Fused cyclic ether

Figure 8.2 Examples of natural tram-fused cyclic ethers brevetoxin B and hemibrevetoxin B.

A highlight in the application of RCM methodology in natural product synthesis is Hirama s total synthesis of ciguatoxin CTX3C (183) [90], including the more recent improved protective group strategy, as depicted in Scheme 34 [90b]. The structure of 183 spans more than 3 nm and is characterized by 12 six- to nine-membered trans-fused cyclic ethers and a spiroannulated terminal tetra-... 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic... 

In the next example, the strategy for the formation of fused cyclic ethers utilized the formation of an intermediate a-heterosubstituted carbon radical, generated by the reaction of (TMS)3Si radical with A-(ethoxycarbonyl)-l, 3-thiazolidine derivative [38]. This intermediate gives intramolecular C — C bond formation in the presence of proximate 1,2-disubstituted double bonds (Reaction 7.27). However, when terminal double bonds are used, the hydrosily-lation of the double bond by (TMS)3SiH can compete with the reduction and prevent forming the desired C—C bond formation. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

FIGURE 24.2 Structures of hemibrevetoxin and brevenal. The short chained brevetoxins are comprised of either four-fused cyclic ether rings comprising the hemibrevetoxin (a) or five-fnsed cyclic ether rings comprising the brevenals (b). (Modified from Bourdelais, A. J., Jacocks, H. M., Wright, J. L. et al., J. Nat. Prod., 68, 2, 2005.)... 

Hemibrevetoxin-B (15) is the smallest cyclic polyether compound produced by K. brevis [15]. Hemibrevetoxin-B has a polyether backbone and a terminal unsaturated aldehyde, similar to brevetoxin, but contains only four fused cyclic ether rings. Cytotoxicity of hemibrevetoxin-B against mouse neuroblastoma cells was reported. 

The same species Karenia brevis, isolated from Florida red tides, was shown to contain tamulamides A and B that included a new seven-fused cyclic ether backbone and amide side chain similar to brevisamide and an aldehyde moiety similar to brevenal (Truxal et al., 2010). 

Recently, Barluenga and Fananas reported tandem intramolecular hydroaUc-oxylation/hydroarylation and hydroaUcoxylation/Prins-Type annulation reactions. In the first communication, they described the cycloisomerization of 5-alkynols with several gold, platinum, and silver catalysts and the application to the synthesis of enantiopure benzo fused cyclic ethers from the chiral pool [150] (Scheme 87). 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

Using this methodology, cyclic ethers of different ring-size can also be constructed. Due to the fact that many natural products of marine origin include fused polycyclic ether structural units, a convenient entry to this structural element is of continuing challenge. 

There are reports of many iterative cyclization strategies for the synthesis of fused polycyclic ethers related to marine natural products, for example, an Sml2-induced reductive cyclization <1999TL2811, 2002T1853> cyclic... 

The titanium -mediated approach toward the ABC framework also proved to be an efficient methodology to access the cA-fused analogue (140) of thyrsiferol. The application of this method toward the trans-fused natural product remains to be investigated and if this execution proves to be successful, the application of this chemistry in the synthesis of cyclic ethers from C-glycosides will become even more valuable. 

Cyclic Ethers. The production of commercially valuable poly(oxymethylene)s from 1,3,5-trioxane (TRO) by chemical polymerization has been object of considerable attention. The first reports on electrochemical polymerization of TRO were by Strobel and Schulz72) who effected the electrolysis in fused monomer, and by Asahara et al.73) who carried out the electrolysis in dry THF (see also Ref.7, pp. 603-4). 

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