A new approach to the stereoselective synthesis of trans-3-carbamoyl-b-lactam moieties† - Publikacja - MOST Wiedzy

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A new approach to the stereoselective synthesis of trans-3-carbamoyl-b-lactam moieties†

Abstrakt

One-pot synthesis of optically active 1,4-disubstituted-3-carbamoyl-azetidinones from 5-[(N-arylamino)- (hydroxyl)methylene]-2,2-dimethyl-1,3-dioxa-4,6-diones and chiral aldimines is achieved via thermal generation of carbamoyl ketenes and subsequent [2+2] cycloaddition. Three possible chiral induction approaches were tested and (R)-(+)-1-phenylethylamine was confirmed as the best chiral auxiliary. Among the four possible diastereoisomers, only two with significant excess of one were formed

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Kategoria:
Publikacja w czasopiśmie
Typ:
artykuł w czasopiśmie wyróżnionym w JCR
Opublikowano w:
NEW JOURNAL OF CHEMISTRY nr 41, wydanie 6, strony 2479 - 2489,
ISSN: 1144-0546
Język:
angielski
Rok wydania:
2017
Opis bibliograficzny:
Anna Z., Ewelina N., Makowiec S.: A new approach to the stereoselective synthesis of trans-3-carbamoyl-b-lactam moieties†// NEW JOURNAL OF CHEMISTRY. -Vol. 41, iss. 6 (2017), s.2479-2489
DOI:
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1039/c7nj00445a
Bibliografia: test
  1. -(4-Fluorophenyl)-4-oxo-N-phenyl-1-(1-phenylethyl)azetidine-3- carboxamide (7ada) and (8ada) Purification by flash chromatography (EtOAc : Hex 1 : 3, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (271 mg, 0.70 mmol, 70%, ratio 75 : 25, yellow oil). Overall de = 50%. otwiera się w nowej karcie
  2. H NMR (500 MHz, CDCl 3 ) d: 8.37 (s, 0.75 H, NH), 8.32 (s, 0.25 otwiera się w nowej karcie
  3. H, NH), 7.55 (d, 0.25 H, J = 8.0 Hz, ArH), 7.47 (d, 1.50 H, J = 8.0 otwiera się w nowej karcie
  4. Hz, ArH), 7.33-7.25 (m, 6.25 H, ArH), 7.23-7.21 (m, 1.75 H, ArH), 7.17-7.07 (m, 2.25 H, ArH), 7.04-6.96 (m, 2 H, ArH), 4.90 (q, 0.75 H, J = 7.0 Hz, CHCH 3 ), 4.82 (d, 1 H, J = 2.5 Hz, H-4), 4.44 (q, 0.25 H, J = 7.0 Hz, CHCH 3 ), 3.92 (d, 0.75 H, J = 2.5 Hz, H-3), 3.89 (d, 0.25 H, J = 2.5 Hz, H-3), 1.79 (d, 0.75 H, J = 7.0 Hz, CH 3 ), 1.43 (d, 2.25 H, J = 7.0 Hz, CH 3 ) ppm. 13 C NMR (125 MHz, CDCl 3 ) d: 165.4 (maj), 164.4 (d, 1 J CF = 235 Hz), 164.0 (min), 163.3 (maj), 163.0 (d, 1 J CF = 246 Hz), 162.1 (maj), 140.2 (min), 139.3 (maj), 137.6 (min), 137.5 (maj), 133.6 (d, 4 J CF = 2 Hz), 129.2 (min), 129.1 (maj), 129.0, 128.9 (d, 3 J CF = 7 Hz) (maj), 128.8 (d, 3 J CF = 7 Hz) (min), 128.3 (maj), 128.1 (min), 127.4 (maj), 127.0 (min), 124.9 (min), 124.0 (maj), 120.2 (min), 120.1 (maj), 116.2 (d, 2 J CF = 21 Hz) (min), 116.1 (d, 2 J CF = 21 Hz) (maj), 63.3, 57.3 (maj), 56.7 (min), 54.9 (min), 53.8 (maj), 19.9 (min), 19.5 (maj) ppm. HRMS (ESI+): m/z calcd for C 24 H 21 FN 2 O 2 Na [M + Na] + 411.1485, found. 411.1470. otwiera się w nowej karcie
  5. N-(4-Methoxyphenyl)-2-oxo-4-phenyl-1-(1- phenylethyl)azetidine-3-carboxamide (7daa) and (8daa) Purification by flash chromatography (EtOAc : Hex 1 : 8, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (280 mg, 0.70 mmol, 70%, ratio 75 : 25, yellow oil). Overall de = 50%. otwiera się w nowej karcie
  6. H NMR (500 MHz, CDCl 3 ) d: 8.26 (s, 0.75 H, NH), 8.20 (s, 0.25 otwiera się w nowej karcie
  7. H, NH), 7.46-7.40 (m, 0.75 H, ArH), 7.40-7.36 (m, 1.25 H, ArH), 7.34-7.28 (m, 6.25 H, ArH), 7.26-7.21 (m, 3 H, ArH), 7.19-7.16 (m, 0.75 H, ArH), 6.85-6.83 (m, 0.75 H, ArH), 6.80-6.77 (m, 1.25 otwiera się w nowej karcie
  8. H, ArH), 4.92 (q, 0.75 H, J = 7.0 Hz, CHCH 3 ), 4.83 (d, 0.75 H, J = 2.0 Hz, H-4), 4.80 (d, 0.25 H, J = 2.0 Hz, H-4), 4.40 (q, 0.25 H, J = 7.0 Hz, CHCH 3 ), 3.92 (d, 0.75 H, J = 2.0 Hz, H-3), 3.89 (d, 0.25 otwiera się w nowej karcie
  9. H, J = 2.0 Hz, H-3), 3.78 (s, 0.75 H, OCH 3 ), 3.77 (s, 2.25 H, OCH 3 ), 1.79 (d, 0.75 H, J = 7.5 Hz, CH 3 ), 1.41 (d, 2.25 H, J = 7.5 Hz, CH 3 ) ppm. 13 C NMR (125 MHz, CDCl 3 ) d: 165.6 (maj), 165.5 (min), 163.4 (min), 163.2 (maj), 156.7 (min), 156.6 (maj), 140.6, 139.5, 138.0, 136.9, 130.8, 129.2, 129.1, 129.0, 128.9, 128.5, 128.2, 128.0, 127.4, 127.2, 127.1, 127.0, 121.9, 121.8, 114.3 (min), 114.2 (maj), 63.2 (maj), 63.2 (min), 57.9 (maj), 57.5 (min), 55.6 (maj), 55.1 (min), 53.7, 20.2 (min), 19.5 (maj) ppm. HRMS (ESI+): m/z calcd for C 25 H 24 N 2 O 3 Na [M + Na] + 423.1685, found. 423.1671. 2-(tert-Butyl)-4-oxo-N-phenyl-1-(1-phenylethyl)azetidine-3- carboxamide (7aea) and (8aea) Purification by flash chromatography (EtOAc : Hex 1 : 5, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (175 mg, 0.50 mmol, 50%, ratio 74 : 26, yellow oil). Overall de = 48%. otwiera się w nowej karcie
  10. H NMR (500 MHz, CDCl 3 ) d: 8.57 (s, 0.74 H, NH), 8.38 (s, 0.26 otwiera się w nowej karcie
  11. H, NH), 7.55-7.50 (m, 1.74 H, ArH), 7.41-7.40 (m, 1.26 H, ArH), 7.37-7.31 (m, 2.26 H, ArH), 7.30-7.26 (m, 3.74 H, ArH), 7.12-7.07 (m, 1 H, ArH), 4.59 (q, 0.26 H, J = 7.5 Hz, CHCH 3 ), 4.50 (q, 0.74 H, J = 7.5 Hz, CHCH 3 ), 3.87 (d, 0.74 H, J = 2.5 Hz, H-3), 3.72 (d, 0.74 H, J = 2.5 Hz, H-4), 3.71 (d, 0.26 H, J = 2.5 Hz, H-3), 3.67 (d, 0.26 H, J = 2.5 Hz, H-4), 1.85 (d, 0.78 H, J = 7.5 Hz, CH 3 ), 1.75 (d, 2.22 H, J = 7.5 Hz, CH 3 ), 0.96 (s, 2.36 H, t Bu), 0.88 (s, 6.63 H, t Bu) ppm. 13 C NMR (125 MHz, CDCl 3 ) d: 166.6 (min), 165.5 (maj), 164.2 (maj), 164.1 (min), 141.5 (maj), 141.2 (min), 137.8 (maj), 137.7 (min), 129.2, 129.1, 128.9, 128.0, 127.7, 127.2, 126.8, 124.7 (min), 124.6 (maj), 120.1 (min), 120.0 (maj), 66.6 (maj), 64.3 (min), 57.4 (maj), 56.7 (min), 55.1 (min), 55.0 (maj), 32.5, 26.5, 26.1, 21.4 (maj), 20.5 (min) ppm. HRMS (ESI+): m/z calcd for C 22 H 26 N 2 O 2 Na [M + Na] + 373.1892, found. 373.1902. 2-(tert-Butyl)-N-(4-methoxyphenyl)-4-oxo-1-(1- phenylethyl)azetidine-3-carboxamide (7dea) and (8dea) Purification by flash chromatography (EtOAc : Hex 1 : 4-1 : 2, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (175 mg, 0.46 mmol, 46%, ratio 70 : 30, yellow oil). Overall de = 40%. otwiera się w nowej karcie
  12. H NMR (500 MHz, CDCl 3 ) d: 8.59 (s, 0.7 H, NH), 8.33 (s, 0.3 H, NH), 7.45-7.40 (m, 3.3 H, ArH), 7.37-7.33 (m, 2 H, ArH), 7.30-7.25 (m, 1.7 H, ArH), 6.84-6.78 (m, 2 H, ArH), 4.60 (q, 0.3 H, J = 7.0 Hz, CHCH 3 ), 4.50 (q, 0.7 H, J = 7.0 Hz, CHCH 3 ), 3.87 (d, 0.7 H, J = 2.5 Hz, H-3), 3.78 (s, 0.9 H, OCH 3 ), 3.77 (s, 2.1 H, OCH 3 ), 3.72 (d, 0.7 H, J = 2.5 Hz, H-4), 3.70 (d, 0.3 H, J = 2.5 Hz, H-3), 3.66 (d, 0.3 H, J = 2.5 Hz, H-4), 1.85 (d, 0.9 H, J = 7.5 Hz, CH 3 ), 1.75 (d, 2.1 H, J = 7.5 Hz, CH 3 ), 0.95 (s, 2.66 H, t Bu), 0.87 (s, 6.34 H, t Bu) ppm. otwiera się w nowej karcie
  13. C NMR (125 MHz, CDCl 3 ) d: 166.8 (min), 166.6 (maj), 163.9, 156.7 (min), 156.5 (maj), 141.6 (maj), 141.2 (min), 131.0 (maj), 130.9 (min), 129.1 (min), 128.9 (maj), 127.9 (min), 127.7 (maj), 127.2 (maj), 126.8 (min), 121.7 (min), 121.6 (maj), 114.3 (min), 114.2 (maj), 66.6 (maj), 64.4 (min), 57.3 (maj), 56.6 (min), 55.7 (min), 55.6 (maj), 55.0 (min), 54.9 (maj), 32.5, 26.5 (min), 26.1 (maj), 21.4 (maj), 20.5 (min) ppm. HRMS (ESI+): m/z calcd for C 23 H 28 N 2 O 3 Na [M + Na] + 403.1998, found. 403.2005. 2-(tert-Butyl)-N-(3-chlorophenyl)-4-oxo-1-(1- phenylethyl)azetidine-3-carboxamide (7cea) and (8cea) Purification by flash chromatography (EtOAc : Hex 1 : 5, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (161 mg, 0.42 mmol, 42%, ratio 71 : 29, yellow oil). Overall de = 42%. otwiera się w nowej karcie
  14. H NMR (500 MHz, CDCl 3 ) d: 9.02 (s, 0.71 H, NH), 8.66 (s, 0.29 otwiera się w nowej karcie
  15. H, NH), 7.71 (s, 1H, ArH), 7.42-7.40 (m, 1.29 H, ArH), 7.36-7.33 (m, 2 H, ArH), 7.30-7.25 (m, 2 H, ArH), 7.23-7.17 (m, 1 H, ArH), 7.15-7.11 (m, 0.71 H, ArH), 7.06-7.00 (m, 1 H, ArH), 4.60 (q, 0.29 H, J = 7.5 Hz, CHCH 3 ), 4.50 (q, 0.71 H, J = 7.5 Hz, CHCH 3 ), 3.93-3.91 (m, 0.71 H, H-3), 3.81-3.78 (m, 0.71 H, H-3), 3.76-3.74 (m, 0.29 H, H-4), 3.71-3.69 (m, 0.29 H, H-4), 1.85 (d, 0.87 H, J = 7.0 Hz, CH 3 ), 1.77 (d, 2.13 H, J = 7.0 Hz, CH 3 ), 0.95 (s, 2.59 H, t Bu), 0.87 (s, 6.43 H, t Bu) ppm. 13 C NMR (125 MHz, CDCl 3 ) d: 166.5, 164.3, 141.4 (maj), 141.1 (min), 138.9 (maj), 138.8 (min), 134.8 (min), 134.7 (maj), 130.1 (min), 130.0 (maj), 129.1 (min), 128.9 (maj), 128.0 (min), 127.8 (maj), 127.2 (maj), 126.8 (min), 124.6 (min), 124.5 (maj), 120.1 (min), 119.9 (maj), 117.9 (min), 117.7 (maj), 66.4 (maj), 64.2 (min), 57.5 (maj), 56.7 (min), 55.2 (maj), 55.1 (min), 32.5, 26.5 (min), 26.1 (maj), 21.4 (maj), 20.5 (min) ppm. HRMS (ESI+): m/z calcd for C 22 H 25 ClN 2 O 2 Na [M + Na] + 407.1502, found. 407.1509. otwiera się w nowej karcie
  16. -(tert-Butyl)-1-(1-(naphthalen-2-yl)ethyl)-4-oxo-N- phenylazetidine-3-carboxamide (7aeb) and (8aeb) Purification by flash chromatography (EtOAc : Hex 1 : 4, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (208 mg, 0.52 mmol, 52%, ratio 55 : 45, yellow oil). Overall de = 10%. otwiera się w nowej karcie
  17. H NMR (500 MHz, CDCl 3 ) d: 8.57 (s, 0.55 H, NH), 8.45 (s, 0.45 otwiera się w nowej karcie
  18. H, NH), 7.86-7.78 (m, 3.90 H, ArH), 7.72-7.66 (m, 0.55 H, ArH), 7.61-7.54 (m, 2.55 H, ArH), 7.51-7.45 (m, 2.55 H, ArH), 7.32- 7.26 (m, 2.45 H, ArH), 7.13-7.04 (m, 1 H, ArH), 4.80 (q, 0.45 H, J = 7.5 Hz, CHCH 3 ), 4.66 (q, 0.55 H, J = 7.5 Hz, CHCH 3 ), 3.91 (d, 0.55 H, J = 2.5 Hz, H-3), 3.78-3.75 (m, 1 H, H-3 H-4), 3.73 (d, 0.45 H, J = 2.5 Hz, H-4), 1.94 (d, 1.35 H, J = 7.5 Hz, CH 3 ), 1.84 (d, 1.65 H, J = 7.5 Hz, CH 3 ), 0.96 (s, 4.03 H, t Bu), 0.88 (s, 4.96 H, t otwiera się w nowej karcie
  19. Bu) ppm. 13 C NMR (125 MHz, CDCl 3 ) d: 166.8 (min), 166.6 (maj), 164.2 (maj), 164.1 (min), 139.1 (maj), 138.6 (min), 137.8 (maj), 137.7 (min), 133.5 (maj), 133.4 (min), 133.0 (min), 132.9 (maj), 129.4, 129.3, 129.2, 129.0, 128.2, 127.9, 126.6 (min), 126.5 (maj), 126.4 (maj), 126.3 (min), 125.7, 125.6 (maj), 125.5 (min), 124.9 (min), 124.7 (maj), 120.1 (min), 120.0 (maj), 66.9 (maj), 64.5 (min), 57.6 (maj), 56.5 (min), 55.2 (min), 55.0 (maj), 32.6, 26.5 (min), 26.2 (maj), 21.5 (maj), 20.2 (min) ppm. HRMS (ESI+): m/z calcd for C 26 H 28 N 2 O 2 Na [M + Na] + 423.2048, found. 423.2032. 2-(tert-Butyl)-4-oxo-1-(1-phenylethyl)-N-(m-tolyl)azetidine-3- carboxamide (7eea) and (8eea) Purification by flash chromatography (EtOAc : Hex 1 : 5, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (138 mg, 0.38 mmol, 38%, ratio 67 : 33, yellow oil). Overall de = 34%. otwiera się w nowej karcie
  20. H NMR (400 MHz, CDCl 3 ) d: 8.39 (s, 0.67 H, NH), 8.32 (s, 0.33
  21. H, NH), 7.44-7.29 (m, 7 H, ArH), 7.24-7.19 (m, 1 H, ArH), 6.97- 6.93 (m, 1 H, ArH), 4.60 (q, 0.33 H, J = 7.2 Hz, CHCH 3 ), 4.66 (q, 0.67 H, J = 7.2 Hz, CHCH 3 ), 3.84 (d, 0.67 H, J = 2.8 Hz, H-3), 3.71-3.69 (m, 1 H, H-3 H-4), 3.66 (d, 0.33 H, J = 2.8 Hz, H-4), 2.36 (s, 0.99 H, ArCH 3 ), 2.35 (s, 2.01 H, ArCH 3 ) 1.87 (d, 0.99 H, J = 7.2 Hz, CH 3 ), 1.76 (d, 2.01 H, J = 7.2 Hz, CH 3 ), 0.98 (s, 3.00 H, t Bu), 0.90 (s, 6.05 H, t Bu) ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 166.4 (min), 166.2 (maj), 164.0 (maj), 163.9 (min), 141.3 (maj), 141.0 (min), 139.0 (min), 138.9 (maj), 137.5 (maj), 137.4 (min), 129.0 (min), 128.9 (maj), 128.8 (min), 128.7 (maj), 127.5 (min), 127.0 (maj), 126.5 (maj), 126.2 (min), 125.3 (min), 125.2 (maj), 120.5 (min), 120.4 (maj), 116.9 (min), 116.8 (maj), 66.6 (maj), 64.2 (min), 57.0 (maj), 56.5 (min), 54.7 (min), 54.6 (maj), 32.3, 26.3 (min), 25.9 (maj), 21.5, 21.2 (maj), 20.3 (min) ppm. HRMS (ESI+): m/z calcd for C 23 H 28 N 2 O 2 Na [M + Na] + 387.2048, found. 387.2039. 2-(tert-Butyl)-4-oxo-1-(1-phenylethyl)-N-(o-tolyl)azetidine-3- carboxamide (7fea) and (8fea) Purification by flash chromatography (EtOAc : Hex 1 : 5, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (160 mg, 0.44 mmol, 44%, ratio 65 : 35, yellow oil). Overall de = 30%. otwiera się w nowej karcie
  22. H NMR (400 MHz, CDCl 3 ) d: 8.33 (s, 1 H, NH), 8.03 (d, 0.65 H, J = 8.0 Hz, ArH), 7.96 (d, 0.35 H, J = 8.0 Hz, ArH), 7.44-7.27 (m, 5 H, ArH), 7.25-7.20 (m, 2 H, ArH), 7.10-7.07 (m, 1 H, ArH), 4.58 (q, 0.35 H, J = 7.2 Hz, CHCH 3 ), 4.52 (q, 0.65 H, J = 7.2 Hz, CHCH 3 ), 3.83 (d, 0.65 H, J = 2.4 Hz, H-3), 3.75 (d, 0.35 H, J = 2.4 Hz, H-3), 3.73 (d, 0.65 H, J = 2.4 Hz, H-4), 3.65 (d, 0.35 H, J = 2.4 Hz, H-4), 2.36 (s, 1.95 H, ArCH 3 ), 2.34 (s, 1.05 otwiera się w nowej karcie
  23. H, ArCH 3 ), 1.89 (d, 1.05 H, J = 7.2 Hz, CH 3 ), 1.77 (d, 1.95 H, J = 7.2 Hz, CH 3 ), 1.01 (s, 3.15 H, t Bu), 0.92 (s, 5.85 H, t Bu) ppm. otwiera się w nowej karcie
  24. C NMR (100 MHz, CDCl 3 ) d: 166.7 (min), 166.5 (maj), 164.0 (maj), 163.9 (min), 141.4 (maj), 141.1 (min), 135.6 (maj), 135.5 (min), 130.5 (maj), 130.4 (min), 128.9 (min), 128.7 (maj), 128.4 (min), 128.2 (maj), 127.8 (min), 127.5 (maj), 126.9 (maj), 126.7 (min), 126.6 (min), 126.5 (maj), 124.9 (min), 124.8 (maj), 122.0 (min), 121.7 (maj), 66.8 (maj), 64.3 (min), 57.1 (maj), 56.6 (min), 54.6 (min), 54.4 (maj), 32.3, 26.3 (min), 25.9 (maj), 21.1 (maj), 20.3 (min), 17.7 (maj), 14.2 (min) ppm. HRMS (ESI+): m/z calcd for C 23 H 28 N 2 O 2 Na [M + Na] + 387.2048, found. 387.2041. 2-(tert-Butyl)-4-oxo-1-(1-phenylethyl)-N-( p-tolyl)azetidine-3- carboxamide (7gea) and (8gea) Purification by flash chromatography (EtOAc : Hex 1 : 5, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (127 mg, 0.35 mmol, 35%, ratio 68 : 32, yellow oil). Overall de = 36%. otwiera się w nowej karcie
  25. H NMR (400 MHz, CDCl 3 ) d: 8.38 (s, 0.68 H, NH), 8.30 (s, 0.32 H, NH), 7.47-7.34 (m, 6 H, ArH), 7.32-7.29 (m, 1 H, ArH), 7.16-7.11 (m, 2 H, ArH), 4.60 (q, 0.32 H, J = 7.2 Hz, CHCH 3 ), 4.52 (q, 0.68 H, J = 7.2 Hz, CHCH 3 ), 3.85 (d, 0.68 H, J = 2.8 Hz, H-3), 3.71-3.69 (m, 1 H, H-3 H-4), 3.66 (d, 0.32 H, J = 2.8 Hz, H-4), 2.35-2.32 (m, 3 H, ArCH 3 ), 1.87 (d, 0.96 H, J = 7.2 Hz, CH 3 ), 1.76 (d, 2.04 H, J = 7.2 Hz, CH 3 ), 0.98 (s, 2.84 H, t Bu), 0.90 (s, 6.15 H, t Bu) ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 166.5 (min), 166.3 (maj), 163.9 (maj), 163.8 (min), 141.3 (maj), 141.0 (min), 135.0 (maj), 134.9 (min), 134.1 (min), 134.0 (maj), 129.5 (min), 129.4 (maj), 128.9 (min), 128.7 (maj), 127.7 (min), 127.5 (maj), 127.0 (maj), 126.5 (min), 119.9 (min), 119.8 (maj), 66.6 (maj), 64.2 (min), 57.0 (maj), 56.5 (min), 54.7 (min), 54.6 (maj), 32.3, 26.3 (min), 25.9 (maj), 21.1 (maj), 20.8, 20.3 (min) ppm. otwiera się w nowej karcie
  26. HRMS (ESI+): m/z calcd for C 23 H 28 N 2 O 2 Na [M + Na] + 387.2048, found. 387.2061. 2-(tert-Butyl)-N-(3-fluorophenyl)-4-oxo-1-(1- phenylethyl)azetidine-3-carboxamide (7hea) and (8hea) Purification by flash chromatography (EtOAc : Hex 1 : 4-1 : 3, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (253 mg, 0.69 mmol, 69%, ratio 65 : 35, yellow oil). Overall de = 30%. otwiera się w nowej karcie
  27. H NMR (400 MHz, CDCl 3 ) d: 8.88 (s, 0.65 H, NH), 8.57 (s, 0.35
  28. H, NH), 7.55-7.51 (m, 1 H, ArH), 7.44-7.30 (m, 5 H, ArH), 7.26- 7.10 (m, 2 H, ArH), 6.84-6.75 (m, 1 H, ArH), 4.62 (q, 0.35 H, J = 7.2 Hz, CHCH 3 ), 4.52 (q, 0.65 H, J = 7.2 Hz, CHCH 3 ), 3.92 (d, 0.65 H, J = 2.8 Hz, H-3), 3.77 (d, 0.65 H, J = 2.8 Hz, H-4), 3.74 (d, 0.35 H, J = 2.8 Hz, H-3), 3.70 (d, 0.35 H, J = 2.8 Hz, H-4), 1.86 (d, 1.05 H, J = 7.2 Hz, CH 3 ), 1.79 (d, 1.95 H, J = 7.2 Hz, CH 3 ), 0.98 (s, 3.15 H, t Bu), 0.90 (s, 5.85 H, t Bu) ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 166.3 (min), 166.2 (maj), 164.0, 162.9 (d, 1 J CF = 243 Hz) (min), 162.8 (d, 1 J CF = 240 Hz) (maj), 141.3 (maj), 140.9 (min), 139.1 (d, 3 J CF = 11 Hz) (maj), 139.0 (d, 3 J CF = 11 Hz) (min), 130.0 (d, 3 J CF = 9 Hz) (min), 129.9 (d, 3 J CF = 9 Hz) (maj), 128.9 (min), 128.7 (maj), 127.8 (min), 127.5 (maj), 127.0 (maj), 126.6 (min), 115.0 (d, 4 J CF = 3 Hz) (min), 114.9 (d, 4 J CF = 3 Hz) (maj), 111.1 (d, 2 J CF = 21 Hz) (min), 111.0 (d, 2 J CF = 21 Hz) (maj), 107.3 (d, 2 J CF = 26 Hz) (min), 107.2 (d, 2 J CF = 26 Hz) (maj), 66.2 (maj), 64.0 (min), 57.2 (maj), 56.5 (min), 55.0 (maj), 54.9 (min), 32.3, 26.3 (min), 25.9 (maj), 21.1 (maj), 20.3 (min) ppm. HRMS (ESI+): m/z calcd for C 22 H 25 FN 2 O 2 Na [M + Na] + 391.1798, found. 391.1786. 2-(tert-Butyl)-N-(4-fluorophenyl)-4-oxo-1-(1- phenylethyl)azetidine-3-carboxamide (7iea) and (8iea) Purification by flash chromatography (EtOAc : Hex 1 : 4-1 : 3, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (283 mg, 0.77 mmol, 77%, ratio 68 : 32, yellow oil). Overall de = 36%. 1 H NMR (400 MHz, CDCl 3 ) d: 8.70 (s, 0.68 H, NH), 8.44 (s, 0.32 H, NH), 7.53-7.49 (m, 2 H, ArH), 7.44-7.30 (m, 5 H, ArH), 7.04-6.95 (m, 2 H, ArH), 4.61 (q, 0.32 H, J = 7.2 Hz, CHCH 3 ), 4.52 (q, 0.68 H, J = 7.2 Hz, CHCH 3 ), 3.90 (d, 0.68 H, J = 2.8 Hz, H-3), 3.75 (d, 0.68 H, J = 2.8 Hz, H-4), 3.72 (d, 0.32 H, J = 2.8 Hz, H-3), 3.68 (d, 0.32 H, J = 2.8 Hz, H-4), 1.87 (d, 0.96 H, J = 7.2 Hz, CH 3 ), 1.78 (d, 2.04 H, J = 7.2 Hz, CH 3 ), 0.97 (s, 2.88 H, t Bu), 0.89 (s, 6.12 H, t Bu) ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 166.4 (min), 166.3 (maj), 164.0 (maj), 163.9 (min), 159.4 (d, 1 J CF = 242 Hz) (min), 159.3 (d, 1 J CF = 242 Hz) (maj), 141.3 (maj), 140.9 (min), 133.6 (d, 4 J CF = 3 Hz) (maj), 133.5 (d, 4 J CF = 3 Hz) (min), 128.9 (min), 128.7 (maj), 127.8 (min), 127.5 (maj), 127.0 (maj), 126.6 (min), 121.6 (d, 3 J CF = 8 Hz) (min), 121.4 (d, 3 J CF = 8 otwiera się w nowej karcie
  29. Hz) (maj), 115.5 (d, 2 J CF = 22 Hz) (min), 115.4 (d, 2 J CF = 22 Hz) (maj), 66.3 (maj), 64.1 (min), 57.2 (maj), 56.5 (min), 54.8 (min), 54.7 (maj), 32.3, 26.3 (min), 25.9 (maj), 21.1 (maj), 20.3 (min) ppm. HRMS (ESI+): m/z calcd for C 22 H 25 FN 2 O 2 Na [M + Na] + 391.1798, found. 391.1789. otwiera się w nowej karcie
  30. N-(3-Fluorophenyl)-2-(2-methylpent-4-en-2-yl)-4-oxo-1-(1- phenylethyl)azetidine-3-carboxamide (7hfa) and (8hfa) Purification by flash chromatography (EtOAc : Hex 1 : 4-1 : 3, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (153 mg, 0.39 mmol, 39%, ratio 65 : 35, yellow oil). Overall de = 30%. 1 H NMR (400 MHz, CDCl 3 ) d: 8.76 (s, 0.65 H, NH), 8.53 (s, 0.35 H, NH), 7.55-7.51 (m, 1 H, ArH), 7.45-7.43 (m, 1 H, ArH), 7.40-7.34 (m, 2 H, ArH), 7.33-7.29 (m, 2 H, ArH), 7.25- 7.12 (m, 2 H, ArH), 6.84-6.76 (m, 1 H, ArH), 5.81-5.70 (m, 1 H, CH 2 CHQCH 2 ), 5.09-5.05 (m, 1 H, CH 2 CHQCH 2 ), 5.00-4.94 (m, 1 H, CH 2 CHQCH 2 ), 4.64 (q, 0.35 H, J = 7.2 Hz, CHCH 3 ), 4.51 (q, 0.65 H, J = 7.2 Hz, CHCH 3 ), 3.99 (d, 0.65 H, J = 2.8 Hz, H-3), 3.82-3.80 (m, 1 H, H-3, H-4), 3.78 (d, 0.35 H, J = 2.8 Hz, H-4), 2.05-1.91 (m, 2 H, CH 2 CHQCH 2 ), 1.87 (d, 1.05 H, J = 7.2 Hz, CH 3 ), 1.79 (d, 1.95 H, J = 7.2 Hz, CH 3 ), 0.94 (s, 2.1 H, C(CH 3 ) 2 ), 0.86 (s, 1.95 H, C(CH 3 ) 2 ), 0.85 (s, 1.95 H, C(CH 3 ) 2 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 166.2 (min), 166.1 (maj), 164.1 (maj), 163.9 (min), 162.9 (d, 1 J CF = 243 Hz) (min), 162.8 (d, 1 J CF = 243 Hz) (maj), 141.3 (maj), 140.9 (min), 139.0 (d, 3 J CF = 10 Hz) (maj), 138.9 (d, 3 J CF = 10 Hz) (min), 133.4 (maj), 133.3 (min), 130.0 (d, 3 J CF = 10 Hz) (min), 129.9 (d, 3 J CF = 10 Hz) (maj), 128.9 (min), 128.7 (maj), 127.8 (min), 127.6 (maj), 127.0 (maj), 126.6 (min), 118.5 (min), 118.4 (maj), 115.0 (d, 4 J CF = 3 Hz) (min), 114.9 (d, 4 J CF = 3 Hz) (maj), 111.1 (d, 2 J CF = otwiera się w nowej karcie
  31. Hz) (min), 111.0 (d, 2 J CF = 21 Hz) (maj), 107.3 (d, 2 J CF = 26 Hz) (min), 107.2 (d, 2 J CF = 26 Hz) (maj), 65.4 (maj), 63.4 (min), 57.5 (maj), 56.6 (min), 54.8 (min), 54.7 (maj), 43.6 (min), 43.4 (maj), 35.3 (maj), 35.2 (min), 23.6 (min), 23.2 (maj), 22.9 (min), 22.4 (maj), 21.3 (maj), 20.4 (min), ppm. HRMS (ESI+): m/z calcd for C 24 H 27 FN 2 O 2 Na [M + Na] + 417.1954, found. 417.1951. otwiera się w nowej karcie
  32. N-(4-Fluorophenyl)-2-(2-methylpent-4-en-2-yl)-4-oxo-1-(1- phenylethyl)azetidine-3-carboxamide (7ifa) and (8ifa) Purification by flash chromatography (EtOAc : Hex 1 : 4-1 : 3, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (193 mg, 0.49 mmol, 49%, ratio 64 : 36, yellow oil). Overall de = 28%. 1 H NMR (400 MHz, CDCl 3 ) d: 8.59 (s, 0.64 H, NH), 8.40 (s, 0.36 H, NH), 7.54-7.50 (m, 2 H, ArH), 7.45-7.42 (m, 1 H, ArH), 7.40-7.34 (m, 2 H, ArH), 7.32-7.29 (m, 2 H, ArH), 7.05- 6.97 (m, 2 H, ArH), 5.81-5.70 (m, 1 H, CH 2 CHQCH 2 ), 5.08-5.05 (m, 1 H, CH 2 CHQCH 2 ), 5.00-4.94 (m, 1 H, CH 2 CHQCH 2 ), 4.64 (q, 0.36 H, J = 7.2 Hz, CHCH 3 ), 4.51 (q, 0.64 H, J = 7.2 Hz, CHCH 3 ), 3.97 (d, 0.64 H, J = 2.4 Hz, H-3), 3.80-3.79 (m, 1 H, H-3, H-4), 3.77 (d, 0.36 H, J = 2.4 Hz, H-4), 2.09-1.91 (m, 2 H, CH 2 CHQCH 2 ), 1.87 (d, 1.08 H, J = 7.2 Hz, CH 3 ), 1.79 (d, 1.92 H, J = 7.2 Hz, CH 3 ), 0.95 (s, 1.08 H, C(CH 3 ) 2 ), 0.94 (s, 1.08 H, C(CH 3 ) 2 ), 0.86 (s, 1.92 H, C(CH 3 ) 2 ), 0.85 (s, 1.92 H, C(CH 3 ) 2 ) ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 166.4 (min), 166.2 (maj), 163.9 (maj), 163.8 (min), 159.4 (d, 1 J CF = 242 Hz) (min), 159.3 (d, 1 J CF = 242 Hz) (maj), 141.4 (maj), 140.9 (min), 133.6 (d, 4 J CF = 3 Hz), 133.5 (maj), 133.4 (min), 128.9 (min), 128.7 (maj), 127.8 (min), 127.6 (maj), 127.0 (maj), 126.6 (min), 121.6 (d, 2 J CF = otwiera się w nowej karcie
  33. Hz) (min), 121.5 (d, 3 J CF = 8 Hz) (maj), 118.5 (min), 118.4 (maj), 115.6 (d, 2 J CF = 22 Hz) (min), 115.5 (d, 2 J CF = 22 Hz) (maj), 65.6 (maj), 63.5 (min), 57.5 (maj), 56.6 (min), 54.7 (min), 54.5 (maj), 43.7 (min), 43.5 (maj), 35.3, 23.6 (min), 23.2 (maj), 22.9 (min), 22.5 (maj), 21.3 (maj), 20.4 (min), ppm. HRMS (ESI+): m/z calcd for C 24 H 27 FN 2 O 2 Na [M + Na] + 417.1954, found. 417.1940. 1-Isopropyl-2-oxo-N-phenyl-4-(2-phenylpent-4-en-2-yl)azetidine- 3-carboxamide (7ahd) and (8ahd) Purification by flash chromatography (EtOAc : Hex 1 : 4, SiO 2 ) gave one fraction, a mixture of two diastereoisomers (188 mg, 0.5 mmol, 50%, ratio 50 : 50, yellow oil). 1 H NMR (400 MHz, CDCl 3 ) d: 8.50 (s, 0.5 H, NH), 7.95 (s, 0.5 H, NH), 7.57-7.54 (m, 1 H, ArH), 7.46-7.21(m, 8 H, ArH), 7.12-7.03 (m, 1 H, ArH), 5.67-5.56 (m, 0.5 H, CH 2 CHQCH 2 ), 5.42-5.31 (m, 0.5 H, CH 2 CHQCH 2 ), 5.14-4.93 (m, 2 H, CH 2 CHQCH 2 ), 4.41 (d, 0.5 H, J = 2.0 Hz, H-3), 4.30 (d, 0.5 H, J = 2.0 Hz, H-3), 3.84 (d, 0.5 H, J = 2.0 Hz, H-4), 3.54 (d, 0.5 H, J = 2.0 Hz, H-4), 3.44 (sep, 0.5 H, J = 6.8 Hz, CH(CH 3 ) 2 ), 2.91 (dd, 0.5 H, 2 J = 14.0 Hz, otwiera się w nowej karcie
  34. J = 5.6 Hz, CH 2 CHQCH 2 ), 2.83 (dd, 0.5 H, 2 J = 14.0 Hz, 3 J = 5.6 Hz, CH 2 CHQCH 2 ), 2.70 (sep, 0.5 H, J = 6.4 Hz, CH(CH 3 ) 2 ), 2.44 (dd, 0.5 H, 2 J = 14.0 Hz, 3 J = 8.4 Hz, CH 2 CHQCH 2 ), 2.33 (dd, 0.5 H, 2 J = 14.0 Hz, 3 J = 8.4 Hz, CH 2 CHQCH 2 ), 1.46 (d, 1.5 H, J = 6.8 Hz, CH(CH 3 ) 2 ), 1.44 (s, 1.5 H, CH 3 ), 1.40 (s, 1.5 H, CH 3 ), 1.25 (d, 1.5 H, J = 6.8 Hz, CH(CH 3 ) 2 ), 1.19 (d, 1.5 H, J = 6.4 Hz, CH(CH 3 ) 2 ), 0.91 (d, 1.5 H, J = 6.4 Hz, CH(CH 3 ) 2 ), ppm. 13 C NMR (100 MHz, CDCl 3 ) d: 169.3, 166.2, 164.0, 163.5, 141.3, 141.0, 137.5, 129.1, 129.0, 128.9, 128.9, 128.8, 128.7, 127.8, 127.5, 127.0, 126.6, 124.5, 124.4, 120.0, 119.9, 119.8, 119.7, 83.1, 66.5, 64.1, 62.2, 57.1, 56.5, 54.8, 54.6, 42.4, 32.3, 28.0, 27.5, 27.4, 26.3, 25.9, 21.1, 20.3, ppm. Notes and references 1 (a) http://apps.who.int/iris/bitstream/10665/148114/1/97892 41564854_eng.pdf?ua=1; (b) http://ec.europa.eu/eurostat/ statistics-explained/index.php/File:Causes_of_death_%E2% 80%94_standardised_death_rate,_2012_%28per_100_000_ inhabitants%29_YB15.png. otwiera się w nowej karcie
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