Novel reactivity in asymmetric conjugate addition and allylic alkylation with Grignard reagents

PhD ceremony: Mr. T. den Hartog, 14.45 uur, Doopsgezinde Kerk, Oude Boteringestraat 33, Groningen

Thesis: Novel reactivity in asymmetric conjugate addition and allylic alkylation with Grignard reagents

Promotor(s): prof. B. Feringa, prof. A.J. Minnaard

Faculty: Mathematics and Natural Sciences

The research described in this thesis is primarily aimed at exploring challenging substrates for Cu-catalyzed asymmetric conjugate addition of, and asymmetric allylic alkylation using Grignard reagents for which multiple selectivity issues exist. In Chapter 1 an introduction on asymmetric catalysis and the earlier mentioned reactions is given.

The first part of this thesis deals with multiple unsaturated Michael acceptors as substrates for asymmetric conjugate addition with Grignard reagents. In chapter 2 the first method for enantioselective 1,6-addition of Grignard reagents, primarily dictated by the catalyst, is described. In chapter 3, initial and primarily structural studies towards a mechanism for extended conjugate additions are performed. From the results of these studies a preliminary model for extended conjugate additions is proposed. In chapter 4 the synthetic application of the asymmetric 1,6-addition for the enantioselective iterative construction of deoxypropionate units is described.

In the second part of this thesis, 4-halocrotonates are explored as substrates. These substrates possess all structural features to either allow allylic alkylation or conjugate addition. In chapter 5, highly warranted α-Me substituted esters and related chiral multifunctional building blocks are synthesized via enantioselective allylic alkylation of benzyl 4-bromocrotonate with MeMgBr. In chapter 6, primarily the enantioselective synthesis of trans 1-alkyl-2-substituted cyclopropanes via tandem conjugate addition-enolate trapping is described.

Finally, in chapter 7 a summary of the current status of these research fields are given and the further perspectives of these fields are discussed.