(6S)-2,2-dibromo-5-[(2-methylpropan-2-yl)oxycarbonyl]-5-azaspiro[2.4]heptane-6-carboxylic acid

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (580 mg, 1.45 mmol) in toluene (6 mL) was added the tris(trimethylsilyl)silane (1.35 mL, 4.36 mmol, 3.0 eq) and AIBN (24 mg, 0.145 mmol, 0.1 eq). The solution was heated at 110° C. for 3 hours. Another batch of tris(trimethylsilyl)silane (0.45 mL 1.45 mmol, 1.0 eq) and AIBN (10 mg) was added. The solution was heated at 110° C. for 2 more hours. A third batch of tris(trimethylsilyl)silane (0.45 mL 1.45 mmol, 1.0 eq) and AIBN (10 mg) was added. The solution was heated at 110° C. for 2 more hours. After being allowed to cool down, the solution was diluted with EtOAc (5 mL). This organic phase was extracted with aqueous K2CO3 (1 M, 10 mL×3). The combined aqueous extractions were cooled (ice/water) and acidified to pH 2 with concentrated HCl. This acidified aqueous phase was extracted with EtOAc (×3), dried (Na2SO4), filtered and evaporated. The residue was dried under vacuum to afford the desired compound as colorless oil (135 mg, 39%). The solution was heated at 110° C. for 2 more hours The solution was heated at 110° C. for 2 more hours to cool down This organic phase was extracted with aqueous K2CO3 (1 M, 10 mL×3) The combined aqueous extractions were cooled (ice/water) This acidified aqueous phase was extracted with EtOAc (×3) dried (Na2SO4) filtered evaporated The residue was dried under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.7 g, 21.8 mmol), 50 wt % hypophosphorus acid (25.9 mL, 9 eq) and triethylamine (44.3 mL, 10 eq) in water (104 mL, 12 volumes) was added V-50 (591 mg, 0.1 eq) in 2 mL of 50% aqueous acetonitrile. The mixture was heated at 100° C. During the heating, additional 0.1 eq of V-50 was added to the reaction mixture every 30 minutes. Totally, 0.7 eq of V-50 was added. After heating at 100° C. for 4 hrs, the reaction mixture was evaporated and treated with 2N NaOH. It was extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2N HCl, extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (3.63 g, 69%) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 4.51-4.42 (m, 1H), 3.48-3.11 (m, 2H), 2.27-1.93 (m, 2H), 1.50/1.45 (two overlapping s, 9H), 0.71-0.59 (m, 4H). During the heating, additional 0.1 eq of V-50 was added to the reaction mixture every 30 minutes Totally, 0.7 eq of V-50 was added After heating at 100° C. for 4 hrs the reaction mixture was evaporated treated with 2N NaOH It was extracted with ethyl acetate (2×50 mL) extracted with ethyl acetate (2×50 mL) The combined organic layers were washed with water and brine dried (Na2SO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of (6S)-5-tert-butyl 6-methyl 1,1-dibromo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (3.05 g, 7.39 mmol) in THF-MeOH-water (35 mL, 14 mL and 14 mL respectively) was added LiOH monohydrate (930 mg, 3 eq). The mixture was stirred at room temperature for 1.5 hr before being evaporated off. The aqueous residue was acidified with 1M HCl, extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (quantitative yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 10.45 (br s, 1H), 4.65-4.45 (m, 1H), 3.99-3.86 (m, 1H), 3.53-3.31 (m, 1H), 2.87-1.95 (m, 2H), 1.86-1.73 (m, 2H), 1.49, 1.48 and 1.44 (3 s, 9H). before being evaporated off extracted with dichloromethane (2×50 mL) The combined organic layers were washed with water and brine dried (Na2SO4) filtered evaporated