7470 J . Org. Chem., Vol. 63, No. 21, 1998
Gosselin and Lubell
-179.0 (c 4.4, CHCl3); lit.8 [R]25D -180 (c 4.4, CHCl3); 1H NMR
δ 7.67-7.63 (m, 2 H), 7.43-7.13 (m, 11 H), 3.62 (s, 3 H), 2.50
(m, 1 H), 2.15-2.11 (m, 2 H), 1.71-1.63 (m, 2 H), 1.44-1.41
(m, 1 H), 1.39-1.21 (m, 1 H), 1.17 (s, 9 H); 13C NMR δ 175.08,
173.73, 80.42, 72.90, 55.33, 51.29, 34.90, 33.58, 27.78, 20.77;
HRMS calcd for C30H34NO4 [M + 1] 472.2488, found: 472.2505.
Anal. Calcd for C30H33NO4: C, 76.41; H, 7.05; N, 2.97.
Found: C, 76.46; H, 7.15; N, 3.02.
(50 mL). The solution was stirred for 2 h, quenched with
aqueous NaH2PO4 (20 mL, 1 M), and diluted with EtOAc (100
mL). The aqueous layer was saturated with solid NaCl and
extracted with EtOAc until TLC of the organic layer showed
no UV-active material. The combined organic layers were
washed with brine, dried, and evaporated to a residue that
was chromatographed using a gradient of 5-100% EtOAc in
hexanes as eluant. First to elute was glutamate 12 (188 mg,
4%), followed by R-tert-butyl N-(PhF)pyroglutamate (17,3 600
mg, 12-13%). Last to elute was â-ketophosphonate 22 (5.04
g, 84%, oil): TLC Rf ) 0.19 (4:1 EtOAc:hexanes); [R]20D -168.7
(2S)-r-ter t-Bu t yl 2-[N-(P h F )Am in o]a d ip a t e (10).
A
stirred solution of diester 9 (504.8 mg, 1.07 mmol) in dioxane
(10 mL) was treated with aqueous LiOH (2.70 mL, 500 mol
%, 2 M), heated at a reflux for 2 h, cooled to room temperature,
and acidified with concentrated H3PO4 to pH 2. The aqueous
layer was saturated with NaCl and extracted with EtOAc until
TLC of the organic layer showed no UV active material. The
combined organic layers were washed with brine (5 mL), dried,
and evaporated to an oil which was chromatographed using a
gradient of 0-10% i-PrOH in CHCl3 as eluant to afford 10
(459 mg, 94% yield) as an oil: TLC Rf ) 0.42 (1:9 i-PrOH:
CHCl3); [R]20D -191.0 (c 1.0, CHCl3); 1H NMR δ 7.72-7.65 (m,
2 H), 7.53-7.13 (m, 12 H), 2.55 (m, 1 H), 2.21 (m, 2 H), 1.73
(m, 2 H), 1.48 (m, 2 H), 1.29 (s, 0.5 H), 1.22 (s, 8 H), 1.16 (s,
0.5 H). 13C NMR δ 179.54, 175.03, 80.67, 73.01, 55.39, 34.65,
33.62, 27.83, 20.53. HRMS calcd for C29H32N04 [M + 1]:
458.2331, found: 458.2342.
1
(c 1.0, CHCl3); H NMR δ 7.68-7.65 (m, 2H), 7.39-7.17 (m,
13H), 3.79 (d, 3H, J ) 11.2), 3.78 (d, 3 H, J ) 11.2), 3.08 (m,
3H), 2.65 (m, 2H), 2.50 (dd, 1H, J ) 5.3, 5.4), 1.66 (m, 2H),
1.18 (s, 9H); 13C NMR (a mixture of keto-enol tautomers) δ
201.29, 201.23, 174.74, 80.81, 72.87, 54.88, 52.93, 52.87, 41.88,
40.60, 40.31, 40.30, 28.98, 27.77; HRMS calcd for C31H37NO6P
[M + 1]: 550.2358, found: 550.2369. Anal. Calcd for C31H36
-
NO6P: C, 67.75; H, 6.60; N, 2.55. Found: C, 67.75; H, 6.74;
N, 2.57.
(2S)-r-ter t-Bu tyl 2-N-(P h F )Am in o-6-oxo-7-(d im eth yl-
p h osp h on yl)h ep ta n oa te (23). A -78 °C solution of dimethyl
methyl phosphonate (244 µL, 2.23 mmol, 250 mol %) in toluene
(23 mL) was treated with n-butyllithium (898 µL, 2.23 mmol,
250 mol %, 2.5 M in hexanes), stirred for 20 min at -78 °C,
and transferred by cannula dropwise over 60 min into a -78
°C solution of R-tert-butyl δ-methyl N-(PhF)aminoadipate (9,
423 mg, 0.89 mmol) in toluene (8.9 mL). The solution was
stirred for 1 h, let warm to room temperature (ca 1 h),
quenched with aqueous NaH2PO4 (5 mL, 1 M), and diluted
with EtOAc (20 mL). The aqueous layer was saturated with
solid NaCl and extracted with EtOAc until TLC of the organic
layer showed no UV-active material. The combined organic
layers were washed with 10 mL of brine, dried, and evaporated
to a residue that was chromatographed using a gradient of
10-100% EtOAc in hexanes as eluant. First to elute was
aminoadipate 9 (21 mg, 5%), followed by â-keto ester 20 (20
mg, 5%). Last to elute was â-keto phosphonate 23 (427 mg,
90%), an oil: TLC Rf ) 0.16 (4:1 EtOAc:hexanes); [R]20D -144.1
(2S)-r-ter t-Bu tyl δ-S-P h en yl 2-[N-(P h F )Am in o]a d ip a te
(11). To a solution of adipate 10 (100 mg, 0.22 mmol) and
TBTU (105 mg, 0.33 mmol, 150 mol %) in CH3CN (2.2 mL)
was added thiophenol (45 µL, 0.44 mmol, 200 mol %). The
mixture was cooled to 0 °C, and Et(iPr)2N (76 µL, 200 mol %)
was added. A slow reaction followed; however, addition of
DMAP (10 mol %) and DCC (150 mol %) accelerated the
reaction as witnessed by TLC. After 24 h, the reaction mixture
was filtered and evaporated to a residue that was chromato-
graphed (5% EtOAc in hexanes) to give thioester 11 (80.6 mg,
67%) as a thick clear oil: 1H NMR δ 7.71-7.68 (m, 2 H), 7.46-
7.34 (m, 10 H), 7.27-7.20 (m, 7 H), 2.55-2.46 (m, 3 H), 1.85-
1.74 (m, 2 H), 1.54-1.36 (m, 2 H), 1.21 (s, 9 H); 13C NMR δ
196.98, 175.05, 80.62, 72.98, 55.41, 43.30, 34.77, 27.87, 21.5;
1
HRMS calcd for
550.2398.
C
35H36NO3S [M + 1]: 550.2416, found:
(c 1.0, CHCl3); H NMR δ 7.69-7.65 (m, 2 H), 7.43-7.18 (m,
11 H), 3.77 (d, 3 H, J ) 11.2), 3.75 (d, 3 H, J ) 11.2), 3.05 (s,
1 H), 2.97 (s, 1 H), 2.49-2.34 (m, 3 H), 1.67-1.60 (m, 2 H),
1.44-1.26 (m, 2 H), 1.18 (s, 9 H); 13C NMR (a mixture of keto-
enol tautomers) δ 201.31, 201.25, 175.07, 80.54, 72.93, 55.37,
52.91, 52.85, 43.53, 41.74, 40.46, 34.52, 27.77, 19.19; HRMS
calcd for C32H39NO6P [M + 1]: 564.2515, found: 564.2521.
Anal. Calcd for C32H38NO6P: C, 68.19; H, 6.80; N, 2.49.
Found: C, 67.77; H, 7.17; N, 2.61.
(2S)-r-ter t-Bu tyl 2-N-(P h F )Am in o-4-oxo-5-(d im eth yl-
p h osp h on yl)p en ta n oa te (21). A -78 °C solution of dimethyl
methyl phosphonate (3.1 mL, 28,2 mmol, 250 mol %) in toluene
(276 mL) was treated with n-butyllithium (11.4 mL, 28.2
mmol, 250 mol %, 2.5 M in hexanes), stirred for 20 min at
-78 °C, and transferred by cannula dropwise over 30 min into
a -78 °C solution of R-tert-butyl â-methyl N-(PhF)aspartate
(3, 5.0 g, 11.29 mmol) in toluene (112 mL). The solution was
stirred for 1 h, warmed to room temperature, quenched with
aqueous NaH2PO4 (40 mL, 1 M), and diluted with EtOAc (50
mL). The aqueous layer was saturated with solid NaCl and
extracted with EtOAc until TLC of the organic layer showed
no UV-active material. The combined organic layers were
washed with brine, dried, and evaporated to a residue that
was chromatographed using 10-100% EtOAc in hexanes as
eluant to give 21 as a colorless solid (4.28 g, 71%): mp 113-
(2S,8S)-Di-ter t-bu tyl 4-Oxo-2,8-bis[N-(P h F )a m in o]n on -
4-en ed ioa te (24). To a stirred solution of â-keto phosphonate
21 (1.20 g, 2.24 mmol) and aldehyde 5 (925 mg, 2.24 mmol,
100 mol %) in CH3CN (16 mL) was added K2CO3 (326 mg, 2.35
mmol, 105 mol %). The mixture was stirred at room temper-
ature for 72 h and evaporated to a residue that was suspended
in toluene and added to a column of silica gel. Chromatogra-
phy using a gradient of 0-10% EtOAc in hexanes and
evaporation of the collected fractions gave 24 (1.61 g, 87%) as
114 °C; TLC Rf ) 0.17 (4:1 EtOAc:hexanes); [R]20 -136.6 (c
a white foam: TLC Rf ) 0.34 (1:4 EtOAc:hexanes); [R]20
D
D
1
1
1.0, CHCl3); H NMR δ 7.69-7.66 (m, 2 H), 7.37-7.16 (m, 12
-160.1 (c 1.0, CHCl3); H NMR δ 7.68-7.61 (m, 4 H), 7.41-
H), 3.78-3.74 (m, 6 H), 3.03 (s, 1 H), 2.97 (s, 1 H), 2.85 (dd, 1
H, J ) 5.3, 5.5), 2.72 (dd, 1 H, J ) 5.9, 16.1), 2.59 (dd, 1 H, J
) 4.9, 16.0), 1.23 (s, 9 H); 13C NMR (a mixture of keto-enol
tautomers) δ 199.17, 199.11, 172.77, 81.39, 73.00, 53.09, 52.95,
52.89, 48.92, 42.25, 40.98, 27.67; HRMS calcd for C30H35NO6P
7.13 (m, 26 H), 6.54-6.50 (m, 1 H), 5.90 (d, 1 H, J ) 16), 3.29
(br s, 1 H), 3.19 (br s, 1 H), 2.93 (t, 1 H, J ) 5.4), 2.64 (m, 2
H), 2.54 (m, 1 H), 2.25 (m, 2 H), 1.21 (s, 9 H), 1.17 (s, 9 H); 13
C
NMR δ 197.05, 173.76, 173.31, 81.09, 80.95, 72.97, 72.93,
55.46, 53.36, 45.05, 38.95, 27.82, 27.69; HRMS calcd for
[M + 1]: 536.2202, found: 536.2181. Anal. Calcd for C30H34
-
C
55H55N2O5 [M + 1]: 823.4111, found: 823.4140.
NO6P: C, 67.28; H, 6.40; N, 2.62. Found: C, 67.11; H, 6.70;
N, 2.61.
(2S,9S)-Di-ter t-bu tyl 5-Oxo-2,9-bis[N-(P h F )a m in o]d ec-
4-en ed ioa te (25). To a stirred solution of â-keto phosphonate
22 (488 mg, 0.88 mmol) in CH3CN (3.15 mL) was added K2-
CO3 (122 mg, 100 mol %). The suspension was stirred 30 min
at room temperature, cooled to 0 °C, and treated with a
solution of aldehyde 5 (367 mg, 0.88 mmol, 100 mol %) in CH3-
CN (3.15 mL). The mixture was stirred at 10 °C for 72 h,
diluted with EtOAc (15 mL), and quenched with NaH2PO4 (3
mL, 1 M). The layers were separated, and the aqueous layer
was extracted with EtOAc (2 × 25 mL). The combined organic
(2S)-r-ter t-Bu tyl 2-N-(P h F )Am in o-5-oxo-6-(d im eth yl-
p h osp h on yl)h exa n oa te (22). A -78 °C solution of dimethyl
methyl phosphonate (2.97 mL, 27.2 mmol, 250 mol %) in Et2O
(500 mL) was treated with n-butyllithium (11.0 mL, 27.2
mmol, 250 mol %, 2.5 M in hexanes), stirred for 20 min at
-78 °C, and transferred by cannula dropwise over 60 min into
a -78 °C solution of R-tert-butyl γ-methyl N-(PhF)glutamate
12 (4.98 g, 1.10 mmol, prepared according to ref 3) in Et2O