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0 °C

The reaction was run in three equal portions and combined for aqueous workup. A 5 L, 3-necked round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide (25.3 g, 53 mmol), acetonitrile (1.9 L), and 2.6 L of water/ice. The mixture was stirred and cooled to 0° C. Iodobenzene diacetate (25.77 g, 80 mmol) was added and the reaction was stirred for 2 h; another 0.5 eq of iodobenzene diacetate was added. The reaction was stirred for 9 h (reaction temp<10° C.). The mixture was charged with 8 eq N,N-diisopropylethylamine and 2 eq acetic anhydride. Over the next thirty minutes, 4 eq N,N-diisopropylethylamine and 2 eq acetic anhydride were added every ten minutes, until the reaction had proceeded to completion (HPLC). The acetonitrile was removed in vacuo; some solid separated from the residue, and this was collected by filtration. The remaining residue was extracted with dichloromethane (3 L, then 1 L). The organic phase was washed sequentially with water, sat. NaHCO3, and brine. The collected solids were added to the organic phase, along with activated carbon (15 g). The mixture was stirred for 30 minutes at 40° C. before being filtered and concentrated in vacuo. The residue was dissolved in EtOAc (1 L), and the resultant solution was stirred at 75° C. for 1 h before being allowed to cool to room temperature. A solid separated and was collected by filtration. This solid was purified further by recrystallization: it was first dissolved in 0.5 L CH2Cl2, then concentrated in vacuo, then re-crystallized from 1 L EtOAc; this was repeated three times. The solids obtained from the mother liquors of the above were recrystallized three times using the same method. The combined solids were recrystallized twice more from acetonitrile (0.7 L) to provide 66 g (84%) of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (purity>99.5% by HPLC). LC/MS for primary peak: [M+H]−=489.4; [M-tBu+H]+=433.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.11 (s, 2H), 4.35 (m, 1H), 4.15 (m, 1H), 4.04 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 2.44 (m, 1H), 2.12 (m, 1H), 1.87-2.05 (m, 4H), 1.87 (s, 3H), 1.55-1.7 (m, 2H), 1.46 (s, 9H). The stereochemical fidelity of the Hofmann rearrangement was confirmed through X-ray crystal structure analysis of this compound, as shown in FIG. 1.

1. stirringthe reaction was stirred for 2 h
2. stirringThe reaction was stirred for 9 h
3. custom(reaction temp<10° C.)
4. customThe acetonitrile was removed in vacuo
5. customsome solid separated from the residue
6. filtrationthis was collected by filtration
7. extractionThe remaining residue was extracted with dichloromethane (3 L
8. washThe organic phase was washed sequentially with water, sat. NaHCO3, and brine
9. additionThe collected solids were added to the organic phase, along with activated carbon (15 g)
10. stirringThe mixture was stirred for 30 minutes at 40° C.
11. filtrationbefore being filtered
12. concentrationconcentrated in vacuo
13. dissolutionThe residue was dissolved in EtOAc (1 L)
14. stirringthe resultant solution was stirred at 75° C. for 1 h
15. temperatureto cool to room temperature
16. customA solid separated
17. filtrationwas collected by filtration
18. customThis solid was purified further by recrystallization
19. dissolutionit was first dissolved in 0.5 L CH2Cl2
20. concentrationconcentrated in vacuo
21. customre-crystallized from 1 L EtOAc
22. customThe solids obtained from the mother liquors of the
23. customabove were recrystallized three times
24. customThe combined solids were recrystallized twice more from acetonitrile (0.7 L)