In a 500 ml round-bottomed flask under nitrogen at rt, D1 (11.1 g, 43.1 mmol) was dissolved in THF (100 ml) to give a pale yellow solution. This solution was cooled to −78° C. and the Tebbe reagent (104 ml of a 0.5 M solution in toluene, 51.8 mmol) was added dropwise. The thick mixture was diluted with further 70 ml of dry toluene. The resulting brown-orange mixture was stirred at this temperature for 30 min and then slowly warmed up to rt and left under stirring for 2 h. The reaction mixture was charged into a dropping funnel and then added dropwise to a 2 L round-bottomed flask containing ˜400 ml of NaOH 1 M aqueous solution cooled at 0° C. At the end of the quench, the resulting grey suspension was diluted with EtOAc (250 ml) and allowed to stir overnight (mechanical stirring). The resulting yellow suspension was then filtered over a Gooch funnel (using Sterimat): salts were washed with EtOAc (˜500 ml). Phases were then separated and the organic layer was washed with brine (2×500 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated to give a deep orange oil. This material was diluted with ˜500 ml of Et2O: some salts precipitated, so the resulting suspension was filtered over a Gooch funnel (using Sterimat). The filtrate was concentrated under vacuum to give 12.4 g of crude 1,1-dimethylethyl(2S)-2-[2-(methyloxy)-2-propen-1-yl]-1-piperidinecarboxylate as an orange-brown oil. The material contained some residual salts (as the overall recovered amount was higher than the theoretical amount). The material was used without further purification in the next reaction and supposed to be pure at 89 wt %. In a 1 L round-bottomed flask under nitrogen at rt 1,1-dimethylethyl(2S)-2-[2-(methyloxy)-2-propen-1-yl]-1-piperidinecarboxylate (12.4 g, 43.1 mmol) was dissolved in THF (125 ml) and water (35 ml) to give a pale yellow solution. NBS (7.67 g, 43.1 mmol) was then added dissolved in ˜100 ml of THF. The resulting grey mixture was stirred at rt for 1 h. Then additional NBS (0.2 eq, 1.5 g) dissolved in 50 ml of THF was added and the reaction mixture stirred at rt for 1 h. The mixture was concentrated under vacuum to remove THF, then was diluted with EtOAc (˜500 ml) and water (200 ml). Phases were separated and the aqueous layer was back-extracted with EtOAc (250 ml). The combined organic layers were dried (Na2SO4) filtered and concentrated to give: 17.8 g of a brown oil. This material was purified by flash-chromatography (Biotage 75L, Cy-EtOAc from 100-0 to 90-10) to give the title compound (6.0 g, 18.7 mmol, 43% yield from D1, two steps) as a slightly yellow oil that solidified upon standing. UPLC: rt=0.79, peaks observed: 344 [M+Na, 100%], 342 [M+Na, 100%], 266 [M-tBu, 100%] and 264 [M-tBu, 100%]. 1H NMR (500 MHz, CDCl3) δ(ppm): 4.72-4.79 (m, 1H), 3.91-4.10 (m, 3H), 2.77-2.97 (m, 3H), 1.49-1.75 (m, 6H), 1.46 (s, 9H).
