Combined, these sequences demonstrate the potential of scaffold 10 to reliably form 3D compound libraries via standard amide formation processes, as well as its potential to be incorporated into peptides as an unnatural amino acid residue. Having explored amidations and esterifications, we next investigated whether cyclisation of the amine and ester moieties, which are clearly close in space, was possible. Gratifyingly, reduction of both carbonyl functionalities was achieved efficiently with LiAlH4, following which direct hydrogenolysis and double mesylation of the crude diol allowed cyclisation to tetracycle 17 which retains a single unreacted mesylate moiety. The ketone moiety also appeared to offer the opportunity to access standard Pd-catalysed diversification routes via conversion to the corresponding enol triflate. Pleasingly, despite concerns regarding the formation of regioisomeric mixtures during enol triflate formation, we observed some selectivity in initial reactions. This was optimized though variation of base (Scheme 3b), with NaHMDS proving optimal, giving access to both N-benzyl and N-PMB systems 18 with good levels of regiocontrol. This selectivity is somewhat surprising given the remote position of the ester moiety, which represents the sole point of asymmetry in the system. We therefore undertook variation of the substrate to probe this further. Interestingly, while switching from N-PMB to N-Bn was found to have relatively little impact (18a vs 18b), moving to N-Me led to a large decrease in selectivity in the formation of compound 20 (Scheme 3). Further, moving from tert-butyl ester 10b to the simple methyl ester 10i again gave a large decrease in regiocontrol in the formation of 21. Such observations are consistent with a relay of stereochemical information across the molecule via the nitrogen substituent, where both a bulky ester and a relatively large amine moiety are required to in order for the remote source of asymmetry to control which side of the ketone moiety is deprotonated by the incoming base. With regiocontrolled access to enol triflates 18 established, we next explored their potential for derivatization via Pd-catalysed cross-coupling. This proved successful, with both N-benzyl and N-PMB systems undergoing Suzuki cross-coupling with a range of aryl and heteroaryl coupling partners as shown by the formation of 19. Such Pd-catalysed processes offer reliable C-C bond formation for the introduction of additional complexity, and combined with the aforementioned functionalisation and the excellent selectivity obtained in the enol triflate formation, this underlines the versatility of such systems to function as tricyclic 3D scaffolds. Following this, the previously observed cyclisation to form mesylate 17 led us to consider whether such a bond formation might permit an overall rearrangement within these polycyclic scaffolds. To this end we took PMB amine 10b and performed ester deprotection followed by activation of the resulting carboxylic acid with thionyl chloride. Gratifyingly, this led to C-N formation with concurrent cleavage of the adjacent C-N bond, giving rise to a mixture of chloride 22 and alkene 23. While chloride 22 could be isolated in moderate yield, inclusion of a DBU-mediated elimination as the final stage of this one-pot process allowed the isolation of only alkene 23 in excellent yield in a single operation. This product again represents a novel and rigid scaffold, possessing an unusual 8-membered ring within a tricyclic framework. Facile derivatization of this system is also possible as shown by the series of reactions in Scheme 4. Addition of allymagnesium bromide proceeded in excellent yield, to give a tertiary alcohol 24 as a 6:1 mixture of diastereomers. Somewhat counterintuitively, addition preferentially occurs to the endo rather than exo face of the molecule; however, this can be rationalised by the relative flexibility of the 8-membered ring and the preference for orientation of the ketone carbonyl anti to the carbonyl of the amide. See SI for full details. Reduction also proved possible, with a simple transfer hydrogenation of the alkene to form compound 25 proving especially facile. This is consistent with the alkene having limited conjugation with the adjacent carbonyl, which is apparent from both the alkenic chemical shifts within the 1 H NMR spectrum as well as the alkene's low reactivity in standard cycloaddition processes. Importantly, conversion of the ketone moiety to the corresponding enol triflate again proved facile, giving diene 26 in good yield. This was found to undergo efficient Suzuki cross-coupling to form 27, thus providing another position for diversification, as well as quantitative reduction via transfer hydrogenation to form the parent system 28.