Subsequent dehydrochlorination on 3 using t-BuOK as the base, and DMF as solvent, 41 afforded exocyclic enol ether 2f (Scheme 2). Finally, adapting a methodology introduced by Nishi and co-workers to assemble 2,2-disubstituted morpholines, enol ether 2f underwent regioselective iodoacetalization upon treatment with N-iodosuccinimide in the presence of N-Boc-ethanolamine (6) to give iodide 7. Subsequent treatment with t-BuOK in DMF effected ring closure to provide bis-morpholine spiroacetal 8. Starting from 17 g (92 mmol) of enol ether 2f delivered target scaffold 8 in 75% yield over the two steps. The structural identity of bis-morpholine spiroacetal 8 was confirmed by single-crystal X-ray diffraction, which revealed both rings adopt chair conformations and the spiroacetal benefits from double anomeric stabilization (Figure ). A solution of 8 in DMSO left in an NMR tube at room temperature on an open bench over three weeks, showed no evidence of decomposition as determined by 1 H-and 13 C-NMR spectroscopy; this scaffold was therefore deemed sufficiently stable for compound library synthesis. We next explored the orthogonal deprotection of the two amines in spiroacetal 8. Standard benzylamine deprotection conditions (Pd/C in MeOH under an atmosphere of H2 with or without acetic acid, and the use of 1-chloroethyl chloroformate in the presence of acid scavengers) proved ineffective. The inclusion of equimolar amounts of hydrochloric acid to facilitate deprotection, led to deprotection of the Boc carbamate. As Cbz carbamates undergo hydrogenolysis more readily, benzylamine 8 was treated with CbzCl in CH2Cl2 at room temperature, to provide carbamate 9 in excellent yield (Scheme 3). Now, hydrogenolysis of carbamate 9, performed on 33 mmol scale, proceeded without event under neutral conditions 47 to deliver secondary amine 10 with the Boc group intact. While a protecting group exchange is undesirable on efficiency grounds, the reaction sequence was straightforward and provided 10 in 95% yield over the two steps. Having access to two differently mono-protected bis-morpholine spiroacetals offered useful flexibility for scaffold decoration. In an initial trial, we focused on decoration with a representative isocyanate, sulfonyl chloride and carboxylic acid, transformations that are widely used for library synthesis. Treatment of amine HCl salt 11•HCl with 2,4-difluoro-1-isocyanatobenzene and pyridine-3-sulfonyl chloride under standard conditions, provided urea 12 and sulfonamide 13, respectively (Scheme 3). Hydrogenolysis of the Cbz carbamate in urea 12 proceeded in excellent yield to provide 14; however, the same reaction with sulfonamide 13 saw recovery of the starting material, even when the carbamate deprotection was performed under acidic conditions to protonate the basic nitrogen in the embedded pyridine (Scheme 3). Turning instead to Boc carbamate 10, decoration with pyridine-3-sulfonyl chloride and 1methyl-1H-pyrazole-4-carboxylic acid, provided sulfonamide 15 and amide 16, respectively, in excellent yields. This time, subsequent Boc deprotections proceeded without event, affording sulfonamide 17•2HCl in 82% yield, and amide 18•HCl in 98% yield, over the two steps.