Exocyclic enol ether

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

Exocyclic enol ethers.1 A route to (E)-cyano- or -methoxycarbonyl substituted exocyclic enol ethers involves hydrogenation and isomerization catalyzed by Pd/C of an endocyclic dienol ether. Thus hydrogenation of la or lb in toluene at - 35° catalyzed by Pd/C gives (E)-2a or 2b as the major product in about 80% yield. 

Another scheme utilizing laevoglucosan lead to phosphonium salt 7 which is the precursor for a Wittig olefination product (an exocyclic enol ether) which is perfectly set up for an intramolecular spiroketalization for milbemycin P3 [87,88]. The same approach was modified to synthesize the fragment containing... 

Different cycloaddition strategies can be used to synthesize spiroketals such as [4+2]-, [3+2]-, [2+2+2]-, and [2+2+l]-cycloadditions (2005JA8260, 2000EJOC873 1995JA6605 2006OL3565 2007CAJ1388). For example, a [3+2]-cycloaddition has been utiHzed to form the bis(benzannulated) spiroketals of y-rubromycin (2011JA6114). The cycloaddition in between diketone 110 and the exocyclic enol ether 111, induced by CAN, led to the 0- andp-quinone spiroketals 112 and 112 in a 1 2 mixture in 58% yield. 

The hetero-Diels-Alder reaction between exocyclic enol ethers... 

Hydroboration of exocyclic enol ether 111 with 9-BBN and following Suzuki-Miyaura reaction with enol triflate 128 proceeded smoothly to generate the cross-coupled product 129 in 81% yield (Scheme 17). Not unexpectedly, the corresponding enol phosphate of 128 proved to be a poor substrate for this complex fragment coupling. Given the structural complexity and sheer size of the respective fragments, this remarkable yield (81%) represents... 

Barluenga and coworkers have studied a strategy leading to spiro tetrahydroquino-lines 142 by combination of a platinum-catalyzed intramolecular hydroxyalkoxy-lation of alkynols, which furnishes in situ exocyclic enol ethers 141, with a Lewis acid-catalyzed Povarov reaction. The starting imine required for this reaction was also generated in situ, from the corresponding aniline and aldehyde (Scheme 3.43) [93]. 

All these results seemed to indicate that this reaction was ideal for the con-stmction of the (—)-berkelic acid skeleton. However, a serious problem was still unresolved at this point how to constmct the additional pyran ring contained in the natural product. Nevertheless, our experience on cycloisomerization reactions led us to speculate on the possibility that a unique metal complex could promote the cycloisomerization of alkynol 15 to give the exo-cyclic enol ether 19 and also that the cycloisomerization of an alkynyl-substituted salicylaldehyde 23 would give 25. Thus, activation of the alkyne of 15 should promote a hydroalkoxylation reaction to give the exocyclic enol ether 19. On the other hand, activation of the alkyne in 23 should promote a cascade cyclization process to finally give the 8//-isochromen-8-one derivative 25. The formal [4-F 2]-cycloaddition reaction between intermediates 19 and 25 would result in the formation of the core structure of (—)-berkehc acid 24 in a very simple way (Scheme 7). 

Danishefsky has described the synthesis of 173 which represents the fully functionalized core of staurosporine, a potent protein kinase C inhibitor. Central to his strategy is incorporation and then unmasking of a double glycosyl donor by activation of (i) an endocyclic enol ether and (ii) an exocyclic enol ether, as outlined in Scheme 36. 

Alternatively, an exocyclic enol ether may be used for the synthesis of spiroacetals, the spirocyclization once again taking place via generation of an oxonium ion intermediate (Scheme 34). 

An alternative method for the synthesis of spiroacetals involves cyclization of a pendant alcohol to an exocyclic enol ether. A recent example of an acid-catalyzed cyclization of an exocyclic enol ether has been reported by Goekjian et al. [79] in their synthesis of the cytotoxic marine metabolite bistramide A, 72 (Scheme 35). Lactone 137 and benzothiazole 138 were coupled in a modified Julia-Koscienski olefination [80] to give the requisite exocyclic enol ether 139 subsequent treatment with catalytic PTSA in dichloromethane afforded the spiroacetal 140 in good yield over two steps. 

The hetero-Diels-Alder reaction (HDA) has been used extensively for the construction of spiroacetals [4], notably in the synthesis of the reveromycins [150-153]. In particular, the recent development of mild methods for the generation of ort/to-quinone methides (o-QM) in the presence of sensitive five-membered exocyclic enol ethers has revealed an alternative route to benzannulated... 

SCHEME 8.1 Synthesis of [n,5]-spiroketals 10 using exocyclic enol ethers 13 as starting materials the last step involves the domino sequence. 

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