Torrente et al.
PhCOO-), 129.5 (Ar,
C
ipso-PhCOO-), 128.4 (Ar, Cmeta
-
1H NMR (CDCl3, 500 MHz) δ: 5.43 (m, 1H, H8), 5.30 (d, J 1-2
) 2.7 Hz, 1H, H1), 4.57 (m, 1H, H5), 4.41 (d, J 6endo-6exo ) 7.2
Hz 1H, H6endo), 4.08 (d, J 3-2 ) 5.4 Hz, 1H, H3), 4.00 (dd,
J 2-1 ) 2.7 Hz, J 2-3 ) 5.4 Hz, 1H, H2), 3.80 (dq, 1H, H9′), 3.74
(dd, J 6exo-6endo ≈ J 6exo-5 ) 7 Hz, 1H, H6exo), 3.50 (dq, 1H, H9),
2.86 (s, 3H, NCH3), 2.60 (dd, J gem ) 13.9 Hz, J ) 2.8 Hz, 1H,
H7′), 2.42 (dd, J gem ) 13.9 Hz, J ) 6.6 Hz, 1H, H7), 1.59 (s,
3H, CH3), 1.33 (s, 3H, CH3), 1.21 (t, J ) 7.1 Hz, 3H, CH3). 13C
NMR (CDCl3, 75 MHz) δ: 111.2 (C(CH3)2), 105.2 (C8), 99.5 (C1),
75.9 (C3), 74.4 (C2, C5), 69.2 (C4), 64.9 (C6), 64.3 (C9), 44.4
(C7), 41.8 (CH3-N), 25.9, 25.8 (CH3, CH3), 15.1 (C10). MS
(EI): 301 (68, M+), 256 (53, M+ - (-ON+-Me)), 214 (62), 200
(42), 159 (100), 142 (82). Anal. Calcd for C14H23NO6: C, 55.81;
H, 7.69; N, 4.65. Found: C, 55.48; H, 7.65; N, 4.53. [R]D)
-128.2 (1.07, CH2Cl2). 19f′. 1H NMR (CDCl3, 300 MHz) δ: 5.33
(dd, J ) 6.6 Hz, J ) 3.7 Hz, 1H, H8), 5.26 (m, 1H, H1), 4.42
(dd, J 6endo-6exo ) 7.2 Hz, J 6endo-5 ) 0.9 Hz, 1H, H6endo), 4.31
PhCOO-), 127.9, 127.8, 126.7 (Ar-CH2Ph), 101.9 (C1), 77.4
(C2#), 76.0 (C5#), 74.9 (C7), 73.9 (C4), 73.4 (C3), 70.8 (C9),
66.0 (C6), 57.2 (C10), 54.6 (C8). (#: these assignments could
be interchanged). MS m/z: 410 [8, (M + 1)+], 409 (30, M+),
333 [0.1, (M + 1 - Ph)+], 304 [0.5, (M - PhCO)+], 105 (100,
PhCO+), 91 [95, (PhCH2)+], 77 (77, Ph+). Anal. Calcd for
(C23H23NO6): C, 67.47; H, 5.67; N, 3.42. Found: C, 67.20; H,
5.80; N, 3.50.
Isoxa zolid in e 20. Benzoate 19d (2.7 g, 8.04 mmol) was
hydrolyzed with 1% aqueous NaOH-CH3OH (1:9, 45 mL). The
reaction mixture was filtered through Celite, the solids care-
fully reextracted with hot methanol, the organic extracts
concentrated, and the residue redissolved in CH2Cl2. Drying
over anhydrous Na2SO4 and concentration gave an oily residue.
1
Chromatography gave 20 (1.8 g, 98%). H NMR (CDCl3, 300
MHz) δ: 5.41 (d, J 1,2) 2.7, 1H; H1), 4.69 (m, 1H; H5), 4.54
(br, 1H; OH), 4.43 (dd, J 7,7′ ) J 7endo,8 ) 8.5, 1H; H7endo), 4.17
(dd, J 9,9′ ≈ J 9endo,8 ≈ 8.3, 1H; H9endo), 3.93 (m, 3H; H2, H6endo,
(m, 1H, H3), 4.09 (d, 1H, H5), 3.96 (dd, J 2-1 ) 2.7 Hz, J 2-3
)
5.3 Hz, 1H, H2), 3.82 (dq, J ) 7.1, 9.5 Hz, 1H, H9), 3.66 (dd,
J 6exo-6endo ) 7.2 Hz, J 6exo-5 ) 5.9 Hz, 1H, H6exo), 3.50 (dq, J )
7.1, 9.5 Hz, 1H, H9′), 3.06 (s, 3H, CH3N), 3.00 (dd, J gem ) 13.8
Hz, J ) 6.6 Hz, 1H, H7′), 2.20 (dd, J ) 13.8, 3.7 Hz, 1H, H7),
1.57 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.21 (t, J ) 7.1 Hz, 3H,
CH3). 13C NMR (CDCl3, 75 MHz) δ: 111.3 (C(CH3)2), 106.1 (C8),
99.6 (C1), 75.7, 75.2, 74.7 (C2, C3, C5), 69.5 (C4), 64.8 (C6),
64.1 (C9), 44.7 (C7), 41.7 (N-CH3), 25.9, 25.8 (CH3, CH3), 15.1
(C10). MS (EI): 301 (16.6, M+), 256 (14, M+ - (ON+-Me)), 214
(17), 200 (11.6), 159 (40), 142 (28), 58 (100). MS (CI): 304 (2,
M+ + 3), 303 (15.6, M+ + 2), 302 (100, M+ + 1). HRMS (CI):
302.1603, calcd for C14H24NO6 302.1611. [R]D ) +8.14 (1.18,
CH2Cl2).
Cycloa d d u ct 19g. A solution of the nitrone 5g (150 mg,
0.52 mmol) and dimethyl acetylenedicarboxylate (1 mL, 8.25
mmol) in dry benzene (1 mL) was stirred at rt for 8 h. The
solvent was removed; column chromatography (AcOEt-hexane
25:75, 40:60) gave 19g (oil, 153 mg, 68%). 1H NMR (250 MHz,
CDCl3) δ: 5.94 (d, J ) 3.6 Hz, 1H, H1), 4.87 (d, J ) 3.6 Hz,
1H, H2), 4.31 (d, J ) 7.6 Hz, 1H, H4), 4.08 (dd, 1H, H6*), 3.95-
3.72 (m, 2H, H6′*, H5*), 3.85 (s, 3H, -OCH3), 3.71 (s, 3H,
-OCH3), 3.14 (s, 3H, CH3), 1.54, 1.40, 1.32, 1.31 (s, s, s, s, 4
CH3). 13C NMR (75.4 MHz, CDCl3) δ: 162.5, 159.0 (CdO,
CdO), 154.4 (Cd), 112.3, 109.3, 105.4 (Cd), 104.3 (C1), 83.7,
80.4, 79.8 (C4*, C3, C2), 73.4 (C5*), 67.6 (C6), 53.0 (CH3O), 52.9
(CH3O), 42.1 (CH3), 26.4, 26.1, 25.9, 24.9 (CH3, CH3, CH3, CH3).
*: these assignments could be interchanged. MS (EI): 429 (5.3,
M+), 414 (68, M+ - CH3), 85 (100). MS (FAB+): 430 (M+ + 1).
HMRS (FAB+): calcd for C19H28NO10 430.1713, found 430.1704.
H9exo), 3.75 (m, 2H; H4, H6exo), 3.64 (dd, J 7,7′ ) 8.3, J 7exo,8
)
4.4, 1H; H7exo), 3.11 (m, 1H; H8), 2.73 (s, 3H; NCH3). 13C NMR
(CDCl3, 75 MHz) δ: 101.0 (C1), 79.5 (C3), 76.3, 76.1, 73.9, 72.9
(C7, C9), 70.1, 65.8 (C6), 54.2 (C8), 39.2 (NCH3). LRMS m/z:
321 [(M + 2)+; 0.1], 230 [(M + 1)+; 13], 229 (M+; 100), 186,
140, 127, 98, 82, 68.
Diol 21. Isoxazolidine 20 (645 mg, 2.81 mmol) and Zn dust
(775 mg, 1.26 mmol, 400 mol %) were refluxed in 60% aqueous
AcOH (18 mL). Once consumed (TLC, MeOH/CH2Cl2, 10:90,
Rf22) 0.14), the solvents were evaporated, the residue dissolved
in CH3OH and treated with 3 N aqueous ammonia. The salts
were filtrated, and the filtrate was concentrated. Last traces
of water were eliminated by azeotropic distillation with
toluene. Chromatography gave 21 as a white solid (521 mg,
81%). 1H NMR (CDCl3-CD3OD, 3:1, 300 MHz) δ: 5.27 (d, J 1,2
) 2.5, 1H; H1), 4.47 (m, 1H; H5), 4.14 (dd, J 7,7′ ≈ J 7,8 ≈ 9.2,
1H; H7), 4.04 (s, 1H; H4), 3.98 (d, J 2,1 ) 2.5, 1H; H2), 3.88 (d,
J 6,6′ ) 8.5, 1H; H6endo), 3.7-3.5 (m, 4H; H6exo, H7′, H9), 2.55
(s, 3H; NCH3), 2.54 (m, 1H; H8). 13C NMR (CDCl3-CD3OD,
3:1, 75 MHz) δ: 99.9 (C1), 78.8, 77.8, 70.2 (C7), 68.9, 67.2 (C3),
65.8 (C6), 57.8 (C9), 47.9 (NCH3), 30.1 (C8). LRMS m/z: 232
[(M + 1)+; 6], 231 (M+; 46), 200 [(M - CH2OH)+; 6], 188, 164,
149, 129 (100), 98, 85, 70, 57.
Cycloa d d u ct 19e. It was obtained (oil, 43 mg, 52%) from
ketone 4e (77 mg, 0.23 mmol), MeNHOH‚HCl (388 mg, 4.63
mmol), pyridine (241 µL, 2.99 mmol), and molecular sieves (50
mg) in EtOH (0.7 mL), following the procedure reported for
19a . Total reaction time 15 h at room temperature and 15 h
at 60 °C. Mixtures of AcOEt-hexane of increasing polarity
(25%, 50%, 70%), were used for chromatography. 1H NMR
Cycloa d d u ct 19h . A solution of nitrone 5h (100 mg, 0.41
mmol) and phenylacetylene (135 µL, 1.23 mmol) in dry benzene
(3 mL) was refluxed for 5 h. Additional phenylacetylene (3
equiv) was added and the reaction mixture refluxed for 6 h.
The solvent was removed. Crystallization (AcOEt) afforded
19h (116 mg, 82%, mp ) 175 °C dec). 1H NMR (250 MHz,
CDCl3) δ: 7.52 (m, 2H, ArH), 7.37 (m, 3H, ArH), 5.98 (d, J )
3.6 Hz, 1H, H1), 5.07 (s, 1H, H7), 4.85 (m, 3H, H2, H3, H4),
3.22 (s, 3H, CH3), 1.51 (s, 3H, CH3), 1.35 (s, 3H, CH3). 13C NMR
(62.9 MHz, CDCl3) δ: 171.7 (C6), 157.6 (C8), 130.2, 128.5, 126.0
(Ar), 127.1 (Cipso), 113.4 (C), 106.8 (C1), 89.2 (C7), 82.3, 82.1,
82.0 (C2, C3, C4), 79.1 (C5), 42.3 (NCH3), 26.9, 26.5 (CH3, CH3).
MS (EI): 347 (11.5, M+ + 2), 346 (3.5, M+ + 1), 345 (14, M+),
(CDCl3, 300 MHz) δ: 7.36-7.27 (m, 5H, ArH), 5.39 (d, J 1-2
)
1.6 Hz, 1H, H1), 4.65 (d, J ) 11.5 Hz, 1H, H10), 4.53 (d, J )
11.5 Hz, 1H, H10′), 4.25 (d, J 5-6exo ) 4.7 Hz, 1H, H5), 4.17
(dd, J gem ) 8.9 Hz, J 9-8 ) 7.5 Hz, 1H, H9), 4.08 (d, J gem ) 8.1
Hz, 1H, H6endo), 4.02 (d, J 3-2 ) 7.1 Hz, 1H, H3), 3.89 (dd,
J gem ) 8.9 Hz, J 9′-8 ) 4.6 Hz, 1H, H9′), 3.80 (dd, J gem ) 8.1
Hz, J 6exo-5 ) 4.7 Hz, 1H, H6exo), 3.75 (dd, J gem ) 13.0 Hz, J 7-8
) 4.3 Hz, 1H, H7), 3.46 (dd, J gem ) 13.0 Hz, J 7′-8 ) 9.5, 1H,
H7′), 3.34 (dd, J 2-3 ) 7.1 Hz, J 2-1 ) 1.6 Hz, 1H, H2), 3.25 (m,
1H, H8), 2.59 (s, 3H, -NCH3), 2.14 (s, 3H, -COCH3). 13C NMR
(CDCl3, 75 MHz) δ: 168.7 (CO), 136.6 (Cipso), 128.6 (Cmeta), 128.3
(Cpara), 128.2 (Cortho), 98.1 (C1), 80.8 (C2), 78.1 (C4), 75.8 (C5),
72.9 (C9#), 72.7 (C10#), 68.1 (C6), 60.2 (C8), 49.1 (C7), 47.9 (C3),
38.6 (-NCH3), 22.2 (-COCH3). MS (EI): 361 (0.07, M+ + 1),
360 (0.89, M+), 168 (29), 91 (100, C7H7). HRMS (EI): 360.1685,
calcd for C19H24N2O5 360.1673.
204 (100), 77 (55, C6H6). HRMS (EI) 345.1197, calcd for C18H19
-
NO6 345.1212. Anal. Calcd for C18H19NO6: C, 61.01; H, 5.57;
N, 3.99. Found: C, 61.25; H, 5.74; N, 4.20. [R]D ) +218.6 (0.7,
CH2Cl2).
Cycloa d d u ct 19h ′. A solution of the nitrone 5h (20 mg,
0.082 mmol) and allyl alcohol (1 mL) was refluxed for 2 h. The
solvent was removed. Flash chromatography (AcOEt/hexane
40%, 50%, 85%) gave 19h ′ (oil, 20 mg, 81%). 1H NMR (250
MHz, CDCl3) δ: 5.98 (d, J ) 3.7 Hz, 1H, H1), 4.85 (d, J ) 2.7
Hz, 1H, H4), 4.80 (d, J ) 3.7 Hz, 1H, H2), 4.77 (d, J ) 2.7 Hz,
1H, H3), 4.42 (m, 1H, CHO), 3.87 (m, 1H, CH2OH), 3.64 (m,
1H, CH2OH), 2.99 (s, 3H, CH3N), 2.70 (m, 1 H, OH), 2.51 (m,
Cycloa d d u cts 19f a n d 19f′. A solution of the nitrone 5f
(120 mg, 0.53 mmol) in benzene (5 mL) was added to a
suspension of molecular sieves (80 mg) in ethyl vinyl ether (1
mL, 5.26 mmol). After 38 h at rt and refluxing for 8 h, the
reaction mixture was filtered. Column chromatography (AcOEt/
hexane 20%, 30%, 50%) gave 19f (oil, 99 mg, 62%), 19f′ (oil,
17 mg, 11%), and some starting ketone 4f (18 mg, 15%). 19f.
4782 J . Org. Chem., Vol. 68, No. 12, 2003