Spiroketal formation

For this chemistry, changing the allylic alcohol to a propargylic alcohol was necessary for spiroketal formation. We also felt that spiroketals could be formed from allylic alcohols and that they would provide alternative products, spiroketals with a vinyl substituent, which would offer access to different types of motifs for applications in synthesis. 

All three alkynes can be incorporated into a single molecule, making the reaction entirely intramolecular. This has been used in a synthesis of Cryptoacetalide 11.60 (Scheme 11.21). The triyne 11.58 was constructed by coupling a diyne 11.56 containing a carboxylic acid with an alkynol 11.57. A ruthenium catalyst was found to be most effective for the cyclotrimerization, combined with microwave heating. The synthesis was completed by deprotection and free-radical spiroketal formation. 

SCHEME 8.2 Potential mechanism of the spiroketal formation via a concerted pathway (left) or zwitterionic open-chain intermediate 10 (right). 

Kozmin and Marjanovic described an ingenious application of the TST-RCM strategy for controlling spiroketal formation in the total synthesis of spirofungin... 

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

Stereocontrol in the formation of spiroketals has been achieved in the alkylation of 2-(benzenesulfonyl)pyrans with allylsilanes <96JOC7860> and using a double carbonyl cycUsation strategy <96SL1065>. Spirocyclisation of protected dihydroxydiketones yields cis- and trans- l,7,9-trioxadispiro[5.1.5.3]hexadecanes the latter isomer is the thermodynamically more stable <96TL5461>. 

Fig. 21 Direct kinetic formation of nonanomeric [6.5]-spiroketals in aqueous media.

Conformation Groups that favor a flattening of the pyranose, a consequence of oxonium ion formation, increase the rate of reactivity. Ley uses 3,4-spiroketals to enforce chairlike structure on the pyranose ring, thus deactivating them toward reaction. 

In recent years hypervalent iodine compounds have been extensively investigated yielding many results of practical synthetic importance. Iodi-nane reagents [e.g., iodoso or iodine(III)] have been prepared in a supported fashion by several groups, mainly as the bis-acetoxy-iodoso derivative28-30 or as the respective dihalogeno compounds.31 Iodoso reagents are employed in the oxidation of hydroquinones as well as phenols, and have been exploited in the formation of spiroketals from various tyrosines. 

The stereoselective formation of spiroketals 242 can be explained in terms of the thermodynamic stability of the three possible products. Oxonium cation 245, formed by the condensation of ortholactone 244b and allylsilyl ether 106a, is in equilibrium with the starting materials. Spiroketal 242 also equilibrates under the reaction conditions with the other anomers. The thermodynamically more stable product 242b, stabilized by a double anomeric effect, is obtained as the only product of the reaction (Scheme 13.89) as the substituents attempt to occupy equatorial positions in the newly generated tetrahydropyran ring. 

On close inspection of the chromatograms, an elevated baseline can be discerned between the terminal peaks of the spiroketals. This peak distortion is caused by interconversion of the stereoisomers during separation. On-column enantiomerization leads to the formation of a plateau between the terminal peaks (Trapp et al., 2001). Such a kinetic phenomenon of molecular interconversion was first observed for 1.6-dioxaspiro[4.4]nonane... 

Different mechanistic interpretations of the formation of an alternating propylene/carbon monoxide copolymer of poly(spiroketal) structure were considered [107, 478, 480, 481, 489]. Any reasonable proposal, however, needs to take into account the nature of the end groups in the copolymer chains. To date this has not been possible owing to the low solubility of the copolymer in solvents other than hexafluoroisopropanol however, this solvent, probably because of its acidic nature, causes transformation of the poly(spiroketal) structure into an isomeric poly(ketone) structure [489]. The formation of a cyclic polymeric structure could be favoured by minor entropy loss due to the intramolecularity of the process [480,481] and by the peculiar conformational situation of the poly(ketone) structure [491]. 

Under most conditions, only the simple polypropylene ketone) is formed in propylene/carbon monoxide alternating copolymerisation. Isomerisation of poly(ketone) to poly(spiroketal) can occur, and it may be assisted by cationic palladium species and protonic acids. It must be emphasised that a low reaction temperature favours the formation of a spiroketal structure [107]. At a temperature above the ceiling temperature, the poly(spiroketal) depolymerises to the more flexible and entropically favoured poly (ketone) [481]. 

Acetals such as C are referred to as spiroketals because their acetal carbon is a spiro atom. (In a spiro compound two rings are connected by a single common atom that is called a spiro atom ). The intermediates in this acetalization are lactols B. They resemble those lac-tols whose rapid formation from y- or 5-hydroxyketones was shown in Figure 9.4. Note that because of the unfavorable reaction entropy, there is often no path hack from spiroketals to the open-chain form Usually, spiroketals cannot be hydrolyzed completely. 

Dihydro-2-hydroxypyrans are formed from propargyl vinyl ethers in a Au(I)-catalysed Claisen rearrangement - heterocyclisation sequence in wet dioxane. Stereochemical features in the substrate are retained in the product. Incorporation of an alkanol function adjacent to the O atom results in the formation of spiroketals (Scheme 3) <06JA8132>. [3-Hydroxyallenes... 

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