Hemiacetal spirocyclization

Di- or tetrahydropyrans with vinyl side chains obtainable by diastereo-selective ring closing metathesis or by addition of vinylmagnesium chloride to appropriately functionalized tetrahydropyranones are converted to spirocyclic hemiacetals under hydroformylation conditions (Scheme 4) [33]. Oxidation yields the corresponding lactones. 

Alternatively, Cossy et al. [65] have recently disclosed a Fe(lll)-catalyzed spirocyclization of a -hydroxy allylic acetate, 73 (Scheme 20). Formation of hemiacetal 74, followed by Fe(III)-catalyzed addition of the alcohol and elimination gives the doubly anomeric spiroacetal 75 in good yield and selectivity. This method has subsequently been used in synthetic studies toward the cytotoxic marine metabolites, the bistramides [66]. Thus, treatment of the hemiacetal 76 under the same conditions afforded the bistramide-like spiroacetal 77 in moderate yield. 

Dehydrative spirocyclization may also be performed on hemiacetals, whereby treatment with a Br0nsted or Lewis acid gives rise to an oxonium ion intermediate. Subsequent attack of the pendant alcohol thus affords the spiroacetal (Scheme 21). 

In their studies toward the avermectin 2b spiroacetal 81, Henryon and Ferezou [67] have utihzed an acid-catalyzed spirocyclization of hemiacetal 80 (Scheme 22). 

Jtmg et al. used a similar strategy in their syntheses of the cytotoxic spiroacetals, auripyrones A 84a [68] and B 84b [69] (Scheme 23). Oxidation of alcohol 82, followed by deprotection of the PMB ether resulted in cyclization to the stable hemiacetals 83a and 83b in good yield. Further oxidation and spirocyclization of the hemiacetal under mild acidic conditions afforded the auripyrones 84a and 84b. 

Yadav et al. [70] have also used this strategy in their total synthesis of pteridic acid A 85 (Scheme 24). Addition of the lithium acetylide derived from 87 to lactone 86, followed by treatment with catalytic CSA and methanol afforded the hemiacetal. Partial hydrogenation over Lindlar s catalyst then gave the Z-alkene hemiacetal 88. The spirocyclization was affected imder mild acidic conditions, affording the spiroacetal framework of pteridic acid A in excellent yield as a single (doubly anomeric) isomer. 

This method has also been utilized by Brimble and coworkers [71] in their formal synthesis of betkelic acid 96 (Scheme 25). Addition of trimethylsilyl enol ether 92 to oxonium ion 93 (generated by treatment of hemiacetal 91 with boron trifluoride diethyl etherate) and subsequent cyclization provided the hemiacetal 94. Finally, hydrogenolysis of the benzyl ethers in the presence of catalytic acid induced spirocyclization, affording the tetracyclic core of berfcelic acid, 95, in moderate yield over 3 steps. 

Electrophilic spirocyclization may also be performed on hemiacetals. This method has been used most recently by Roush et al. [124] in the synthesis of a model spiroacetal fragment toward integramycin (Scheme 55). Thus, a 1 1.3 mixture of ketone 231 and hemiacetal 232 was treated with NIS in dichloromethane to... 

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