Structure-Activity Investigations of Analogues of the C15-C26 Phorboxazoles Segment

Abstract

A variety of analogues of phorboxazole C15-C26 segment have been prepared via three different reaction sequences. Structure activity investigations of the oxazole substitution pattern point to a pharmacophoric lead structure.

Total Synthesis of Siphonazoles by the Use of a Conjunctive Oxazole Building Block

“…While the anion of 21 added to aldehydes to form the anticipated adducts in modest yield, that of sulfone 22 failed to undergo the same reaction. This is in accord with the observations of Hoffmann . Fortunately, it transpired that the combination of TiCl 4 and Et 3 N promotes a smooth Knoevenagel-type condensation of 22 with aldehydes, leading to alkylidene derivatives in excellent yield, albeit as mixtures of geometric isomers.…”

“…The exiguous volume of literature on the chemistry of 2-(sulfonyl)methyloxazole-4-carboxylates suggests that the anions of these species are exceedingly poor nucleophiles. To wit, the anion of 14 (Scheme ) fails to add to aldehydes, preventing the occurrence of Julia reactions. Once again, the peculiar behavior of these compounds is attributable to the effect of the 4-COOR functionality in that analogues lacking a 4-carbonyl group, e.g., 15 , do participate in Julia-type processes, though not very efficiently.…”

“…Once again, the peculiar behavior of these compounds is attributable to the effect of the 4-COOR functionality in that analogues lacking a 4-carbonyl group, e.g., 15 , do participate in Julia-type processes, though not very efficiently. Indeed, Wittig technology is superior for olefination reactions involving 2-methyloxazole donors. − Clearly, in order to reach 1 − 2 by the intended route, it was necessary to circumvent the unfavorable reactivity profile of 2-(sulfonyl)methyloxazole-4-carboxylates.…”

Development of an Oxazole Conjunctive Reagent and Application to the Total Synthesis of Siphonazoles

“…In accord with Hoffmann, , the anion of 71 , generated by deprotonation with NaH à la Fujita, failed to add to aldehydes. More significantly, even the presumably more reactive lithio derivative of 70 , prepared by deprotonation with LDA, added to aldehydes inefficiently, underscoring the unfavorable influence of the 4-COOR group.…”

“…While a limited volume of literature exists concerning the chemistry of 2-(sulfonyl)methyloxazole-4-carboxylates, the anions of these species are known to be poor nucleophiles. For instance, Hoffmann discovered that the metalated 64 (Scheme ) fails to add to aldehydes, , precluding the occurrence of Julia reactions. Once again, the COOMe substitutent must be responsible for such a behavior, for Williams demonstrated that sulfonyloxazoles lacking such a group, e.g., 65 , do undergo Julia−Kocienski reactions, albeit in only 45−50% yield …”