1-(1,1-Dimethylethyl) 3-methyl-1,3-azetidinedicarboxylate

[Note: Since cyanoazetidine 26 is volatile, acombined procedure designed to maximize the yield is provided here. However, if azetidine 26 is already inhand, follow just the NaOH hydrolysis step.] To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (22)(150 mg, 0.823 mmol, 1 equiv.) in dry THF (3 mL) was added LiHMDS (1M in THF, 0.905 mL, 0.905 mmol, 1.1equiv.) at '78 oC and stirred for 30 min. at the same temperature. Methyl iodide (77 muL, 1.23 mmol, 1.5 equiv.)was added via syringe and stirred at '78 oC for 45 min. followed by stirring at rt for 1 h. The resulting mixturewas quenched with NH4Cl (2 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic extractswere washed with brine (3 mL), dried over Na2SO4, and concentrated. Compound 26 was used in the next stepwithout further purification. A solution of NaOH (115 mg, 4.12 mmol, 5 equiv.) in H2O (3 mL) was slowly addedto a solution of tert-butyl 3-cyano-3-methylazetidine-1-carboxylate (26) in MeOH (3 mL) and then refluxeduntil judged complete by TLC (ca. 4 h). The reaction mixture was cooled to rt and the MeOH was removed in vacuo. The mixture was neutralized with 10 percent aq. citric acid (3 mL) and extracted with CH2Cl2 (3 x 10 mL). Thecombined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give thedesired product 27 (107.5 mg, 61percent for 2 steps). Physical State: white crystalline solid (mp 135'136 oC); 1HNMR (500 MHz, CDCl3): [mixture of rotamers] delta 6.71 (br s, 1H, COOH minor rotamer), 5.91 (br s, 1H, COOHmajor rotamer), 4.25 (d, J 8.5 Hz, 2H, major), 4.19 (d, J 8.4 Hz, 2H, minor), 3.69 (d, J 8.5 Hz, 2H, minor), 3.68 (d, J 8.6 Hz, 2H, major), 1.55 (s, 3H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3): [mixture of rotamers] delta 179.3(major), 178.5 (minor), 156.6 (minor), 156.5 (major), 80.3 (minor), 80.1 (major), 58.5 (br, major + minor, 2 x2C), 39.1 (minor), 38.7 (major), 28.5 (major, 3C), 28.5 (minor, 3C), 23.1 (minor), 22.6 (major); HRMS (ESI-TOF):calc'd for C10H16NO4 [M-H] 214.1079; found 214.1080.The BB-25-1 (0.1g, 0.46mmol) and ammonium acetate (0.035g, 0.046mmol) was dissolved in nitrogen, the nitrogen compound - twodimethylformamide (2mL), followed by addition of 2- (7-azo-benzo triazole) - N, N, N ', N' - tetramethyluronium hexafluorophosphate(0.265g, 0.697mmol) and N, N - diisopropylethylamine (0.18g, 1.39mmol), the reaction It was stirred for 16 hours at room temperaturewhen.After completion of the reaction was added ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfatedrying, filtration, solvent was removed under reduced pressure to give the title compound BB-25-2 (white solid, 0.05 g of, crude), crude without puretechnology used in the next reactionTo a stirring solution of intermediate 18 (87 mg, 0.2 mmol) and 1-(tert-butoxycarbonyl)-3- methylazetidine-3-carboxylic acid SM 1 (43 mg, 0.2 mmol) in DCM (10 mL) was added Et3N (40 mg, 0.4 mmol) followed by T3P (50percent in EtOAc) (254 mg, 0.4 mmol) and stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM. Combined organic extracts weredried over anhydrous Na2504 and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography eluting with 5percent MeOH in DCM to afford compound 1(80mg, 63percent) as alight yellow solid. LC-MS: m/z = 631.2 [M+H]To a stirring solution of intermediate 42 (50 mg, 0.1 mmol) and 1-(tert-butoxycarbonyl)-3- methylazetidine-3-carboxylic acid SM 1 (43 mg, 0.2 mmol) in DCM (10 mL) was added Et3N (30mg, 0.3 mmol) followed by T3P (50percent in EtOAc) (190 mg, 0.3 mmol) and stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM. Combined organic extracts were dried over anhydrous Na2504 and concentrated under reduced pressure to obtain cmde product, which was purified by silica gel column chromatography eluting with 5percent MeOH in DCM to afford compound 1 (50 mg, 73 percent) as a light yellow solid. LC-MS: m/z = 577.2 [M+H-Boc]To a stirring solution of intermediate 40 (168 mg, 0.37 mmol) and SM 1(80 mg, 0.37 mmol) in DCM (20 mL) was added Et3N (75 mg, 0.8 mmol) followed by T3P (50percent in EtOAc) (470 mg, 0.8 mmol) and stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM. Combined organic extracts were dried over anhydrous Na2504 and concentrated underreduced pressure to obtain crude product, which was purified by silica gel column chromatography eluting with 5percent MeOH in DCM to afford compound 1 (100 mg, 41 percent) as a light yellow solid. LCMS: m/z = 549.3 [M+H-Boc]

Molecular Weight:215.25
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:215.11575802
Monoisotopic Mass:215.11575802
Topological Polar Surface Area:66.8
Heavy Atom Count:15
Complexity:286
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes