Tris-oxazoles

An iterative Hantzsch reaction was applied for the synthesis of the tris-oxazole fragment of the natural product mycalolide A. The reaction between primary amide 200 and ethyl bromopyruvate in a basic medium followed by dehydration with TFAA gave oxazole 201 (Scheme 58) <1997TL5445>. The ester was converted into primary amide and the process was repeated twice to give the tris-oxazole. 

Chattopadhyay, S. K., and Pattenden, G. (1998). Total synthesis of ulapualide A, a novel tris-oxazole containing macrolide from the marine nudibranch Hexabranchus sanguineus. Tetrahedron Lett. 39,6095-6098. 

Armstrong s success in preparing tra/is-4-alkenyloxazoles (vide supra) was a good precedent for Panek and co-workers general approach to trans-2-a ksay -oxazoles. These workers explored synthetic routes to trans-2-alkenyloxazoles as a means of introducing the C(25)-C(26) trans double bond of the tris-oxazole containing... 

Conversion of 1545 to the 4-cyanooxazole 1546 occurred uneventfully via a three-step sequence. Repetition of the entire five-step reaction sequence with 1546 gave the bis-oxazole, 1547 from which the tris-oxazole, 1548a was prepared by a third five-step iteration. Finally, acetylation of 1548a and cleavage of the O-TBS group afforded the desired target tris-oxazole 1549, which was then suitably functionalized for further elaboration to 1195. 

Panek and co-workersdescribed syntheses of suitably bis-functionalized tris-oxazoles as intermediates leading to kabiramide C, halichondramide, and ulapualide A based on sequential application of a modified Hantzsch condensation methodology (Scheme 1.395). For example, condensation of cinnamide with ethyl... 

At this point, the 2-styryl group was converted to the corresponding aldehyde via a two-step hydroxylation-oxidation sequence followed by reduction to the alcohol 1552. The timing for unmasking the primary alcohol was critical to the success of their strategy. The overall synthesis of the tris-oxazole was less efficient when the primary alcohol was unmasked at the monooxazole stage, whereas solubihty issues were encountered when this reaction sequence was attempted on the fuUy elaborated tris-oxazole. 

Amidation of the ester and protection of the alcohol gave 1553, which was elaborated to the tris-oxazole 1554 via a third modified Hantzsch condensation-cyclodehydration sequence followed by DIBAL-H reduction of the ester. 

Panek and co-workers ° modified this reaction sequence to complete the first asymmetric synthesis of a tris-oxazole 1559, which incorporated the C(9)... 

Panek s group ° employed the Schlosser-Wittig olefination reaction of an in situ-generated tris-oxazole phosphonium salt to incorporate the trans double bond of an advanced intermediate leading to ulapualide A (Scheme 1.397). Model studies that precedent this work were described in Scheme 1.298. Thus reaction of 1560 with 1561 in the presence of excess triethylphosphine and one equivalent of LDA generated 1562 in excellent yield as a single double-bond isomer. This result was noteworthy in that it demonstrated the viability of this type of bond construction in the presence of a potentially labile p-alkoxy substituent. 

Chattopadhyay and Pattenden first demonstrated the viability of such a synthetic strategy in a model system designed to construct the basic tris-oxazole core. The oxazole amino alcohol 1573 was prepared from Gamer s acid " 1572 in four steps (Scheme 1.401). Serine benzyl ester was the starting material for 2-(acetoxymethyl)-4-oxazolecarbonyl chloride 1574. Acylation of 1573 with 1574 produced the bis-oxazole amide 1575. The differentially functionalized model tris-oxazole 1576 was then prepared from 1575 in two straightforward steps. 

Subsequently, Kempson and Pattenden " applied this strategy to prepare a model for the complete tris-oxazole macrolide core of ulapualides (Scheme 1.402). 

Medicinally relevant, Doi, Takahashi and co-workers derivatized the tris-oxazole subunit of the antiproliferative telomestatin with a Stille reaction (as well as Suzuki reaction and Pd-catalyzed amination reaction) utilizing a 5 -bromooxazole... 

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