Exploring the Chemical Diversity of the Spiroacetal Scaffold: The Synthesis of Spiroacetal Triazole, Tetrazole and Peptide Hybrids

Abstract

Spiroacetals are found in many natural products such as insect pheromones, plant and marine toxins. These spiroacetal natural products have inspired the synthesis of simplified spiroacetals which retain the spiroacetal pharmacophore and other essential elements needed for biological activity, while reducing structural complexity and allowing for more efficient syntheses. This thesis describes the studies performed to explore the chemical diversity of the spiroacetal scaffold by the generation of novel hybrid structures. Part 1 of this thesis is focussed on the enantioselective synthesis of C-linked spiroacetal triazole and spiroacetal tetrazole analogues. Triazoles and tetrazoles have similar geometries and electronic properties to that of the peptide bond, but are more resistant to enzymatic and chemical modification. The spiroacetal triazole analogues 401 were accessed from the Copper-catalysed Azide-Alkyne-Cycloaddition between various azides and the bisanomericially stabilised acetylenic spiroacetal 410a, which in turn can be prepared from the acidic cyclisation of (3S,11S)-alkynol 509a. Diastereopure alkynol 509a is available from (S)-δ-valerolactone 307 via a highly diastereoselective enzymatic kinetic resolution and several reliable Grignard additions. (S)-δ-Valerolactone 307 is accessed from (R)-glycidol (496) by literature procedures. [Figure ommitted] The spiroacetal-tetrazoles 402 were envisaged to be accessed from the 1,3-dipolar cycloaddition between azides and cyanospiroacetal 491a, which is obtained from the acidic cyclisation of cyanohydrin 564a. The nitrile moiety of 564a was installed by cyanide addition of the corresponding aldehyde prepared from the common alkene intermediate 510. Attempts to perform the cycloaddition between 1-azidooctane and cyanospiroacetal 491a proved unsuccessful. However, the analogous cycloaddition between sodium azide and cyanospiroacetal 491a proceeded to afford spiroacetal-1H-tetrazole 577. [Figure omitted] Part 2 of this thesis describes the synthesis of spiroacetal amino acid 639 and its incorporation into cyclic spiroacetal peptide 640 by Fmoc solid phase peptide synthesis (SPPS). It was proposed that the conformationally locked spiroacetal motif could append substituents in a defined orientation to induce a turn structure. Turn structures such as β-turns and β-hairpins are secondary structural elements found in proteins which have important roles in protein structure and function. The cyclic spiroacetal peptide 640 was prepared from the macrocyclisation of the linear peptide chain 711, which was assembled using Fmoc SPPS. Spiroacetal amino acid 639 was synthesised from azido-spiroacetal 751 via several functional group manipulations. Azido-spiroacetal 751 is in turn available from the common alkene intermediate 510 via acidic cyclisation and a Sharpless asymmetric dihydroxylation.