The direct catalytic asymmetric aldol reaction

Abstract

Asymmetric aldol reactions are a powerful method for the construction of carbon-carbon bonds in an enantioselective fashion. Historically this reaction has been performed in a stoichiometric fashion to control the various aspects of chemo-, diastereo-, regio- and enantioselectivity, however, a more atom economical approach would unite high selectivity with the use of only a catalytic amount of a chiral promoter. This critical review documents the development of direct catalytic asymmetric aldol methodologies, including organocatalytic and metal-based strategies. New methods have improved the reactivity, selectivity and substrate scope of the direct aldol reaction and enabled the synthesis of complex molecular targets (357 references).

Scheme 1

The direct catalytic asymmetric aldol and issues of selectivity.

Scheme 2

Mechanism of type I (RAMA FDP) and type II (fuculose-1-phosphate) aldolases.

Scheme 3

Hajos-Parrish-Eder-Sauer-Wiechert aldol reaction.^,

Scheme 4

Proline-catalyzed enol-exo and transannular cyclizations.^,

Scheme 5

Mechanism of the intermolecular proline-catalyzed aldol.

Scheme 6

Side products obtained in the proline-catalyzed aldol reaction.

Scheme 7

Off-cycle processes that are ameliorated by the addition of water.

Scheme 8

Alternative oxazolidinone mechanism proposed by Seebach and Eschenmoser.

Scheme 9

Use of the proline-catalyzed hydroxyacetone aldol reaction for the synthesis of brassinolide.

Scheme 10

Trimerization of acetaldehyde.

Scheme 11

Application of the aldehyde aldol reaction to the syntheses of prelactone B and callipeltoside C.^,

Scheme 12

MacMillan’s direct aldol/Mukaiyama aldol sequence: application to the synthesis of (−)-littoralisone.

Scheme 13

Proline-catalyzed sugar synthesis.

Scheme 14

Improved reactivity and enantioselectivity with primary amine catalysts for sterically-hindered substrates.^,

Scheme 15

Additional acceptors and donors.

Scheme 16

Potential mechanisms for the direct aldol catalyzed by tertiary amines and quaternary ammonium salts.

Scheme 17

Intermolecular aldol-lactonization.^–

Scheme 18

Cinchona alkaloid-catalyzed aldol reactions of glycine Schiff bases.

Scheme 19

Alternate cinchona derivatives.^,

Scheme 20

Maruoka’s C₂-symmetric quaternary ammonium salt 216.^,

Scheme 21

Additional non-cinchona derived quaternary ammonium salts.^,

Scheme 22

Quinidine-catalyzed direct aldol of hydroxyacetone.

Scheme 23

Diazo ester aldol catalyzed by cinchona alkaloid derivative 224.^,

Scheme 24

Cinchona alkaloid-catalyzed aldol-cyclization.

Scheme 25

Oxindole aldol reaction with ethyl trifluoropyruvate.

Scheme 26

Gold-catalyzed direct catalytic aldol reaction.^–

Scheme 27

Silver-catalyzed direct aldol reaction.^,

Scheme 28

Palladium catalysts for the direct aldol of α-isocyanocarboxylates and aldehydes.^–

Scheme 29

Rhodium-catalyzed direct aldol reaction of α-cyanocarboxylates.

Scheme 30

Rhodium-catalyzed aldol reaction of cyclohexanone and cyclopentanone.

Scheme 31

Rare-earth alkoxide catalyzed aldol reaction.

Scheme 32

Barium BINOL-derived catalyst for the direct aldol.^,

Scheme 33

BINOL-based catalysts for the aldol reaction of 2-hydroxy-1-phenylethanone.^,

Scheme 34

Linked BINOL catalyst for the direct aldol reaction.

Scheme 35

Titanium BINOL catalyst for the direct aldol reaction.

Scheme 36

Linked-BINOL zinc-catalysts for the Synthesis of 1,2-diols.^,

Scheme 37

Application of catalyst 248 to glycine Schiff bases.

Scheme 38

Zirconium-BINOL catalyzed diazo ester aldol.

Scheme 39

Lanthanum-lithium-BINOL-catalyzed ynone aldol and its application to the synthesis of fostriecin.^,

Scheme 40

ProPhenol-catalyzed aldol reaction of aryl ketones.

Scheme 41

ProPhenol-catalyzed acetone aldol.

Scheme 42

Dinuclear zinc ProPhenol-catalyzed aldol for the synthesis of syn diols.

Scheme 43

ProPhenol-catalyzed ynone aldol and its application to the synthesis of dephosphofostriecin.^,

Scheme 44

Dinuclear zinc ProPhenol-catalyzed aldol reaction of methyl vinyl ketone.

Scheme 45

BINOL-derived zincate catalyst for the aldol reaction of aryl ketones and aryl aldehydes.

Scheme 46

Magnesium-ProPhenol catalyzed diazo ester aldol.

Scheme 47

Calcium-catalyzed aldol of acetophenone.

Scheme 48

Zinc-diamine catalyzed acetone aldol.

Scheme 49

Zinc-proline catalyzed acetone aldol.^,

Scheme 50

Copper-catalyzed aldol of trifluoropyruvate.

Scheme 51

Spiroborate ester-catalyzed acetone aldol.

Scheme 52

Zinc-proline catalyzed aldol.

Scheme 53

Dinuclear nickel Schiff base catalyzed aldol.

Scheme 54

Cinchonine-BINOL-titanium catalyzed diazo acetate aldol.

Scheme 55

Copper-catalyzed aldol reaction of aryl aldehydes.