Ethers, cyclic allyl

The thermal isomerization of 70 required heating at high temperature to proceed efficiently (Eq. 3.1.45) [57]. It appeared that transition state T was adopted preferentially to S in order to prevent the development of a 1,3-diaxial interaction in the prehminary expectation. If this kinetic ordering were adopted, the new C-C bond would be installed as to the butyronitrile side chain in the desired manner. Actually, 70, however, isomerizes preferentially via S to set an axial bond and dehver 71 and 72 in a 2.7 1 ratio. 

The rearrangement has occurred stereospecifically from the desired a-face of the double bond to provide optically active 73, presumably via a chair transition state (Eq. 3.1.46) [58]. This rearrangement has significant imphcations for the enantiospecific synthesis of the macroHne/sarpagine/ajmaline alkaloids, because 

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An interesting extension of this reaction is shown in the asymmetric kinetic resolution of cyclic allylic ether 44 under alkene coupling conditions. Use of (R)-12 as the catalyst gives (R)-45 in > 99% ee at 58% conversion. The ethylated product 46 is also formed in the reaction in 94% ee (Eq. 7) [25]. The reaction is effective for six- to eight-membered 3-oxacycloalkenes 47 as well as for a wide variety of alkoxycycloalkenes 48 [27], with some resolution dependency on the ring size of 47 (Fig. 2) [26]. 

Catalytic RCM and another Zr-catalyzed process, the kinetic resolution of cyclic allylic ethers, joined forces in our laboratories in 1995 to constitute a fully-cata-lytic two-step synthesis of optically pure 2-substituted chromenes. These structural units comprise a critical component of a range of medicinally important agents (see below). Our studies arose from unsuccessful attempts to effect the catalytic kinetic resolution of the corresponding chromenes [13] a representative example is illustrated in Eq. 3. 

As depicted in Eqs. 6.5—6.7, kinetic resolution of a variety of cyclic allylic ethers is effected by asymmetric Zr-catalyzed carbomagnesation. Importantly, besides six-membered ethers, seven- and eight-membered ring systems can readily be resolved by the Zr-catalyzed protocol. 

Figure 6.3. Various modes of addition of cyclic allylic ethers to an (ebthi)Zr—alkene complex.

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

For more recent catalytic asymmetric approaches towards this class of cyclic allylic ethers, see B.M. Trost, F. D. Toste,... 

C. W. Johannes, M. S. Visser, G. S. Weatherhead, A H. Hoveyda Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (SJUUD-Nebivolol J. Am Chem Soc 1998, 120, 8340-8347. For development of the enantioselective methodology, see M. S. Visser, J. P. A. Harrity, A. H. Hoveyda Zirconium-Catalyzed Kinetic Resolution of Cyclic Allylic Ethers. An Enantioselective Route to Unsaturated Medium Ring Systems , J. Am Chem Soc 1996,118, 3779-3780. 

Acyclic and cyclic allylic ethers and acetals react normally with dihalocarbenes at the C=C bond [e.g. 77, 85, 108,114,121,122], Carbene insertion into the C=C bond of allylic ketones, which can be complicated by competitive reaction by the carbonyl group, can also be effected via the initial formation of the acetal and has been used in the synthesis of cyclonona-3,4- and -4,5-dienones from cyclooctenones [125],... 

A similar set of reactions has been carried out with cyclic allyl ethers and alkylmagnesium halides using the same nickel catalyst, however, the optical yields are generally low (< 60 %)21 with the exception of the following example213. The optical purity and configuration of the product was established by chemical correlation with 3-ethvlhexanedioic acid. 

Carbon-carbon coupling of radicals observed in the photo-Kolbe reaction could also be observed with other surface generated radicals. Kisch and coworkers have shown, for example, that cyclic allylic ethers undergo alpha deprotonation under photoelectrochemical activation, producing radicals that can be oxygenated, Eq. (29). On colloidal zinc sulfide, hydrogen evolution accompanies the photocatalytic... 

Cycloaddition to a cyclic allyl ether The key step in a synthesis of lineatin (3), the aggregation pheromone of the bark beetle, is the addition of dichloroketene to the alkene 1. Under usual conditions (POCl3, 8,156) the desired adduct is obtained in 7% yield. Fortunately, substitution of 1,2-dimethoxyethane for POCl3 increases the yield of 2 to 50-60%. 

Although mechanistically different, a successful kinetic resolution of cyclic allyl ethers has recently been achieved by zirconium catalysis [2201. Other metals such as cobalt [221], ruthenium [222], and iron [2231 have been shown to catalyze allylic alkylation reactions via metal-allyl complexes. However, their catalytic systems have not been thoroughly investigated, and the corresponding asymmetric catalytic processes have not been forthcoming. Nevertheless, increasing interest in the use of alternative metals for asymmetric alkylation will undoubtedly promote further research in this area. 

In the preparation of cyclic ethers by diene-ene RCM, there is a competition between the formation of cyclic allyl ether with a smaller ring size and of cyclic pentadienyl ether with a larger ring size (Scheme 24). In particular, in the competition between five- and seven-membered ring formation, both dihydrofuran and dihydrooxepine derivatives are formed in comparable amounts, whereas in the competition between seven- and nine-membered rings, a dihydrooxepine forms exclusively <2006JOC3977>. 

The transition metal-catalyzed addition of alcohols to unsaturated systems has not been widely investigated. Reports on addition of alcohols to 1,3-diene [24] or allene [25] have appeared but have very limited scope. We recently reported the palladium/benzoic acid-catalyzed inter- and intramolecular addition of alcohols to alkynes in which various acyclic and cyclic allylic ethers are produced [26], The Pd-catalyzed addition of alcohols to alkylidenecyclopropanes proceeds smoothly providing a powerful tool for synthesis of allylic ethers [27a]. An intramolecular version of the hydroalkoxylation has been demonstrated in which the phenol-tethered alkylidenecyclopropanes undergo facile cyclization to give exomethylene products [27b],... 

Interestingly, cyclic allylic ethers do not give analogous coupling products with zirconium-benzyne complexes.47 Reaction of 52 with 2,5-dihydrofuran... 

Oxidation ofS,6-dihydropyranes. These cyclic allylic ethers are oxidized by PCCr directly to a, 3-unsaturated 8-lactones. 

Hodgson et al. have further expanded upon this methodology to epoxides derived from unsaturated hetero- (oxa and aza)cycles, such that the /3-leaving group is retained in the product after elimination. Their initial studies examined epoxides derived from cyclic allylic ethers (i.e., 3,4-epoxytetrahydrofuran, Scheme 48), from which alkylated ene diols were obtained in good yields <20010L3401, 2002S1145>. 

Reactions with Oxygen Nucleophiles. The hist report of the reaction of oxygen nucleophiles was for the deracemization of cyclic allylic ethers, for example, the palladium(0)-catalyzed reaction of 2-cyclohexeny 1-1 -methyl carbonate with sodium pivalate afforded the pivalate ester in 94% yield and 92% ee. This reaction was extended to other cyclic allylic carbonates. 

Thus, the kinetic resolution of a variety of pyrans [123] and cyclic allyl ethers (six-, seven- and eight-membered vinyl systems) was investigated [124]. In all cases, a very high enantioselectivity of the remaining starting materials was obtained. 

Allylic ethers, especially cyclic allylic ethers, may insert dichlorocarbene into a C-H bond in a competitive proccss (see Houben-Weyl, Vol. 4/3, pp 169,180 181 and Vol. E19b, p 1556). However, allyl benzyl and diallyl ether form 2-benzyloxymethyl- and 2-allyloxymethyl-sub-stituted 1,1-dichlorocyclopropane, respectively, by using the chloroform/base/phase-transfer catalyst method. 

Allylic ethers, particularly cyclic allylic ethers, may enter a competitive reaction with dibromocarbene of insertion into a C-H bond. In the example of the formation of 3 and 4, a suitable workup of the reaction mixture allows isolation of pure cyclopropane 3. ... 

Zr-Catalyzed Kinetic Resolution of Cyclic Allylic Ethers. 12... 

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of cyclic allylic ethers is readily demonstrated in the example provided in Scheme 7. Optically pure starting allylic ether, obtained by the above-mentioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford chromene in >99% ee [18]. Unlike unsaturated pyrans discussed above, chiral 2-substituted chromenes are not readily resolved by the Zr-catalyzed protocol. Optically pure styrenyl ethers, such as that shown in Scheme 7, are readily obtained by the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

Fi . 4.3. Various iruxles of addition of cyclic allylic ethers lo a (EBTHI)Zr-alkcnc complex. 

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