Synthesis and applications of derivatives of 1,7-diazaspiro[5.5]undecane

Spiroaminals are an understudied class of heterocycle. Recently, the Barrett group reported a relatively mild approach to the most simple form of spiroaminal; 1,7-diazaspiro[5.5]undecane (I). This thesis consists of the development of novel synthetic methodologies towards the spiroaminal moiety. The first part of this thesis focuses on the synthesis of aliphatic derivatives of I through a variety of methods from the classic Barrett approach which utilises lactam II, through to de novo bidirectional approaches which utilise diphosphate V and a key Horner-Wadsworth-Emmons reaction with aldehyde VI. The second part of this thesis concentrates on the synthesis of tetrahydrospirobiquinolines and their derivatives. The methodology developed utilises simple conditions, withstands a range of functional groups, and allows many substrates to be accessed under mild conditions. These compounds showed higher aminal stability relative to their aliphatic counterparts and were further derivatised by bromination, alkylation and cross-coupling techniques, all proceeding with the retention of the aminal centre. The final part of this thesis details theattempts to complex these newly isolated compounds to a variety of elementsacross the periodictable, as well asinitial investigations into their biological activities.Open Acces

Synthesis and Reactions of Benzannulated Spiroaminals: Tetrahydrospirobiquinolines

An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from <i>o</i>-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding <i>o</i>,<i>o</i>′-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation–spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and <i>N</i>-alkylation, all of which proceeded with preservation of the spirocyclic core

Bidirectional Synthesis of Di-<i>tert</i>-butyl (2<i>S</i>,6<i>S</i>,8<i>S</i>)- and (2<i>R</i>,6<i>R</i>,8<i>R</i>)‑1,7-Diazaspiro­[5.5]­undecane-2,8-dicarboxylate and Related Spirodiamines

Efficient syntheses of both enantiomers of a spirodiamine diester from (l)- and (d)-aspartic acid are described. The key transformation was the conversion of Boc-protected <i>tert</i>-butyl aspartate into the derived aldehyde, two-directional Horner–Wadsworth–Emmons olefination, hydrogenation, and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approach to derivatives of 1,7-diaza­spiro­[5.5]­undecane is described

Bidirectional Synthesis of Di-<i>tert</i>-butyl (2<i>S</i>,6<i>S</i>,8<i>S</i>)- and (2<i>R</i>,6<i>R</i>,8<i>R</i>)‑1,7-Diazaspiro­[5.5]­undecane-2,8-dicarboxylate and Related Spirodiamines

Efficient syntheses of both enantiomers of a spirodiamine diester from (l)- and (d)-aspartic acid are described. The key transformation was the conversion of Boc-protected <i>tert</i>-butyl aspartate into the derived aldehyde, two-directional Horner–Wadsworth–Emmons olefination, hydrogenation, and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approach to derivatives of 1,7-diaza­spiro­[5.5]­undecane is described