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.

As a parallel to the rapid growth of asymmetric catalysis, chiral imida-zolidinon-HX salts 124a-c were used as catalysts for Michael-type alkylations between indoles and a,(3-unsaturated aldehydes with high levels of enan-tioselectivity and reaction efficiency. This chiral catalyst system is the first reported nonchelating catalyst for indole alkylation. It was assumed that the catalyst reacts with the unsaturated aldehydes to yield the chiral and highly reactive imimum intermediate, which influences both the LUMO-lowering... 

In line with the mechanistic rationale of LUMO-lowering iminium activation, MacMillan hypothesized that intermediate 2, generated from the secondary amine 1 and an a,/f-un saturated aldehyde, could be activated towards cydoaddi-tion with an appropriate diene (Scheme 3.1). The Diels-Alder reaction would form iminium ion cydoadduct 5 that, in the presence of water, would hydrolyze to yield the enantioenriched product 6 and regenerate the chiral imidazolidinone catalyst 1. 

They further investigated the fact that BF3 complexation lowers the energy of the Tt o orbital, making the carbonyl more susceptible to nucleophilic attack [9] and the fact that the extent of LUMO lowering is a little greater in the anti com-... 

C-Substituted Olefins. First let us consider the effect of merely adding conjugation (C-), as we do in going from ethylene to butadiene. This is easy, because we know how the molecular orbitals of butadiene lie in relation to those of ethylene (Fig. 2-12) the HOMO is raised in energy and the LUMO lowered. 

Concerted four electron cycloaddition reactions are not thermally allowed. All this really means is that the transition state for an allowed process is much lower than that of a nonallowed process. HOMO-LUMO theory can explain why the concerted 2 + 2 cycloaddition of two ethylenes is not favored. Bonding overlap between a HOMO and a LUMO lowers the transition state energy of the allowed process, making it favorable. With the concerted 2 + 2 cycloaddition of two ethylenes, no such transition state stabilization is achieved, as shown in Figure 12.17. Any bonding overlap is exactly cancelled out by an equivalent antibonding overlap, yielding no net stabilization. 

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... 

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