Stable Phosphonamide Transition State Analogues
(DMSO-d6) δ 10.58 (dd, J ) 9, J ) 2.7); 31P NMR (DMSO-d6)
δ 25.05 (q, J ) 2.7); 1Η ΝΜR (DMSO-d6) δ 4.95 (qAB, 2H, J AB
12.4), 5.63 (m, 1H), 7-8.8 (15 H), 8.74 (d, 1H, J ) 10.2); 13C
NMR (DMSO-d6) δ 52.28 (dq, J ) 73, J ) 37), 65.89, 127.01-
136.44 (m), 156.2 (d, J ) 4.5). Anal. Calcd for C22H19F3NO3P:
C, 60.97; H, 4.42; N, 3.23. Found: C, 60.64; H, 4.38; N, 3.32.
Similarly with (BnO)2P(O)NHCHCF3OH 3c, the product 4m
was obtained in less than 30 min: IR 3157, 1289; 19F NMR
(CDCl3) δ 4.8 (pseudo t: dd, J ) 7.1); 31P NMR (CDCl3) δ 6.9
C, 48.72; H, 5.98; N, 6.03. Found: C, 48.76; H, 5.89; N, 5.69.
Chromatography on silica gel with AcOEt/petroleum ether/
acetic acid (10/40/1) as eluant yielded pure 4f1 (0.2 g), 4f2 (0.21
g), and 0.05 g of a mixture of them. 4f1: mp 112 °C; Rf 0.36;
[R]25 + 17° (c ) 5, dioxane); 19F NMR (CDCl3) δ 6.75 (pseudo
D
t: dd, J ) 8.2); 31P NMR (CDCl3) δ 10.55 (q, J ) 6.3); 1H NMR
(CDCl3) δ 1.3 (m, 15H), 4.87 (m, 4H), 5.06 (s, 2H), 5.42 (d, 1H,
J ) 8.9), 7.29 (s, 5H), 7.52 (m, 1H); 13C NMR (CDCl3) δ 18.9,
23.6 (d, J ) 5.5), 24.24 (d, J ) 3), 48.24 (dq, J ) 160.2, J )
32.3); 50.21, 66.92, 73.5, 73.6, 122.59 (dq, J ) 7.9, J ) 281.1),
128.1, 128.3, 128.5, 136.23, 155.76, 173.01 (d, J ) 5.7). 4f2:
1
(d, J ) 20.28), 13.79 (dq, J ) 20.43, J ) 7); H NMR (CDCl3)
δ 1.26 (m, 6H), 4.14 (m, 6H), 5.04 (d, J ) 7.14, 2H), 7.31 (s,
10H); 13C NMR δ 16.28 (d, J ) 5.7), 16.23 (d, J ) 5.7), 53.82
(dq, J ) 156.6, J ) 37.8), 63.9 (d, J ) 6.9), 63.8 (d, J ) 6.9),
68.45 (d, J ) 4.5), 68.50 (d, J ) 4.5), 123.54 (ddd, J ) 281, J
) 9.8, J ) 3.1), 128.54-127.6 (5s), 135.89, 136.04. Anal. Calcd
for C20H26F3NO6P2: C, 48.49; H, 5.29; N, 2.83. Found: C, 48.76;
H, 5.37; N, 2.81.
mp 135 °C; Rf 0.26; [R]25 -32 (c ) 5, dioxane); 19F NMR
D
(CDCl3) δ 6.85 (pseudo t: dd, J ) 8.1); 31P NMR (CDCl3) δ 10.55
1
(q, J ) 6.2); H NMR (CDCl3) δ 1.29 (m, 15H), 4.3-4.89 (m,
4H), 5.08 (s, 2H), 5.4 (d, 1H, J ) 9.2), 7.28 (s, 5H), 7.6 (m,
1H); 13C NMR (CDCl3) δ 18.92, 23.5 (d, J ) 5.7), 24.1 (d, J )
4.1), 48.12 (dq, J ) 158.1, J ) 31.3), 50.12, 66.8, 73.4, 73.52,
122.67 (dq, J ) 7.8 J ) 284.4), 128, 128.3, 128.6, 136.3, 155.7,
173.11 (d, J ) 5.7).
Meth od B. Illu str a tive P r oced u r e. N-Ben zyloxyca r -
bon yl r-Am in o â-Tr iflu or o Dip h en ylp h osp h on a te (4d ).
A solution of hemiaminal 3a , diphenyl phosphite 8d (5.6 g,
23.9 mmol, 6 equiv), and triethylamine (0.53 g, 5.2 mmol, 1.3
equiv) in dioxane (7 mL) was kept at room temperature until
completion of the reaction (1.5 h by 19F NMR; the 31P NMR
spectrum showed two new products in 1/1 ratio δ 5.1 (4d ) and
-2 (coupled: d, J ) 636, 12). The reaction mixture was
concentrated to dryness, taken up in dichloromethane (60 mL),
and treated as above (method A). IR 3270, 1727; 19F NMR
(CDCl3) δ 5.71 (pseudo t: dd, J ) 7.9); 31P NMR (CDCl3) δ 5.1
Meth od C. Illu str a tive P r oced u r e. N-Ben zyloxyca r -
bon yl r-Am in o â-Tr iflu or o Dieth ylp h osp h on a te (4a ).
Under magnetical stirring, the pale yellow solution resulting
from the addition of trifluoroaceticanhydride (1 g, 4.7 mmol)
to a pyridine (10 mL) solution of the hemiaminal 3a (0.63 g, 4
mmol) was added dropwise in a few minutes to a dichlo-
romethane (8 mL) solution of the phosphite 8a (1.15 g, 8.3
mmol) followed by addition of trimethylchlorosilane (2.17 g,
20 mmol). After completion of the reaction (less than 30 min),
the mixture was concentrated to dryness and the residue was
taken up in dichloromethane and treated as above (method
A).
Similarly with the hemiaminal 3a and the phosphite 8b,
the product 4b was obtained: IR 3210, 1725; 19F NMR (DMSO-
d6) δ 7.4 (pseudo t: dd, J ) 7.9); 31P NMR (DMSO-d6) δ 16.77
(q, J ) 7.8); 1H NMR (DMSO-d6) δ 3.75 (d, 3H, J ) 10.5) 4.85
(m, 1H), 5.15 (s, 2H), 7.38 (s, 5H), 8.66 (d, 1H, J ) 8.66); 13C
NMR (DMSO-d6) δ 55.63 (d, J ) 6.5), 53.82 (d, J ) 6.45), 49.8
(dq, J ) 156, J ) 32), 66.5, 123.31 (dq, J ) 281, J ) 10), 127.86,
128, 128.31, 136.32, 156.2 (d, J ) 6.1). Anal. Calcd for C12H15F3-
NO5P: C, 42.24; H, 4.43; N, 4.10. Found: C, 42.03; H, 4.27; N,
3.98.
1
(q, J ) 7.3); H NMR (CDCl3) δ 5.16 (2H), 6 (m, 1H), 7.2 (mf,
11H), 7.13 (s, 5H); 13C NMR (CDCl3) δ 51.11 (dq, J ) 162.5, J
) 32.5), 66.7, 123.16 (q, J ) 294.1), 120.2-130 (m: 9 signals
incorporating two d δ 120.2, 120.3, J ) 3.7), 149.1 (d, J ) 9.3),
149.42 (d, J ) 9.3), 156.28 (d, J ) 6.2). Anal. Calcd for
C
22H19F3NO5P: C, 56.78; H, 4.12; N, 3.01. Found :C, 56.48; H,
4.09; N, 2.94.
Similarly with hemiaminal 3′a , the product 4′c was obtained
(exothermic reaction and crystallization in the reaction mix-
ture after a few minutes; 12 was characterized by 31P NMR in
the filtrate): IR 3314, 1724; 31P NMR (DMSO-d6) δ 6.59
(coupled: d, J ) 20.7); 1H NMR (DMSO-d6) δ 5.18 (s, 2H), 5.34
(dd, 1H, J ) 20.6, J ) 10.5), 6.7-7.3 (mf, 15H), 9.31 (dd, 1H,
J ) 10.5, J ) 1.9); 13C NMR (DMSO-d6) δ 70.45 (d, J ) 165.21),
72.44, 102.43 (d, J ) 17.93), 125.83-155.63 (m), 162.16 (d, J
) 6.45). Anal. Calcd for C22H19Cl3NO5: C, 51.33; H, 3.72; N,
2.72. Found :C, 51.20; H, 3.66; N, 2.77.
Similarly with the hemiaminal 3b and the phosphite 8a ,
the product 4c was obtained: IR 3198, 1719; 19F NMR (CDCl3)
1
δ 13.06 (m); 31P NMR (CDCl3) δ 19.4 (m); H NMR δ 1.31 (m,
6H), 4.11 (m, 4H), 4.8 (m, 1H), 5.17 (s, 2H), 7.33 (br s, 6H);
13C NMR (CDCl3) δ 16.21 (d, J ) 5.7), 55.9 (dt, J ) 155.6, J )
29.9), 63.94 (d, J ) 4.2), 67.92, 126.7 (dt, J ) 10.1, J ) 296),
128.2, 128.5, 128.6, 135.6, 155.65 (d, J ) 6.35). Anal. Calcd
for C14H19ClF2NO5P: C, 43.59; H, 4.96; N, 3.63. Found: C, 43.3;
H, 4.94; N, 3.57.
Similarly with the two diastereoisomers 3c1 and 3c2,
products 4e1 and 4e2 were obtained (reaction over in less than
15 min): Rf (AcOEt/petroleum ether 1:3) 0.3, 0.24; 19F NMR
(dioxane) δ 7.55 (pseudo t: dd, J ) 8.4), 7.04 (pseudo t: dd, J
) 8.4); 31P NMR (dioxane) δ 6.2 (m: two overlapping q). Anal.
Calcd for C25H24N2O6P: C, 55.98; H, 4.51; N, 5.22. Found: C,
55.56; H, 4.50; N, 5.07. By crystallization in MeOH (4 g), 0.53
g yielded 0.175 g (66%) of a single diasteroisomer as white
crystals: mp 135-137 °C; Rf 0.3; IR 3297, 1691, 1670; 19F NMR
(DMSO-d6) δ 8.54 (dd, J ) 8.6); 31P NMR (DMSO-d6) + 7.45
Similarly with the two diastereoisomers 3c1 and 3c2 or with
a single diasteroisomer, products 4h 1 and 4h 2 were obtained
(reaction over in 3 h): 19F NMR (CH2Cl2) δ 6.02 (pseudo t: dd,
J ) 8.2), 6.42 (pseudo t: dd, J ) 8.2); 31P NMR (CH2Cl2) δ 5.27
(q, J ) 8.2), 5.69 (q, J ) 8.2). The attempted selective
crystallization of either 4h 1 or 4h 2 in MeOH or Et2O-hexane
mixtures proved to be unsuccessful and accompanied by the
slow degradation of the products.
With the hemiaminal 3a and the ammonium salt of hypo-
phosphorous acid in situ silylated in the presence of hexam-
ethyldisilazane41,42 (1 equiv) and trimethylchlorosilane (2
equiv), the compound 4i was formed. The extraction procedure
was modified: the residue of the reaction mixture was first
treated with a ∼10% citric acid solution and extracted with
chloroform. To the aqueous layer was added DCHA (8 equiv),
and the dicyclohexylammonium salts of both the compound
4i and trifluoroacetic acid were extracted with chloroform (five
times). After neutralization with Amberlyst 15 resin, the
insoluble material (the dicyclohexylammonium resin and
product 4i) was filtered after 2 h and taken up in water. After
filtration and concentration to dryness, NMR-pure product 4i
was obtained: IR, 3291, 2454, 1704; 19F NMR (DMSO-d6) δ
1
(q, J ) 7.2); H NMR (DMSO-d6) δ 1.25 (d, 3H, J ) 7.2), 4.37
(dq, 1H), 5.03 (s, 2H), 5.62 (m, 1H), 7.08-7.64 (m, 16H), 9.4
(d, 1H, J ) 8.6); 13C NMR (DMSO-d6) 17.97, 48.64 (dq, J )
163.2, J ) 32,5), 49.6, 65.28, 123.1 (dq, J ) 282.1, J ) 10.6),
115.1-130 (m, 9 signals), 136.9, 149.1 (d, J ) 9.5), 149.2 (d, J
) 13), 155.65, 173.99. Attemped preparative chromatography
with the same eluant as for the analytical chromatography
proved ineffective.
Following Seebach’s method (1.5 equiv of titanate, 24 h, at
70 °C, in 2-propanol), the preceding esters 4e1 and 4e2 are
transesterified into 4f1 and 4f2 without reaction on the
urethane N-protecting group.43 Anal. Calcd for C19H28F3N2O6P:
(41) Issleib, K.; Mo¨gelin, W.; Balzuweit, A. Z. Anorg. Allg. Chem.
1985, 530, 16.
(42) Boyd, E. A.; Ragan A. C.; J ames, K. Tetrahedron Lett. 1992,
33, 813.
(43) Shapiro, G.; Marzi, M. J . Org. Chem. 1997, 62, 7096.
J . Org. Chem, Vol. 68, No. 22, 2003 8429