Zaragozic acid core

The Ireland variant of the Claisen rearrangement relies on the generation of the vinyl moiety of the double unsaturated system by enolization of an ester. The principle of this technique is given in Scheme 11.42 and it allows the transformation of allylic alcohol 177 into 180 via ester 178 and the ketene acetal 179. Application of this chemistry to the construction of the chiral quaternary carbon atom of the zaragozic acid core is shown in Scheme 11.47 [142]. Additional examples of this rearrangement are found in Section 11.5.2.2. 

An efficient synthesis of the 7-deoxy zaragozic acid core was deveioped by M.A. Calter and co-workers. The assembly of this complex structure was based on the interrupted Feist-Benary reaction, which produces highiy oxygenated dihydrofuranols that can be isolated. To this end, the sodium enolate of malondialdehyde was reacted with 2-bromo-3-oxo-diethyl succinate in benzene at room temperature to afford 29% of the c/s-dihydrofuranol. This product was converted to the zaragozic acid core in four steps. 

Scheme 16.39 Construction of zaragozic acid core hy Brogan and Zercher via Fl. 21-shift of ketal-derived oxonium ylide.

Three other modifications of the standard conditions provide synthetically useful strategies for the preparation of dihydrofurans. One method, called the interrupted Feist-Benary reaction, utilizes milder reaction conditions to stop the final dehydration step. For example, Calter combined bromide 47 with dicarbonyl 48 to produce dihydrofuran 49 as a mixture of diastereomers. He examined the scope and diastereoselectivity of this process and applied this reaction toward the synthesis of the polycyclic core of the zaragozic acids. A method principally designed to yield practical syntheses of cyclic ketodiesters also furnished a dihydrofuran via a variation of the interrupted Feist-Benary reaction. ... 

Scheme 8.5 Synthesis of the bicydic acetal core of zaragozic acid C.

The kinetics and thermodynamics of the ketalization of dihydroxyketones 145 have been examined (Equation 12) <1997T11179> the major aim of the study was to better understand these kinds of cyclizations for the synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of the zaragozic acids 147. 

Toward the synthesis of zaragozic acids, a novel family of fungal metabolites that has been shown to be picomolar competitive inhibitors of squalene synthease, Hodgson s group and Hashimoto s group have used cyclic carbonyl ylide formation/[3 + 2]-cycloaddition approach. " In Hashimoto s synthesis, the 2,8-dioxabicyclo[3,2,l]octane core... 

Zaragozic Acids The zaragozic acids (squalestatins) are a class of competitive inhibitors of mouse, rat, and HepG2 squalene synthases, which also display antifungal activity [104]. The characteristic structural feature of this family of natural products is its highly oxygenated core. 

The AD was also used in the synthesis of (+)-zaragozic acid C (90) by Carreira, who prepared the dioxabicyclooctane core by dihydroxylation of the late precursor 94 [107]. 

Intermolecular cycloaddition also proceeds smoothly. The 2,8-dioxabicyclo-[3,2.1]octane core system 379 of zaragozic acid 380 was constructed by the intramolecular carbonyl ylide formation from 376 catalysed by Rh2(OAc)4, followed by intermolecular 1,3-dipolar cycloaddition of the electron-deficient dipolarophile 377 as shown by 378 as a single diastereomer out of four possible diastereomers [124],... 

The oxonium ylide 390 is generated by the interaction of carbene with the unshared electron pair of the oxygen atom of ether 389, and subsequent sigmatropic rearrangement affords 391 [126]. The reaction was applied to the diastereoselective construction of 2,8-dioxabicyclo[3.2.1]octane, the core system 394 of zaragozic acid. The Rh-catalysed reaction of diazo ester 392 generates the bicyclic oxonium ylide 393 from the acetal, and its exocyclic 2,3-shift affords 394 [127]. 

The rhodium(II)-induced tandem cyclization-cycloaddition process has also been applied with notable success to the core structure of zaragozic acid by the Merck research group <94TL9185>. Zaragozic acid A (20) was discovered as a metabolite from an unidentified... 

Further studies by the Hodgson group are still in progress with the fully oxygenated 6,7-dioxy core of zaragozic acid. 

A related strategy starting from a uronic acid was reported to construct the core stmcture of zaragozic acid [122,123]. The key point was the formation of the C4-C5 bond using aldol condensation. As shown in Scheme 11.40, methyl uronate 168 was first treated with KHMDS at —100°C, and then treated with a premixed solution of cerium chloride and (l )-glyceraldehyde acetonide to give the expected aldol as a mixture of diastereoisomers in a yield of 65 to 70%. 

Guijar, M K, Das, S K, Kunwar, A C, Studies towards the synthesis of the highly oxygenated bicyclic core of zaragozic acid incorporation of three quaternary chiral carbon centres, Tetrahedron Lett, 36, 1937-1940, 1995. 

Fraisse, P, Hanna, 1, Lallemand, J Y, Short synthesis of the bicyclic core of the zaragozic acids, Tetrahedron Lett., 39, 7853-7856, 1998. 

Taillefumier, C, Lakhrissi, M, Chapleur, Y, Two novel strategies for the construction of the core acetal of the zaragozic acids, Synlett, 697-700, 1999. 

Two different approaches to the core structure of the zaragozic acids are based on the generation of oxonium ylides. 

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