Evolution of a Cycloaddition–Rearrangement Approach to the Squalestatins: A Quarter-Century Odyssey

Abstract

The highs, lows, and diversions of a journey leading to two syntheses of 6,7-dideoxysqualestatin H5 is described. Both syntheses relied on highly diastereoselective n-alkylations of a tartrate acetonide enolate and subsequent oxidation–hydrolysis to provide an asymmetric entry to β-hydroxy-α-ketoester motifs. The latter were differentially elaborated to diazoketones which underwent stereo- and regioselective Rh(II)-catalysed cyclic carbonyl ylide formation–cycloaddition and then acid-catalysed transketalisation to generate the 2,8-dioxabicyclo[3.2.1]octane core of the squalestatins/zaragozic acids at the correct tricarboxylate oxidation level. The unsaturated side chain was either protected with a bromide substituent during the transketalisation or introduced afterwards by a stereoretentive Ni-catalyzed Csp3–Csp2 cross-electrophile coupling.1 Introduction 2 Racemic Model Studies to the Squalestatin/Zaragozic Acid Core3 Asymmetric Model Studies to a Keto α-Diazoester3.1 Dialkyl Squarate Desymmetrisation3.2 Tartrate Alkylation3.2.1 Further Studies on Seebach’s Alkylation Chemistry 4 Failure at the Penultimate Step to DDSQ 5 Second-Generation Approach to DDSQ: A Bromide Substituent Strategy 5.1 Stereoselective Routes to E-Alkenyl Halides via β-Oxido Phosphonium Ylides 5.2 Back to DDSQ Synthesis6 An Alternative Strategy to DDSQ: By Cross-Electrophile Coupling7 Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing α-Ketoester Intermediates8 Summary