Peptides as catalysts for asymmetric 1,4-addition reactions of aldehydes to nitroolefins

Wiesner, Markus. Peptides as catalysts for asymmetric 1,4-addition reactions of aldehydes to nitroolefins. 2009, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8883

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Within this thesis, the development of peptides as highly efficient catalysts for asymmetric
conjugate addition reactions of aldehydes to nitroolefins is described.
The tripeptide TFA*H-Pro-Pro-Asp-NH2 1 was originally developed and established as an
efficient catalyst for asymmetric aldol reactions. Based on insight gained from conformational
analysis it was predicted that 1 and closely related peptides may also serve as catalysts for
asymmetric 1,4-addition reactions. Indeed, TFA*H-D-Pro-Pro-Asp-NH2 21 proved to be a
highly effective catalyst for asymmetric conjugate addition reactions of aldehydes to
nitroolefins. A broad scope of different substrate combinations including aliphatic and
aromatic nitroolefins as well as linear, ?-branched and aromatic aldehydes reacted readily in
the presence of as little as 1 mol% of 21 to the desired ?-nitroaldehydes in high yields (82-99
%), high diastereoselectivities (syn:anti = 4:1->99:1) and very high enantioselectivities (88-98
% ee). Thus, 21 proved to be significantly more active and applicable to a broader substrate
scope compared to other amine based catalysts that had previously been developed for 1,4-
addition reactions of aldehydes to nitroolefins. In addition, the peptidic catalyst 21 also
offered solutions to other challenges encountered with the other amine based catalysts and
allowed for using only a small excess of the aldehyde providing the products within a
reasonable reaction time.
Analysis of the structural and functional prerequisites for high catalytic efficiency within
catalysts 21 led then to the establishment of the closely related peptide TFA*H-D-Pro-Pro-
Glu-NH2 56 as an even more effective catalyst for conjugate addition reactions of aldehydes
and nitroolefins including the functionalised ?-nitroacrolein dimethylacetal (up to quant.
yields, syn:anti ratio up to >99:1, up to 99 % ee). Even nitroethylene, the simplest of all
nitroolefins, reacts readily with functionalised and non-functionalised aldehydes. The
derivatisation of the corresponding products offered a new entry into the synthesis of
monosubstituted ?2-amino acids, previously only accessible by using chiral auxiliaries.
Extensive kinetic studies allowed for further insight into the reaction mechanism and led to
the establishment of improved reaction conditions. Only as little as 0.1 mol% of 56 was
required for the corresponding reactions, which is the lowest catalyst loading that has been
achieved for enamine catalysis to date. A further benefit of the peptidic catalyst is that, in
contrast to many other organocatalysts, no additives are necessary to obtain the desired
products in very high yields and selectivities. Further conformational studies indicated that
peptide 56 is more rigid than usual tripeptides but still bear a significant degree of
conformational freedom. Therefore, the right degree of flexibility might be the key to the
effectiveness of peptides as asymmetric catalysts.
These studies demonstrate the high potential of short peptides as efficient catalysts and
establish a basis for further investigations. These may include the application of peptides as
catalysts for other 1,4-addition reactions using different Michael donors (e.g. ketones,
malonates, nitroalkanes) and Michael acceptors (e.g. ?,?-unsaturated aldehydes and ketones,
?-disubstitued nitroolefins). Also new challenging transformations such as e.g. ?-alkylation
of aldehydes or complex cascade reactions might become accessible by using peptides as
Advisors:Wennemers, Helma
Committee Members:Pfaltz, Andreas
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Organische Chemie (Gademann)
UniBasel Contributors:Wiesner, Markus and Wennemers, Helma and Pfaltz, Andreas
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8883
Thesis status:Complete
Number of Pages:228 S.
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:51
Deposited On:30 Apr 2010 08:55

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