5740 J . Org. Chem., Vol. 61, No. 17, 1996
Agami et al.
13C NMR: 21.4, 30.4, 39.8, 52.9, 54.8, 55.4, 68.4, 126.0, 128.5,
129.2, 136.4, 168.3, 168.7, 172.4. IR (CHCl3): 1650, 1730, 1760
19.1, 28.7, 36.5, 44.7, 52.0, 55.1, 57.7, 69.9, 126.2, 127.7, 128.7,
138.9, 168.2, 170.8. IR (CHCl3): 1660, 1730, 1760 cm-1. [R]20
:
D
cm-1. [R]20D: -27.6 (c 0.74, CHCl3). HRMS: calcd for C16H17
NO5 m/ z ) 303.1106, obsd m/ z ) 303.1108.
-
+76.4 (c 1.2 CHCl3). HRMS: calcd for C17H19NO5 m/ z )
317.1263, obsd m/ z ) 317.1263.
Na 2CO3-Med ia ted Ep im er iza tion of Com p ou n d 12. A
solution of compound 12 (0.1 g, 3.3 mmol) in abolute ethanol
(10 mL) was stirred at rt during 3 h in the presence of Na2-
CO3 (0.11 g). The mixture was then filtrated and the solvent
was evaporated. NMR of the crude product corresponded to
compound 15.
[4S-4r,8r,9r,9a r]-1-Oxo-8-m eth yl-4-p h en ylocta h yd r o-
p yr id o[2,1-c][1,4]oxa zin e-9-ca r boxylic Acid Meth yl Ester
(20). A 1 M solution of BH3/THF complex in THF (3.2 mL,
3.2 mmol) was added at 0 °C to a solution of compound 19
(0.5 g, 1.6 mmol) in THF (25 mL). The mixture was stirred at
room temperature for 1.5 h and then hydrolyzed by water (15
mL). The reaction mixture was extracted with dichlo-
romethane, and evaporation of the organic layers gave a
residue which was submitted to flash chromatography (E/PE
40/60). Compound 20 was obtained as a yellow oil (0.43 g,
91%). 1H NMR: 1.24 (d, J ) 6.9 Hz, 3H), 1.42-1.43 (m, 1H),
1.66 (dq, J ) 4.4 and 12.4 Hz, 1H), 1.81-1.88 (m, 2H), 2.76-
2.80 (m, 1H), 3.14 (d, J ) 2 Hz, 1H), 3.40-3.42 (m, 1H), 3.60
(dd, J ) 3.2 and 10.6 Hz, 1H), 3.75 (s, 3H), 4.15 (dd, J ) 3.4
and 10.9 Hz, 1H), 4.24 (t, J ) 10.7 Hz, 1H), 7.28-7.38 (m,
[4S-4r,9r,9a r]-1-Oxo-4-p h en ylocta h yd r op yr id o[2,1-c]-
[1,4]oxa zin e-9-ca r boxylic Acid Meth yl Ester (13). A solu-
tion of compound 12 (0.26 g, 0.85 mmol) in THF (7 mL) was
added dropwise to a 10 M THF solution of BH3/Me2S (0.2 mL,
1.9 mmol). The mixture was stirred for 2 h at rt. Water was
then added, and the aqueous solution was extracted with
dichloromethane. After evaporation, the residue was chro-
matographed (E/PE 50/50) to furnish compound 13 as a white
solid (0.20 g, 82%): mp 124 °C. 1H NMR: 1.36-1.56 (m, 3H),
1.72 (td, J ) 3.4 and 10.7 Hz, 1H), 2.35-2.39 (m, 1H), 2.65-
2.79 (m, 1H), 3.10 (d, J ) 2.3 Hz, 1H), 3.47-3.48 (m, 1H), 3.55
(dd, J ) 3.1 and 10.6 Hz, 1H), 3.74 (s, 3H), 4.10 (dd, J ) 3.1
and 10.8 Hz, 1H), 4.29 (t, J ) 10.7 Hz, 1H), 7.21-7.31 (m,
5H). 13C NMR: 22.3, 26.5, 43.3, 51.9, 52.0, 63.1, 65.4, 72.6,
128.1, 128.6, 128.9, 136.2, 169.1, 172.3. IR (CHCl3): 1725,
1
5H). Irradiation of the H NMR 3.14 signal (H-9a) causes the
3.42 resonance (H-9) to change to a doublet (J ) 3.7 Hz). 13C
NMR: 19.7, 29.5, 35.1, 48.3, 51.4, 52.2, 62.9, 66.9, 72.7, 128.1,
128.7, 129.0, 136.1, 168.9, 171.5. IR (CHCl3): 1720, 1730 cm-1
.
[R]20D: +43 (c 0.96, CHCl3). MS m/ e 303 (31) (M+), 186 (46),
104 (100), 96 (38), 84 (74). HRMS: calcd for C17H21NO4 m/ z
) 303.1470, obsd m/ z ) 303.1471.
1735 cm-1
. : +66 (c 0.3, CHCl3). Anal. Calcd for
[R]20
D
C16H19NO4: C, 66.41; H, 6.61; N, 4.84. Found: C, 66.31; H,
6.54; N, 4.81.
[4S -4r,7â]-1,6-Dioxo-7-m e t h yl-4-p h e n yl-1,3,4,6,7,8-
h exa h yd r op yr id o[2,1-c][1,4]oxa zin e-9-ca r b oxylic Acid
Meth yl Ester 24. A solution of compound 9 (1.9 g, 7.7 mmol)
in THF (30 mL) and methacryloyl chloride (3 mL, 31 mmol)
was refluxed with stirring for 24 h. After cooling, the reaction
mixture was poured into an aqueous solution saturated with
sodium hydrogen carbonate, and the aqueous layer was
extracted with dichloromethane. The combined organic layers
were dried (MgSO4) and evaporated under reduced pressure.
The crude residue was obtained as a solid (an epimeric mixture
at C7, 90/10) which was recrystallized in absolute ethanol to
give pure compound 24 (2.1 g, 87%): mp 96 °C. 1H NMR: 1.30
(d, J ) 6.9 Hz, 3H), 2.47 (dd, J ) 12.8 and 17.7 Hz, 1H), 2.73-
2.79 (m, 1H), 2.96 (dd, J ) 6.9 and 17.7 Hz, 1H), 3.85 (s, 3H),
4.62 (dd, J ) 1.6 and 11.8 Hz, 1H), 4.74 (dd, J ) 2.9 and 11.8
Hz, 1H), 5.68 (s, 1H), 7.17-7.39 (m, 5H). 13C NMR: 15.1, 30.4,
33.9, 52.1, 53.1, 70.2, 121.5,125.9, 128.1, 128.5, 129.2, 136.1,
[4S-4r,9r,9a â]-1-Oxo-4-p h en ylocta h yd r op yr id o[2,1-c]-
[1,4]oxa zin e-9-ca r boxylic Acid Meth yl Ester (16). A solu-
tion of compound 15 (0.1 g, 0.33 mmol) in THF (5 mL) was
dropped into a 1 M solution of BH3/THF complex (3.3 mL, 3.3
mmol) in THF and cooled to 0 °C. Once the addition was over,
the mixture was hydrolyzed with water and then extracted
with dichloromethane. Evaporation of the combined organic
layers gave an oily residue which was chromatographed on
silica gel (E/PE 50/50) Compound 16 was isolated as a white
solid (0.6 g, 63%): mp 108 °C. 1H NMR: 1.55-1.91 (m, 4H),
2.55-2.57 (m, 1H), 2.72-2.74 (m, 1H), 3.00-3.02 (m, 1H), 3.77
(s, 3H), 3.95 (dd, J ) 5.7 and 6.1 Hz, 1H), 4.06 (d, J ) 6.6 Hz,
1H), 4.37 (dd, J ) 7.2 and 11.6 Hz, 1H), 4.65 (dd, J ) 5.6 and
11.6 Hz, 1H), 7.20-7.43 (m, 5H). 13C NMR: 22.6, 25.1, 41.8,
52.0, 52.2, 57.8, 61.7, 71.5, 127.9, 128.3, 128.9, 136.4, 170.2,
159.4, 167.6, 169.9. IR (CHCl3): 1640, 1690, 1720, 1740 cm-1
.
173.5. IR (CHCl3): 1725, 1735 cm-1
CHCl3). Anal. Calcd for C16H19NO4: C, 66.41; H, 6.61; N, 4.84.
Found: C, 66.38; H, 6.76; N, 4.88.
. : -41 (c 0.6
[R]20
D
[R]20D: +54.8 (c 1.1, CHCl3). HRMS: calcd for C17H17NO5 m/ z
) 315.1106, obsd m/ z ) 315.1106.
[4S-4r,7â,9â,9a r]-1,6-Dioxo-7-m eth yl-4-p h en ylocta h y-
d r op yr id o[2,1-c][1,4]oxa zin e-9-ca r boxylic Acid Meth yl
Ester (25) a n d [4S-4r,7â,9â,9a â]-1,6-Dioxo-7-m eth yl-4-
p h en yloct a h yd r op yr id o[2,1-c][1,4]oxa zin e-9-ca r b oxyl-
ic Acid Meth yl Ester (26). A mixture of compound 24 (0.7
g, 2.2 mmol) and 5% Pd on carbon (0.3 g) in ethanol/ethyl
acetate (1/1, 80 mL) was stirred under hydrogen (1 atm) for 2
h. The catalyst was filtered on Celite, and the filtrate was
evaporated. The residue was chromatographed on silica gel
(E/PE 80/20, then Et2O). The following compounds were
obtained by order of elution:
[4S -4r,8r]-1,6-Dioxo-8-m e t h yl-4-p h e n yl-1,3,4,6,7,8-
h exa h yd r op yr id o[2,1-c][1,4]oxa zin e-9-ca r b oxylic Acid
Meth yl Ester (18). Crotonic anhydride (1.7 mL, 11.6 mmol)
was added to a solution of compound 9 (2.2 g, 8.9 mmol) in
THF (50 mL). The black solution was refluxed for 10 days.
After cooling, the mixture was poured into a saturated aqueous
solution of sodium hydrogen carbonate. The aqueous layer was
extracted with dichloromethane, and the combined organic
layers were dried over MgSO4 and evaporated. The residue
was purified by flash chromatography (E/PE 80/20). Com-
pound 18 was obtained as a yellow solid (2.1 g, 76%): mp 57
°C. 1H NMR: 1.28 (d, J ) 7.0 Hz, 3H), 2.57 (dd, J ) 3.4 and
15.5 Hz, 1H), 2.81-2.88 (m, 2H), 3.86 (s, 3H), 4.68-4.71 (ABX
system J AB ) 12, J AX ) 1.8, and J BX ) 2.8 Hz, 2H), 5.87 (bs,
1H), 7.28-7.41 (m, 5H). 13C NMR: 17.7, 29.5, 36.9, 49.9, 52.8,
69.9, 124.8, 126.2, 128.5, 128.9, 129.2, 136.0, 158.1, 166.7,
167.8. IR (CHCl3): 1635, 1685, 1720, 1735 cm-1. [R]20D: +95.9
(c 1.1 CHCl3). HRMS: calcd for C17H17NO5 m/ z ) 315.1106,
obsd m/ z ) 315.1105.
[4S-4r,8r,9r,9a r]-1,6-Dioxo-8-m eth yl-4-p h en ylocta h y-
d r op yr id o[2,1-c][1,4]oxa zin e-9-ca r boxylic Acid Meth yl
Ester 19. A solution of compound 18 (1.3 g, 4.1 mmol) in
absolute ethanol (70 mL) was placed with 5% palladium on
carbon (0.37 g) under an atmosphere of hydrogen for 2.5 h.
The mixture was filtered on Celite and then evaporated.
Compound 19 was obtained as a white solid (1.1 g, 85%): mp
129 °C. 1H NMR: 1.07 (d, J ) 6.1 Hz, 3H), 2.25-2.44 (m,
3H), 3.28-3.32 (m, 1H), 3.74 (s, 3H), 4.44 (d, J ) 12.1 Hz,
1H), 4.50 (d, J ) 4.6 Hz, 1H), 4.68 (dd, J ) 3.4 and 12.2 Hz,
1H), 5.29 (d, J ) 3 Hz, 1H), 7.12-7.41 (m, 5H). 13C NMR:
Com p ou n d 26: 0.42 g (59.6%), mp 111 °C. 1H NMR: 1.13
(d, J ) 6.7 Hz, 3H), 1.85-1.92 (m, 1H), 2.29-2.40 (m, 2H),
3.28-3.32 (m, 1H), 3.67 (s, 3H), 4.50 (dd, J ) 7.5 and 12 Hz,
1H), 4.63 (d, J ) 5.2 Hz, 1H), 4.69 (dd, J ) 5.5 and 12 Hz,
1H), 5.60 (dd, J ) 5.5 and 7.5 Hz, 1H), 7.19-7.27 (m, 5H). 13
C
NMR: 16.7, 27.8, 35.3, 39.9, 52.3, 52.7, 54.8, 68.4., 126.3, 128.2,
129.0, 136.0, 167.6, 171.2, 172.1. [R]20D: +37 (c 1.1, CHCl3).
HRMS: calcd for C17H19NO5 m/ z ) 317.1263, obsd m/ z )
317.1262.
Com p ou n d 25: 0.12 g (17%), mp 185 °C. 1H NMR: 1.17
(d, J ) 6.9 Hz, 3H), 1.76 (dd, J ) 12 and 12 Hz, 1H), 2.30
(ddd, J ) 3.1, 5.8, and 13.1 Hz, 1H), 2.38-2.46 (m, 1H), 3.23
(ddd, J ) 3.1, 10.6, and 13 Hz, 1H), 3.73 (s, 3H), 4.41 (dd, J )
1.2 and 12.2 Hz, 1H), 4.74 (d, J ) 10.5 Hz, 1H), 4.78 (dd, J )
3,1 and 12.1 Hz, 1H), 5.29 (d, J ) 2.6 Hz, 1H), 6.99-7.28 (m,
5H). 13C NMR: 16.6, 32.3, 36.1, 41.7, 52.7, 55.3, 57.7, 69.6,
125.6, 128.0, 129.0, 138.5, 168.4, 170.7, 172.6. [R]20D: +63 (c
0.7, CHCl3). Anal. Calcd for C17H19NO5: C, 64.34; H, 4.41;
N, 6.03. Found: C, 64.28; H, 4.33; N, 6.08.