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 Core
3 Asymmetric Model Studies to a Keto α-Diazoester
3.1 Dialkyl Squarate Desymmetrisation
3.2 Tartrate Alkylation
3.2.1 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 Synthesis
6 An Alternative Strategy to DDSQ: By Cross-Electrophile Coupling
7 Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing α-Ketoester Intermediates
8 Summary
Key words
zaragozic acid - squalestatin - tartrate alkylation - squarate - α-ketoester - cross-coupling - alkene protection - ozonolysis
