Medium-sized cyclic ethers

The acetal [1,2]-Wittig rearrangement protocol is also applicable to the synthesis of medium-sized cyclic ethers. For example, a reaction of the 9-membered cyclic acetal 37 with lithium piperidide provides the 8-membered ring ether 38 in good yield along with high diastereoselectivity (equation 20) . 

The use of oxocarbenium ions provides an efficient method for the preparation of heterocycles, especially of medium-sized cyclic ethers. 

New synthetic methods for construction of medium-sized cyclic ethers and convergent coupling of polyether fragments 01YGK193. 

Medium-Sized Cyclic Ethers (7- to 10-Membered Rings)... 

Ravelo, J.L, Regueiro, A., and Martin, J.D. (1992) New synthetic strategy for the construction of troras-fused medium sized cyclic ethers synthesis of the IJK framework of the polyether ciguatoxin. Tetrahedron Lett., 33, 3389-3392. 

Major advances were also made in the field of ARCM. Notable examples of this process are shown in Scheme 2 and include AROM <02JA10779>, and the desymmetrization reactions of acetals <00TL9553> and ethers <02JA2868>. Especially noteworthy are the ARCM to yield medium-sized, cyclic amines that occur in high yield and enantiomeric excess in the absence of solvent <01JA6991> [—m indicates the site of RCM]. 

Further, medium-sized lactones have been prepared by a thermal elimination-Claisen rearrangement sequence, of unsaturated selenoxide cyclic acetals (equation 198)710. The reaction affords reasonable yields of these useful lactones upon treatment with DBU and a siloxy species at 185 °C. The reaction has been used as the key step in the synthesis of (-l-)-laurencin, which contains an 8-membered cyclic ether moiety711. 

The majority of these substances are cyclic ethers of medium ring size. The first of them, isolated by Me and coworkers in the 1960s, was laurencin (2)." Numerous total syntheses of several members of this structurally interesting substance class have been published to date. ... 

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. 

Coupling of reactive alkoxyalkenylsilanes has been applied to the synthesis of medium-sized rings. The cyclic silyl ether 54 was converted to cyclodeca-3,5-dienol (55) at room temperature [104]. In many silane coupling reactions, it has been claimed that ligandless r-allylpalladium chloride is an effective catalyst precursor. Possibly, chloride ion is essential for transmetallation as compared with unreactive Pd(OAc)2. 

An intramolecular version of this process has also been developed [59]. A series of cyclic silyl ether substrates bearing a tethered electrophile undergo the crosscoupling reaction to produce medium-size rings (Scheme 7.33). By this method, 9-, 10-, 11-, and 12-membered cycloalkadienes can easily be synthesized. This is significant because the synthesis of rings of this size - particularly with a 1,3-ds-ds-diene unit - is challenging due to the unfavorable entropic and enthalpic factors associated with such a transformation [60]. 

The 2-thiopyridone (78) is reportedly a superior reagent for the activated ester approach to macrolides, requiring no further activation s (e.g. with Ag ions). The selenolactonization procedure has been used for a reasonably efficient synthesis (ca. 50% yield) of the macrolide derivatives (80 n = 11 or 13) from the unsaturated acids (79) using the iV-phenylseleno-derivatives of suc-cinimide or phthalimide as carriers of the PhSe function. Trost and Verhoeven have reported more examples of the efficient preparation of medium-sized macrolides via Pd° 7r-complexes of allyl acetates (2,152). Further reports have appeared on the preparation of ten-membered keto-macrolides by oxidative ring cleavage of suitable cyclic ethers (c/. 3, 142, 143). 

Molecules of cyclic ethers, with the exception of EO, are not planar although the deviation from planarity in the four- and five-membered rings is small. The free electron pairs on the oxygen atoms behave sterically like medium-sized substituents. 

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