(2E,4S)-4-(Benzyl-cyanomethyl-amino)-hex-2-enoic acid ethyl
ester 19. Yield: 84%; Rf: 0.66 (AcOEt–PE, 1 : 1); [a]25 −37
(c 1.1, CHCl3); dH(300 MHz, CDCl3, Me4Si): 0.95 (t, 3H, JD= 7.3,
CH3), 1.31 (t, 3H, J = 7.1, CH3), 1.57–1.58 (m, 2H, CH2CH3),
3.21–3.29 (m, 1H, CHN), 3.37 (d, 1H, J = 17.9, CHHCN), 3.45
(d, 1H, J = 17.9, CHHCN), 3.68 (d, 1H, J = 13.5, CHHPh),
3.80 (d, 1H, J = 13.5, CHHPh), 4.22 (q, 2H, J = 7.0, CH2O),
6.03 (d, 1H, J = 15.7, CHCOOEt), 6.90 (dd, 1H, J = 8.6, 15.7,
(3R,4S,5R)-(1-Benzyl-2-cyano-4-phenyl-azetidin-3-yl)-acetic
acid ethyl ester 23. R = Ph: overall yield: 58%. Cis–trans ratio,
38 : 62.
Yield: 22%; Rf: 0.72 (E–CyH, 60 : 40); [a]2D5 +91.6 (c 0.4,
CHCl3); dH(250 MHz, CDCl3, Me4Si): 1.08 (t, 3H, J = 7.5,
CH3), 2.61 (dd, 1H, J = 4.6, 12.9, CHHCO2Et), 2.73–2.98 (m,
2H, CHHCO2Et and CHCH2), 3.70 (AB syst., 2H, J = 13.3,
CH2Ph), 3.97 (brquad, 3H, J = 7.1, OCH2 and CHPh), 4.34 (d,
1H, J = 7.1, CHCN), 7.18–7.38 (m, 10H, Ar); dC(62.9 MHz,
CDCl3, Me4Si): 14.2 (CH3), 34.2 (CH2), 40.6, 55.3 (CH), 56.0,
61.0 (CH2), 72.7 (CH), 115.7 (CN), 127.1, 127.7, 128.6, 128.8,
129.2 (CHAr), 136.5, 139.5 (CqAr), 170.7 (CO); Anal. Calcd.
for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 74.93; H,
6.73; N, 8.02%.
=
CH CHCO2Et), 7.27–7.34 (m, 5H, Ph); dC(62.9 MHz, CDCl3,
Me4Si): 10.1, 14.2 (CH3), 24.6, 38.5, 54.9, 60.6 (CH2), 64.6 (CH),
115.7 (CN), 124.5 (CH), 127.8, 128.7, 128.8, 129.1 (CHAr), 137.1
(Cq Ar), 146.3 (CH), 170.0 (CO); MS (IC, NH3): m/z: 286.6,
256.9, 91.9; Anal. Calcd. for C17H22N2O2: C, 71.30; H, 7.74; N,
9.78. Found: C, 71.29; H, 7.82; N, 9.76%.
(3S,4R,5R)-(1-Benzyl-2-cyano-4-phenyl-azetidin-3-yl)-acetic
acid ethyl ester 24. Yield: 36%; mp: 68–70 ◦C; Rf: 0.5 (E–CyH,
1 : 1); [a]2D5 −68.7 (c 1.5, CHCl3); dH(250 MHz, CDCl3, Me4Si):
1.10 (t, 3H, J = 6.8, CH3), 2.48 (ABX syst., 1H, CHHCO2Et),
2.50 (ABX syst., 1H, CHHCO2Et), 2.83 (dquad, 1H, J = 5.9
and 6.0, CHCH2), 3.49 (d, 1H, J = 7.7, CHPh), 3.52 (d, J =
12.9, CHHPh), 3.75 (d, 1H, J = 7.1, CHCN), 3.83 (d, J = 12.9,
CHHPh), 4.00 (dquad, 2H, J = 1.5 and 7.4, CH2O), 7.18–7.38
(m, 10H, Ar); dC(62.9 MHz, CDCl3, Me4Si): 14.2 (CH3), 36.4
(CH2), 43.6, 53.1 (CH), 59.9, 61.2 (CH2), 71.3 (CH), 118.9
(CN), 127.1, 128.0, 128.5, 128.6, 128.7, 129.6 (CHAr), 135.0,
139.8 (CqAr), 170.3 (CO); Anal. Calcd. for C21H22N2O2: C,
75.42; H, 6.63; N, 8.38. Found: C, 75.27; H, 6.72; N, 8.12%.
(2E,4S)-4-(Benzyl-cyanomethyl-amino)-hept-2-enoic acid
ethyl ester 20. Yield: 92%; Rf: 0.7 (AcOEt–PE, 1 : 1); [a]D25
−37 (c 1.1, CHCl3); dH(300 MHz, CDCl3, Me4Si): 0.95 (t, 3H,
J = 7.1, CH3), 1.30 (t, 3H, J = 7.1, CH3), 1.31–1.90 (m, 4H,
(CH2)2CH3), 3.32–3.38 (m, 1H, CHN), 3.43 (s, 2H, CH2CN),
3.68 (d, 1H, J = 13.5, CHHPh), 3.84 (d, 1H, J = 13.5, CHHPh),
4.24 (q, 2H, J = 7.0, CH2O), 6.03 (d, 1H, J = 14.2, CHCOOEt),
=
6.90 (dd, 1H, J = 8.6, 14.7, CH CHCO2Et), 7.25–7.35 (m, 5H,
Ph); dC(62.9 MHz, CDCl3, Me4Si): 14.0, 14.2 (CH3), 19.0, 33.8,
38.5, 54.9, 60.6 (CH2), 63.0 (CH), 115.8 (CN), 124.3 (CH), 127.8,
128.7, 128.8 (CHAr), 137.1 (Cq Ar), 146.5 (CH), 165.9 (CO).
(2E,4S)-4-(Benzyl-cyanomethyl-amino)-5-methyl-hex-2-enoic
acid ethyl ester 21. Yield: 94%; Rf: 0.53 (AcOEt–PE, 2 : 8);
[a]2D5 −32 (c 3.3, CHCl3); dH(300 MHz, CDCl3, Me4Si): 0.91 (d,
3H, J = 6.8, CH3), 1.01 (d, 3H, J = 6.8, CH3), 1.35 (t, 3H,
J = 7.1, CH3), 2.03–2.10 (m, 1H, CHMe2), 3.48 (dd, 1H, J =
7.1 and 9.8, CHN), 3.35 (d, 1H, J = 17.6, CHHCN), 3.43 (d,
1H, J = 17.6, CHHCN), 3.43 (d, 1H, J = 13.5, CHHPh), 3.43
(d, 1H, J = 13.5, CHHPh), 4.22 (q, 2H, J = 7.1, OCH2CH3),
6.00 (d, 1H, J = 15.8, CHCOOEt), 6.85 (dd, 1H, J = 10 and
(3R,4S,5S)-(1-Benzyl-2-cyano-4-methyl-azetidin-3-yl)-acetic
acid ethyl ester 25. R = Me: overall yield: 74%. Cis–trans
ratio, 37 : 63.
Yield: 27%; Rf: 0.59 (E–CyH, 1 : 1); [a]2D5 +101.5 (c 0.2, CHCl3);
IR (neat): 2966, 2925, 2848, 2223, 1726 cm−1; dH(250 MHz,
CDCl3, Me4Si): 1.05 (d, 3H, J = 6.2, CH3), 1.18 (t, 3H, J =
7.1, CH3), 2.54–2.70 (m, 3H, CHCH2CO2Et), 3.10–3.23 (m,
1H, CHCH3), 3.62 (d, 1H, J = 13.3, CHHPh), 3.75 (d, 1H,
J = 13.3, CHHPh), 4.06 (q, 2H, J = 7.1, CH2O), 4.30 (d, 1H,
J = 5.9, CHCN), 7.18–7.30 (m, 5H, Ar); dC(62.9 MHz, CDCl3,
Me4Si): 14.3, 19.8 (CH3), 34.5 (CH2), 37.8, 55.9 (CH), 56.5, 61.0
(CH2), 66.5 (CH), 116.1 (CN), 127.6, 128.6, 129.2 (CHAr), 136.9
(CqAr), 171.1 (CO); Anal. Calcd. for C16H20N2O2: C, 70.56; H,
7.40; N, 10.29. Found: C, 70.63; H, 7.58; N, 10.18%.
=
15.7, CH CHCO2Et), 7.22–7.35 (m, 5H, Ph); dC(62.9 MHz,
CDCl3, Me4Si): 14.2, 17.8, 20.1 (CH3), 28.7 (CH), 38.6, 54.9,
60.4 (CH2), 69.2 (CH), 115.6 (CN), 125.9 (CH), 127.8, 128.7,
130.2 (CHAr), 137.1 (Cq Ar), 144.2 (CH), 165.5 (CO); MS (CI,
NH3): m/z: 301.2, 300.3, 257.3, 108.0, 90.9; Anal. Calcd. for
C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C, 71.98; H,
7.98; N, 9.27%.
(3S,4S,5S)-(1-Benzyl-2-cyano-4-methyl-azetidin-3-yl)-acetic
acid ethyl ester 26. Yield: 47%; Rf: 0.47 (E–CyH, 1 : 1); [a]D25
−15.8 (c 0.5, CHCl3); IR (neat): 2980, 2925, 2863, 2238, 1726,
1491, 1450 cm−1; dH(250 MHz, CDCl3, Me4Si): 1.02 (d, 3H, J =
5.9, CH3), 1.19 (t, 3H, J = 7.15, CH3), 2.42 (d, 1H, J = 3.1,
CHHCO2Et), 2.45 (d, 1H, J = 0.9, CHHCO2Et), 2.52–2.67
(m, 1H, CHCH2), 2.90 (qd, 1H, J = 6 and 7.5, 1H, CHCH3),
3.35 (d, 1H, J = 7.4, CHCN), 3.64 (AB syst., 2H, J = 12.9,
CH2Ph), 4.08 (q, 2H, J = 7.1, CH2O), 7.19–7.27 (m, 5H, Ar);
dC(62.9 MHz, CDCl3, Me4Si): 14.3, 20.6 (CH3), 36.7 (CH2),
41.0, 54.3 (CH), 60.8, 61.2 (CH2), 65.8 (CH), 119.0 (CN), 128.0,
128.6, 129.4 (CHAr), 135.7 (CqAr), 170.6 (CO); Anal. Calcd.
for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.54;
H, 7.51; N, 10.24%.
(2E,4S)-4-(Benzyl-cyanomethyl-amino)-6-methyl-hept-2-
enoic acid ethyl ester 22. Yield: 77%; Rf: 0.43 (E–CyH, 85 :
15); [a]2D5 −16 (c 1.1, CHCl3); dH(300 MHz, CDCl3, Me4Si): 0.83
(d, 6H, J = 6.8, 2CH3), 1.31 (t, 3H, J = 7.2, CH3), 1.40–2.69 (m,
3H, CH2CHMe2), 3.35–3.48 (m, 3H, CHN, CH2CN), 3.66 (d,
1H, J = 13.4, CHHPh), 3.85 (d, 1H, J = 13.4, CHHPh), 4.23
(q, 2H, J = 7.1, OCH2CH3), 6.02 (d, 1H, J = 16, CHCOOEt),
=
6.89 (dd, 1H, J = 8 and 16, CH CHCO2Et), 7.21–7.35 (m,
5H, Ph); dC(62.9 MHz, CDCl3, Me4Si): 14.2, 22.1, 23.1 (CH3),
24.6 (CH), 38.3, 40.5, 54.7, 60.6 (CH2), 61.2 (CH), 116.6 (CN),
124.3 (CH), 127.8, 128.7, 130.2 (CHAr), 137.1 (Cq Ar), 146.2
(CH), 165.5 (CO); MS (CI, NH3): m/z: 315.2, 314.3, 256.8,
92.4; Anal. Calcd. for C19H26N2O2: C, 72.58; H, 8.33; N, 8.91.
Found: C, 72.69; H, 8.48; N, 8.80%.
(3R,4S,5S)-(1-Benzyl-2-cyano-4-ethyl-azetidin-3-yl)-acetic
acid ethyl ester 27. R = Et: overall yield: 73%. Cis–trans ratio,
42 : 58.
General procedure for azetidine formation
To a solution of amino ester (1.19 mmol) in THF (5 mL) was
added, at −78 ◦C, a solution of LiHMDS (1 M solution in THF,
1.42 mL, 1.42 mmol). The mixture was gradually warmed to
−10 ◦C over a period of 2 h and the progress of the reaction was
monitored by TLC. After completion, hydrolysis by a saturated
aqueous solution of ammonium chloride was followed by the
usual workup (AcOEt). Flash chromatography of the residue
on silica gel (eluant: AcOEt–PE, 5 : 95 then 1 : 9) gave 2,3-cis-
isomers, followed by 2,3-trans-isomers.
Yield: 31%; Rf: 0.69 (AcOEt–PE, 2 : 8); [a]25 +83 (c 0.6,
CHCl3); dH(300 MHz, CDCl3, Me4Si): 0.90 (t, 3H,DJ = 7.5, CH3),
1.27 (t, 3H, J = 7.5, CH3), 1.50–1.56 (m, 2H, CH3CH2), 2.64–
2.84 (m, 3H, CHCH2CO2Et), 3.16 (q, 1H, J = 6.8, CHN), 3.74
(d, 1H, J = 13.2, CHHPh), 3.87 (d, 1H, J = 13.2, CHHPh), 4.18
(q, 2H, J = 7.1, CH2O), 4.38 (d, 1H, J = 7.4, CHCN), 7.27–7.31
(m, 5H, Ar); dC(62.9 MHz, CDCl3, Me4Si): 9.3, 14.1 (CH3), 27.0,
35.0 (CH2), 35.3, 55.6 (CH), 56.8, 60.9 (CH2), 71.6 (CH), 117.0
=
(CN), 127.4, 128.4, 128.9 (CHAr), 138.1 (CqAr), 171.4 (C O);
3 9 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 2 6 – 3 9 3 6