2856
A. El-Gokha, G. Maas / Tetrahedron 67 (2011) 2849e2857
52.65 (d, J¼7.4 Hz, POC), 53.44 (d, J¼6.2 Hz, POC), 58.59 (d,
J¼5.9 Hz, CcpCH2N), 60.58 (CH2Ph), 127.48 (d, J¼2.5 Hz), 128.07,
128.32, 128.49, 128.63, 129.60 (d, J¼4.6 Hz), 130.45, 131.61, 134.19,
obtained as a mixture of four isomers. The crude product was pu-
rified by Lobar column chromatography eluting with ethyl acetate.
Two major fractions were obtained, both as highly viscous colorless
oils (combined yield: 0.40 g, 80%). The first fraction was a 1.75:1
mixture of the two Z-cyclopropanes Z-20 I and II; the second
fraction was a mixture of Z-20 I, Z-20 II, E-20 I, and E-20 II.
135.45 (d, J¼1.40 Hz) (all CPh) ppm. 31P NMR:
d
¼30.57 ppm. 11B
NMR:
d
¼ꢂ15.40 ppm. MS (CI, 100 eV): m/z (%)¼372 (100, [MꢂH]),
360 (19, MꢂBH2).
A mixture of isomers (E)-17 I and (E)-17 II was obtained as
a semisolid white compound. IR (NaCl):
Data for the mixture of four diastereomers: IR (NaCl):
n
¼3436
n
¼3165 (w, br, NH), 2376
(m, br, NH), 1738 (vs, C]O), 1602 (m), 1493 (s), 1447 (s), 1237 (vs, br,
P]O),1111 (s), 1033 (vs, br, POC), 954 (m), 922 (m), 849 (m), 827 (s),
733 (vs), 702 (vs) cmꢂ1. HRMS ((þ)-ESI): m/z¼378.1441 (calcd
378.1446 for C16H26NNaO5P, [MþNa]).
(m)/2321 (m)/2275 (w) (BH), 1492 (m), 1455 (m), 1229 (s, P]O),
1167 (m), 1069 (s), 1033 (vs, POC), 912 (s), 848 (m), 827 (m), 733 (s),
701 (s) cmꢂ1. 1H NMR: Table 2. 13C{1H} NMR, (E)-17 I:
d
¼16.42 (d,
J¼5.5 Hz, CcpCH3), 23.76 (d, J¼1.8 Hz, CcpCH2N), 25.70 (d, J¼2.9 Hz,
CcpH2), 29.28 (d, J¼186.6 Hz, PCcp), 52.64 (d, J¼7.0 Hz, POCH3), 52.57
(d, J¼6.2 Hz, POCH3), 60.28 (d, J¼2.9 Hz, CcpCH2NþH), 61.17 (CH2Ph),
127.44 (d, J¼2.2 Hz), 127.72 (d, J¼2.2 Hz), 128.79, 128.85, 128.93 (d,
J¼1.5 Hz), 129.33, 129.77, 130.81 (d, J¼2.6 Hz), 133.69, 135.06 (d,
Data for Z-20 I: 1H NMR: Table 2. 13C{1H} NMR:
d¼18.70
(CHCH3), 20.92 (CcpCH3), 23.71 (CcpH2), 28.52 (d, J¼1.8 Hz,
CcpCH2N), 30.11 (d, J¼184.8 Hz, PCcp), 51.57 (COOCH3), 52.11e52.75
(CcpCH2N, POCH3), 56.75 (NCHCH3), 126.94, 127.71 (d, J¼2.2 Hz),
128.27, 129.91 (d, J¼5.1 Hz), 132.23, 136.64 (d, J¼1.8 Hz) (all CPh),
J¼1.5 Hz) (all CPh) ppm; (E)-17 II:
d
¼17.29 (d, J¼5.9 Hz, CcpCH3),
175.95 (C]O) ppm. 31P NMR:
d
¼30.36 ppm.
23.58 (d, J¼2.9 Hz, CcpH2), 24.46 (d, J¼1.5 Hz, CcpCH2N), 30.44 (d,
J¼186.6 Hz, PCcp), 52.71 (d, J¼4.5 Hz, POC), 52.76 (d, J¼6.6 Hz, POC),
59.49 (CH2Ph), 61.17 (d, J¼2.2 Hz, CcpCH2N), 127.60 (d, J¼2.2 Hz),
128.22 (d, J¼2.6 Hz), 128.55, 128.65 (d, J¼1.5 Hz), 128.68, 129.49 (d,
J¼5.5 Hz), 129.73, 130.97 (d, J¼2.6 Hz), 134.13, 134.60 (d, J¼1.1 Hz)
Data for Z-20 II: 1H NMR: Table 2. 13C{1H} NMR:
d¼18.81
(CHCH3), 20.98 (CcpCH3), 23.74 (CcpH2), 28.33 (d, J¼1.8 Hz,
CcpCH2N), 30.09 (d, J¼184.4 Hz, PC), 51.55 (COOCH3), 52.64e52.79
(CcpCH2N, POCH3), 56.90 (NCHCH3), 126.97, 127.79 (d, J¼2.6 Hz),
128.27, 129.76 (d, J¼5.5 Hz), 132.25, 136.70 (d, J¼1.8 Hz) (all CPh),
(all CPh) ppm. 31P NMR:
NMR:
d
¼28.67 (isomer II), 29.20 (I) ppm. 11B
175.88 (C]O) ppm. 31P NMR:
d
¼30.45 ppm.
d
¼ꢂ15.20 (isomer I), ꢂ15.10 (II) ppm. HRMS ((þ)-ESI):
Mixture of Z-20 I, Z-20 II, E-20 I, and E-20 II: 1H NMR data for the
E-isomers: Table 2. 31P NMR:
¼30.60 (E-20 I), 30.47 (E-20 II) ppm.
m/z¼396.1874 (calcd 396.1876 for C20H29BNO3PNa, [MþNa]) for the
mixture of four isomers. MS (CI, 100 eV): m/z (%)¼372 (100, [Mꢂ1]),
360 (49, MꢂBH2).
d
3.5.5. (2S)-Methyl 2-(20-dimethoxyphosphoryl-10-methyl-20-phenyl-
cyclopropyl-10- methylamino)-3-phenylpropanoate (21). The pro-
cedure as given for 15 was used. Starting from imine 19
(29:29:22:20 mixture), amine 21 was obtained as a mixture of four
isomers in the molar ratio 30:30:21:19 (E-21 I/E-21 II/Z-21 I/Z-21
II). The crude product was purified by column chromatography
over silica gel eluting with a mixture of ethyl acetate and cyclo-
hexane (9:1). Two major fractions were obtained as highly viscous,
colorless oils (combined yield: 0.42 g, 84%): (a) (E)-21, isomers I and
II (1:0.85 ratio); (b) (Z)-cyclopropane Z-21, isomers I and II (1:0.85
ratio) (note that in both cases, the isomer ratio does not exactly
reproduce the ratio before chromatography).
3.5.3. Methyl 2-(2-dimethoxyphosphoryl-1-methyl-2-phenylcyclopr
opyl-1-methylamino)acetate (16). The procedure as given for 15
was used. The crude product was purified by Lobar column chro-
matography eluting with a mixture of dichloromethane and
methanol (9.5:0.5) to afford a diastereomeric mixture of 16 (E/
Z¼64:36) as a highly viscous, slightly yellow oil; yield: 0.41 g (82%).
The diastereomers could not be separated by chromatography over
alumina 90 (eluent: ethanol) or RP-18 (eluent: ethanol, acetonitrile,
or chloroform). A partial separation was possible by preparative
layer chromatography over silica gel (SIL G-200 UV254, Macher-
eyeNagel, 2 mm, 20ꢃ20 cm; eluent: ethanolepetroleum ether-
etriethylamine (10:90:0.1)); from 18 mg of the mixture, a fraction
with Rf¼0.28 furnished 15 mg of the E/Z mixture and 25 mg of (Z)-
16 as an oil, which was not pure by 1H NMR spectroscopy, however.
Crystallization from CH2Cl2/n-pentane afforded very soft colorless
crystals, mp 150 ꢁC.
Data for the mixture of four diastereomers: IR (NaCl):
n
¼3335
(w, br, NH), 1738 (s, C]O), 1602 (w), 1493 (m), 1447/1446 (m), 1236
(s, br, P]O), 1111 (m), 1032 (s, br, POC), 912 (m), 849 (m), 827 (m),
732 (s) cmꢂ1. MS (CI, 100 eV): m/z (%)¼432 (100, [Mþ1]), 400 (11,
M), 372 (7, M), 340 (21), 253 (9). HRMS ((þ)-ESI): m/z¼432.1934
(calcd 432.1940 for C23H31NO5P, [MþH]).
IR (NaCl):
1447 (m),1235 (s, P]O),1182 (m), 1149 (w), 1066,1032 (s, POC), 913
(s), 850 (m), 826 (m), 732 (s), 703 (m) cmꢂ1. 1H NMR: Table 2. 13
{1H} NMR, (Z)-16:
n
¼3335 (w, br, NH), 1742 (s, C]O), 1601 (w), 1492 (m),
Data for the mixture of E-21 I and II: 1H NMR: Table 2. 13C{1H}
NMR, isomer I:
d
¼17.80 (d, J¼5.1 Hz, CcpCH3), 22.60 (d, J¼2.6 Hz,
C
CcpH2), 27.59 (d, J¼1.8 Hz, CcpCH2N), 30.56 (d, J¼184.8 Hz, PCcp),
39.41 (CH2Ph), 51.15 (COOCH3), 52.39 (d, J¼7.0 Hz, P(OCH3)2), 54.03
(d, J¼1.8 Hz, CcpCH2N), 63.05 (NCHCO), 126.40, 126.78 (d, J¼2.6 Hz),
127.60 (d, J¼2.6 Hz), 128.05, 128.94, 129.15, 129.89 (d, J¼5.5 Hz),
131.25 (d, J¼2.9 Hz), 136.35 (d, J¼1.8 Hz), 137.16 (all CPh), 174.60 (C]
d
¼20.58 (CcpCH3), 23.39 (d, J¼2.9 Hz, CcpH2),
27.99 (d, J¼1.8 Hz, CcpCH2N), 29.66 (d, J¼185.2 Hz, PCcp), 50.18
(CH2CO), 51.10 (COOCH3), 52.25 (d, J¼6.9 Hz, POCH3), 52.36 (d,
J¼6.9 Hz, POCH3), 53.75 (d, J¼5.9 Hz,
CcpCH2N), 126.59 (d,
J¼2.6 Hz), 127.36 (d, J¼2.6 Hz), 127.93 (d, J¼1.5 Hz), 129.41, 131.84
(d, J¼2.9 Hz), 136.21 (d, J¼1.8 Hz) (all CPh), 172.30 (C]O) ppm; (E)-
O); isomer II:
d
¼17.59 (d, J¼5.1 Hz, CcpCH3), 22.71 (d, J¼2.6 Hz,
CcpH2), 27.27 (d, J¼2.2 Hz, CcpCH2N), 30.00 (d, J¼185.2 Hz, PCcp),
39.32 (CH2Ph), 51.12 (COOCH3), 52.33 (d, J¼7.0 Hz, P(OCH3)2), 54.34
(d, J¼1.8 Hz, CcpCH2N), 62.63 (NCHCO), 126.37, 126.86 (d, J¼2.6 Hz),
127.79 (d, J¼2.6 Hz), 128.08, 129.02, 129.06, 129.55 (d, J¼5.5 Hz),
131.02 (d, J¼2.9 Hz), 136.19 (d, J¼1.8 Hz), 137.29 (all CPh), 174.28 (C]
16:
d
¼17.34 (d, J¼5.5 Hz, CcpCH3), 22.60 (d, J¼2.6 Hz, CcpH2), 26.97
(d, J¼1.8 Hz, CcpCH2N), 30.04 (d, J¼185.2 Hz, PCcp), 50.33 (CH2CO),
51.03 (COOCH3), 52.04 (d, J¼6.9 Hz, POCH3), 52.13 (d, J¼6.9 Hz,
POCH3), 55.65 (d, J¼2.2 Hz, CcpCH2N), 126.67 (d, J¼2.6 Hz), 127.44
(d, J¼2.6 Hz), 127.99 (d, J¼1.5 Hz), 129.47, 130.85 (d, J¼2.6 Hz),
O) ppm. 31P NMR:
d¼30.19 (I), 30.30 (II) ppm.
136.20 (d, J¼1.8 Hz) (all CPh), 172.08 (C]O) ppm. 31P NMR:
d
¼30.31
Data for the mixture of Z-21 I and II: 1H NMR: Table 2. 13C{1H}
NMR, isomer I:
(E), 30.57 (Z) ppm. MS (CI, 100 eV): m/z¼342 (100, [Mþ1]), 310 (10),
269 (7), 253 (20, M), 159 (11), 129 (20). HRMS ((þ)-ESI): m/
z¼342.1465 (calcd 342.1470 for C16H25NO5P, [MþH]).
d¼20.95 (CcpCH3), 23.56 (d, J¼3.3 Hz, CcpH2), 28.50
(d, J¼1.8 Hz, CcpCH2N), 30.18 (d, J¼185.2 Hz, PCcp), 39.54 (CH2Ph),
51.51 (COOCH3), 52.13 (d, J¼5.9 Hz, CcpCH2N), 52.62e52.75 (P
(OCH3)2, both isomers), 63.31 (NCHCO), 126.53, 127.00, 127.85 (d,
J¼2.6 Hz), 128.26, 128.31, 129.26, 129.80 (d, J¼4.8 Hz), 132.31 (d,
J¼2.9 Hz), 136.78 (d, J¼1.8 Hz), 137.29 (all CPh), 174.93 (C]O); iso-
3.5.4. (2S)-Methyl 2-(20-dimethoxyphosphoryl-10-methyl-20-phenyl-
cyclopropyl-10-methylamino)propanoate (20). The procedure as
given for 15 was used. Starting from imine 18, amine 20 was
mer II:
d¼20.97 (CcpCH3), 23.72 (d, J¼3.3 Hz, CcpH2), 28.55 (d,