Synthesis And Applications Of Ferrocene-based Nucleophilic Catalysts

This thesis mainly focused on the design and synthesis of novel ferrocene-based nucleophilic catalysts and their applications in catalytic asymmetric reactions. Combining chiral amidine with ferrocene scaffold, a newly class of central-planar hydrid chiral PIP catalysts were developed. In the kinetic resolutions of aryl alkyl carbinols, aryl alkenyl carbinols, bulky (hetero)aryl alkyl carbinols and asymmetric synthesis of 2,3-disubstitued dihydrobenzofuran, our optimum catalyst exhibit better enantioselectivity than catalysts reported previously with single chiral element. The thesis involves following four aspects:1. Design and synthesis of novel ferrocene-based nucleophilic catalystsNovel chiral ferrocene nucleophilic catalysts (Fc-PIP), containing both central and planar chiral elements, were developed via incorporating chiral amidine with ferrocene backbone. We synthesized this class of catalysts through construction of ferrocene monomer, coupling reaction, hydrolysis and ring closure, and relative configuration of catalysts were assigned by X-ray diffraction of (S, Rp)-la. In the coupling reaction, a pair of diastereoisomer was formed and could be separated by column chromatography, which make our catalysts synthetically straightforward compared with previously planar chiral DMAP derivatives separated by chiral preparative HPLC.2. The applications of Fc-PIP in the kinetic resolution of aryl alkyl carbinols and aryl alkenyl carbinols.We employed newly ferrocene-based catalysts to the kinetic resolution of aryl alkyl carbinols, and a remarkably efficient catalyst with high selectivity factors (S) was identified, up to 1892, which implied it was the first example for nonenzymatic nucleophilic catalyst displaying enzymatic level of selectivity in catalysis. The optimum catalyst Fc-PIP, whose planar chirality matched with central chirality, was more reactive and selective in this reaction than chiral amidine catalyst (Cl-PIQ) with single central chirality. In addition, on the basis of experimental data, we conjecture stacked transition state can be considered as the exclusive reaction manifold and theπ-πand cation-πinteractions of the stacked conformer are the main factors for attaining the high selectivity and reactivity in our catalytic system.The kinetic resolution of challenging sp2-sp2 carbinols, aryl alkenyl carbinols, using Fc-PIP was also developed, which gave S up to 24, and 99% ee for some unreacted alcohols.3. The application of Fc-PIP in the kinetic resolution of bulkyl (hetero)aryl alkyl carbinolsWe have demonstrated that Fc-PIP catalyzed the asymmetric acyl transfer of a range of versatile bulky alcohols with remarkable efficiency, affording the unreacted alcohols in extremely high enantiomeric excess (>99%) and in good yields (43.3-49.6%; idea conversion 50%). In view of rarely efficient synthesis of this kind of chiral alcohols, our strategy unequivocally offered a practical solution to this challenge. 4. Asymmetric synthesis of 2,3-disubstitued dihydrobenzofuran catalyzed by Fc-PIPA highly efficient asymmetric intramolecular Michael addition-lactonization process of keto acids employing Fc-PIP was developed, which gave a range of chiral 2,3-disubstitued dihydrobenzofuran with high enantioselectivities (up to 98%) and diastereoselectivities (up to 99/1).