Unsaturated Imines for the Synthesis of Glutamic Acid Analogues

Supporting Information © Wiley-VCH 2005

69451 Weinheim, Germany

Moonen et al. Page 1

Novel One-pot Tandem 1,4-1,2-addition of Phosphites to α,β-

Unsaturated Imines for the Synthesis of Glutamic Acid Analogues

Kristof Moonen, Ellen Van Meenen, Annelies Verwée, Christian V. Stevens

Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience

Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium.

Contents:

Experimental data Page 2

Product characterization Page 3 – 8

PAP 6a Page 3

PAP 6b Page 3

PAP 6c Page 4

PAP 6d Page 4

PAP 6e Page 5

PAP 6f Page 5

PAP 6g Page 6

PAP 6h Page 6

PAP 6i Page 7

PAP 6j Page 7

PAP 6k Page 8

Sample spectra (1H,

13C and

31P NMR) Page 9 - 11

Mechanistic evidence Page 12

Free phosphonic acids Page 16


1. Experimental data

General

All 1H-NMR spectra were recorded at room temperature (22°C) using a JEOL ECX300 spectrometer (300

MHz) with CDCl3 as a solvent and tetramethylsilane (TMS) as internal standard. 13C-NMR spectra were

recorded at 75 MHz and 31P-NMR spectra at 121 MHz. The absolute value of the coupling constants (J)

in Hz and assignments of 1H and

13C peaks were determined using COSY, HSQC, HMBC and DEPT

experiments. IR spectra were measured using a Perkin – Elmer Spectrum One spectrometer. MS spectra

were measured using an Agilent 1100 mass spectrometer using electron spray ionisation (ESI, 4000 V).

General procedure for the preparation of dialkyl trimethylsilyl phosphite (DAPTMS)

30 mmol Of dialkyl phosphite (DAP) in 40 mL of dry dichloromethane is mixed with 33 mmol of

triethylamine (1.1 eq.) in an oven dry flask under a nitrogen atmosphere. The mixture is then cooled to

0°C and 33 mmol of TMSCl (1.1 eq.) is added using a syringe. After reacting 1 h at 0°C, the DAP is

completely converted to the DAPTMS (this can easily be seen in 31P-NMR (DAP: δ = 5 – 15 ppm;

DAPTMS: δ = 120 – 130 ppm). The triethylammonium chloride salts are removed by filtration (care has

to be taken to avoid contact with moisture) and the dichloromethane is evaporated in vacuo. Then, 20 mL

of dry diethyl ether is added to the residue in order to precipitate the remaining triethylammonium

chloride from the mixture. After filtration and evaporation of the solvent, the DAPTMS is obtained as a

clear, colorless liquid and can be stored for several weeks at -20°C when kept away from moisture.

General procedure for the synthesis of 3-phosphonyl aminoalkyl phosphonates (PAP’s) 6

5 mmol of an α,β-unsaturated imine 5 in 15 mL of dry dichloromethane is allowed to stirr at room

temperature under a nitrogen atmosphere. Then, 10 mmol of DAPTMS and 2.5 mmol of sulfuric acid

(1 eq. of H+) are added consecutively. CAUTION: the reaction proceeds very vigorously upon addition of

sulfuric acid and the solvent may start to boil. The mixture is allowed to react for 1 h at room temperature

and is then poured into 20 mL of an aqueous saturated NaHCO3 solution. The organic phase is recovered

and the remaining aqueous phase is washed twice with 5 mL of dichloromethane. The PAP is obtained in

satisfactory purity after drying (MgSO4) and evaporation of the solvent. In order to have the PAP’s at

higher purity, an acid/base extraction can be performed. Also column chromatography with silica gel as a

stationary phase and a mixture of CH3CN, EtOAc and MeOH (50/47/3) as a mobile phase is appropriate.


2. Product characterization

Signals of the major and minor isomers are indicated as ‘m’ and ‘M’ whenever possible.

{3-(Diethoxy-phosphonyl)-3-[2-(1H-indol-3-yl)-ethylamino]-1-phenyl-propyl}-phosphonic acid

diethyl ester (6a)

Ratio: 29/71

1H-NMR δδδδ (300 MHz, ppm): 1.04 – 1.27 (multiplet, 2 x 12H, CH3, m+M); 2.11-2.41 (multiplet, 2H,

CH2CH, m+M); 2.43 – 2.54 (~t, 1H, NCH, M); 2.63-2.71 (multiplet, 1H, CHAHBN, M); 2.78 (t,

3J(H,H) = 6.6 Hz, 2H, CH2Cq=, m); 2.84 (t,

3J(H,H) = 6.6 Hz, 2H, CH2Cq=, M); 2.89 – 2.98 (multiplet,

3H, CH2N, NCH, m); 3.16 – 3.24 (multiplet, 1H, CHAHBN, M); 3.45 – 3.56 (multiplet, 2 x 1H, CHPh,

m+M); 3.59 – 4.13 (m, 2 x 8H, OCH2, m+M); 6.85 (d, J = 2.2 Hz, 1H, =CH, m); 6.91 (d, J = 2.2 Hz, 1H,

=CH; M); 7.00 – 7.41 (multiplet, 2 x 8H, CHarom, m+M, 3 x CHindole, m+M); 7.49 (d, 3J(H,H) = 7.7 Hz,

1H, CHCq,indole, m); 7.56 (d, 3J(H,H) = 7.7 Hz, 1H, CHCq,indole, M); 9.58 (s(br.), 2 x 1H, NHindole, m+M).

13C-NMR δδδδ (75 MHz, ppm): 16.13 (CH3, m); 16.22 (CH3, m); 16.34 (CH3, M); 16.42 (CH3, M); 25.92

(CH2Cq=, m); 26.44 (CH2Cq=, M); 30.15 (d, 2J(C,P) = 6.9 Hz, CH2CH, M); 30.94 (CH2CH, m); 39.89

(dd, 1J(C,P) = 138.5 Hz,

3J(C,P) = 13.9 Hz, CHPh, M); 40.67 (dd,

1J(C,P) = 136.2 Hz,

3J(C,P) = 6.9 Hz,

CHPh, m); 48.04 (d, 3J(C,P) = 6.9 Hz, CH2N, m); 48.35 (CH2N, M); 51.70 (dd,

1J(C,P) = 144.2 Hz,

3J(C,P) = 16.2 Hz, NCH, M); 52.75 (dd,

1J(C,P) = 150.0 Hz,

3J(C,P) = 12.7 Hz, NCH, m); 61.74, 61.83,

61.87, 61.93, 62.29, 62.38, 62.47, 62.61 (OCH2, m+M); 111.39 (CHCqNindole); 112.62 (=Cq, m); 112.93

(=Cq, M); 118.63, 118.66 (CHindole); 121.37 (CHCHCqC=); 122.41 (=CH); 127.30 (CHarom); 127.42

(Cq,indole); 128.55 (2 x CHarom); 129.28 (d, 3J(C,P) = 6.9 Hz, 2 x CHarom, m); 129.48 (d,

3J(C,P) = 6.9 Hz, 2

x CHarom, M); 134.84 (d, 2J(C,P) = 6.9 Hz, Cq,arom, M); 136.17 (d,

2J(C,P) = 6.9 Hz, Cq,arom, m); 136.64

(CqN). 31P-NMR δδδδ (121 MHz, ppm): 28.22 (m); 29.04 (m); 29.04 (d,

4J(P,P) = 9.7 Hz, M); 29.99 (d,

4J(P,P) = 9.7 Hz, M). IR (film):1232 cm

-1 (P=O); 1030 cm

-1 (br, P-O). MS m/z (%): 551 (100) [M+H

+].

[3-Benzylamino-3-(dimethoxy-phosphonyl)-1-phenyl-propyl]-phosphonic acid diethyl ester (6b)

Ratio: 19/81

1H-NMR: (300 MHz, ppm) δ: 1,71 (s (br), 1H, NH), 2,08-2,50 (multiplet, 2x 2H, CHPCH2CHP, m+M),

2,58 (~td, J = 12,1 Hz, J = 2,3 Hz, 1H, PCHN, M), 2,89 (1H, ~quintet, J = 6,9 Hz, PCHNH, m), 3,43-

4,04 (2x 15H, multiplet, 4x OCH3, PCHPh, CH2Ph, m+M), 7,01-7,08 (2x 10H, multiplet, CH(Ph), m+M).

13C-NMR: (75 MHz, ppm) δ: 30,18 (d,

2J(C,P) = 8,1 Hz, CH2, M), 30,58 (CH2, m), 39,18 (dd,

1J(C,P) =

139,6 Hz, 3J(C,P) = 13,8 Hz, PCHPh, M), 39,73 (d,

1J(C,P) = 137,3 Hz, PCHPh, m), 49,94 (dd,

1J(C,P) =

148,8 Hz, 3J(C,P) = 16,1 Hz, PCHNH, M), 50,57 (dd,

1J(C,P) = 145,4 Hz,

3J(C,P) = 12,7 Hz, PCHNH,

m), 50,96 (OCH3), 50,98 (d, 3J(C,P) = 6,9 Hz, CH2Ph, m), 51,41 (OCH3), 51,52 (CH2Ph, M), 51,65


(OCH3), 52,05 (OCH3), 52,75 (OCH3), 126,54 (CH(Ph)), 126,62 (CH(Ph)), 126,92 (CH(Ph)), 127,76

(CH(Ph)), 127,88 (CH(Ph)), 128,19 (CH(Ph)), 128,71 (CH(Ph)), 128,86 (CH(Ph)), 128,94 (CH(Ph)),

134,11 (d, 2J(C,P) = 5,8 Hz, Cq(Ph), M), 135,32 (d,

2J(C,P) = 6,9 Hz, Cq(Ph), m), 139,01 (Cq(Ph), m),

139,53 (Cq(Ph), M). 31P-NMR: (121 MHz, ppm) δ: 30,41 (m), 31,23 (m), 31,27 (d,

4J(P,P) = 9,7 Hz, M),

32,08 (d, 4J(P,P) = 9,7 Hz, M). IR: (film): 3467 cm

-1 (N-H), 1243 cm

-1 (br, P=O), 1030 cm

-1 (br, P-O).

MS: m/z (%) : 442 (100) [M+H+], 333 (8) [M

+- PO(OCH3)2].

[3-Benzylamino-3-(diethoxy-phosphonyl)-1-phenyl-propyl]-phosphonic acid diethyl ester (6c)

Ratio: 29/71

1H-NMR δδδδ (300 MHz, ppm): 1.07 (t,

3J(H,H) = 6.6 Hz, 3H, CH3, m); 1.09 (t,

3J(H,H) = 7.2 Hz, 3H,

CH3, M); 1.26 – 1.36 (multiplet, 2 x 9H, CH3, m+M); 2.04 – 2.48 (multiplet, 2 x 2H, CH2, m+M); 2.55

(td, J = 11.8 Hz, JH-P = 2.2 Hz, 1H, NCHP, M); 2.81 – 2.94 (multiplet, 1H, NCHP, m); 3.53 – 4.19

(multiplet, 2 x 7H, CH2N, CHP, OCH2, m+M); 7.12 – 7.36 (multiplet, 2 x 10H, CHarom, m+M). 13C-NMR

δδδδ (75 MHz, ppm): 16.20, 16.28, 16.37, 16.46, 16.52, 16.60 (CH3); 30.68 (d, 2J(C,P) = 8.1 Hz, CH2, M);

31.15 (CH2, m); 40.32 (dd, 1J(C,P) = 139.6 Hz,

3J(C,P) = 14.4 Hz, CHP, M); 40.89 (dd,

1J(C,P) = 137.3 Hz,

3J(C,P) = 5.8 Hz, CHP, m); 51.17 (dd,

1J(C,P) = 141.9 Hz,

3J(C,P) = 16.2 Hz, NCHP,

M); 51.57 (d, 3J(C,P) = 8.1 Hz, NCH2, m); 51.74 (dd,

1J(C,P) = 150.0 Hz,

3J(C,P) = 13.3 Hz, NCHP, m);

52.03 (NCH2, M); 61.82, 61.91, 62.03, 62.31, 62.42, 62.49, 62.58, 62.68 (OCH2); 126.99, 127.09, 127.28,

127.31, 128.24, 128.37, 128.42, 128.56, 128.59, 129.35, 129.44, 129.50, 129.60 (CHarom, m + M); 135.07

(d, 2J(C,P) = 5.8 Hz, Cq,arom, M); 136.21 (d,

2J(C,P) = 6.9 Hz, Cq,arom, m); 139.72 (Cq,arom, m); 140.31

(Cq,arom, M). 31P-NMR δδδδ (121 MHz, ppm): 28.16 (m); 28.91 (d,

4J(P,P) = 9.7 Hz, M); 28.99 (m); 29.86

(d, 4J(P,P) = 9.7 Hz, M). IR (film): 3306 cm

-1 (NH); 1243 cm

-1 (P=O); 1051 cm

-1, 1026 cm

-1 (P-O). MS

m/z (%): 498 (100) [M+H+], 360 (37).

[3-(Dimethoxy-phosphonyl)-3-isopropylamino-1-phenyl-propyl]-phosphonic acid diethyl ester (6d)

Ratio: 32/68

1H-NMR: (300 MHz, ppm) δ: 0,67 (d,

3J(H,H) = 6,1 Hz, 3H, CH3, M), 0,73 (d,

3J(H,H) = 6,1 Hz, 3H,

CH3, m), 0,94 (d, 3J(H,H) = 6,3 Hz, 3H, CH3, m), 0,98 (d,

3J(H,H) = 6,3 Hz, 3H, CH3, M), 1,55 (s(br),

1H, NH), 2,02-2,20 (multiplet, 2x 1H, CHaHb, m+M), 2,41-2,52 (multiplet, 2x 1H, CHaHb, m+M), 2,64

(td, J = 11,6 Hz, JHP = 2,8 Hz, 1H, PCHNH, M), 2,76-2,84 (multiplet, 1H, PCHNH, m), 2,81 (septet,

3J(H,H) = 6,3 Hz, 1H, CH(CH3)2, m), 3,01 (septet x d,

3J(H,H) = 6,1 Hz,

4J(H,P) = 2,8 Hz, 1H,

CH(CH3)2, M), 3,47 (d, 3J(H,P) = 10,5 Hz, 3H, OCH3, m), 3,49 (d,

3J(H,P) = 10,5 Hz, 3H, OCH3, M),

3,69 (d, 3J(H,P) = 10,5 Hz, 3H, OCH3, M), 3,71 (d,

3J(H,P) = 10,5 Hz, 3H, OCH3, M), 3,72 (d,

3J(H,P) =

10,5 Hz, 3H, OCH3, m), 3,74 (d, 3J(H,P) = 10,5 Hz, 3H, OCH3, M), 3,75 (d,

3J(H,P) = 10,5 Hz, 3H,


OCH3, m), 3,77- 3,81 (multiplet, 2x 1H, CHP(Ph), m+M), 3,80 (d, 3J(H,P) = 10,5 Hz, 3H, OCH3, m),

7,26-7,36 (multiplet, 5H, CH(Ph)). 13C-NMR: (75 MHz, ppm) δ: 22,11 (CH3, M), 22,37 (CH3, m), 23,15

(CH3, m), 24,01 (CH3, M), 30,53 (d, 2J(C,P) = 8,1 Hz, CH2, M), 31,33 (s(br), CH2, m), 39,63 (dd,

1J(C,P)

= 141,9 Hz, 3J(C,P) = 10,4 Hz, PCHPh, M), 40,47 (d (br),

1J(C,P) = 137,3 Hz, PCHPh, m), 46,04 (d,

3J(C,P) = 9,2 Hz, CH(CH3)2, m), 46,28 (CH(CH3)2, M), 48,55 (dd,

1J(C,P) = 145,4 Hz,

3J(C,P) =

12,7 Hz, PCHNH, M), 49,27 (dd, 1J(C,P) = 153,5 Hz,

3J(C,P) = 13,9 Hz, PCHNH, m), 52,59 (OCH3),

52,68 (OCH3), 52,83 (OCH3), 53,26 (OCH3), 53,37 (OCH3), 53,67 (OCH3), 127,50 (CH(Ph)), 128,66

(CH(Ph)), 129,30 (CH(Ph)), 129,38 (CH(Ph)), 129,61(CH(Ph)), 129,69 (CH(Ph)), 134,50 (d, 2J(C,P) =

6,9 Hz, Cq(Ph), M), 135,58 (d, 2J(C,P) = 6,9 Hz, Cq(Ph), m).

31P-NMR: (121 MHz, ppm) δ: 30,66 (m),

31,28 (m), 31,62 (d, 4J(P,P) = 9,7 Hz, M), 32,10 (d,

4J(P,P) = 9,7 Hz, M). IR: (film): 3477 cm

-1 (N-H),

1245 cm-1 (br, P=O), 1051 cm

-1 (br, P-O). MS: m/z (%) : 394 (100) [M+H

+], 285 (12) [M

+-PO(OCH3)2],

176 (2) [M+-2PO(OCH3)2].

[3-(Diethoxy-phosphonyl)-3-isopropylamino-1-phenyl-propyl]-phosphonic acid diethyl ester (6e)

Ratio: 33/67

1H-NMR δδδδ (300 MHz, ppm): 0.70 (d,

3J(H,H) = 6.1 Hz, 3H, CH3CH, M); 0.72 (d,

3J(H,H) = 6.1 Hz, 3H,

CH3CH, m); 0.94 (d, 3J(H,H) = 6.3 Hz, 3H, CH3CH, m); 0.99 (d,

3J(H,H) = 6.3 Hz, 3H, CH3CH, M); 1.08

(t, 3J(H,H) = 6.9 Hz, 3H, CH3, m); 1.12 (t,

3J(H,H) = 7.3 Hz, 3H, CH3, M); 1.26 – 1.36 (multiplet, 2 x 9H,

CH3, m+M); 1.97 – 2.53 (multiplet, 2 x 2H, CH2, m+M); 2.60 (td, J = 11.6 Hz, J = 2.5 Hz, 1H, NCHP,

M); 2.71 – 2.81 (multiplet, 1H, NCHP, m); 2.86 (septet, 3J(H,H) = 6.3 Hz, 1H, NCH, m); 3.06 (septet x d,

3J(H,H) = 6.3 Hz,

4J(H,P) = 2.6 Hz, 1H, NCH, M); 3.54 – 3.79 (multiplet, 2 x 1H, CHP, m+M); 2.81 –

4.21 (multiplet, 2 x 8H, OCH2, m+M); 7.22 – 7.41 (multiplet, 2 x 5H, CHarom, m+M). 13C-NMR δδδδ (75

MHz, ppm): 16.21, 16.29, 16.37, 16.46, 16.50, 16.58 (CH3, m+M); 22.16 (CH3CH, M); 22.43 (CH3CH,

m); 23.16 (CH3CH, m); 24.05 (CH3CH, M); 30.58 (d, 2J(C,P) = 6.9 Hz, CH2, M); 31.51 (CH2, m); 40.98

(dd, 1J(C,P) = 136.7 Hz,

3J(C,P) = 4.0 Hz, CHP, m); 41.19 (dd,

1J(C,P) = 136.2 Hz,

3J(C,P) = 15.0 Hz,

CHP, M); 46.02 (d, 3J(C,P) = 4.0 Hz, NCH, m); 46.19 (NCH, M); 49.03 (dd,

1J(C,P) = 140.8 Hz,

3J(C,P)

= 17.3 Hz, NCHP, M); 49.64 (dd, 1J(C,P) = 152.9 Hz,

3J(C,P) = 14.4 Hz, NCHP, m); 61.71, 61.75, 61.81,

61.85, 61.94, 62.37, 62.46, 62.54, 62.58, 62.63 (OCH2, m+M); 127.29 (CHarom, m+M); 128.47 (CHarom,

m); 128.49 (CHarom, M); 129.49 (d, 3J(C,P) = 6.9 Hz, CHarom, m); 129.78 (d,

3J(C,P) = 6.9 Hz, CHarom, M);

135.05 (d, 2J(C,P) = 6.9 Hz, Cq,arom, M); 136.10 (d,

2J(C,P) = 6.9 Hz, Cq,arom, m).

31P-NMR δδδδ (121 MHz,

ppm): 28.41 (m); 28.94 (m); 29.09 (d, 4J(P,P) = 9.7 Hz, M); 29.70 (d,

4J(P,P) = 9.7 Hz, M). IR (film):

3300 cm-1 (NH); 1243 cm

-1 (P=O); 1047 cm

-1 (br, P-O). MS m/z: 450 (100) [M+H

+], 312 (65) [M

+-

PO(OCH2CH3)2].


[3-tert-Butylamino-3-(dimethoxy-phosphoryl)-1-phenyl-propyl]-phosphonic acid diethyl ester (6f)

Ratio: 49/51

1H-NMR: (300 MHz, ppm) δ: 0,89 (s, 3H, CH3, m), 0,96 (s, 3H, CH3, M), 2,11-2,38 (multiplet, 2x 1H,

CHaHb, m+M), 2,39-2,56 (multiplet, 2x 1H, CHaHb, m+M), 2,72 (ddd, J = 15,1 Hz, J = 11,3 Hz, J =

3,3 Hz, 1H, NHP, m), 3,02 (ddd, J = 16,0 Hz, J = 8,3 Hz, J = 4,7 Hz, 1H, NHP, M), 3,45 (d, 3J(H,P) =

10,5 Hz, 3H, OCH3, m), 3,48 (d, 3J(H,P) = 10,5 Hz, 3H, OCH3, m), 3,51-3,84 (multiplet, 2x 1H, CHP,

m+M), 3,68 (d, 3J(H,P) = 10,7 Hz, 3H, OCH3, m), 3,73 (d,

3J(H,P) = 10,5 Hz, 3H, OCH3, M), 3,74 (d,

3J(H,P) = 10,7 Hz, 3H, OCH3, M), 3,75 (d,

3J(H,P) = 10,2 Hz, 3H, OCH3, M), 3,76 (d,

3J(H,P) = 10,2 Hz,

3H, OCH3, M), 3,81 (d, 3J(H,P) = 10,2 Hz, 3H, OCH3, m), 7,25-7,44 (multiplet, 2x 5H, CH(Ph), m+M).

13C-NMR: (75 MHz, ppm) δ: 29,78 (CH3, M), 30,32 (CH3, m), 32,98 (CH2, m), 35,19 (CH2, M), 40,00

(d, 1J(C,P) = 140,8 Hz, CHP, m), 40,42 (d,

1J(C,P) = 138,5 Hz, CHP, M), 46,78 (dd,

1J(C,P) = 160,4 Hz,

3J(C,P) = 17,3 Hz, CHPN, m), 47,48 (dd,

1J(C,P) = 151,1 Hz,

3J(C,P) = 13,8 Hz, CHPN, M), 50,99 (Cq,

M), 51,84 (Cq, m), 52,68, 53,34, 54,25 (OCH3, m+M), 127,42 (CH(Ph), m), 127,56 (CH(Ph), M), 128,61

(4x CH(Ph), 2x m + 2x M), 129,65 (2x CH(Ph), m+M), 129,71 (2x CH(Ph), m+M), 135,13 (d, 2J(C,P) =

6,9 Hz, Cq, M), 135,45 (d, 2J(C,P) = 6,9 Hz, Cq, m).

31P-NMR: (121 MHz, ppm) δ: 30,60 (M), 31,00 (d,

4J(P,P) = 5,9 Hz, m), 31,14 (M), 31,88 (d,

4J(P,P) = 5,6 Hz, m). IR: (film): 3469 cm

-1 (N-H), 1235 cm

-1

(br, P=O), 1051 cm-1 (br, P-O). MS: m/z (%): 408 (100) [M+H

+].

[3-tert-Butylamino-3-(diethoxy-phosphoryl)-1-phenyl-propyl]-phosphonic acid diethyl ester (6g)

Ratio: 36/64

1H-NMR δδδδ (300 MHz, ppm): 0.89 (s, 3H, CH3Cq, m); 0.97 (s, 3H, CH3Cq, M); 1.05 (t,

3J(H,H) = 7.1 Hz,

3H, CH3, m); 1.12 (t, 3J(H,H) = 7.1 Hz, 3H, CH3, M); 1.26 – 1.36 (multiplet, 2 x 9H, CH3, m+M); 2.10 –

2.33 (multiplet, 2 x 1H, CHAHB, m+M); 2.39 – 2.60 (multiplet, 2 x 1H, CHAHB, m+M); 2.70 (ddd,

J = 16.1 Hz, J = 11.3 Hz, J = 3.3 Hz, 1H, NCHP, m); 3.00 (ddd, J = 16.0 Hz, J = 8.3 Hz, J = 4.7 Hz, 1H,

NCHP, M); 3.63 – 4.28 (multiplet, 2 x 9 H, OCH2, CHP, m+M); 7.22 – 7.46 (multiplet, 2 x 5H, CHarom,

m+M). 13C-NMR δδδδ (75 MHz, ppm): 16.21, 16.27, 16.38, 16.46, 16.55 (CH2CH3); 29.56 (CH3, m); 30.12

(CH3, M); 32.87 (d, 2J(C,P) = 6.9 Hz, CH2,M); 35.10 (CH2, m); 40.28 (dd,

1J(C,P) = 136.1 Hz,

3J(C,P) = 9.2 Hz, CHP, M); 41.04 (d,

1J(C,P) = 136.1 Hz, CHP, m); 46.88 (dd,

1J(C,P) = 159.2 Hz,

3J(C,P) = 17.9 Hz, NCHP, m); 47.84 (dd,

1J(C,P) = 152.29 Hz,

3J(C,P) = 13.9 Hz, NCHP, M); 51.01

(NCq, m); 51.81 (d, 3J(C,P) = 9.2 Hz, NCq, M); 61.76, 61.85, 62.31, 62.41, 62.51, 63.02, 63.12 (OCH2);

127.23, 127.38, 128.45, 129.75, 129.84, 129.95 (CHarom); 135.58 (d, 2J(C,P) = 6.9 Hz, Cq,arom, m); 135.93

(d, 2J(C,P) = 8.1 Hz, Cq,arom, M).

31P-NMR δδδδ (121 MHz, ppm): 28.74 (s(br.), m); 28.84 (d,

4J(P,P) = 6.0 Hz, M); 28.91 (s(br.), m); 29.64 (dd,

4J(P,P) = 6.0 Hz, M). IR (film): 3308 cm

-1 (NH); 1243

cm-1 (P=O); 1049 cm

-1, 1028 cm

-1 (P-O). MS m/z: 464 (100) [M+H

+], 326 (56) [M

+-PO(OCH2CH3)2].


{2-[(Dimethoxy-phosphonyl)-isopropylamino-methyl]-6,6-dimethyl-bicyclo[3.1.1]hept-3-yl}-

phosphonic acid dimethyl ester (6h)

Ratio: 22/78

1H-NMR δδδδ (300 MHz, ppm): 0.98 – 1.22 (multiplet, 2 x 13H, CH3Cq, CH3CH, CHAHB, m+M); 1.73

(s(br.), 2 x 1H, NH, m+M); 1.88 – 1.95 (multiplet, 2 x 1H, CqCHCH2, m+M); 2.10 – 2.20 (multiplet, 2 x

2H, CH2CHP, m+M); 2.23 – 2.32 (multiplet, 1H, CHAHB, M); 2.34 – 2.40 (multiplet, 2 x 1H, CqCHCH,

m+M); 2.41 – 2.49 (multiplet, 1H, CHAHB, m); 2.56 – 2.79 (mumtiplet, 2 x 1H, NCHP, m+M); 2.90 –

2.95 (multiplet, 1H, CHPCH2, m); 2.98 – 3.04 (multiplet, 2H, CHPCH2, NCHP, M); 3.13 (septet x d,

3J(H,H) = 6.3 Hz,

3J(H,P) = 2.5 Hz, 2 x 1H, CHCH3, m+M); 3.52 (dd, J = 17.6 Hz, J = 3.3 Hz, 1H,

NCHPm); 3.72 – 3.84 (multiplet, 2 x 12H, OCH3,m+M). 13C-NMR δδδδ (75 MHz, ppm): 21.69 (CH3Cq);

22.64 (CH3CH, M); 23.71 (CH3CH, M); 24.06 (CH3, m); 25.06 (dd, 1J(C,P) = 139.6 Hz,

3J(C,P)

= 11.5 Hz, CHPCH2, M); 25.60 (CH3, m); 26.44 (dd, 1J(C,P) = 139.6 Hz,

3J(C,P) = 16.2 Hz, CHPCH2,

m); 26.51 (d, 2J(C,P) = 4.6 Hz, CH2CHP); 27.06 (CH3Cq); 28.35 (CH3, m); 29.51 (CH2, M); 34.59 (CH2,

m); 37.68 (Cq, M); 37.84 (Cq, m); 38.73 (d, 3J(C,P) = 4.6 Hz, CqCHCH2, M); 40.41 (CqCHCH2, m); 40.59

(CHCHP); 40.67 (CHCHP); 43.42 (d, 3J(C,P) = 5.8 Hz, CqCHCHM); 43.80 (d,

3J(C,P) = 11.5 Hz,

CqCHCHm); 46.74 (CHCH3, m+M); 51.74 (OCH3, m); 51.91 (d, 2J(C,P) = 8.1 Hz, OCH3, M); 52.61 (d,

2J(C,P) = 6.9 Hz, OCH3, M); 52.87 d,

2J(C,P) = 6.9 Hz, OCH3, M); 53.18 (d,

1J(C,P) = 132.7 Hz,

NCHPm); 53.48 (d, 2J(C,P) = 6.9 Hz, OCH3, M); 55.30 (d,

1J(C,P) = 148.8 Hz, NCHPM).

31P-NMR δδδδ

(121 MHz, ppm): 31.59 (d, 4J(P,P) = 3.0 Hz, M); 32.87 (d,

4J(P,P) = 2.2 Hz, m); 37.83 (d,

4J(P,P) = 2.2 Hz, m); 39.02 (d,

4J(P,P) = 3.0 Hz, M);. IR (film): 3311 cm

-1 (NH); 1235 (P=O); 1054 (br.,

P-O). MS m/z: 412 (100) [M+H+], 302 (7) [M

+-PO(OCH3)2].

{2-[(Dimethoxy-phosphonyl)-tert-butylamino-methyl]-6,6-dimethyl-bicyclo[3.1.1]hept-3-yl}-

phosphonic acid dimethyl ester (6i)

Ratio: 12/88

Due to the low abundance of the minor isomer, peak identification in 1H- and

13C-NMR was limited to the

major (M) isomer.

1H-NMR: (300 MHz, ppm) δ: 0,99 (s, 3H, CH3), 1,13 (s, 9H, CH3), 1,13-1,15 (multiplet, 1H, CHaHb),

1,19 (s, 3H, CH3, M), 1,90 (s(br), 1H, CqCHCH2), 2,08-2,32 (multiplet, 3H, CH2CHP, CHaHb, m+M),

2,42 (s (br), 1H, CqCHCH,), 2,55-2,88 (multiplet, 2x 1H, CHCHP, CHP), 3,20 (~t, J = 10,3 Hz, 1H,

NCHP). 13C-NMR: (75 MHz, ppm) δ: 22,99 (CH3Cq, M), 25,93 (dd,

1J(C,P) = 139,6 Hz,

3J(C,P) =

13,9 Hz, CHP), 27,21 (CH3Cq), 29,96 (br, CH2), 30,49 (3x CH3), 37,74 (Cq), 39,80 (d, 3J(C,P) = 4,6 Hz,

CqCHCH2), 41,68 (s (br), CHCHCHP), 43,12 (d, 3J(C,P) = 5,8 Hz, CqCHCH), 50,78 (NCq), 51,90 (d,

2J(C,P) = 8,1 Hz, OCH3), 52,72 (d,

2J(C,P) = 6,9 Hz, OCH3), 53,18 (d,

2J(C,P) = 6,9 Hz, OCH3), 54,23 (d,


2J(C,P) = 6,9 Hz, OCH3), 54,22 (dd,

1J(C,P) = 148,8 Hz, NCHP).

31P-NMR: (121 MHz, ppm) δ: 31,59

(d, 4J(P,P) = 3,7 Hz, M), 34,07 (m), 37,79 (m), 38,95 (d,

4J(P,P) = 3,7 Hz, M). IR: (film) : 3320 cm

-1 (N-

H), 1227 cm-1 (br, P=O), 1051 cm

-1 (br, P-O). MS: m/z (%) : 426 (100) [M+H

+].

[3-tert-Butylamino-3-(dimethoxy-phosphonyl)-1-methyl propyl] phosphonic acid dimethyl ester (6j)

Ratio: 36/64

1H-NMR: (300 MHz, ppm) δ: 0,95 (s, 9H, 3x CH3, m), 0,96 (s, 9H, 3x CH3, M), 0,99-1,23 (multiplet, 2x

3H, CH3, m+M), 1,32-2,00 (multiplet, 2x 3H, CH2, NH, m+M), 2,02-2,32 (multiplet, 1H, CHP, m+M),

2,98 (ddd, J = 15,4 Hz, J = 9,9 Hz, J = 5,5 Hz, 1H, NCHP, m), 3,13 (dt, J = 16,2 Hz, J = 7,4 Hz, 1H,

NCHP, M), 3,75 (d, 3J(H,P) = 10,5 Hz, 3H, OCH3, m), 3,61 (d,

3J(H,P) = 10,5 Hz, 3H, OCH3, m), 3,75

(d, 3J(H,P) = 10,5 Hz, 3H, OCH3, M), 3,76 (d,

3J(H,P) = 10,5 Hz, 3H, OCH3, M).

13C-NMR: (75 MHz,

ppm) δ: 13,39 (d, 2J(C,P) = 4,6 Hz, CH3, m), 14,72 (d,

2J(C,P) = 4,6 Hz, CH3, M), 26,34 (dd,

1J(C,P) =

141,9 Hz, 3J(C,P) = 6,9 Hz, CHP, M), 27,03 (d,

1J(C,P) = 139,6 Hz, CHP, m), 29,71 (3x CH3, m), 29,97

(3x CH3, M), 34,72 (CH2, s (br), m), 35,02 (CH2, s (br), M), 46,94 (d, 1J(C,P) = 145,4 Hz, NCHP, M),

47,00 (d, 1J(C,P) = 163,8 Hz, NCHP, m), 51,37 (d,

3J(C,P) = 5,8 Hz, NCq, m), 51,79 (d,

3J(C,P) = 8,1 Hz,

NCq, M), 52,41 (d, 3J(C,P) = 8,1 Hz, OCH3, M), 52,66 (d,

3J(C,P) = 12,7 Hz, OCH3, M), 53,74 (d,

3J(C,P)

= 6,9 Hz, OCH3, m), 54,29 (s(br), OCH3, m). 31P-NMR: (121 MHz, ppm) δ: 30,61 (d,

4J(P,P) = 2,2 Hz,

m), 31,75 (d, 4J(P,P) = 5,2 Hz, M), 37,11 (d,

4J(P,P) = 2,2 Hz, m), 37,99 (d,

4J(P,P) = 5,2 Hz, M). IR:

(film): 3470 cm-1 (N-H), 1231 cm

-1 (br, P=O), 1034 cm

-1 (br, P-O). MS: m/z (%): 346 (100) [M+H

+].

[3-tert-Butylamino-3-(dimethoxy-phosphonyl)-1,1-dimethyl-propyl] phosphonic acid dimethyl ester

(6k)

1H-NMR: (300 MHz, ppm) δ: 1,15 (s, 9H, 3x CH3), 1,26 (d,

3J(H,P) = 5,2 Hz, 3H, CH3), 1,32 (d,

3J(H,P) = 5,2 Hz, 3H, CH3), 1,65-1,82 (multiplet, 1H, CHaHb), 1,91 (s(br), 1H, NH), 2,15-2,30 (multiplet,

1H, CHaHb), 3,36 (dt, J = 13,5 Hz, J = 6,3 Hz, 1H, CHP), 3,75 (d, 3J(H,P) = 10,2 Hz, 3H, OCH3), 3,76 (d,

3J(H,P) = 10,2 Hz, 3H, OCH3), 3,77 (d,

3J(H,P) = 10,2 Hz, 3H, OCH3), 3,80 (d,

3J(H,P) = 10,2 Hz, 3H,

OCH3). 13C-NMR: (75 MHz, ppm) δ: 20,67 (CH3), 20,73 (CH3), 28,81 (3x CH3), 34,98 (dd,

1J(C,P) =

139,6 Hz, 3J(C,P) = 8,1 Hz, CqP), 38,43 (d,

2J(C,P) = 6,9 Hz, CH2), 45,11 (dd,

1J(C,P) = 150,0 Hz,

3J(C,P) = 12,1 Hz, CHP), 50,28 (d,

3J(C,P) = 4,6 Hz, NCq), 51,25 (d,

2J(C,P) = 8,1 Hz, OCH3), 51,72 (d,

2J(C,P) = 8,1 Hz, OCH3), 51,82 (d,

2J(C,P) = 8,1 Hz, OCH3), 52,18 (d,

2J(C,P) = 8,1 Hz, OCH3).

31P-

NMR: (121 MHz, ppm) δ: 31,36 (d, 4J(P,P) = 3,0 Hz), 38,85 (d,

4J(P,P) = 3,0 Hz). IR: (film): 3429 cm

-1

(N-H), 1242 cm-1 (P=O), 1049 cm

-1 (br, P-O). MS : m/z (%): 360 (100) [M+H

+], 250 (7) [M

+-

PO(OCH3)2].


3. Sample spectra of compound 6f




4. Mechanistic evidence

The structure of all 1,2-adducts mentioned in the text was confirmed via a separate synthesis. When

imines 5 are reacted with 2 equivalents of dialkyl phosphite in methanol at reflux temperatures (2 – 3 h),

exclusive formation of 1,2-addition products is observed. The resulting α-aminophosphonates can be

obtained in pure form after acid-base extraction or column chromatography. Satisfactory IR, MS, 1H-

NMR, 31P-NMR and

13C-NMR data were obtained for all adducts.

In order to support the mechanism that was proposed in scheme 1, several experiments were performed in

order to look for the suggested intermediate 1,4-adduct, whether in its enamine (10) or imine form (11).

When the reaction was performed using 2 eq. of DAPTMS and 1 eq. of sulfuric acid, the reaction

proceeded very fast at room temperature and monitoring of intermediates was impossible. When 2 eq. of

triethylammonium chloride (Et3NHCl, coming from the generation of the DAPTMS, see “general

procedure for the preparation of DAPTMS”) was used as an activator and proton source in stead of

sulfuric acid, the reaction proceeded very sluggishly (complete conversion only in several days of reflux).

When the reaction was monitored under these conditions, only starting material, PAP and 1,2-addition

product was detected using NMR (see figure 2). This means the second addition should proceed very fast

compared to the formation of the 1,4-adduct, causing it to disappear immediately upon generation.

Looking more carefully to the mechanism, it was reasoned that protons are consumed stoechiometrically

in the reaction. When subequivalent amounts of protons (0.2 eq. H+) were added, the reaction stopped

after an initial phase and the 1,4-adduct started to build up (see figure 3). However, when water was

added for work-up, protons from the water were used to convert the 1,4-adduct very fast to the

corresponding PAP and no identification of the intermediate was possible.

Three experiments were performed to prove the structure of the intermediate.

Experiment A: Imine 5c was reacted with 1 eq. of AlCl3 and 0.9 eq. of DEPTMS in dry dichloromethane

under a nitrogen atmosphere. The AlCl3 was supposed to act as an activator of the reaction (complexation


with the imine nitrogen atom, compared to protonation of the imine by sulfuric acid), leaving no protons

in the reaction medium. Only 0.9 eq. of DEPTMS was used in order to avoid the presence of an excess of

DEPTMS during the work-up. After 2 h at room temperature, a fast extraction using 1 M NaOH(aq)

resulted in a large amount of 1,4-adduct next to PAP 6e. The resulting 31P-spectrum is depicted at the top

in figure y. The PAP 6e is recognized as two doublets and two singlets, while the large singlet at ± 28

ppm is from the 1,4-adduct in its imine form 11 (a clear aldimine proton resonance is observed at 7,6 ppm

in the 1H-NMR spectrum, no vinylic protons were visible).

Experiment B: Imine 5c was reacted with 0.9 eq. of DEPTMS and 0.1 eq. of H2SO4 in dry

dichloromethane under a nitrogen atmosphere. As can be seen in figure 3, a small amount of PAP is

formed very fast initially, but then the reaction blocks, building up slowly the same 1,4-adduct, which can

again be isolated after basic extraction (since no DEPTMS was left during extraction), giving a similar

31P-spectrum (second plot in figure 4). When neutral water was added for work-up of the reaction, also

aldehyde 17 was detected at 27.6 ppm, resulting from hydrolysis of 16 during work-up (3rd plot in figure

4).

Experiment C: In order to prove the structure of the 1,4-adduct, imine 16 was synthesized using a

literature procedure. Exclusive 1,4-addition to tBu imine 5d was reported using triethyl phosphite and

formic acid in ethanol.[12] Imines similar to 16 with a tBu group in stead of the iPr group were suggested

as intermediates and were treated with oxalic acid in water to yield the corresponding aldehydes 17. The

intermediate imines were never isolated in the reported article and spectral data are only available for the

aldehyde 17. Therefore, imine 5c was reacted with 0.96 eq. of triethyl phosphite and 1.04 eq. of formic

acid in ethanol. Complete conversion took place in 1 h at room temperature. The 31P-spectrum after

evaporation of the ethanol is shown as the fourth plot in figure 4 (no aqueous work-up was performed,

causing a little broadening of the peaks of the ‘crude’ reaction mixture. Mind that traces of PAP 6e are

also formed under these conditions). This clearly shows that the intermediate is the same product in all

three experiments. Upon hydrolysis using 1 M oxalic acid in water, the same aldehyde is obtained in all

three experiments (δ(31P) = 27.6 ppm, plot five in figure 4). However, the reported value for aldehyde 17


is 24.4 ppm. Also a very low chemical shift (9.0 ppm) was reported for the aldehyde proton, causing a

little bit suspicion. Therefore, the experiment was repeated exactly as reported using imine 5d. Aldehyde

17 was obtained in pure form using column chromatography. Spectral data were now in agreement with

our previous results: δ(31P) = 27.6 ppm and the aldimine proton appears as a multiplet at 9.67 ppm in

1H-

NMR. The structure was confirmed using 2D COSY and HSQC experiments:

1H-NMR: (300 MHz, ppm) δ: 1,11 (t,

3J(H,H) = 7,2 Hz, 3H, CH3), 1,28 (t,

3J(H,H) = 7,2 Hz, 3H, CH3),

3,05 – 3,26 (multiplet, 2H, CH2), 3,67 – 4,14 (multiplet, 5H, OCH2, CHP), 7,23 – 7,39 (multiplet, 5H,

CHarom), 9.66 – 9.69 (multiplet, 1H, CHO). 13C-NMR: (75 MHz, ppm) δ: 16,18, 16,26, 16,34, 16,41

(CH3), 37,96 (d, 1J(C,P) = 140,8 Hz, CHP), 44,02 (d,

2J(C,P) = 2,3 Hz, CH2), 62,16, 62,25, 62,94, 63,03

(OCH2), 127,57 (d, J(C,P) = 2,3 Hz, CHarom), 128,70 (d, J(C,P) = 2,3 Hz, CHarom), 129,13 (d,

J(C,P) = 5,7 Hz, CHarom), 135,20 (d, 2J(C,P) = 6,9 Hz, Cq,arom), 198,97 (d,

3J(C,P) = 15,0 Hz, CHO).

31P-

NMR: (121 MHz, ppm) δ: 27,64. IR: (film): 1725 cm-1 (C=O); 1243 cm

-1 (P=O); 1050, 1027 cm

-1 (P-

O). MS : m/z (%): 271 (100) [M+H+].


Figure 4: a) Results of experiment A after alkaline work-up. PAP 6e can be clearly distinguished (28.4 – 29.8 ppm)

next to imine 11 (28 ppm). b,c) Results of experiments B after alkaline (b) or neutral (c) work-up. The same peaks

are visible. The hydrolysis product of imine 11 is observed at 27.6 ppm. (d) This spectrum of the crude reaction

mixture of experiment C after evaporation of the solvent shows that imine 11 is formed almost exclusively under

these conditions, next to very small amounts of PAP. (e) Spectrum of the pure aldehyde 17.


5. Free phosphonic acids

General procedure:

To an oven dry flask, 5 mmol of PAP is added together with 10 mL of dry dichloromethane under an

nitrogen atmosphere. Then, 25 mmol of TMSBr is added drop wise and the mixture is stirred at room

temperature. After 1 h, 2 mL of water is added and stirring is continued for 1 h at room temperature,

during which precipitation occurs. Finally, the solvent and excess water are evaporated at reduced

pressure.

Representative example (obtained as a poorly soluble powder starting from PAP 6d in 75% yield.

Spectral data are collected in D2O as a solvent):

1H-NMR: (300 MHz, ppm) δ: 0,84 (d,

3J(H,H) = 6,3 Hz, 3H, CH3, M), 1,04 (d,

3J(H,H) = 6,3 Hz, 3H

CH3, m), 1,05 (d, 3J(H,H) = 6,3 Hz, 3H, CH3, M), 1,16 (d,

3J(H,H) = 6,3 Hz, 3H, CH3, m), 2,19-2,39

(multiplet, 2x1H, CHaHb, m+M), 2,47-2,56 (multiplet, 2x1H, CHaHb, m+M), 2,76 (~t, J = 11,3 Hz, 1H,

PCHN, m), 2,07 (ddd, J = 12,9 Hz, J = 9,1 Hz, J = 3,3 Hz, 1H, PCHN, M), 3,30-3,58 (multiplet, 2x2H,

CH(CH3)2, CHP), m+M), 7,23-7,31 (multiplet, 2x5H, CHarom, m+M). 13C-NMR: (75 MHz, ppm) δ:

17,56 (CH3, M), 18,04 (CH3, m), 18,49 (CH3, M), 18,86 (CH3, m), 28,06 (CH2), 41,42 (dd, 1J(C,P) =

133,8 Hz, 3J(C,P) = 12,7 Hz, PCHPh, M), 42,03 (d,

1J(C,P) = 135,0 Hz, PCHPh, m), 49,97 (dd,

1J(C,P) =

143,1 Hz, 3J(C,P) = 18,5 Hz, PCHN, m), 50,26 (CH(CH3)2, M), 51,00 (d,

1J(C,P) = 111,9 Hz, PCHN, M),

51,74 (CH(CH3)2, m), 128,02, 128,18, 129,15, 129,23 (CHarom), 134,28 (Cq,arom). 31P-NMR: (121 MHz,

ppm) δ: 12,71 (M), 12,89 (d, 4J(P,P) = 3,7 Hz, m), 25,21 (d,

4J(P,P) = 3,7 Hz, m), 25,72 (M). IR: (KBr):

3414 cm-1 (N-H), 1245 cm

-1 (br, P=O), 1026 cm

-1 (br, P-O). MS : m/z (%): 336 (100), [M-H

+].

Documents

Unsaturated Imines for the Synthesis of Glutamic Acid Analogues