydropyran fragment 76 of bryostatin 1 via radical cyclization reaction of the a-alkoxyacrylate 75, capitalizing on the higher activity of Z-vinyl radicals [51] (Scheme 27). In the syn-... 

Scheme 5 Transvinylation and acetahzation from vinyl ether substrates...

Notably, the reaction of vinyl ether substrate (X = O) could be conducted at room temperature. In addition, the indole-based substrate could also cyclize rapidly and gave the tricyclic product 108, the core of the protein kinase C (PKC) inhibitor, in 90% yield and 70% ee. 

Later, Yamamoto and Maruoka reported improved Lewis acids (153b) and (153c), namely, aluminium tris (2-a-naphthyl-6-phenylphenoxide) (ATNP) and aluminium tris (l-a-naphthyl-3-phenylnaphthoxide) (ATBN), respectively (Scheme 6.163) [192d, 193]. These Lewis acids effectively catalyze asymmetric Claisen rearrangement of simple allyl vinyl ether substrates without a substituent on the vinyl group. 

The stereochemistry of the product formed in the cycloaddition reaction depends on the approach of the substrate. There are two different approaches by which the reaction can proceed - endo and exo. For the reaction of e.g., a / , y-un-saturated a-keto ester with an ethyl vinyl ether there are four possible approaches... 

Other substrates were tested the results are summarized in Table 5.2. Vinyl ethers (2b-2d) also worked well to afford the corresponding tetrahydroquinoline derivatives (3a-3e) in good to high yields with good to excellent diastereo- and en-antioselectivity (entries 1-10). Use of 10 mol% of the chiral catalyst also gave the adducts in high yields and selectivity (entries 2 and 6). As for additives, 2,6-di-t-bu-... 

A model for the intermediate consisting of substrates 36 and 8a coordinated to catalyst 37a was proposed as shown in Scheme 6.30 [74]. In the model 39 the two triflate ligands are dissociated from copper. The ligands are arranged around copper as a trigonal bipyramid and it should be noted that in this model the oxygen atom of the vinyl ether 8a also coordinates to the metal center. However, another tetrahedral intermediate consisting of only the catalyst and the nitrone could also account for the absolute selectivity of the reaction. 

The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has also been demonstrated on a number of other substrates. These studies showed that this methodology has potential applications in organic synthesis. In Eq. 12.72, the unprotected vinyl ether in a 2.5 1 water-methanol solvent with an equivalent of sodium hydroxide underwent rearrangement to give the aldehyde in 85% yield.157... 

Nitrooxazoles and 4-nitroisoxazoles 480 are versatile substrates for domino cycloaddition reactions with ethyl vinyl ether 481 to form the tricyclic nitroso acetals 482 and 483 (Equation 129) <1999T13809, 2001T4237>. 

Copper(II) triflate has also been used for the carbenoid cyclopropanation reaction of simple olefins like cyclohexene, 2-methylpropene, cis- or rran.y-2-butene and norbomene with vinyldiazomethane 2 26,27). Although the yields were low (20-38 %), this catalyst is far superior to other copper salts and chelates except for copper(II) hexafluoroacetylaeetonate [Cu(hfacac)2], which exhibits similar efficiency. However, highly nucleophilic vinyl ethers, such as dihydropyran and dihydrofuran cannot be cyclopropanated as they rapidly polymerize on contact with Cu(OTf)2. With these substrates, copper(II) trifluoroacetate or copper(II) hexafluoroacetylaeetonate have to be used. The vinylcyclopropanation is stereospecific with cis- and rra s-2-butene. The 7-vinylbicyclo[4.1.0]heptanes formed from cyclohexene are obtained with the same exo/endo ratio in both the Cu(OTf)2 and Cu(hfacac)2 catalyzed reaction. The... 

Considering the above-mentioned facts, according to which simple diazoketones yield dihydrofurans with ketene acetals but cyclopropanes with enol ethers, one exports an interlink between these clear-cut alternatives to exist, i.e. substrates from which both cyclopropanes and dihydrofurans result. In fact, providing an enol ether with a cation-stabilizing substituent in the a-position creates such a situation The Rh2(OAc)4-catalyzed decomposition of -diazoacetophenone in the presence of ethyl vinyl ether produces mainly cyclopropane 82 (R=H), but a small amount of dihydro-... 

The observation of a primary solvent deuterium isotope effect (kH/fa>) = 2-4 on the specific acid-catalyzed hydrolysis of vinyl ethers provides evidence for reaction by rate-determining protonation of the alkene.69 Values of kHikD 1 are expected if alkene hydration proceeds by rate-determining addition of solvent to an oxocarbenium ion intermediate, since there is no motion of a solvent hydron at the transition state for this step. However, in the latter case, determination of the solvent isotope effect on the reaction of the fully protonated substrate is complicated by the competing exchange of deuterium from solvent into substrate (see above). 

Examples of the behavior of other substituted vinyl substrates upon exposure to the action of trifluoroacetic acid and triethylsilane are known. For example, -butyl vinyl ether, when reacted at 50° for 10 hours, gives -butyl ethyl ether in 80% yield (Eq. 65).234 In contrast, -butyl vinyl thioether gives only a 5% yield of n-butyl ethyl sulfide product after 2 hours and 15% after 20 horns of reaction.234 It is suggested that this low reactvity is the result of the formation of a very stable sulfur-bridged carbocation intermediate that resists attack by the organosilicon hydride (Eq. 66). 

Among the clusters derivatized by these methods, [ Mo(tacn) 3(PdCl)(n3-S)4]3+ (tacn = 1,4,7-triazacyclononane) is noteworthy, since this cluster can bind the substrate molecules such as alkene and CO at its tetrahedral Pd site generated by dissociation of the Cl anion. More interestingly, it has turned out that addition of ROH and RCOOH to various alkynes proceeds at this Pd site to give vinyl ethers and vinyl carboxylates catalytically.53 These reactions represent one of the yet rare examples that are catalyzed by well-defined cubane-type clusters with retention of their core structures. 

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