Synthesis of 3-azaspirocyclic orthoamides
Creators: name: Nazarian, Zohreh
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Chapter 1 Chapter one provides background on the [3,3]-sigmatropic rearrangement of N,O-diacyl hydroxylamines and N,N-diacyl hydrazines. Specifically it explains the [3,3]-sigmatropic rearrangement of N,O-diacyl hydroxylamines bearing Boc-protected α-amino acid on the O-acyl group. Hydroxamic acids as the building blocks of these precursors were synthesized via a procedure adopted by Hoffmann. To prepare N,O-diacyl hydroxylamines, hydroxamic acids were reacted with various Boc-protected α-amino acids. The [3,3]-sigmatropic rearrangement of N,O-diacyl hydroxylamines, each featuring an α-amino acid side chain, led to the formation of a new class of compounds “3-azaspirocyclic orthoamides”. This applied method was found to be feasible for the synthesis of a variety of this new class of compounds. Chapter 2 In this Chapter, 3-azaspirocyclic orthoamides (described in Chapter 1) were synthesized from the corresponding Boc-protected α-hydroxyamides in a comparable method employed for the synthesis of N-analogues of cyclic orthoester as reported by Kamimura. Boc-protected α-hydroxyamides were prepared via reaction of α-hydroxyamides and Boc-protected amino acids in an analogous fashion to that employed for the preparation of N,O-diacyl hydroxylamines described in Chapter 1. The assigned stereochemistry to the starting material in Kamimura type route defined the stereochemistry of the newly formed stereogenic centre in the product. The established methodology was applied to the synthesis of several selected target molecules. Chapter 3 A model of presumed intermediates in the cascade process was synthesized and used to find out which stereocentre of the spirocyclic compound controls diastereoselectivity. Presumed intermediates were prepared from reactions of R and S- mandelamide derivatives with Boc-protected alanine as was described in Chapter 2. The prepared intermediates were subjected to the Kamimura type reaction conditions. (described in Chapter 2). Obtained crystallography results from the R-mandelamide derivative showed identical configurations as the spirocyclic compound from the cascade route which led us to conclude that spirocyclisation in the cascade process is likely to proceed in an identical manner as the R-mandelamide derived route. NMR comparisons of the spirocyclic compound from the cascade route with spiro compounds from the Kamimura type route showed that liquid spiro resulting from R-mandelamide derivative has different chemical shifts from the liquid isomer resulting from S-mandelamide derivative and liquid isomer from the cascade route, led us to conclude that whereas the rearrangement is stereorandom in the cascade process, spirocyclisation is stereoselective. This Chapter also describes that varying the ratio of the reagents from 2 to 1 in Kamimura type route leads to the formation of silyl carbamate. To investigate whether Boc group detaches before or after the [3,3]-sigmatropic shift occurs, t-Bu ester was replaced with methyl ester in R-mandelamide derivative. This resulted in no spirocyclic compound which highlights the need for the presence of Boc in spirocyclisation. A mechanistic pathway based on these observations was proposed.