Maerten et al.
(3S)-3-(Diisopropoxyphosphoryl)hexyl 4-nitrobenzoate (ent-11c).
Colorless oil. The ee was determined by HPLC using a Daicel
Chiralcel OD column [hexane/iPrOH 95:5]; flow rate ) 1.0 mL/
min; τ major ) 12.2 min, τ minor ) 14.0 min; [R]23D ) +10.4 (c 0.5,
compound was obtained after FC purification (eluent: Et2O/MeOH
98/2). Colorless oil. The ee was determined by HPLC using a Daicel
Chiralpak AD column [hexane/iPrOH 98:2]; flow rate ) 1.0 mL/
min; τmajor ) 25.6 min, τminor ) 28.3 min; [R]23 ) -10.3 (c 0.5,
D
1
CH2Cl2, 82% ee); H NMR (CDCl3) δ 8.28 (d, J ) 8.0 Hz, 2H),
CH2Cl2, 59% ee); 1H NMR (CDCl3) δ 7.19-7.15 (m, 2H), 6.68 (t,
J ) 6.8 Hz, 1H), 6.61 (d, J ) 8.0 Hz, 2H), 3.76 (s, 3H), 3.73 (s,
3H), 3.27-3.23 (m, 2H), 2.02-1.69 (m, 4H), 1.51-1.37 (m, 4H),
0.91 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3) δ 148.0, 129.2, 117.2,
112.7, 52.4 (m), 41.9 (d, J ) 7.7 Hz), 33.2 (d, J ) 131.2 Hz),
30.7, 28.1, 20.8, 20.7, 14.0; 31P NMR (CDCl3) δ 37.2 (s); HRMS
calcd for C14H24NO3PNa [M + Na]+ 308.1391, found 308.1402.
Procedure for the Phosphonic Acids Synthesis. The alcohol
9h was mixed with 10 equiv of bromotrimethylsilane for 36 h. The
excess of bromotrimethylsilane was then evaporated, and the
mixture was hydrolyzed with distilled H2O for 5 h. H2O was then
evaporated and the crude dried under high vacuum conditions,
affording the desired product 12 in 80% yield. Colorless oil. The
ee was determined by realkylation of 11 (see below) (82% ee);
[R]20D ) +44.4 (c 1.0, MeOH); 1H NMR (D2O) δ 7.45-7.30 (m,
5H), 3.52 (br s, 1H), 3.35 (br s, 1H), 3.18-3.28 (q, 1H), 2.25 (br
s, 1H), 2.15 (br s, 1H); 13C NMR (D2O) δ 136.1 (d, J ) 7.4 Hz),
129.2 (d, J ) 6.4 Hz), 128.6 (d, J ) 2.5 Hz), 127.4 (d, J ) 3.2
Hz), 59.2 (d, J ) 16.9 Hz), 41.4 (d, J ) 132.8 Hz), 31.4 (d, J )
2.5 Hz); 31P NMR (D2O) δ 27.9 (s); HRMS calcd for C9H13O4PNa
[M + Na]+ 239.0449, found 239.0446.
8.19 (d, J ) 8.4 Hz, 2H), 4.72 (m, 2H), 4.50 (t, J ) 6.8 Hz, 2H),
2.17 (m, 1H), 1.96 (m, 1H), 1.80 (m, 2H), 1.46 (m, 3H), 1.30 (m,
12H), 0.91 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3) δ 164.5, 150.5,
135.6, 130.6 (m), 123.5, 70.0 (d, J ) 5.7 Hz), 64.2 (d, J ) 8.5
Hz), 33.6 (d, J ) 141.5 Hz), 30.6 (d, J ) 3.9 Hz), 27.5 (d, J ) 2.8
Hz), 24.1 (m), 20.7 (d, J ) 10.9 Hz), 14.0; 31P NMR (CDCl3) δ
30.0 (s).
(3R)-3-(Diisopropoxyphosphoryl)pentyl 4-nitrobenzoate (11e).
Colorless oil. The ee was determined by HPLC using a Daicel
Chiralcel OD column [hexane/iPrOH 97:3]; flow rate ) 1.0 mL/
min; τminor ) 21.4 min, τmajor ) 22.8 min; [R]23 ) -11.6 (c 0.5,
D
1
CH2Cl2, 85% ee); H NMR (CDCl3) δ 8.29 d, J ) 9.2 Hz, 2H),
8.20 (d, J ) 9.2 Hz, 2H), 4.72 (m, 2H), 4.49 (t, J ) 6.8 Hz, 2H),
2.19 (m, 1H), 1.98 (m, 1H), 1.81 (m, 2H), 1.57 (m, 1H), 1.31 (m,
12H), 1.05 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 164.5, 150.5,
135.6, 130.6, 123.5, 70.0 (m), 64.2 (d, J ) 8.9 Hz), 35.3 (d, J )
141.2 Hz), 27.0 (d, J ) 2.9 Hz), 24.1 (m), 21.5 (d, J ) 3.7 Hz),
12.2 (d, J ) 10.3 Hz); 31P NMR (CDCl3) δ 30.5 (s); HRMS calcd
for C18H28NO7PNa [M + Na]+ 424.1501, found 424.1501.
(3R,5Z)-3-(Diisopropoxyphosphoryl)non-5-en-1-yl 4-nitroben-
zoate (11f). Colorless oil. The ee was determined by HPLC using
a Daicel Chiralcel OD column [hexane/iPrOH 98:2]; flow rate )
Procedure for the Methylation of the Phosphonic Acid. The
phosphonic acid 12 (25 mg, 0.12 mmol) was dissolved in 0.2 mL
of a mixture of MeOH and CH2Cl2 (5:1) under N2. A 2.0 M solution
of (trimethylsilyl)diazomethane in hexanes (0.35 mL, 0.70 mmol,
6 equiv) was added dropwise over 30 s. After 2 h, the reaction
was concentrated in vacuo. The crude residue was purified by FC
on Iatrobeads (Et2O/MeOH 98/2) to provide the desired product
9h′′ in 60% yield (18 mg, 0.07 mmol), which was directly used
for ee determination by chiral HPLC. Colorless oil. The ee was
determined by HPLC using a Daicel Chiralcel AD column [hexane/
1.0 mL/min; τminor ) 21.9 min, τmajor ) 24.4 min; [R]23 ) -2.0
D
(c 0.5, CH2Cl2, 84% ee); 1H NMR (CDCl3) δ 8.28 (d, J ) 7.2 Hz,
2H), 8.20 (d, J ) 7.2 Hz, 2H), 5.40 (m, 1H), 5.29 (m, 1H), 4.73
(m, 2H), 4.50 (t, J ) 6.8 Hz, 2H), 2.20 (m, 3H), 2.03 (m, 3H),
1.85 (m 2H), 1.50 (m, 1H), 1.31 (m, 12H), 0.93 (t, J ) 7.2 Hz,
3H); 13C NMR (CDCl3) δ 164.5, 150.4, 135.6, 132.9 (m), 130.7,
127.6 (m), 123.5, 70.1 (m), 64.1 (d, J ) 8.3 Hz), 36.2 (d, J )
141.7 Hz), 28.5 (d, J ) 13.6 Hz), 27.5 (d, J ) 12.8 Hz), 25.0 (d,
J ) 39.2 Hz), 24.1, 20.6, 14.3; 31P NMR (CDCl3) δ 30.5 (s); HRMS
calcd for C22H34NO7PNa [M + Na]+ 478.1971, found 478.1961.
(3R)-5-(tert-Butyldimethylsilanyloxy)-3-(diisopropoxyphospho-
ryl)pentyl 4-nitro benzoate (11g). Colorless oil. The ee was
determined by HPLC using a Daicel Chiralcel OD column [hexane/
iPrOH 80:20]; flow rate ) 1.0 mL/min; τmajor ) 14.7 min, τminor
)
1
15.5 min (82% ee); [R]20 ) +15.4 (c 1.0, CH2Cl2); H NMR
D
(CDCl3) δ 7.38-7.22 (m, 5H), 3.69 (d, J ) 11.6 Hz, 3H), 3.66 (br
s, 1H), 3.51 (d, J ) 10.4 Hz, 3H), 3.47 (br s, 1H), 3.32 (m, 1H),
2.32 (m, 1H), 2.17 (m, 1H); 13C NMR (CDCl3) δ 135.6 (s), 129.2
(d, J ) 6.8 Hz), 128.6 (d, J ) 2.2 Hz), 127.3 (d, J ) 3.1 Hz), 59.9
(d, J ) 13.5 Hz), 40.5 (d, J ) 138.1 Hz), 33.4 (d, J ) 2.9 Hz),
30.3; 31P NMR (CDCl3) δ 31.6 (s); HRMS calcd for C11H17O4PNa
[M + Na]+ 267.0762, found 267.0760.
iPrOH 97:3]; flow rate ) 1.0 mL/min; τminor ) 13.2 min, τmajor
)
14.8 min; [R]23 ) -10.8 (c 0.5, CH2Cl2, 82% ee); 1H NMR
D
(CDCl3) δ 8.28 (d, J ) 8.4 Hz, 2H), 8.19 (d, J ) 8.4 Hz, 2H),
4.72 (m, 2H), 4.51 (t, J ) 6.8 Hz, 2H), 3.75 (t, J ) 6.0 Hz, 1H),
2.20 (m, 1H), 2.03 (m, 3H), 1.67 (m, 1H), 1.32 (m, 12H), 0.85 (s,
9H), 0.03 (s, 6H); 13C NMR (CDCl3) δ 164.5, 150.4, 135.7, 130.7,
123.5, 70.2 (m), 64.2 (d, J ) 9.4 Hz), 60.5 (d, J ) 10.3 Hz), 31.7
(d, J ) 2.7 Hz), 30.2 (d, J ) 142.0 Hz), 27.7, 25.7, 24.1 (d, J )
3.0 Hz), 18.2, -5.4; 31P NMR (CDCl3) δ 30.3 (s); HRMS calcd
for C24H42NO8PSiNa [M + Na]+ 554.2315, found 554.2318.
(3S)-3-(Diisopropoxyphosphoryl)-3-(2-furyl)propyl 4-nitroben-
zoate (11l). Yellow oil. The ee was determined by HPLC using a
Daicel Chiralpak AD column [hexane/iPrOH 90:10]; flow rate )
1.0 mL/min; τmajor ) 23.6 min, τminor ) 27.2 min; [R]23D ) +30.2
(c 0.5, CH2Cl2, 74% ee); 1H NMR (CDCl3) δ 8.27 (d, J ) 7.6 Hz,
2H), 8.13 (d, J ) 7.6 Hz, 2H), 7.34 (m, 1H), 6.33 (m, 1H), 6.31
(m, 1H), 4.67 (m, 2H), 4.58 (m, 1H), 4.42 (m, 1H), 4.26 (m, 1H),
3.38 (m, 1H), 2.50 (m, 1H), 2.39 (m, 1H), 1.29 (m, 9H), 1.11 (d,
J ) 6.4 Hz, 3H); 13C NMR (CDCl3) δ 164.4, 150.5, 149.2 (d, J )
8.7 Hz), 142.0, 135.4, 130.7, 123.5, 110.9 (m), 108.4 (m), 71.3
(m), 63.8 (d, J ) 15.7 Hz), 36.1 (d, J ) 148.0 Hz), 28.7 (d, J )
1.8 Hz), 24.0 (m), 23.6; 31P NMR (CDCl3) δ 21.8 (s); HRMS calcd
for C20H26NO8PNa [M + Na]+ 462.1294, found 462.1300.
Reductive Amination of Aldehyde 3a. To a solution of aldehyde
3a in dichloroethane were added aniline (1 equiv), NaBH(OAc)3
(1.5 equiv), and AcOH (1 equiv) at rt, and the resulting mixture
was stirred for 4 h. Then, the solution was successively washed
with a 1 M NaOH aq solution and brine, and the organic layer was
dried over MgSO4, and the solvent was evaporated. The pure
Procedure for the Strecker Reaction. The aldehyde 3h (60
mg, 0.2 mmol) is dissolved in a mixture of Et2O (0.2 mL), and an
aqueous solution of NH3 (0.2 mL) then NH4Cl (10.7 mg, 0.2 mmol,
1 equiv) and NaCN (9.8 mg, 0.2 mmol, 1 equiv) are successively
added. The reaction is stirred for 30 h, and then the crude is directly
charged by chromatography using Iatrobeads to afford the pure
product 13 in 75% yield. Less polar diastereoisomer: colorless oil;
1
[R]20 ) +11.0 (c 0.5, CH2Cl2); H NMR (CDCl3) δ 7.35-7.25
D
(m, 5H), 4.66 (m, 1H), 4.43 (m, 1H), 3.40 (br m, 1H + 1H), 2.38
(m, 2H), 1.67 (br d, 2H), 1.29 (m, 6H), 1.22 (d, J ) 6.4 Hz, 3H)
0.82 (d, J ) 6.4 Hz, 3H); 13C NMR (CDCl3) δ 134.6 (d, J ) 6.7
Hz), 129.4 (d, J ) 6.6 Hz), 128.7 (d, J ) 2.2 Hz), 127.7 (d, J )
2.7 Hz), 122.0, 71.5 (d, J ) 7.3 Hz), 70.5 (m), 40.9 (d, J ) 141.4
Hz), 40.4 (d, J ) 16.8 Hz), 35.9, 30.3, 24.2 (d, J ) 3.0 Hz), 24.0
(m), 23.2 (d, J ) 5.6 Hz); 31P NMR (CDCl3) δ 25.6 (s); HRMS
calcd for C16H25N2O3PNa [M + Na]+ 347.1500, found 347.1500.
More polar diastereoisomer: colorless oil; [R]20D ) +32.3 (c 2.0,
1
CH2Cl2); H NMR (CDCl3) δ 7.40-7.25 (m, 5H), 4.68 (m, 1H),
4.38 (m, 1H), 3.42 (t, J ) 8.0 Hz, 1H), 3.25 (m, 1H), 2.39 (m,
2H), 2.00 (br d, 2H), 1.30 (m, 6H), 1.21 (d, J ) 6.4 Hz, 3H), 0.86
(d, J ) 6.4 Hz, 3H); 13C NMR (CDCl3) δ 134.5 (d, J ) 6.9 Hz),
129.2 (d, J ) 6.7 Hz), 128.8 (d, J ) 2.3 Hz), 127.8 (d, J ) 3.0
Hz), 121.1, 71.6 (d, J ) 7.3 Hz), 70.6 (m), 42.3 (d, J ) 18.0 Hz),
42.1 (d, J ) 141.1 Hz), 36.1, 30.3, 24.2 (d, J ) 2.8 Hz), 23.9 (m),
23.1 (d, J ) 5.3 Hz); 31P NMR (CDCl3) δ 25.7 (s).
8902 J. Org. Chem., Vol. 72, No. 23, 2007