10.1002/ejoc.201700536
European Journal of Organic Chemistry
FULL PAPER
The fraction collected at 60 ºC – 125 ºC (0.5 mbar) was discarded.
The system was cooled down and charged with new containers and
condenser (this procedure is necessary!).
13C NMR (101 MHz, CDCl3) of both diastereomers δ 173.06 (s), 172.98
(s), 145.05 (s), 144.93 (s), 128.46 (s), 128.38 (s), 127.11 (s), 127.07 (s),
127.03 (s), 126.95 (s), 84.07 (s), 83.37 (s), 78.20 (s), 77.56 (s), 64.84 (s),
64.79 (s), 63.29 (s), 62.91 (s), 60.79 (s), 60.76 (s), 55.31 (s), 55.06 (s),
50.26 (s), 50.01 (s), 47.74 (s), 47.60 (s), 23.08 (s), 22.88 (s), 14.30 (s).
The fraction collected at 125 ºC – 129 ºC (0.5 mbar) to afford the title
compound (98.7-101.0 g, 85.0-86.9% yield) as a colorless liquid.
MS (EI, m/z): 289 (M +).
1H NMR (400 MHz, DMSO) δ 7.37 – 7.20 (m, 5H, Ph), 4.59 (d, J = 5.8
Hz, 1H, CCHHO), 4.46 (d, J = 6.6 Hz, 1H, CCHHO), 4.36 (d, J = 5.8 Hz,
1H, CCHHO), 4.32 (d, J = 6.6 Hz, 1H, CCHHO), 4.13 (m, 2H, CH3CH2O),
3.60 (m, 2H, CH2Ph), 3.14 (dd, J = 8.4, 6.4 Hz, 1H), 3.03 (d, J = 9.0 Hz,
1H), 2.86 (t, J = 9.0 Hz, 1H), 2.72 (d, J = 9.0 Hz, 1H), 2.55 (m, 1H), 1.22
(t, 3H, J = 7.0 Hz, CH3).
Anal. calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.81; H,
8.19; N, 4.95.
6-Benzyl-2-thia-6-aza-spiro[3.4]octane-8-carboxylic acid ethyl ester
(4a)
13C NMR (101 MHz, DMSO) δ 172.95 (s, CO2Et), 139.09 (s, Ph, C),
128.86 (s, Ph, CH), 128.67(s, Ph, CH), 127.37(s, Ph, CH), 82.45 (s,
CCH2O), 77.35 (s, CCH2O), 64.20 (s), 60.76(s), 59.22(s), 56.05(s),
49.84(s), 47.82(s), 14.62 (s, CH3).
Pale yellow oil. B. p. 140 – 148 ºC (0.5 mbar). Purified by column
chromatography (Hex/MTBE (70%/30%). 66% (A), 83% (B) yield.
1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H, Ph), 4.36 – 4.07 (m, 2H,
CH2CH3), 3.65 (s, 2H, CH2Ph), 3.51 (d, J = 8.9 Hz, 1H), 3.41 (d, J = 9.5
Hz, 1H), 3.16 (d, J = 8.9 Hz, 1H), 3.03 – 2.50 (m, 6H), 1.31 (t, J = 6.9 Hz,
3H, CH2CH3).
MS (EI, m/z): 275 (M +).
Anal. calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C,
70.11; H, 7.41; N, 5.40.
13C NMR (101 MHz, DMSO) δ 172.50 (s, CO2Et), 139.26 (s, Ph, C),
128.84 (s, Ph, CH), 128.70 (s, Ph, CH), 127.37 (s, Ph, CH), 66.00 (s),
60.79 (s), 59.20 (s), 55.25 (s), 53.08 (s), 52.74 (s), 37.10 (s), 33.62 (s),
14.68 (s, CH3).
(S)-6-Benzyl-2-oxa-6-aza-spiro[3.4]octane-8-carboxylic acid ethyl
ester ((S)-3a)
Colorless liquid. 99.9% еe, [α]20D =-6.9, retention time 19.92 min.
MS (EI, m/z): 291 (M +).
1H NMR (400 MHz, DMSO) δ 7.37 – 7.20 (m, 5H, Ph), 4.59 (d, J = 5.8
Hz, 1H, CCHHO), 4.46 (d, J = 6.6 Hz, 1H, CCHHO), 4.36 (d, J = 5.8 Hz,
1H, CCHHO), 4.32 (d, J = 6.6 Hz, 1H, CCHHO), 4.13 (m, 2H, CH3CH2O),
3.60 (m, 2H, CH2Ph), 3.14 (dd, J = 8.4, 6.4 Hz, 1H), 3.03 (d, J = 9.0 Hz,
1H), 2.86 (t, J = 8.9 Hz, 1H), 2.72 (d, J = 9.0 Hz, 1H), 2.55 (m, 1H), 1.22
(t, 3H, J = 7.0 Hz, CH3).
Anal. calcd for C16H21NO2S: C, 65.95; H, 7.26; N, 4.81. Found: C, 65.72;
H, 7.43; N, 4.53.
6-Benzyl-2,2-dioxo-2-thia-6-aza-spiro[3.4]octane-8-carboxylic
ethyl ester (5a)
acid
13C NMR (101 MHz, DMSO) δ 172.95 (s, CO2Et), 139.09 (s, Ph, C),
128.86 (s, Ph, CH), 128.67(s, Ph, CH), 127.37(s, Ph, CH), 82.45 (s,
CCH2O), 77.35 (s, CCH2O), 64.20 (s), 60.76(s), 59.22(s), 56.05(s),
49.84(s), 47.82(s), 14.62 (s, CH3).
Brown solid. M. p. 65 – 68 ºC. 87% (A), 90% (B) yield.
1H NMR (400 MHz, DMSO) δ 7.29 (m, 5H, Ph), 4.36 (d, J = 13.5 Hz, 1H),
4.26 – 4.03 (m, 4H), 3.97 (dd, J = 3.1, 13.8 Hz, 1H), 3.69 (d, J = 13.2 Hz,
1H, CHHPh), 3.65 (d, J = 13.2 Hz, 1H, CHHPh), 3.3 (m, 1H), 2.84 (m,
4H), 1.22 (t, J = 7.1 Hz, 3H, CH3).
MS (EI, m/z): 275 (M +).
Anal. calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.56; H,
7.31; N, 5.37.
13C NMR (126 MHz, DMSO) δ 171.85 (s, CO2Et), 138.56 (s, Ph, C),
128.45 (s, Ph, CH), 128.33 (s, Ph, CH), 127.06 (s, Ph, CH), 73.64 (s,
CH2SO2), 70.35 (s, CH2SO2), 63.94 (s), 60.79 (s), 58.45 (s), 54.43 (s),
49.76 (s), 33.58 (s, C), 14.04 (s, CH2CH3).
(R)-6-Benzyl-2-oxa-6-aza-spiro[3.4]octane-8-carboxylic acid ethyl
ester ((R)-3a)
MS (EI, m/z): 323 (M +).
Anal. calcd for C16H21NO4S: C, 59.42; H, 6.55; N, 4.33. Found: C, 59.22;
H, 6.28; N, 4.58.
Colourless liquid. 61.7% еe, retention time 23.32 min.
1H NMR (400 MHz, DMSO) δ 7.37 – 7.20 (m, 5H, Ph), 4.59 (d, J = 5.8
Hz, 1H, CCHHO), 4.46 (d, J = 6.6 Hz, 1H, CCHHO), 4.36 (d, J = 5.8 Hz,
1H, CCHHO), 4.32 (d, J = 6.6 Hz, 1H, CCHHO), 4.13 (m, 2H, CH3CH2O),
3.60 (m, 2H, CH2Ph), 3.14 (dd, J = 8.4, 6.4 Hz, 1H), 3.03 (d, J = 9.0 Hz,
1H), 2.86 (t, J = 8.9 Hz, 1H), 2.72 (d, J = 9.0 Hz, 1H), 2.55 (m, 1H), 1.22
(t, 3H, J = 7.0 Hz, CH3).
6-Benzyl-2,6-diaza-spiro[3.4]octane-2,8-dicarboxylic acid 2-tert-butyl
ester 8-methyl ester (6a)
Colorless oil. Purified by column chromatography (Hex/MTBE (40%/60%).
89% (A), 93% (B) yield.
13C NMR (101 MHz, DMSO) δ 172.95 (s, CO2Et), 139.09 (s, Ph, C),
128.86 (s, Ph, CH), 128.67(s, Ph, CH), 127.37(s, Ph, CH), 82.45 (s,
CCH2O), 77.35 (s, CCH2O), 64.20 (s), 60.76(s), 59.22(s), 56.05(s),
49.84(s), 47.82(s), 14.62 (s, CH3).
1H NMR (500 MHz, DMSO) δ 7.33 – 7.22 (m, 5H, Ph), 3.92 (d, J = 8.5 Hz,
1H CHHNBoc), 3.84 – 3.77 (m, 2H, 2×CHHNBoc), 3.71 (m, 4H,
CHHNBoc, OMe), 3.62 (m, 2H, CH2Ph), 3.10 – 3.00 (m, 2H), 2.93 (d, J =
9.2 Hz, 1H), 2.79 – 2.71 (m, 1H), 2.67 (d, J = 9.2 Hz, 1H), 1.41 (s, 9H,
Boc).
MS (EI, m/z): 275 (M +).
Anal. calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.48; H,
7.85; N, 5.28.
t
13C NMR (126 MHz, DMSO) δ 172.91 (CO2Me), 155.76 (s, CO2 Bu),
138.11 (s, Ph, C), 128.15 (s, Ph, CH), 127.93(s, Ph, CH), 126.73(s, Ph,
CH), 79.06 (s, C(CH3)3), 64.13 (s), 61.36 (s), 59.17 (s), 56.01 (s), 55.77
(s), 51.50 (s), 50.46 (s), 41.91 (s), 27.96 (s, C(CH3)3).
Ethyl
carboxylate (3b)
6-((R)-1-phenylethyl)-2-oxa-6-azaspiro[3.4]octane-8-
MS (CI, m/z): 361 (M+H +).
Anal. calcd for C20H28N2O4: C, 66.64; H, 7.83; N, 7.77. Found: C, 66.32;
H, 8.17; N, 7.41.
Yellow oil. 39% (A), 46% (B) yield.
1H NMR (400 MHz, CDCl3) of both diastereomers δ 7.43 – 7.00 (m, 5H,
Ph), 4.70 – 3.92 (m, 7H, 2×CH2O, CH3CH2O, NHCH3), 3.31 – 2.48 (m,
5H, CHCO2Et, 2×CH2N), 1.40 – 1.03 (m, 6H, 2×CH3).
6-Benzyl-6-aza-spiro[3.4]octane-8-carboxylic acid ethyl ester (7a)
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