Reagents and conditions: A) 6, Yb(OTf)3 (25 mol%), DCE, 55 °C, 16 h, 83%; B) LiBr, AcOH, THF, 0 °C to rt, 1h, quant.; C) Dess-Martin periodinane, CH2Cl2, rt, 10 min, 92%; D) 6, DIPEA, CH2Cl2, rt, 16 h; E) CSA, toluene, rt, 16 h, 52% over two steps (d.r. 1.4:1); F) n-BuLi, THF, ˗78 °C, 30 min, then DMF, 2.5 h, 56% (from 12a) or 42% (from 12b); G) TBAF, THF, 0 °C, 30 min, 53% 1 or 64% 2; H) 9, B(OH)3 (25 mol%), DCE, 75 °C, 16 h, 88%. CCDC accession code of 12a: CCDC 2244111. effected in excellent yield by bromide addition followed by DMP oxidation. N-Alkylation of 6 with bromoketone 11 afforded hemiketal 6, initially in 46% isolated yield postpurification (see SI). Gratifyingly, degradation of 5 during purification could be avoided by using crude material in the subsequent acid-mediated spiroketalisation step, to give a mixture of the desired spiroketals 12a and 12b in an improved 52% yield over two steps. Epimers 12a and 12b were separable, and an X-ray structure of the major product 12a was obtained. This structure unambiguously confirmed that spiroketal 12a possessed the desired S stereochemistry at the spirocentre as in lycibarbarine A (1). Bromides 12a and 12b were then advanced to lycibarbarine A (1) and B (2) separately, completing their first total syntheses and enabling confirmation of their structural assignments. Individual late-stage formylation of bromides 12a and 12b proceeded smoothly via the respective aryl lithium species. Subsequent silyl deprotection then afforded 1 and 2. Pleasingly, the 1 H and C NMR spectra, and optical rotation data were in agreement with those reported for the natural products lycibarbarine A (1) and B ( ) respectively (Supporting Information). Importantly, no epimerisation of the spiroketal centre was observed by NMR analysis during the final two steps, and it was concluded that the assigned S stereochemistry of the spirocentre in bromospiroketal 12a was retained in lycibarbarine A (1) and similarly the R stereochemistry for lycibarbarine B (2), thus confirming the assigned absolute stereochemistry of these natural products. With lycibarbarines A (1) and B (2) in hand, we next investigated their isomerisation to lycibarbarine C (3) and their interconversion by epimerisation. Treatment of 1 or 2 with an excess of either PPTS or PTSA (see Supporting Information) led to no detectable epimerisation or isomerisation to give 3, until eventual degradation of 1 and 2 took place using more forcing conditions (see SI for details). This is in direct contrast to analogous carbohydrate 6,5-spiroketal structures, which undergo facile rearrangement to the 6,6-spiroketal isomer in acidic conditions. These results provided the initial evidence that the lycibarbarines were not interconvertible, and that either the dication 4 does not form under the examined conditions, or it devolves to a decomposition pathway due to its unstable nature. Attention was initially directed to silyl deprotection of 5, followed by acid mediated spiroketalisation of 13, to enable access to the 6,6-spiroketal scaffold of 3 (Scheme 4). While the deprotection of 5 using TBAF proceeded smoothly, subsequent treatment of 13 with a variety of Brønsted and Lewis acidic conditions failed to provide access to the desired 6,6spiroketal 14 (Scheme 4 and Supporting Information). In many cases the substrate 13 was returned with partial degradation, but use of camphorsulfonic acid effected tandem acetonide deprotection/spiroketalisation, to afford 15 (d.r. 1.2:1) in up to 68% yield over two steps. Given that the acetonide moiety of 13 is labile under acidic conditions, and a clear kinetic preference for 6,5-spiroketal 15 was observed, we decided to change the protecting group strategy to prevent formation of the 5,6-spiroketal and selectively obtain the 6,6spiroketal product. We proceeded to focus on the synthesis of the desired 6,6spiroketal lycibarbarine C (3) via a modified protecting group strategy. To this end, alkene 16 was prepared in 2 steps from 2-deoxy-D-ribose (see Supporting Information for details). We then installed the acid-stable O-TIPS protecting group at the key C-2 hydroxyl group, and subsequent epoxidation gave 17 in good yield (Scheme 5). Epoxide 17 was then advanced to bromoketone 18 in two steps. Subsequent N-alkylation of bromoketone 18 with tetrahydroquinoline 6 proceeded smoothly, and subsequent acid-mediated spiroketalisation afforded the desired 6,6-spiroketal 19. This result marked the first synthetic access to the 6,6-spiroketal framework of lycibarbarine C (3). The two epimers of the lycibarbarine C (3) scaffold, major product 19a and minor product 19b, were separable. The stereochemistry of the spiroketal core was determined using key nOe correlations observed for the minor isomer 19b. The conformation of the tetrahydropyran ring was determined by nOe correlations between axial H-3 and H-5; the nOe correlation between H-10' and Hax-6 established an S configuration of the spirocentre. This result confirmed that the major product 19a possessed the same R stereochemistry of the spirocentre as the natural product 3. Spiroketal 19a was hence taken forward to complete the synthesis. Elaboration of 19a to the natural product 3 was achieved by late-stage formylation of the aryl bromide, followed by deprotection of the silyl ether (Scheme 5). Importantly, no isomerisation of 3 to 1 or 2 was observed upon deprotection of the silyl ether. The spectroscopic and optical rotation data were in agreement with those previously reported. The stereochemistry of the spirocentre was confirmed from key nOe correlations for lycibarbarine C (3), which were consistent with those observed by Chen and co-workers in the isolation report. The strong nOe correlation between axial H-15 and Hax-17 confirmed the configuration of the tetrahydropyran ring, whilst weaker correlations between H-7 and both H-15 and Hax-17 confirmed retention of the R stereochemistry of the spirocentre of 3.