Abstract
In the presence of a suitable acid or base, α-hydroxyaldehydes, ketones, and imines can undergo isomerization that features the 1,2-shift of an alkyl or aryl group. In the process, the hydroxy group is converted to a carbonyl and the aldehyde/ketone or imine is converted to an alcohol or amine. Such α-ketol/α-iminol rearrangements are used in a wide variety of synthetic applications including asymmetric synthesis, tandem reactions, and the total synthesis and biosynthesis of natural products. This review explores the use of α-ketol rearrangements in these contexts over the past two decades.
Highlights
When treated with base, acid, heat, or light, many α-hydroxyaldehydes, ketones, or imines 1 undergo a 1,2-shift of one of the α-substituents to the adjacent unsaturated carbon, with a concomitant proton transfer to form compounds of type 2 (Figure 1) [1]
While the reaction is generally reversible, the product can be favored through four common strategies: (1) the use of aldehydes (R′ = H), which are usually less stable than their ketone counterparts; (2) ring expansion (Z, R = cyclic) or contraction (Z, R′ = cyclic) of strained cyclic α-ketols; (3) the use of α-dicarbonyl compounds (R′ = acyl, ester, amide, etc.), which lead to more stable β-dicarbonyl compounds; or (4) the use of imines (X = NR′′), which lead to more stable α-amino ketones
Base-catalyzed isomerization yields 44, which is apparently more stable despite the reduction in conjugation. Another example of a tandem α-ketol rearrangement was used in the total synthesis of delitschiapyrone A (49), a cytotoxic natural product with previously demonstrated efficacy against several cancer cell lines
Summary
Acid, heat, or light, many α-hydroxyaldehydes, ketones, or imines 1 undergo a 1,2-shift of one of the α-substituents to the adjacent unsaturated carbon, with a concomitant proton transfer to form compounds of type 2 (Figure 1) [1]. Base-catalyzed isomerization yields 44, which is apparently more stable despite the reduction in conjugation Another example of a tandem α-ketol rearrangement was used in the total synthesis of delitschiapyrone A (49), a cytotoxic natural product with previously demonstrated efficacy against several cancer cell lines. The authors structurally characterized asperflotone and asperfloroid and demonstrated their immunosuppressive activity against IL-6 production in induced THP-1 cells As they noted, these two steroids may be attractive targets for total synthesis, perhaps incorporating the Figure 14: Enzyme-catalyzed α-ketol rearrangements. The one-pot conversions occurred successfully over a wide range of monosubstituted anilines, including various para-alkyl groups (65–72% yield), para-alkoxy and para-halogen substituents (45–69%), ortho-methyl (74%), and Figure 20: Synthesis of tryptamines 110 via a ring-contracting α‐iminol rearrangement. The rearrangement was triggered by saponification of the benzoyl ester in 126, resulting in a 90% yield of 127
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