ethyl (1r,3r,5r)-2-boc-2-azabicyclo[3.1.0]hexane-3-carboxylate synthesis

6synthesis methods

Product Name:ethyl (1r,3r,5r)-2-boc-2-azabicyclo[3.1.0]hexane-3-carboxylate
CAS Number:871727-37-6
Molecular formula:C13H21NO4
Molecular Weight:255.31

75-11-6
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ethyl (1r,3r,5r)-2-boc-2-azabicyclo[3.1.0]hexane-3-carboxylate

871727-37-6
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$154.00/100 mg

871727-40-1 Synthesis

(1S,3R,5S)-2-tert-Butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

871727-40-1
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Yield: 39% ， 7%

Reaction Conditions:

Stage #1:1-tert-butyl 2-ethyl (2R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate with diethylzinc in toluene at -40; for 0.5 h;
Stage #2:diiodomethane in toluene at -40 - 20; for 4.5 h;

Steps:

4.5 2-tert-Butyl 3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (4a) and 2-tert-butyl 3-ethyl(1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5a)
To a solution of 3a (13.8g, 57.2mmol) in toluene (400mL) was added dropwise 1.1M diethylzinc solution in toluene (114mL, 126mmol) at -40°C, and the reaction mixture was stirred at the same temperature for 30min. After addition of diiodomethane (61.3g, 229mmol) in toluene (50mL) at -40°C, the reaction mixture was stirred at -40°C--20°C for 30min, at 0°C for 2h and at room temperature for 2h. To the reaction mixture was added satd NaHCO₃ (500mL) and EtOAc (500mL), and the mixture was filtered through a pad of Celite. The filtrate was separated, and the organic layer was dried over MgSO₄, and concentrated in vacuo. The residue was purified by column chromatography (n-Hexane/EtOAc=98:2→50:50) to give 4a (5.69g, 39%, colorless oil) and 5a (1.09g, 7%, colorless oil). 4a: ¹H NMR (300MHz, CDCl₃) δ 0.62-0.79 (1H, m), 0.85-0.94 (1H, m), 1.22-1.31 (3H, m), 1.39-1.56 (10H, m), 1.98-2.06 (1H, m), 2.48-2.68 (1H, m), 3.41-3.59 (1H, m), 4.09-4.25 (2H, m), 4.45-4.66 (1H, m). 5a: ¹H NMR (300MHz, CDCl₃) δ 0.39-0.53 (1H, m), 0.72-0.88 (1H, m), 1.19-1.33 (3H, m), 1.37-1.65 (10H, m), 2.14-2.29 (1H, m), 2.28-2.42 (1H, m), 3.37-3.59 (1H, m), 3.91-4.12 (1H, m), 4.08-4.28 (2H, m).

References:

Asano, Moriteru;Hashimoto, Kentaro;Saito, Bunnai;Shiokawa, Zenyu;Sumi, Hiroyuki;Yabuki, Masato;Yoshimatsu, Mie;Aoyama, Kazunobu;Hamada, Teruki;Morishita, Nao;Dougan, Douglas R.;Mol, Clifford D.;Yoshida, Sei;Ishikawa, Tomoyasu [Bioorganic and Medicinal Chemistry,2013,vol. 21,# 18,p. 5725 - 5737]