Direct Catalytic Asymmetric Synthesis of Highly Functionalized 2‐Methylchroman‐2,4‐diols via Barbas–List Aldol Reaction

Abstract

A practical and sustainable chemical process for the synthesis of highly substituted aldol<-->lactol products was achieved for the first time through the asymmetric Barbas-List aldol (BLA) reaction of 2-hydroxybenzaldehydes with acetone in the presence of a catalytic amount of trans-4-OH-L-proline (see scheme).

Unexpected Beneficial Effect of ortho-Substituents on the (S)-Proline-Catalyzed Asymmetric Aldol Reaction of Acetone with Aromatic Aldehydes

“…The 2-hydroxynaphthaldehyde-derived aldol adduct 5k, which is in equilibrium with its closed lactol form, has been reported to form with poor enantioselectivity (63:37 er) when using trans-4-OH-(S)-proline as catalyst. 13 Similarly we obtained a disappointing enantiomeric ratio for 5k (66:34). In contrast, when 2-methoxynapththaldehyde was used, we were pleased to obtain aldol product 5l with exceptionally high enantiomeric excess, as would be expected considering the positive effect of ortho substituents presented herein.…”

Recent Developments in Asymmetric Organocatalytic Domino Reactions

“…The reaction provided the corresponding chiral lactols in moderate yields and enantioselectivities (26-90% ee). [130] On the other hand, a range of chiral 4,5-disubstituted isoxazoline N-oxide products 279a-e, 279f and 279g have been prepared by Jørgensen et al through two novel asymmetric domino Henry reaction-cyclization reactions of in situ generated a-brominated aldehydes with ethyl nitroacetate, and of in situ generated epoxides with tert-butyl nitroacetate, respectively (Scheme 73). [131] Remarkable enantioselectivities of up to 99% ee were obtained combined Scheme 70.…”

Asymmetric organocatalytic synthesis of six-membered oxygenated heterocycles

“…29 A series of both electron-withdrawing and electron-donating substituted 2-hydroxybenzaldehydes was reacted with 14 equiv of acetone to obtain the corresponding aldol/lactol products, which co-exist in a fast dynamic equilibrium. The aldol/lactol ratios varied from 99:1 to 1:99, being 1:1 in most cases, and yields in the range 40-90% and enantioselectivities of up to 90% were achieved.…”