In contrast to reductive amination reactions involving dialdehyde 3, a double Mannich reaction would necessarily generate far greater stereochemical complexity, and stereocontrol of this process was therefore a key concern. Our starting point was thus tert-butyl system 9a, where we envisaged that the bulky ester would potentially offer stereocontrol in the key enolate addition step, thereby relaying the stereochemical information from the initial norbornene-forming Diels-Alder cycloaddition. Oxidative cleavage was initially attempted via both one-step and two-step approaches; however, both one-step approaches using either ozone or OsO4 in the presence of sodium periodate led to considerable loss of mass. Gratifyingly however, a twostep approach proved considerably more successful, in which intermediate diol was directly reacted with sodium periodate to form dialdehyde 7. Optimization of conditions permitted Os(VI) pre-catalyst loadings as low as 0.3 mol% with quantitative yield over two steps. The resulting aldehyde proved to be highly sensitive and was thus used directly in the subsequent double-Mannich reaction step without purification. While conditions for performing double Mannich reactions on succinaldehyde to form tropinone systems are well developed, such reactions are typically performed under aqueous conditions which limits the solubility of hydrophobic species such as 7. We initially focused on the use of benzylamine as the amine partner (Table ), which showed that while such reactions can be performed with water as sole solvent (entry 1), increasing the reaction scale became challenging due to a significant lack of homogeneity. We therefore undertook the small screen of organic co-solvents as shown in Table . Surprisingly, yields for all systems were high and all reactions proceeded with high levels of stereoselectivity. However, several systems were far from homogenous, leading to considerable issues with stirring. Moving to water-dioxane systems reduced this issue, resulting in somewhat increased yields and far greater ability to perform reaction scale up. In all cases essentially a single diastereomer of product 8 was observed, suggesting that the bulky tert-butyl ester offered sufficient steric control. The stereochemistry of the product was confirmed by single crystal XRD, demonstrating that attack of the acetone-derived enolate on the intermediate iminium ion occurs from the opposite face to the bulk ester moiety. Table . Optimisation of the double-Mannich reaction. With optimal reaction conditions identified we next undertook a study of the substrate scope of the reaction. As shown in Scheme 3, the reaction tolerated variation of both norbornene and amine components. Use of simple methyl esters as activating groups in the initial Diels-Alder reaction led to lower yields, in part because of the formation of more complex reaction mixtures, together with their greater water solubility reducing the product isolation in the intermediate oxidation steps. Importantly, both endo and exo norbornene stereoisomers gave clean conversion to opposite product diastereomers. Further, the inclusion of heterocyclic moieties were found to be well tolerated across all three steps as shown by the formation of pyridine 10d and furan 10f. Substituted benzylamines could also be employed as shown by the formation of PMB system 10b, and simple alkyl amines also proved viable substrates as shown in the formation of methyl amine system 10i. Use of other activating moieties also proved possible albeit with a decrease in yield, with nitrile 10j being formed in low yield, again relating to low mass recoveries within the oxidation sequence. Given the low cost of all starting materials and the intended use of the products as scaffolds for diversification, reaction scale-up was also explored. Gratifyingly, multi-gram scale synthesis was easily achieved in three cases, with products being obtained in near identical yield to the smaller scale reactions. Scheme 2. Scope of the oxidative cleavage/double Mannich reaction sequence.