Aldol Reactions with Kinetic Resolution: Scope and Limitations of Ketal- and Dithioketal-Protected β‑Ketoaldehydes

• Published in: Journal of organic chemistry Vol. 77; no. 23; pp. 10789 - 10803
• Main Authors: Ward, Dale E, Kazemeini, Alieh
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 07-12-2012
• Subjects: Chemistry; Exact sciences and technology; Kinetics and mechanisms; Organic chemistry; Reactivity and mechanisms; Ketoaldehyde; Titanium IV; Enantioselectivity; Prediction; Chiral compound; Selectivity; Aldehyde; Ketone; Chemical reaction kinetics; Diastereoselectivity; Aldol condensation; Aldol; Stereoselectivity; Acetal; Racemic; Optical resolution; Enantiomer; Chemical synthesis; Kinetic resolution; Enolate; Protection; Diastereomer
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo302142v

The multiplicativity rule suggests that aldol coupling of chiral reactants will proceed with substantial mutual kinetic enantioselection (MKE) (racemic reactants) or via a highly enantioselective kinetic resolution (KR) (one enantiopure reactant) if the relative topicity is highly selective and the ketone enolate and aldehyde each have high diastereoface selectivity. The scope and limitations of that paradigm were explored by determining the stereoselectivities of aldol reactions of ketone 1a (known to give 3,5-trans aldol adducts with high selectivity) with a series of ketal- and dithioketal-protected β-ketoaldehydes (±)-5 (predicted to have high Felkin diastereoface selectivity). Using racemic reactants, all reactions of the (c-Hex)2B enolates (highly anti-selective relative topicity) were remarkably selective and gave the 3,5-trans-3,1″-anti-1″,2″-syn adduct, one of eight possible diastereomers, via a diastereoselective (dr > 20) preferential reaction (MKE > 17) of like reactant enantiomers [i.e., (3R)-1a + (R)-5 and (3S)-1a + (S)-5]. Reactions of the corresponding Ti(IV) “ate” enolates (anticipated syn-selective relative topicity) were much less selective, and only those of MOM-protected 1a with dithiolane-protected (±)-5 (i.e., X = S, n = 1) gave high selectivity in favor of the 3,5-trans-3,1″-syn-1″,2″-syn adduct via a diastereoselective (dr > 20) preferential reaction (MKE ≥ 6) of unlike reactant enantiomers [i.e., (3R)-1a + (S)-5 and (3S)-1a + (R)-5]. Analogous reactions of the (c-Hex)2B and Ti(IV) “ate” enolates of enantiopure (+)-1a (R = MOM) with (±)-5c (R2 = Me, X = S, n = 1) occurred with KR to give the corresponding enantiopure adducts with the expected stereoselectivity. The adducts have applications in polyproionate synthesis.