Synthesis of a-carboxyphosphinopeptides
1273
and petroleum ether at -20°C. Yield 3.3 g (52%). White
powder, mp 74–77°C. Rf = 0.29 (S4). 1H NMR
(600 MHz; CDCl3): mixture of two diastereoiso-
mers * 76:24, only signals of the major isomer are given:
0.87 (3H, t, J = 7.2, CH3), 1.28 and 1.35 (2H, two m,
CH2), 1.38 (9H, s, t-Bu), 1.36 and 1.47 (2H, two m, CH2),
1.62 and 1.90 (2H, two m, CH2), 2.90–3.00 (2H, m, P–
CH2), 4.26 (1H, m, N–CH–P), 5.10 (4H, m, 29 CH2–O),
5.39 (1H, d, J = 10.0, NH), 7.30–7.35 (10H, m, 29 C6H5).
13C NMR (150.9 MHz; CDCl3): 13.80 (CH3), 22.16 (CH2),
27.75 (39 CH3 (t-Bu)), 28.04 (d, J(C,P) = 11.8, CH2),
28.57 (d, J(C,P) = 4.1, CH2), 36.13 (d, J(C,P) = 76.5,
P–CH2), 50.28 (d, J(C,P) = 107.4, N–CH–P), 66.99
(d, J(C,P) = 6.6, CH2–O), 67.06 (CH2–O), 82.82 ([C
\(t-Bu)), 127.88 (29 Ar–CH), 127.93 (29 Ar–CH), 128.10
(Ar–CH), 128.37 (Ar–CH), 128.44 (29 Ar–CH), 128.48
(29 Ar–CH), 135.99 (d, J(C,P) = 7.0, Ar–C), 136.20
(Ar–C), 156.17 (d, J(C,P) = 5.8, N–CO–O), 165.82 (d,
J(C,P) = 4.4, –CO–O). IR (KBr, mmax cm-1) 3,202, 3,089,
3,036, 2,975, 1,719, 1,550, 1,394, 1,365, 1,369, 1,294,
1,259, 1,211, 1,165, 1,045, 1,007,742, 733, 698. HRMS
(ESI) calculated for C26H36NNaO6P [M ? Na]? 512.2172;
found: 512.2170.
47.01 ([ CH- (Fmoc)), 50.80 (d, J(C,P) = 110.1, N–CH–
P), 65.80 (CH2–O), 120.35 (Ar–CH), 120.36 (Ar–CH),
125.52 (Ar–CH), 125.64 (Ar–CH), 127.26 (Ar–CH),
127.32 (Ar–CH), 127.88 (Ar–CH), 127.89 (Ar–CH),
140.96 (Ar–C), 140.98 (Ar–C), 143.95 (Ar–C), 144.15
(Ar–C), 156.54 (d, J(C,P) = 4.7, N–CO–O), 168.24 (d,
J(C,P) = 5.7, COOH). IR (KBr, mmax cm-1) 3,294, 1,720,
1,678, 1,534, 1,239, 987, 758, 741. HRMS (ESI) calculated
for C22H27NO6P [M ? H]? 432.1571; found: 432.1569.
Methyl[((R,S)-1-{[(benzyloxy)carbonyl]amino}pentyl)
(adamantyloxy)phosphoryl]acetate (22)
Phosphinic acid 5 (0.95 g; 2.7 mmol) and 1-bromoada-
mantane (0.58 g; 2.7 mmol) were refluxed in 20 mL of
chloroform. Silver oxide (1.25 g; 5.4 mmol) was added in
five equal portions during 1 h, and the reaction mixture was
refluxed for an additional 1 h. The solvent was evaporated
under reduced pressure, the residue was treated with die-
thyl ether and filtered through a Celite pad. The filtrate was
concentrated in vacuo to give a brown oil, which was
purified by flash chromatography on silica gel using elution
with a linear gradient of ethanol in chloroform. Yield 1 g
(76%). Semisolid. Rf = 0.39 (S4). 1H NMR (600 MHz;
CDCl3): mixture of two diastereoisomers * 1:1, many
signals are doubled—those clearly identified are given
connected with symbol ? in data below: 0.89 (3H, t,
J = 7.2, CH3), 1.28 and 1.31 (2H, two m, CH2), 1.36 and
1.46 (2H, two m, CH2), 1.56 and 1.91 (2H, two m, CH2),
1.61 (6H, m, 39 CH2, (Ada)), 2.06 (6H, m, 39 CH2
(Ada)), 2.16 (3H, m, 39 CH (Ada)), 2.90 and 3.10 (2H, dd,
J = 14.3, 19.0 and dd, J = 14.3, 15.0, P–CH2) ? 3.00 and
3.03 (2H, dd, J = 14.3, 17.8 and dd, J = 14.3, 15.8,
P–CH2), 3.70 (3H, s, OCH3), 4.12 (1H, m, N–CH–P), 5.12
and 5.15 (2H, 29 d, J = 12.3) ? 5.13 (2H, s, CH2–O),
4.95 ? 5.30 (1H, 29 d, J = 10.6, NH), 7.30–7.38 (5H, m,
C6H5). 13C NMR (150.9 MHz; CDCl3): 13.87 ?13.90
(CH3), 22.23 ? 22.29 (CH2), 27.86 ? 27.92 (d, J(C,P) =
11.6, CH2), 28.29 ? 28.42 (29 d, J(C,P) = 2.6 ? 3.6,
CH2), 31.16 ? 31.17 (39 CH (Ada)), 35.57 ? 36.02 (39
CH2 (Ada)), 36.94 ? 37.45 (29 d, J(C,P) = 76.0 ? 75.3,
P–CH2), 44.03 ? 44.15 (29 d, J(C,P) = 3.6 ? 3.5, 39
CH2 (Ada)), 50.82 ? 50.89 (29 d, J(C,P) = 111.4 ?
115.2, N–CH–P), 52.48 ? 52.50 (OCH3), 66.98 ? 67.13
(CH2–O), 84.36 ? 84.68 (29 d, J(C,P) = 10.4 ? 10.4,[C
\(Ada)), 127.95–128.51 (59 Ar–CH), 136.22 ? 136.39
(Ar–C), 156.08 ? 156.27 (29 d, J(C,P) = 6.2 ? 7.2,
N–CO–O), 166.73 ? 167.26 (29 d, J(C,P) = 4.2 ? 4.5,
–CO–O). IR (CHCl3, mmax cm-1) 2,919, 2,857, 1,723,
1,509, 1,456, 1,277, 1,241, 1,048, 999, 984, 698. HRMS
(ESI) calculated for C26H39NO6P [M ? H]? 492.2510;
found: 492.2508.
[((R,S)-1-{(9H-Fluoren-9-ylmethoxycarbonyl]amino}
pentyl)(hydroxy)phosphoryl]acetic acid (21)
Phosphinic acid 9 (0.25 g; 1.2 mmol) was dissolved in
3 mL of 10% aqueous Na2CO3 and a solution of Fmoc-Cl
(0.31 g; 1.2 mmol) in 3 mL of dioxane was added drop-
wise at 0°C. After stirring for 2 h at 0°C, the mixture was
allowed to stand overnight at room temperature. The
dioxane was evaporated under reduced pressure and the
acidity of the aqueous solution was adjusted to a pH of
about 1 whilst efficiently cooling with ice. The solution
was extracted with ethyl acetate (39 10 mL), and the
combined organic layers were dried with Na2SO4 before
filtering and removing the solvent in vacuo. The residual
oil was purified by RP-HPLC (G1, see General). Yield
1
185 mg (36%). White powder. Rf = 0.32 (S2). H NMR
(600 MHz; DMSO): 0.84 (3H, t, J = 7.0, CH3), 1.22 and
1.30 (2H, two m, CH2), 1.22 and 1.34 (2H, two m, CH2),
1.51 and 1.73 (2H, two m, CH2), 2.72 (2H, m, P–CH2),
3.73 (1H, m, N–CH–P), 4.22 (1H, t, J = 7.2, CH (Fmoc)),
4.30 (1H, dd, J = 10.6 and 7.2, –CHaHb–O (Fmoc)), 4.33
(1H, dd, J = 10.6 and 7.2, –CHaHb–O (Fmoc)), 7.30 (1H,
m, Ar–CH), 7.32 (1H, m, Ar–CH), 7.40 (1H, m, Ar–CH),
7.41 (1H, m, Ar–CH), 7.48 (1H, d, J = 9.5, NH), 7.72 (1H,
m, Ar–CH), 7.74 (1H, m, Ar–CH), 7.88 (2H, m, 29 Ar–
CH). 13C NMR (150.9 MHz; DMSO): 14.09 (CH3), 21.86
(CH2), 27.09 (d, J(C,P) = 2.8, CH2), 28.05 (d,
J(C,P) = 12.1, CH2), 35.81 (d, J(C,P) = 76.5, P–CH2),
123