Styrenyl ethers

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

Zr-Catalyzed Kinetic Resolution of Functionalized Styrenyl Ethers 123... 

Scheme 8. Zr-catalyzed kinetic resolution of allylic styrenyl ethers may be followed by a Ru-or Mo-catalyzed rearrangement to afford 2-substituted chromenes...

Catalytic Ru-Catalyzed Rearrangements of Terminal Styrenyl Ethers... 

As the examples in Scheme 9 illustrate, treatment of a styrenyl ether, such as 35, with 5 mol%Ru catalyst la under an atmosphere of Ar (14 h) leads to the formation of 36 and 37 in 42% and 41% isolated yield, respectively. When the reaction is performed under an atmosphere of ethylene, 36 is obtained in 91 % yield. Furthermore, as exemplified by the conversion of 38a to 39a, electronic properties of the aromatic moieties exhibit little influence on the facility of the catalytic heterocycle synthesis. Eight-membered rings are appropriate substrates as well (Scheme 9 38b—>39b). 

Scheme 9. Ru-catalyzed rearrangement of styrenyl ethers proceeds efficiently under 1 atm ethylene to afford a range of 2-substituted chromenes...

Scheme 10. Mechanism proposed for the Ru-catalyzed rearrangement of terminal styrenyl ethers...

As mentioned above, we planned to obtain optically pure styrenyl ethers through Zr-catalyzed kinetic resolution [5] subsequent metal-catalyzed rearrangement would afford optically pure chromenes. However, as shown in Scheme 11, the recovered starting material (40) was obtained with <10% ee (at 60% conversion) upon treatment with 10 mol% (,R)-(EBTHI)Zr-binol (3b) and five equivalents of EtMgCl (70°C, THF). We conjectured that, since the (EBT-HI)Zr-catalyzed reaction provides efficient resolution only when asymmetric alkylation occurs at the cyclic alkene site, competitive reaction at the styrenyl terminal olefin renders the resolution process ineffective. Analysis of the H NMR spectrum of the unpurified reaction mixture supported this contention. Indeed, as shown in Scheme 11, catalytic resolution of disubstituted styrene 49... 

Scheme 11. Zr-catalyzed resolution of disubstituted cycloheptenyl styrenyl ethers, unlike those of terminal styrene derivatives, can be carried out efficiently...

Scheme 12. In the Ru-catalyzed conversion of disubstituted styrenyl ethers to chromenes the presence of ethylene is required for reaction efficiency as well as high yield of monomer formation...

With an effective catalytic resolution of allylic styrene ethers in hand, we focused our attention on the Ru-catalyzed reaction of disubstituted styrenyl ethers (e.g., 49). When we treated (S)-49 with 10 mol% la under an atmosphere of Ar (Scheme 12), we found chromene formation to be sluggish 25-30% of dimer (S,S)-50 was isolated after 48 h at 45°C, together with substantial amounts of oligomeric materials. 

In contrast to the reaction carried under an Ar atm, when (S)-49 was treated with 10 mol% la under an atmosphere of ethylene (22°C, CH2C12,24 h), (S)-41 was obtained in 81% isolated yield and >98% ee (Scheme 12). As expected, the use of ethylene atmosphere proved to be necessary for preferential monomer formation (10% of the derived dimer was also generated). These results indicate that the presence of ethylene is imperative for efficient metal-catalyzed chromene formation as well for processes involving disubstituted styrenyl ethers (25-30% yield of dimer 50 under argon). 

Subsequent mechanistic studies suggested that the abovementioned effect of ethylene on reaction efficiency is connected to a mechanistic divergence that exists for reactions of terminal styrenyl ethers versus those of disubstituted styrene systems [13b]. Whereas with monosubstituted styrenyl substrates the initial site of reaction is the terminal alkene, with disubstituted styrene systems the cyclic ji-systems react first. This mechanistic scenario suggests two critical roles for ethylene in the catalytic reactions of disubstituted styrenes ... 

Transformations of the more highly substituted styrenyl ethers are notably more facile under an atmosphere of ethylene due to the presence of the more reactive LnRu=CH2 (formed by the reaction of la or lb with ethylene) [20]. Under an atmosphere of Ar and after the first turnover has transpired, LnRu= CHCH3 is likely the participating catalyst. When the reaction is performed under ethylene, LnRu=CHCH3 is immediately converted to LnRu=CH2. Reactions of monosubstituted styrenes do not require ethylene to proceed smoothly because, as illustrated in Scheme 10, with this class of starting materials, the more reactive LnRu=CH2 is formed following the first catalytic cycle. 

Based on the above principles, cyclopentenyl substrates that bear a disubstituted styrenyl ether should readily afford the desired chromenes by the catalytic... 

Scheme 13. Reaction pathway for the Ru-catalyzed reactions of disubstituted styrenyl ethers in the absence of ethylene atmosphere...

An advantage of the metal-catalyzed conversion of styrenyl ethers to chromenes is that control of relative stereochemistry on the carbocyclic substrate before catalytic synthesis of chromenes can lead to the formation of various functionalized heterocycles that are diastereomerically pure (Table 1). 

Scheme 17. The tandem Zr-catalyzed kinetic resolution and Mo-catalyzed conversion of styrenyl ethers to chromenes is used in the first convergent and enantioselective total synthesis of the antihypertensive agent (S,R,R,R) nebivolol...

There is much more left to be done in the area of catalytic RCM. It is likely that many elegant and creative uses of catalytic RCM are in the making. Judging by the related developments in recent years, it is also likely that catalytic RCM will influence positively the development of numerous other ongoing metal-catalyzed or uncatalyzed reactions. The advent and utility of complexes la, lb and 2 will undoubtedly inspire organic chemists to devise new and useful transformations, where these transition metal systems are effectively utilized (e.g., styrenyl ether rearrangements) [40]. 

Catalytic transformations of both terminal and disubstituted styrenyl ethers will be discussed in this article. In the former case, since the starting material and the product are isomeric, the Ru-catalyzed process constitutes a catalytic rearrangement. 

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of exocyc-lic allylic ethers is demonstrated by the example provided in Scheme 6.9. The optically pure starting allylic ether, obtained by the aforementioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford the desired chromene in >99% ee [20], Unlike the 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 6.9, are obtained by means of the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

As the representative examples in Scheme 6.11 illustrate, similar stragies may be applied to the corresponding alkenyl ethers (vs. styrenyl ethers) [26], The Zr-catalyzed kinetic resolution/Ru-catalyzed metathesis protocol thus delivers optically pure 2-substituted di-hydrofurans that cannot be accessed by resolution of the five-membered ring heterocycles (see Scheme 6.8). It should be noted, however, that the efficiency of the Zr-catalyzed resolution is strongly dependent, and not in a predictable manner, not only on the presence but the substitution of the acyclic alkene site of the diene substrate. The examples shown in Scheme 6.11 clearly illustrate this issue. 

In an effort to confront these deficiencies, we have developed a procedure for the surface derivatization of small glass (sol-gel) [41] pellets and applied it to the synthesis of supported Ru catalysts [42]. As shown in Scheme 11.8, the Unker and the active metal carbene were installed in a sin e step. Treatment of (71) with allylchlorodi-methylsilane and a full equivalent of (4,5-dihydroIMES)PCy3Cl2Ru=CHPh (29) led to rapid ROCM and metaUation of the styrenyl ether (-> 72). Preweighed monolithic (smallest dimension > 1 mm) sol-gels were then added to the solution, and substi-... 

The six-membered ring 85 is obtained from the allylamine 84 [31]. The sulfur-containing ring 87 was obtained from 86 using the Mo catalyst. The Ru catalyst is not active for this reaction [32]. The (S, f )-chromene derivative 89 was obtained in 97% yield by the Mo-catalysed intramolecular metathesis of (S,f )-cycloheptenyl styrenyl ether 88 under an atmosphere of ethylene. In the absence of ethylene, 89 and its dimer were obtained. The enantioselective total synthesis of (.S, / ,/ , / )-ncbivoIoI (90) has been carried out from 89 [33]. No cyclization of the cyclopentene 91 was observed, because the highly strained cyclobutane intermediate 92 is difficult to form. 

A few examples of polymer supported olefin metathesis have been reported recently. Hoveyda formed styrenyl ether complexes of several mthenium-based olefin metathesis catalysts that were then incorporated into a dendrimer stmcture (273) (Scheme 23), reporting good conversions over 6 cycles albeit with diminishing mthenium content. Yao used a similar chelating ligand to incorporate olefin... 

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