Mono spiroacetals

Scheme 8 Kulinkovich coupling/ring-opening strategy toward mono(benzaimulated) spiroacetals...

Brimble and Haym have used dehydrative spirocycUzation to achieve the synthesis of a range of simple mono(benzaimulated) spiroacetals. The requisite dihydroxy-ketones were prepared via a Kulinkovich coupling/ring-opening strategy [52] (Scheme 8). Subsequent removal of the protecting groups under acidic conditions afforded the mono(benzannulated) spiroacetals 26 in moderate yield. 

Alternatively, using a benzyl ether-protecting group, an efficient tandem hydro-genation/deprotection/cycUzation sequence was demonstrated [53] (Scheme 10). Direct hydrogenation of the HWE products unmasks the dihydroxyketones from which the mono(benzannulated) spiroacetals 36 are derived. 

Scheme 9 HWE/chemoselective reduction strategy toward mono(benzannulated) spiroacetals [53]...

Nagorny et al. [75] have used the chiral phosphoric acids (5)-TRIP 120 and its enantiomer to catalyze the asymmetric dehydrative spirocyclization of dihy-dropyrans 122 (Scheme 29). Treatment of the achiral substrates with (S)-TRIP afforded the doubly anomeric 6,6- and 6,7-spiroacetals 123 in excellent yield and selectivity. Conversely, use of (/ )-TRlP as the catalyst afforded the mono-anomeric spiroacetals 124 in high yield and good enantioselectivity. 

The use of chiral substrates was also examined (Scheme 30). The contra-thermodynamic mono-anomeric spiroacetals 126a were selectively obtained when (S)-TRIP was used as the catalyst. The selectivity could be reversed using (R)-TRIP, however the ratio of 126b to 126a was much lower. 

Using their imidophosphate dimer 121, unsubstituted dihydropyran and dihydrofuran alcohols 130 gave the corresponding spiroacetals 129 in good yield with excellent stereocontrol, favoring the contra-thermodynamic mono-anomeric spiroacetal (Scheme 32). The thermodynamic spiroacetal could also be obtained using ent-121 in comparable yield and enantioselectivity. 

Mono(benzannulated) Spiroacetals Gold, Rhodium, Iridium,... 

In addition, several Rh(I)- and Ir(I)-based catalysts have been found to catalyze the intramolecular hydroalkoxylation of aromatic alkynes to give mono (benzannulated) spiroacetals (Fig. 4). 

Deslongchamps et al. [109] have also applied their mercury(II) protocol to mono (benzaimulated) spiroacetals (Scheme 50). Thus, treatment of alkyne diol 201 with catalytic Hg(OTf)2 afforded the 6,6-spiroacetal 205 in excellent yield. The THP-protected alcohol could also be used directly in the reaction with only a small drop in yield. 

Scheme 50 Deslongchamps et al. s Hg(II)-catalyzed synthesis of mono(benzaimulated)-spiroacetals [109]...

Shair et al. [123] have used an electrophilic spirocychzation in their synthesis of cephalostatin 1 (Scheme 54). The spiroacetal of the western half, 228, was obtained by treatment of the endocyclic enol ether 226 with PhSeBr, giving the mono-anomeric spiroacetal 227 in excellent yield. Transformation to the desired doubly anomeric spiroacetal 228 was achieved by reductive removal of the bromide, followed by epimerization with CSA. 

This method has also been extended to the synthesis of mono(benzaimulated) spiroacetals [139, 140] (Scheme 66). For both the threo and erythro glycal-deiived epoxides, the retention spiroacetals 265a and 266b could be obtained selectively using the Ti(Oi-Pr)4 protocol. The inversion spiroacetals 265b and 266a could be accessed upon addition of MeOH or AcOH to the reaction mixture however, the selectivity was much lower. 

Scheme 66 Tan et al. s selective syntheses of mono(benzannulated) spiroacetals via intramolecular epoxide ring opening [139, 140]...

Alternatively, the HDA approach toward mono(benzannulated) spiroacetals can make use of aliphatic dienes, rather than o-QM, as the 4n reaction partner. This strategy has been demonstrated most recently by Belmont et al. [163], where HDA between a variety of furoquinolines 313 and acrolein affords the spiroacetals 314 in good yield and selectivity (Scheme 77). 

The use of intramolecular hydrogen abstractiOTi for the formation of both mono-and bis(benzannulated) spiroacetals has been explored recently by Brimble and coworkers [179-181] (Scheme 88). The observed mixtures of 5,5- and 6,5-spiroacetals were attributed to the weaker influence of the anomeric effect in five-membered rings, while the 5,6- and 6,6-spiroacetals could undergo... 

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