Natural products cyclic ethers

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-... 

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. 

Cyclization of mixed acetals (13,300).4 This reaction is a particularly useful route to eight-membered cyclic ethers (oxocanes) and provides the first practical route to a natural oxocene, (- )-laurenyne (3), from an optically active mixed acetal 1. Thus cyclization of 1 followed by O-desilylation affords 2 as the only cyclic product. Remaining steps to 3 involved C-desilylation, for which only HF/pyridine is useful, introduction of unsaturation into the C2-side chain, and extension of the C8-side chain. Exploratory studies showed that unsaturation at the p- or y-positions to the cite of cyclization of 1 prevent or retard cyclization with a wide variety of Lewis acids. The cyclization is apparently more tolerant of substitution in the terminator position, C3-Q, of the oxocene. 

Anodic C, C-coupling is a very powerful tool to synthesize cyclic compounds with high regio- and stereoselectivity. It involves inter- and intramolecular coupling of arylolefins, dienes, enolethers, phenol ethers, and aromatic amines and often opens a quick entry into complex natural products in a few steps. Although the mechanism is fully established in only a few cases, it does appear to involve the coupling of two radical cations at the site of their highest radical density and is further controlled by steric constraints. This important type of reaction is reviewed in Chap. 5 and in Refs. [89, 90]. 

Aryltellnrinyl acetates, generated as previously described from the corresponding tellurinic anhydrides and acetic acid, add to hydroxy olefins, giving tellurinylated cyclic ethers. The reaction is performed in refluxing acetic acid or in chloroform in the presence of BFj EtjO. Owing to their hygroscopicity and intractable nature, the products are reduced with hydrazine hydrate, and isolated as tellurides (as for the aminotellurinylation reactions). 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

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... 

Stereocontrolled syntheses of macrolides and macrolactams are well developed. Much remains to be done toward the efficient enantioselective construction of five and suc-membered cyclic ethers and amines. Four recent natural product syntheses illustrate the current state of the art. 

Reduced furan rings occur in many important anhydrides, lactones, hemiacetals and ethers. Maleic anhydride is frequently used as a dienophile in Diels-Alder reactions and it is a component of alkyd resins. Several unsaturated y-lactones are natural products, while the furanose sugars are cyclic hemiacetals. 

Viewed (and drawn) in a terpene-like perspective, C-glycosyl compounds are in fact functionalized tetrahydrofurans and tetrahydropyrans. As such, they can be considered as versatile chirons for the synthesis of a variety of natural products containing cyclic ether motifs, such as in the ionophores. 

With complex (102) as catalyst, reaction (107) has been used to prepare a precursor of the natural product curvularin.482 If cyclic ethers are used instead of alcohols, w-haloesters are... 

Recall that p-toluenesul Innate (tosylate) is a good leaving group in nucleophilic substitution reactions. The nucleophile that displaces tosylate from carbon is the alkoxide ion derived from the hydroxyl group within the molecule. The product is a cyclic ether, and the nature of the union of the two rings is that they are spirocyclic. 

The Claisen rearrangement has been instrumental in the synthesis of a number of natural products.279-289 Many useful derivatives have been prepared using the Claisen-type rearrangement including enol ethers,290 amides,291-293 esters and orthoesters,294-296 acids,297-298 oxazolines,299 ketene acetals,300-301 and thioesters.302 Many of these variants use a cyclic primer to control relative and absolute stereochemistry. The Claisen and oxy Cope provide the best candidates for scale up as a result of the irreversible nature of these reactions. 

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