5,6-and 6,6-Spiroacetals

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... 

The 6,5,6- and 6,6,6-bis-spiroacetals 413 and 415 could also be accessed by substituting the TBS-protected alcohol with a second allyl substituent, allowing sequential RRM-RRM reactions (Scheme 99). The 6,5,6-bis(spiroacetal) 413 was obtained in moderate yield, while the yield of the 6,6,6-bis(spiroacetal) 415 was much higher. 

The synthesis of spiroacetals was improved by using new simple and readily accessible Rh(COD)2 complexes that allowed excellent conversions and an overall reduction of reaction times [33]. Moreover, very recently a dual metal catalytic system (Rh(l) and lr(I)) was successfully utilized for these reactions on alkynediols, and in some cases it works more efficiently than the single metal catalyst [34]. The combination of the two metal complexes ([Rh(bpm)(CO)2]BAr4 and [Ir (bpm)(CO)2]BAr4 (bpm = bis(l-pyrazolyl)methane, BAt4 = tetrakis[3,5-bis (trifluoromethyl)phenyl]borate) acted cooperatively to promote an efficient dual activation pathway for both the 5-exo and 6-endo cyclization in which the Rh(I) preferentially promotes the 6-membered ring formation, while the Ir(I) in preference promotes the 5-membered cyclization of alkynediols. 

The alkylation of metalated imines, hydrazones, 4,5-dihydrooxazoles, 4,5-dihydroisoxazoles, 5,6-dihydro-4/7-1,2-oxazines and 2,5-dialkoxy-3,6-dihydropyrazines (i.e., azaenolates) is a commonly used method in asymmetric synthesis of enantiomerically enriched aldehydes, ketones, spiroacetals, amines, /J-oxo esters, carboxylic acids, lactones, 1,3-amino alcohols, /(-hydroxy ketones and amino acids. 

The cydization of the hydroxy enol ether 5, performed with trifluoroacetic acid in benzene, leads to a single spiroacetal 6. On the other hand, when treated with acetic acid in benzene, 5 gives an equimolar mixture of spiroacetals 6 and 7. It is worth mentioning, however, that on treatment with trifluoroacetic acid this mixture leads exclusively to 6. These results show that the cydization, performed with either acetic acid/benzene or trifluoroacetic acid/benzene, proceeds under kinetic or thermodynamic control, respectively152. 

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. 

Attention then turned to synthesis of the C28-C38 spiroacetal from alkyne triol 173. Alkyne triol 173 was obtained as a 1 1.5 mixture of l,3-antUl,3-syn epimers. As seen in Aponick et al. s earlier work [106], the regioselectivity of the Au(I)-catalyzed spirocycUzation was profoundly influenced by the relative stereochemistry of the 1,3-diol. Thus, the, 3-syn triol gave a mixture of the 6,6- and 5,7-spiroacetals 174—175, while the, 3-anti triol gave the desired 6,6-spiroacetal 174 selectively. 

Treatment of the alkynes 190 with Hg(OTf)2 in acetonitrile afforded the spiroacetals 191 in excellent yield. In cases where both 5-exo-dig and 6-exo-dig cyclization was possible (m = 2, n — 2), 6-exo-dig was favored, giving only 6,6-spiroacetals as the product. However, in substrates where both 6-exo-dig and 5-endo-dig cyclizations were possible m = 1, = 1,2), 5-endo-dig was favored. The unsaturated spiroacetals 193 could be accessed from triol alkynes 192 in similarly excellent yield via a cyclization/elimination sequence upon treatment with Hg(OTf)2. Deslongchamps et al. [105] had also used this method in their synthesis of hippuristanol, where treatment of 194 with Hg(OTf>2 afforded 195 in excellent yield. 

Messerle and coworkers [99-103] in particular, have studied a range of these catalysts (Scheme 48). As seen in Xue et al. study, substrates where 5-exo-dig and 6-endo-dig cyclization can compete (i.e., where n = 2) give a mixture of spiroacetals. In additimi, where n = 1, the benzopyran 220 is often obtained as a minor product, with varying selectivity. 

However, treatment of the substrate 201b with catalyst 213 afforded a 11 1 mixture of the 6,5- and 5,6-benzannulated spiroacetals 204 and 203. 

Thus, AgOTf-catalyzed cycloisomerization of alkyne diol 300 gives the dienophUe, while cycloisomerization of aldehyde 301 generates the o-QM. Cycloaddition of 302 and 303 then affords the 5,6-spiroacetal core 304, which is isolated after hydrogenation of the double bond in 83 % yield as a 2 1 mixture of diastereomers. 

The cycloisomerization/cycloaddition cascade approach has been extended to bis (benzannulated) 5,6-spiroacetals recently by Xue et al. [166] (Scheme 80). Thus, Cu (I)-catalyzed cycloisomerization of aUcynol 327 gives the enol ether 329, which then undergoes HDA with the o-QM 330, generated in situ from 328 under flie thermal reaction conditions. The bis(benzannulated) spiroacetals 331 were obtained in good yield and selectivity (dr >20 1), favoring the doubly anomeric configuration. 

An alternative cycloaddition approach to bis(benzannulated) spiroacetals has been explored by Pettus and coworkers in their synthesis of Y-rubromycin 58. Based on the [3+2]-cycloaddition of an enol ether with a p-diketone-derived zwitterion [167], early studies on simple substrates afforded the 5,6-spiroacetal in moderate yield [168, 169]. 

A related, ring-rearrangement metathesis (RRM) strategy has been reported by Blanchard and coworkers [193] for the synthesis of a variety of spiroacetals (Scheme 98). Treatment of the oxabicycles 405 with second-generation Grubbs catalyst initiated the RRM cascade, affording the unsaturated 5,6-spiroacetals 409 in excellent yields. The 6,6-spiroacetal 411 could also be accessed using the oxabicyclo[3.2.1]octenone 410 as the substrate for the RRM. 

Pikho and co-workers50 found that nonanomeric [6,5]-spiroketals (having a pyranoside moiety with an equatorial CO acetal bond) can be formed under conditions of kinetic control. For instance, 62 undergoes acid catalyzed spiroacetalization giving the anomeric (most stable) acetal 63... 

Recordings from Staphylininae [115] include 3-methylbutanal, the corresponding alcohol, and its acetate, various ketones such as 4-methyl-3-hexanone, 4-methyl-3-heptanone, 5-methyl-3-hexanone (and the corresponding alcohol), 2-heptanone, 6-methyl-2-heptanone, 6-methyl-5-hepten-2-one as well as methyl-cyclopentene and methylfuran. In addition, the secretions of Ontholestes murinus contain the spiroacetals (2S,6R,8S)-2,8-dimethyl-l,7-dioxaspiro[5,5]-... 

The oxidation of alkoxides instead of alcohols is an alternative to achieve the desired oxidation. A spiro-cyclization of (5) occurred, when it was electrolyzed in EtOH containing both EtONa and LiBF4 to afford 61% of the spiroacetal (6)... 

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