Activations LUMO-lowering

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

Figure 11.4. Hydrogen-bonding and Br0nsted acid complexation modes for the LUMO-lowering activation of substrates inherent to the field of Brpnsted acid catalysis.

Scheme 3. Strategies for LUMO-lowering activation of electrophiles in stereoselective F-C alkylation.

In 2000, MacMillan and his co-workers presented the first enantioselective organocatalytic 1,3-dipolar cycloaddition of nitrones 187 and a,p-unsaturated aldehydes 28 (dipolarphiles) to afford the e do-(45)-isoxazolidine adducts 188, Scheme 3.59 [75]. With the LUMO-lowering activation of a,p-unsaturated aldehydes 28 and enforced formation of (fi)-iminium isomer, the HClO -salt of catalyst 30 effectively promote cycloaddition of the dipolarphile. In addition, e do-cycloaddition effectively alleviated nonbonding interaction between the nitrone phenyl group and the neopentyl methyl substituent on the catalyst framework. Later, in 2002, Karlsson and Hbgberg reported the organocatalytic enantioselective 1,3-dipolar cycloaddition of... 

The introduction of an alternative organocatalytic strategy for the Diels-Alder reaction was an important contribution from MacMillan. This strategy is based on the LUMO-lowering activation of substrates via formation of an intermediate. The a,p-unsaturated fragment is activated towards reaction with the diene by the formation of the iminium ion (Scheme 18.3). 

Scheme 51 LUMO-lowering activation of a,(3-unsaturated carbonyl compounds by secondary amines and Lewis acids...

Besides the utilization of chiral secondary amines to achieve a LUMO-lowering activation as well as face discrimination, the use of achiral secondary amines in combination with a chiral counterion also proved to be highly promising for such transformations. This strategy resembles the use of achiral metal catalysts in combination with a chiral ligand to achieve a stereoselective transformation (206-208). It is due to Benjamin List that the elegant concept of asymmetric counteranion-directed catalysis (ACDC) has found widespread applications in organocatalysis at the present time (209-212). 

Since the publication of these works, the concept of LUMO-lowering activation of a,P-unsaturated aldehydes has been extended to a broad number of transformations. As examples we can cite the utilization of a-branched aldehydes [7], intramolecular reactions [44-46], and the use of anilines derivatives as nucle-ophihc aromatic systems [47, 48]. Diarylprolinol silyl ether analogs were also successfully used in such approaches. An example with 4,7-dihydroindoles, which after oxidation afford 2-substituted indole derivatives, is illustrated in Scheme 35.2 [11]. 

In addition to the LUMO-lowering activated enantioselective Diels-Alder reactions of enals, MacMillan s group revealed that this catalytic strategy was also amenable to [3 -I- 2] cycloadditions between nitrones and a, 3-unsaturated aldehydes to provide isoxa-zolidines in high yields, moderate diastereoselectivity, and moderate enantioselectivity... 

Iminium catalysis consists in the addition of primary or secondary amines to an a,(3-unsaturated carbonyl (Scheme 11.2, eq 1). " The transient iminium ion has its lowest unoccupied molecular orbital (LUMO) lowered, activating the substrate toward the attack of a nucleophile and creating the new stereocenter. Liberation of the catalyst furnishes the enantioenriched Michael adduct. 

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