Spiroacetal synthesis, intramolecular

The reaction is effective with electron-rich carbonyls such as trimethylsilyl esters and thioesters, as Table 20 indicates. Lactones ate substrates for alkylidenation however, hydroxy ketones are formed as side products, and yields are lower than with alkyl esters. Amides are also effective, but form the ( )-isomer predominantly. This method has been applied to the synthesis of precursors to spiroacetals (499) by Kocienski (equation 115). ° The reaction was found to be compatible with THP-protected hy- oxy groups, aromatic and branched substituents, and alkene functionality, although complex substitution leads to varying rates of reaction for alkylidenation. Kocienski and coworkers found the intramolecular reaction to be problematic. As with the CrCb chemistry, this reaction cannot be used with a disubstituted dibromoalkane to form the tetrasubstituted enol ether. Attempts were made to apply this reaction to alkene formation by reaction with aldehydes and ketones, but unfortunately the (Z) ( )-ratio of the alkenes formed is virtu ly 1 1. ... 

The transition metal-catalyzed intramolecular hydroalkoxylaticHi approach for the synthesis of spiroacetals has increased in popularity in the last decade. A variety of... 

The hydroalkoxylation of an internal alkyne to afford a spiroacetal was first described by Utimoto in 1983 [85]. Using PdCl2 or PdCl2(PhCN)2 as catalyst, the spiroacetals 158 were obtained in high yield (Scheme 39). The method was not adopted as a general tool for the synthesis of spiroacetals for some time, with only a few reports exploiting the approach [86, 87]. Recent applications of palladium-catalyzed intramolecular alkyne hydroalkoxylation include syntheses of spirolaxine methyl ether [88] and enantiomers of the natural cephalosporoUdes [89]. 

Ramana et al. [89] opted for a Pd(II) catalyst for the intramolecular hydroalkoxylation of alkyne 186 in their synthesis of the enantiomeric cephalosporolides 189a and 189b (Scheme 44). The spirocyclization afforded a 1 1 mixture of the spiroacetals 187, which were then elaborated to the ent-natural products via hydrolysis of the isopropylidene acetal, followed by oxidation and Barton-McCombie deoxygenation. 

Lee et al. [110] have reported the synthesis of bis(spiroacetals) using an intramolecular aUcyne hydroalkoxylation strategy (Scheme 46). Treatment of diynes 196 with catalytic Ph3PAuCl/AgOTf under microwave irradiation afforded the bis (spiroacetals) 197-198 in moderate to good yield, generally favoring the trans-bis (spiroacetal) 197. 

Brimble et al. [127] for the synthesis of bis(benzannulated)-spiroacetals 238 (Scheme 58). Deprotection of the EOM group in chromones 236 prompted intramolecular oxa-Michael addition of the resulting phenol in most cases. In the two examples where only the free phenol 237 was recovered, the spirocyclization could be induced by heating the neat phenol with dry potassium carbonate under micro-wave irradiation. The resulting bis(benzannulated) 6,6-spiroacetals were obtained in low to moderate yields. 

Scheme 61 Double intramolecular hetero-Michael addition in the synthesis of spiroacetals...

Another of the well-established methods for the synthesis of a-hydroxy spiroacetals is through the intramolecular ring opening of an epoxide (Scheme 64). 

Scheme 103 Intramolecular ring opening of a cyclopropane for the synthesis of spiroacetals [195]...

Werz et al. [195] have reported the synthesis of unsaturated spiroacetals 422 via intramolecular ring opening of spirocyclopropanes 421 (Scheme 103). Oxidation of the alcohol and subsequent acid-catalyzed ring opening affords the spiroacetals 422 in low to good yield. 

The same catalyst was used for the double intramolecular hydroalkoxylation reaction for the synthesis of a series of spiroacetals starting from internal and terminal alkynediols [32] (Scheme 15). 

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