We were drawn to spiroacetals. This class of spirocycle is ubiquitous across natural products, many of which display potent and diverse biological activities. While the hydrolytic instability of acyclic acetals might raise a safety flag owing to the aldehyde/ketone hydrolysis product, we argued that the increased stability of spiroacetals and their abundance in natural products justify their inclusion in compound screening libraries and potential to deliver attractive starting points for drug discovery. Aliphatic nitrogen heterocycles are privileged structural motifs for drug discovery. The tetrahydro-1,4-oxazineor morpholineframework is particularly widespread, and synthetic routes to this scaffold, its prevalence in drugs, and pharmacological activity have been extensively reviewed. Compared with other aliphatic nitrogen heterocycles, the presence of the electron-withdrawing oxygen atom renders the ring comparatively electron-deficient, attenuating the basicity of the nitrogen atom [pKa (conjugate acid of morpholine in DMSO) = 9.15, cf. pKa (conjugate acid of piperidine in DMSO) = 10.85]; this affords a balanced lipophilicity-hydrophilicity profile that can be used to improve solubility without compromising permeability. The embedded ether also provides a second H-bond acceptor that can be used to improve potency and selectivity. Physicochemical properties can be further modulated by ready substitution around the ring, which can also enhance binding. Azaspiro systems have been accessed in various ways, and azaspiro scaffolds incorporating a morpholine exhibit diverse bioactivity. Examples include AZD-2115, a dual-acting M3 receptor antagonist/2-adrenergenic receptor agonist, 8a NK1antagonists, and potent HIV protease inhibitors, while a pyrrolomorpholine spiroacetal forms the core of the shensongine and acortatarin classes of natural products, which display antioxidant activity. Taken together, we postulated that a spiro-bis-morpholine [1,7-dioxa-4,10-diazaspiro[5.5]undecane] framework (Figure ) would provide an attractive scaffold for compound library assembly, especially if a scalable route could be developed that enabled sequential decoration of the two amine functionalities. We envisaged orthogonally protected spiro bis-morpholine I could be accessed in two steps from enol ether II (Scheme 1), using an electrophile-mediated regioselective functionalization of the exocyclic alkene with an ethanolamine bis-nucleophile III to assemble the spiroacetal and second morpholine ring. Stoltz and co-workers prepared a range of morpholine exocyclic enol ethers II via an intramolecular Ni(COD)2-catalyzed 1,7-Dioxa-4,10-diazaspiro[5.5]undecane as a novel scaffold for compound library synthesis. cross-coupling reaction of the corresponding iodo-aminoalcohol IV. As all of their substrates contained a tertiary amine (R 1 = alkyl), we were keen to investigate, and hopefully expand, the scope of this attractive cross-coupling methodology for our purposes (Table ).