Homoallyl ethers, synthesis

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>. 

Acyclic acetals are simple protecting groups for aldehydes and ketones, and we have previously reported their synthesis catalyzed by Bi(OTf)3 [104]. Acyclic acetals can also be converted to other useful functional groups. For example, allylation of acyclic acetals to give homoallyl ethers has been well investigated, and we have reported a Bi(OTf)3-catalyzed method for the same [105]. The success of Bi(OTf)3-catalyzed formation and allylation of acyclic acetals prompted us to develop a one-pot method for the synthesis of homoallyl ethers from aldehydes, catalyzed by bismuth triflate. A one-pot process saves steps by eliminating the need for isolation of the intermediate and thus minimizes waste. Three one-pot procedures for the synthesis of homoallyl ethers were developed [106]. 

Yadav JS, Subba Reddy VB, Srihari P (2000) Scandium triflate catalyzed allylation of acetals and gem-diacetates a facile synthesis of homoallyl ethers and acetates. Synlett 673... 

Wieland LC, Zerth HM, Mohan RS (2002) Bismuth triflate catalyzed allylation of acetals a simple and mild method for synthesis of homoallyl ethers. Tetrahedron Lett 43 4597 1600... 

Anzalone PW, Baru AR, Danielson EM, Hayes PD, Nguyen MP, Panico AF, Smith RC, Mohan RS (2005) Bismuth compounds in organic synthesis a one-pot synthesis of homoallyl ethers and homoallyl acetates from aldehydes catalyzed by bismuth triflate. J Org Chem 70 2091-2096... 

Mekhalfia A, Marko IE (1991) The silyl modified Sakurai (SMS) reaction. An efficient and versatile one-pot synthesis of homoallylic ethers. Tetrahedron Lett 32 4779 1782... 

The ruthenium indenylidene IX catalyzed the ring dosing metathesis of a homoallyl ether diene to give a bicydic compound, which is an intermediate for the synthesis of different marine natural products (Equation 8.10) [63]. 

A wide variety of silyl ethers can be employed, leading to functionalized homo-allylic alcohols or ethers. This three-component coupling reaction, which generates in a single operation a range of homoallylic ethers, does not require the initial and independent synthesis of the acetal (or ketal) derived from 6. 

Oxonine with homoallyl ether side chain was a suitable intermediate for RCM synthesis of oxonines with annulated oxepine ring <2004TL7567>. 

The final approach was elegantly presented by Panek [44]. Several optically active ( )-crotylsilanes are available via stereoselective Ireland-Claisen rearrangement of enantiomerically pure vinylsilanes. Addition of the chiral crotylsilanes to acetals or to mixtures of aldehyde and trimethylsilyl methyl ether is effected by la to afford homoallylic ethers in exceedingly high diastereo- and enantioselectivity (Sch. 13). Occasionally a stoichiometric amount of la is required for allylation of aliphatic acetals, preserving the excellent level of asymmetric induction. The synthesis of (-F)-macbecin I involving triple use of the strategy imderscores the utility of the la-catalyzed asymmetric allylation [44c]. 

Panek and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

Silver-initiated ring cleavage of bicyclo[1.1.0]butanes in protic solvents leads predominantly to mixtures of cyclopropanes and the corresponding dienes, e.g. a mixture of the norcarane ether 32 and the corresponding homoallylic ether 33 is observed in the reaction of 2,6-dimethyl-tricyclo[4.1.0.0 ]heptane (31) with silver perchlorate. This reaction is of little practical value for the synthesis of cyclopropane derivatives from bicyclo[1.1.0]butanes. 

The aUylation of acetals with y-substituted allylsilanes is occasionally highly syn-selective [362]. Panek et al. have succeeded in highly diastereo- and enantioselective synthesis of homoallyl ethers by aUylation using homochiral a,y-disubstituted allylsilanes [334] (Section 10.3.1.3). 

Zerth, H.M., Leonard, N.M., Mohan, R.S. (2003) Synthesis of homoallyl ethers via alkylation of acetals in ionic liquids catalyzed by trimethylsilyl trifluoromethanesulfonate. Org. Lett., 5,55-57. 

Modified Sakurai reaction.3 The original reaction involved the TiCI4-catalyzed addition of allyllrimclhylsilanc to aldehydes and ketones or the acetals and kctals to form homoallylic alcohols or ethers (7,370-371). Marko et al. have extended this reaction to a synthesis of homoallylic ethers by a Lewis acid catalyzed reaction of allyl-trimcthylsilanc with a carbonyl compound and a trimethylsilyl ether. 

Metzger, J.O., andU. Biermann, Ethylaluminium Dichloride Induced Reactions of Acetals with Unsaturated Carhoxyhc Esters Synthesis of Homoallyl Ethers, Liebigs Ann. 1851-1854 (1996). 

In recent years, ring-closing olefin metathesis (RCM) has attracted organic chemists as a versatile cyclization method via carbon-carbon bond formation, and had a great impact on the synthesis of natural products [29,30]. In the syntheses of dihydropyrans of marine macrolides, allyl homoallyl ethers 28 have been cyclized to dihydropyrans 29 via RCM. This methodology has been seen in the syntheses of laulimalide by Mulzer [31,32], Crim-mins [33], and Nelson [34] (Scheme 9). 

The allylation of a carbonyl compound, or equivalent thereof (aldehydes, ketones, acetals, ketals, enones, acid chlorides, epoxides, etc.), performed with an allylsilane 39 promoted by a Lewis acid (TiCl, SnCl, BF3-OEt2, AICI3, EtjAlCl, etc.) is known as Hosomi-Sakurai reaction (Scheme 12.11, Eq. 1) [68, 69]. This reaction was first described in 1976, allowing the synthesis of homoallylic alcohols 43 from aldehydes and ketones 40 [70]. A year later, the authors extended the method to ketals 41, which provide homoallylic ethers 44 (Scheme 12.11, Eq. 2) [71], and to a,p-unsaturated ketones 42 (Scheme 12.11, Eq. 3) [72]. 

In this chapter, only the most recent multicomponent versions of the Hosomi-Sakurai reaction will be covered [68b], in particular those that allowed the synthesis of homoallylic ethers through the combination of an aldehyde (or ketone) with a silyl ether or the corresponding alcohol and an allylsilane (Scheme 12.13, Eq. 1). And also, the synthesis of homoallylic amines where the allylsilane reacts with an imine in situ formed from the carbonyl compound and an amine is known as aza-Sakurai reaetion (Scheme 12.13, Eq. 2). 

Silyl-Modified Sakurai Reaction Secondary and tertiary homoallylic ethers are impotant building blocks in the synthesis of biologically active compounds. In 1991, Marko et al. developed an efficient method for the synthesis of those... 

SCHEME 12.13 Multicomponent (aza-)Hosomi-Sakurai reactions synthesis of homoallylic ethers (Eq. 1) and synthesis of homoaUylic amines (Eq. 2). 

A year later, after Maikd s first article about SMS reaction, Tietze et al. published a stereoselective version of the same reaction using trimethylsilyl ether of (lR,2R)-Af-trifluoro-acetylnorpseudoephedrin, which acts as chiral auxiliary [77]. Since then, Tietze s group has been working extensibly in the domino multicomponent allylation reaction (MCAR) for the stereoselective synthesis of homoallylic ethers... 

SCHEME 12.16 Domino multicomponent allylation reaction (MCAR) for the stereoselective synthesis of homoallylic ethers and alcohols, a proposed mechanism. 

Mohan has also worked in the multicomponent synthesis of nonchiral homoallyl ethers starting from aldehydes, aUcoxytrimethylsilanes, and trimethylallyl silanes using bismuth triflate (Bi(OTf)3-xHjO) [86] and iron(III) tosylate (Fe(0Ts)3 6H20) [87] as inexpensive and relatively noncorrosive catalysts. 

Finally, Chen s work on the direct allylation of carbonyl compounds using benzyl alcohol in the multicomponent Sakurai reaction catalyzed by selective and green solid acids, such as sihcomolybdic acid (SMA-SiO ) [92] or perchloric acid (HClO -SiOj) [93], both supported on silica gel, should be mentioned. In some cases, the use of preformed acetals as substrates provided better results. These methods allowed the synthesis of a broad number of homoallylic ethers in moderate to high yields in a short reaction time. Significantly, catalyst loading of HClO -SiOj is only 2mol%. 

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