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

Chapter 1
1.4.2.4 Proline based diamine catalysts
Proline derivatives are very common in organocatalysis and an enormous number of variations
have been synthesized. One of the reasons for their successful use is the less hindered
nucleophilic secondary nitrogen on the pyrrolidine ring. By converting the carboxylic acid group
of proline, one can easily reach secondary-tertiary diamine organocatalysts (Figure 1.5). These
types of bifunctional catalysts are very common for asymmetric Michael additions.
Examples of proline based bifunctional catalysts, used in asymmetric Michael additions are
shown in Figure 1.5. All these diamines work on the same mechanism as shown in Scheme 1.13.
Herein, I will shortly discuss some of the best examples.
Barbas and coworkers 28 reported direct catalyticasymmetric Michael addition in brine. They used
a pyrrolidine based bifunctional catalyst (Figure 1.5, 27) for the addition of various ketones and
aldehydes to nitroolefins. Using cyclohexanone (2.0 equiv) as Michael donor, they obtained upto
99% yield, 98:1 dr and upto 97% ee with 10 mol% loading of the diamine, in 48h. On the other
hand, the same reaction conditions did not show the same level of catalytic activity when using
cyclopentanone as Michael donor (96h reaction, 75% yield, 77:23 dr and 80% ee).
Kotsuki and coworker 29 designed chiral pyrrolidine catalysts with a pyridine base moiety
adjacent to a stereogenic carbon (Figure 1.5, 28). The author mentioned that the pyridine base
will facilitate enamine formation from ketone precursors by abstracting the α-hydrogen. They
used their catalyst for asymmetric Michael addition of ketones and aldehydes to nitroolefins and
obtained up to 100% yield, 99:1 dr and 98% ee. They account that the resulting pyridinium ring
shields one side of the enamine double bond within the transition state, and the nitroolefins
approach from the non-shielded side to give the desired Michael product in high enantio- and
diastereoselectivity.
Singh in 2007 30 reported a pyrrolidine based bifunctional catalyst for the asymmetric Michael
addition of ketones to aryl and alkyl nitroolefins (Figure 1.5, 29). Mostly, they obtained brilliant
results with their catalsyt i.e. up to 98% yield, 99:1 dr and 99% ee. Out of 26 examples studied,
they obtained mediocre results not only with acetone but also with challenging cyclopentanone as
compared to compared to other ketones. The same catalyst system provided an 89% yield for
21