Allyl ether synthesis

The ether can be formed by the typical Williamson ether synthesis using a strong base and the cinnamyl bromide. Many of the methods used for allyl ether synthesis should be applicable. 

SCHEME 17.21. Asymmetric Claisen rearrangement by way of asymmetric di(allyl) ether synthesis. 

Nelson SG, Wang K. Asymmetric Claisen rearrangements enabled by catalytic asymmetric di(allyl) ether synthesis. J.Am. Chem. Soc. 2006 128(13) 4232-4233. 

The 7, i5-unsaturated alcohol 99 is cyclized to 2-vinyl-5-phenyltetrahydro-furan (100) by exo cyclization in aqueous alcohol[124]. On the other hand, the dihydropyran 101 is formed by endo cyclization from a 7, (5-unsaturated alcohol substituted by two methyl groups at the i5-position. The direction of elimination of /3-hydrogen to give either enol ethers or allylic ethers can be controlled by using DMSO as a solvent and utilized in the synthesis of the tetronomycin precursor 102[125], The oxidation of the optically active 3-alkene-l,2-diol 103 affords the 2,5-dihydrofuran 104 in high ee. It should be noted that /3-OH is eliminated rather than /3-H at the end of the reac-tion[126]. 

An interesting feature of the synthesis is the use of allyl as a two-carbon extension unit. This has been used in the stereospecific synthesis of dicyclohexano-18-crown-6 (see Eq. 3.13) and by Cram for formation of an aldehyde unit (see Eq. 3.55). In the present case, mannitol bis-acetonide was converted into its allyl ether which was ozonized (reductive workup) to afford the bis-ethyleneoxy derivative. The latter two groups were tosylated and the derivative was allowed to react with its precursor to afford the chiral crown. The entire process is shown below in Eq. (3.59). 

Thermal [3,3] Claisen rearrangement of the 3-substituted phenyl allyl and pro-pargyl ethers synthesis of 4-halobenzo[d]furans 98H(48)2173. 

Recently, Charette et al. have also demonstrated this behavior in the stereoselective cyciopropanations of a number of enantiopure acyclic allylic ethers [47]. The high degree of acyclic stereocontrol in the Simmons-Smith cyclopropanation has been extended to synthesis several times, most notably in the synthesis of small biomolecules. Schollkopf et al. utilized this method in their syntheses of cyclopropane-containing amino acids [48 a, b]. The synthesis of a cyclopropane-containing nucleoside was also preformed using acyclic stereocontrol [48c]. 

Unlike the acid-catalyzed ether cleavage reaction discussed in the previous section, which is general to all ethers, the Claisen rearrangement is specific to allyl aryl ethers, Ar—O—CH2CH = CH2. Treatment of a phenoxide ion with 3-bromopropene (allyl bromide) results in a Williamson ether synthesis and formation of an allyl aryl ether. Heating the allyl aryl ether to 200 to 250 °C then effects Claisen rearrangement, leading to an o-allylphenol. The net result is alkylation of the phenol in an ortho position. 

With the polycyclic framework of the natural product intact, the completion of the total synthesis only requires a short sequence of reactions. At this juncture, the decision was made to address the problem of reconstituting the A-ring lactone. It was hoped that a selective oxidation of the A-ring allylic ether could be achieved. 

Allyllithium reagents have also been used in the synthesis of (Z)-y-alkoxyallylboronates 23 2 5. Stereoselectivity is excellent in these reactions since the (Z)-y-alkoxyallyl carbanions prepared by metalation of allyl ethers are stabilized by chelation. The (Z)-y-alkoxyallyl(diisopinocam-pheyl)boranes are prepared at low temperature by an analogous procedure and must be used at — 78 "C otherwise reaction diaslereoselectivity suffers owing to the facile isomerization to the -isomer26. 

Alternative conditions for reductive decyanations can be used. The allylic ether in compound 26, an intermediate in a total synthesis of (-)-roxaticin, was prone to reduction when treated with lithium in liquid ammonia. Addition of the substrate to an excess of lithium di-ferf-butylbiphenylide in THF at -78°C, and protonation of the alkyllithium intermediate provided the reduced product 27 in 63% yield, as a single diastereomer (Eq. 7). a-Alkoxylithium intermediates generated in this manner are configurationally stable at low temperature, and can serve as versatile synthons for carbon-carbon bond forming processes (see Sect. 4). 

The scope of this methodology was extended to the enantioselective rearrangement of difluorovinyl allyl ethers by these authors, furnishing a novel powerful tool for the synthesis of chiral p-substituted a,a -difluorocarbonyl compounds. As shown in Scheme 10.36, moderate to good enantioselectivities... 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

A final crucial step in this synthesis was an anionic [2,3]-sigmatropic rearrangement of an allylic ether in Step D-4 to introduce the C(l) carbon. 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

Gold(I)-catalyzed synthesis of dihydrobenzo[ >]furans from aryl allyl ethers was reported as depicted below <06SL1278>. Highly efficient AuCl3/AgOTf-catalyzed atom-economical annulation of phenols with dienes was developed. This annulation generated various dihydrobenzo[ >]furans under mild conditions <06OL2397>. 

In their synthesis of the natural product carpanone, Ley and coworkers described the microwave-assisted Claisen rearrangement of an allyl ether (Scheme 6.80 a)... 

The isomerization of allyl ethers and allyl acetals to vinyl ethers or vinyl acetals, respectively, has found many applications in organic synthesis (Equation (17)). Various transition metal catalysts have been reported in the literature for the isomerization of allyl ethers and allyl acetals. 

Allylic amination is important for the solid-phase organic synthesis.15 The solid-phase allylic aminations are devised into the G-N bond formation on solid support and the deprotection of allyl ethers. As a novel deprotection method, the palladium-catalyzed cyclization-cleavage strategy was reported by Brown et al. (Equation (4)).15a,15b The solid-phase synthesis of several pyrrolidines 70 was achieved by using palladium-catalyzed nucleophilic cleavage of allylic linkages of 69. 

Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Ru- and Mo-Catalyzed Synthesis of 2-Substituted Chromenes... 

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. 

Using AD mix-a or AD mix-/ as the dihydroxylation agent, various olefins can be dihydroxylated with high ee.57,67b 72 As an example, in Scheme 4-33, aryl-allyl ethers undergo dihydroxylation yielding products with good ee. The procedure can be used as an alternative for the synthesis of (2S )-propranolol.73... 

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]. 

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. 

An irreversible consecutive reaction as a driving force to shift an unfavorable Cope rearrangement equilibria in the needed direction can be illustrated by the Cope-Claisen tandem process used for the synthesis of chiral natural compounds243. It was found that thermolysis of fraws-isomeric allyl ethers 484 or 485 at 255 °C leads to an equilibrium mixture of the two isomers in a 55 45 ratio without conversion into any other products (equation 184). Under the same conditions the isomer 487 rearranges to give the Cope-Claisen aldehyde 491 (equation 185). Presumably, the interconversion 484 485 proceeds via intermediate 486 whose structure is not favorable for Claisen rearrangement. In contrast, one of the two cyclodiene intermediates of process 487 488 (viz. 490 rather than 489) has a conformation appropriate for irreversible Claisen rearrangement243. 

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],... 

This method can be extended for the synthesis of allyl alkyl ethers from alcohols with allyl acetate. Thus, the iridium cationic complex [lr(cod)2] BFc, catalyzes the allylation of alcohols 71 with allyl acetate 72 to afford allyl ethers 73 (Equation 10.14) [30]. 

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