Kirjahaku

Sesquiterpenoid- and steroid-amino acid conjugates demonstrate a broad array of interesting biological properties, as the different segments of the conjugate function collectively to regulate conformation, recognition, transport and solubility. The current project involved developing a facile methodology to synthesize metabolically stable facially amphiphilic conjugates by appending either amino acids (chapter 2) or cationic metal ligand-amino acid complexes (chapter 3) as hydrophilic segments on steroid progesterone and sesquiterpene amorpha-4,11-diene scaffolds. Aminosteroids and C-11 substituted steroids have attracted long lasting interest due to their diverse pharmacological properties. As the stereoselective C- 11β functionalization of a steroid imposes severe steric hindrance due to the C-18 and C-19 angular methyl groups, access to 11β-aminoprogesterone is a challenge. Chapter 2 describes stereoselective syntheses of a new family of aminosteroids: 11β-aminoprogesterone (11 -NH2-Pro) (76) and its derivatives, including its glycine 77 and L-/D- alanine- 78/79 based conjugates, by nucleophilic substitution or reductive amination.

The development of green catalysts (organocatalysts) for fundamental carbon-carbon bond forming reactions is challenging. The organocatalytic Michael addition of ketones to nitroalkenes is of special interest as it generates two contiguous stereocenters and the products (γ- nitro ketones) are useful intermediates. This reaction can be efficiently catalyzed by pyrrolidine-based chiral, secondary diamines and triamines. The use of a protic acid in conjunction with the amine catalyst is beneficial and the Michael addition products (syn diastereomers) are obtained with excellent enantioselectivities (up to 99% ee) and diastereoselectivity (up to 50:1 dr) for cyclic ketones and nitroalkenes derived from aromatic aldehydes. The effect of changes in the catalyst and protic acid structure, variation of catalyst/protic acid combinations and effect of structural changes in the ketone and nitroalkenes are discussed. The application of the chiral triamines in Michael reactions involving iminium ion intermediates has been examined. The attempted syntheses of pyrrolidine-based organocatalysts with guanidine-containing side chains as well as catalysts based on the camphor scaffold are presented.