Spiroketals, conformation

This series of experiments establishes that 9A (Fig. 2) is the most stable spiroketal conformation it also demonstrates the importance of two electronic effects in the same function. The value of 1.4 kcal/mol for an anomeric effect must, however, be considered as a minimum value, because similar conclusions would have been reached with a value as high as 1.7 kcal/mol. 

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. 

Spiroketals based upon such structures as l,7-dioxaspiro[5.5]undecane (18), occur frequently in natural products. Accordingly, an extensive amount of literature relates to the isolation and total synthesis of this type of compound. This literature was reviewed104 in 1989. The authors of Ref. 104 listed three factors that influence conformational preferences in these systems. They are (7) steric influences, (2) anomeric and related effects, and (3) intramolecular hydrogen bonding and other chelation effects. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

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. 

Cyclization of a mixture of dl and meso dihydroxyketones T3 and 14 under mild acid conditions gave a mixture of the three isomeric spiroketals 15, 16, and 17. Low temperature C nmr analysis confirmed that isomers lj> and 16 are conformationally rigid and that they exist in the conformations 15A and 16A respectively. Using the same technique, isomer V7 was shown to exist as a mixture of conformers 17A and 17B as predicted. Furthermore, acid equilibration of lj> (or 16) gave a =97 3 mixture of isomers 15 and 16, and when isomer V7 was treated under the same conditions it was converted into a 97 3 mixture of 2j> and 26. These results are completely consistent with the analysis made above. 

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]. 

The fact that the substituents on the side chains can control the conformation of the spiroketal centre means that it is not necessary to worry about that centre in a synthesis, provided you are trying to make the spiroketal that has the double anomeric stabilization (both oxygens axial) and that has any substituents equatorial on the rings. A recent (1997) synthesis of a single enantiomer of some fruit-fly pheromones from an aspartic acid-derived bromodiol is shown overleaf. It involves three different-sized oxygen heterocycles. 

Several other natural, acyclic carboxylic ionophores are known. Among these, salinomycin is notable for its unusual tricyclic spiroketal ring system. Further, the ester of salinomycin affords complexes that have a helical, rather than circular," conformation.lonomycin " is likewise notable as the first example of a dibasic ion-ophore to be discovered. lonomycin has a high affinity for divalent cations such as Ca and Cd, owing to the presence of an enolized p diketone. 

They found that the eonformations of the polymers that contain the ketone units only are not affected by the cis-trans isomerization. On the other hand, the keto/spiroketal polymers drastically change in the main-chain conformations. 

A final TST example involved insightful conformational control as a design element in the total synthesis of spirofungin A by Marjanovic and Kozmin. The key spiroketalization involved deprotection of the benzyl protecting groups of 38 with concomitant hydrogenation of the two olefins to provide a keto-diol confor-mationally constrained by the bissilyl ether tether. In situ cycliza-tion delivered the desired 1,3-diaxially encumbered spiroketal 39 as a single diastereomer in near-quantitative yield (eq 11). ... 

The analysis provided for the conversion of 89 to a spiroketal is abbreviated. What other chair conformations are available to 87 and SS. What products would result from cyclization through 88 and/or these additional confor-mations. What would be the expected product if thermodynamics controlled the entire cyclization process. (Calcimycin-10)... 

Descotes et al. reported an approach to the synthesis of crombenine that involves 8-hydrogen abstraction from an acetal to generate the required spiroketal structure. Unfortunately the required 2,4-dioxy substituents lower the yield from 87% when R = H to 20 and 0% when R = OAc and OMe. Because p-methoxy groups deactivate triplet phenyl alkyl ketones by causing the lowest triplet to become n,n, electronic and conformational effects apparently combine to lower values so much that they barely compete with phosphorescence. Moreover, the bulk of the cyclic ether very likely worsens the conformational problem common to o-alkoxyphenyl ketones. 

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