Ph.D. Thesis_AS_Publishing version for IRC_12 ... - Jacobs University

Chapter 1
1.4.2.1 Steric based catalysts
Unlike all other bifunctional catalsyts, steric based catalysts lack the presence of a tertiary or
secondary nitrogen as the site for in situ hydrogen bond formation. In steric catalysts, a
nuceophilic nitrogen makes the enamine and the bulky group on the catalyst block one face of the
enamine and the electrophile approach from the least hindered side of enamine to promote the
reaction. These types of catalysts are common in asymmetric Michael additions and the most
examined ones are proline derivatives and some of them are non-proline based (Figure 1.1, 7).
Figure 1.1 represents a few examples of these alternative types of proline-based catalysts. Herein,
I will discuss a few of the catalysts from Figure 1.1.
Hayashi in 2005, 21 showed that silylation of prolinol can dramatically improve its catalytic
activity (Figure 1.1, 4). They acquire excellent results with unsubstituted aldehyde additions to
nitroolefins (e.g. 10 mol% 4, offers 85% yield, 96:4 dr and 99% ee in a 5h reaction). However,
their catalysts reveal comparatively poor results when using α-substituted aldehydes (e.g. for
isobutyraldehyde addition, 10 mol% 4, 85% yield, 68% ee in 96h).
In 2007, Córdova and coworkers used the same catalyst (Figure 1.1, 4) for asymmetric Michael
addition of aldehydes to maleimides. 22 They also had promising results when using unsubstituted
aldehydes additions to maleimides (e.g. 10 mol% 4, offers upto 91% yield, 15:1 dr and >99% ee).
However, their catalyst did not show a productive result when using α-substituted aldehydes (e.g.
for isobutyraldehyde addition, 10 mol% 4, offers only 40% yield with 51% ee).
Jørgensen and coworkers 23 used chiral amines (Figure 1.1, 6) as organocatalysts for the
asymmetric Michael addition. They investigated two possible structures for the enamine
intermediate (8 and 9, Figure 1.2). After calculating the energy for structures 8 and 9, they found
structure a to be the most stable. Further investigations proved that one of the 3,5-dimethylphenyl
groups on the catalyst shields the Re-face and thus the Si-face is available for approach.
Barros and coworkers 24a used chiral piperazine derivatives as organocatalysts (Figure 1.1, 7).
They used their catalyst for asymmetric Michael addition of aldehydes to nitroolefins. Their
catalyst showed comparatively low activity for α-substituted aldehydes, e.g. isobutyraldehdye
addition to trans-β-nitrostyrene which gave 75% ee and only 36% yield in 11 days reaction. They
15