Catalyzed asymmetric acyl halide-aldehyde cyclocondensation: A new strategy for catalyzed asymmetric aldol bond construction

Catalyzed asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions have been developed as catalyzed direct aldol reaction variants. The AAC reactions utilize acyl halides (acetyl bromide or propionyl bromide) as the enolate surrogate, which generate ketene in situ in the presence of a tertiary amine base (diisopropylethylamine), a variety of aldehydes as electrophiles, and a substoichiometric amount (10 mol%) of optically active Al(III)-triamine complex as Lewis acid catalyst, through a catalyzed ketene-aldehyde cycloaddition mechanism, to afford highly enantiomerically enriched β-lactones (≥90% ee) as masked aldol adducts. The operational simplicity of these reactions and the use of inexpensive, commercially available reaction components are particularly attractive characteristics.*; The optically active β-lactones offer considerable versatility as intermediates or building blocks for asymmetric organic synthesis. Appropriate tuning of nucleophile reactivity can lead to scission of the β-lactone ring from either the C_carbonyl–O or C_alkyl–O bond. β-Lactone ring openings using alcohols or amines as nucleophiles via addition and elimination at the carbonyl residue, afford ester and amide aldol-type adducts. “Soft” nucleophiles, such as cuprates and azides, tend to open the β-lactone ring via S_N2 reaction pathway, which provides entry to β-amino acids and β-dialkyl carboxylates. Moreover, 4-alkyne-substituted β-lactones are subject to S_N2 ′ nucleophilic substitution analogous to that observed for activated propargylic alcohols, rendering β-lactones as precursors to allene derivatives.; The utility of the catalyzed AAC and the ensuing β-lactone ring opening reactions have been demonstrated by the concise asymmetric total syntheses of the antibiotic marine natural products malyngolide and tanikolide, in which the lactone β-stereocenter was relayed to the O-bonded quaternary carbon stereocenter through an optically active allene intermediate. By extending this chemistry to construct an all carbon quaternary center, the key transformation toward the synthesis of the antitumor natural product rhazinilam was realized.*; *Please refer to dissertation for diagrams.