Stereoselective synthesis cyclic ethers

This procedure illustrates a general method for the stereoselective synthesis of ( P)-disubstitnted alkenyl alcohols. The reductive elimination of cyclic /3-halo-ethers with metals was first introduced by Paul3 and one example, the conversion of tetrahydrofurfuryl chloride [2-(chloromethyl)tetrahydrofuran] to 4-penten-l-ol, is described in an earlier volume of this series.4 In 1947 Paul and Riobe5 prepared 4-nonen-l-ol by this method, and the general method has subsequently been applied to obtain alkenyl alcohols with other substitution patterns.2,6-8 (I )-4-Hexen-l-ol has been prepared by this method9 and in lower yield by an analogous reaction with 3-bromo-2-methyltetra-hydropyran.10... 

Addition to thionolactones cyclic ethers. A wide variety of alkyliithium reagents add to the C=S group of thionolactones. The adducts, after reaction with CH,I, can be isolated in high yield as mixed methyl thioketals. The methylthio group can be removed by reduction with triphenyltin hydride (AIBN) to give cyclic ethers. The reaction is not dependent on the ring size and can be stereoselective, as shown by the synthesis of the ether lauthisan (2) from a thionolactone (1). 

Bordeau and coworkers have described an efficient and stereoselective synthesis of kinetic silylenol ethers. Less highly substituted silylenolates are regiospecifically prepared in high yield, around room temperature under kinetic conditions, from unsymmetric cyclic ketones and [(DA)2Mg] in THF/heptane (equation 68). 

If the olefin is chiral (entries 23-25) high diastereoselectivity has been observed, when the center of asymmetry is at C-3 of cyclic silyl enol ethers (entry 24). Cyclopropanation then occurs trans to the substituent at this carbon 57) exclusively, and due to the very mild cleavage conditions this mww-relationship is preserved in the subsequent ring opening (vide infra). This protocol has been applied to introduce a side chain during the stereoselective synthesis of a prostaglandin58> and of dicranenone A 59). 

It was shown that cyclization of the hydroxy epoxides promoted by Eu(fod)3 (fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) proceeds via an exo-mode, providing the corresponding disubstituted eight- and nine-membered cyclic ethers in excellent yields <2003TL2709>. This method was used for the stereoselective total synthesis of (+)-laurallene, as indicated in Scheme 19 <2003TL3175>. 

Denmark and Marcin showed that 2,2-disubstituted 1-nitroalkenes undergo facile MAD-promoted [4 -r 2] cycloaddition with n-butyl vinyl ether in toluene at 0 °C to give cyclic nitronates as anomeric mixtures in good yield [173]. This method is a promising route to the stereoselective synthesis of disubstituted pyrrolidines and can thus be applied to the synthesis of the biologically active pyrrolidine alkaloid, mesembrine (Sch. 134). 

Through the efforts of the Overman research group, the acetal-vinylsilane cyclization reaction has been shown to be a useful strategy for the stereoselective preparation of a variety of medium-sized oxygen heterocycles. This cyclization strategy has been used successfully in the asymmetric synthesis of the marine natural product (-)-laurenyne (40a), an eight-membered cyclic ether. These molecules are members of an unusual class of C-15 nonisoprenoid metabolites. 

We selected the natural product thyrsiferol as an ideal target to test our ideas. Its total synthesis was envisioned to proceed as illustrated in the Scheme 28. The successful coupling between aldehyde 84 and vinyl iodide 82 via a Nozaki-Hiyama-Kishi (NHK) reaction [66] had been demonstrated previously [29]. We therefore sought to model our final steps after precedence presented by Forsyth for the union of these two fragments. The focus of our synthetic strategy centered around the stereoselective synthesis of the ABC framework (84) of thyrsiferol (1) as a scaffold to validate the scope of the Cp2TiCl reaction with epoxides toward the assembly of Q-C-glycosides and cyclic ethers. 

Betancort, J. M., Martin, T., Palazon, J. M., Martin, V. S. Stereoselective Synthesis of Cyclic Ethers by Intramolecular Trapping of Dicobalt Hexacarbonyl-stabilized Propargylic Cations. J. Org. Chem. 2003, 68, 3216-3224. 

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

Yamamoto found that the seven-membered cyclic ether 178 could be formed stereoselectively via BF3 OEt2-promoted intramolecular allylation of the [(Z)-y-alkoxyallyl]stannane 177 (Eq. (11.12)) [108]. This methodology was applied to the synthesis of hemibrevetoxin B [105]. 

The [2+2]photocycloaddition of 5-arylfuran-2,3-diones (496) to trimethylsilyl-oxyethylenes (495) occurs with high regio- and stereoselectivity to efficiently yield polyfunctionalised cyclobutanes (497). ° A convenient four step stereoselective synthesis of ( + )-norasteriscanolide (500) has used the [2+2]photoadduct (499) from 2-cyclopentenone and the trimethylsilyl enol ether (498) to assemble the 5/8 ring system present in many terpenoids. 2-Naphthaldehyde undergoes regio-and stereoselective [2+2]photoadditon to the cyclic ketene silyl acetals (501) to... 

Optically active C synthons are obtained by stereoselective hydrogenation of methyl-substituted pentadien-l-ols with baker s yeast. They represent useful building blocks for the synthesis of <5- and y-cyclic ethers or lactones37. 

Vinylogous sulfonates are valuable radical acceptors for the stereoselective synthesis of cyclic ethers [48]. Evans used the Z-vinylogous sulfonate 73 for preparation of the intermediate 74, which will be used in the synthesis of mucocin [49] (Scheme 26). More recently, an intermediate in the synthesis of garsubellin A was prepared via E -vinylogous sulfonate radical cyclization by Nicolaou [50]. 

The extention of radical cyclization of (bromomethyl)dimethylsilyl allyl ethers to propargyl analogs 17 has been studied by Malacria and coworkers. The intermediate exocyclic vinyl radical 18 can be either trapped by the hydrogen atom to give, after simple chemical transformations, the trisubstituted alkene 19 (equation 25) or can be added intramolecularly to give cyclic products when suitably located double bonds are present (equations 26 and 27). An attempt to apply this methodology to the stereoselective synthesis of angular and linear triquinane has also been performed. When = t rt-butyl,... 

A stereoselective synthesis of five- to seven-membered cyclic ethers has been achieved by de-iodonative ring-enlargement of cyclic ethers having an iodoalkyl substituent. For example, the reaction of tetrahydrofuran derivative 360 with (diacetoxyiodo)toluene proceeds under mild conditions to afford ring-expanded product 361 (Scheme 3.144). The use of hexafiuoroisopropanol (HFIP) as solvent in this reaction is critical [462]. 

Readily available /3-hydroxy-esters (e.g. 49) can be converted into butyrolactones (e.g. 50) simply by treatment with concentrated sulphuric acid. Cyclic ether-lactones (52) are available from hydroxy-acids (51) by iodolactonization followed by dehalogenation with silver acetate. A stereoselective total synthesis of the antifungal mould metabolite (53) has been reported. ... 

---