A. Sartori et al. / Tetrahedron 64 (2008) 11697–11705
11703
4.10–4.30 (m, 5H, OCH2CH3 and H200), 3.81 (s, 3H, OMe), 3.58 (d,
2.0 equiv), TMSOTf (97
m
L, 2.0 equiv), Et3N (74
m
L, 2.0 equiv), re-
J¼9.1 Hz, 1H, H2), 2.71 (dqd, J¼9.1, 7.0, 3.2 Hz, 1H, H10), 1.28 (br t,
action temperature ꢀ78 ꢁC, reaction time 4 h. Silica gel flash
chromatographic purification (hexane/EtOAc 33:67) afforded
compound 17 (68.5 mg, 83% yield). Data for 17: a white solid; mp
124–126 ꢁC; IR (neat) nmax 2983, 1738, 1697, 1602, 1333, 1274,
J¼7.1 Hz, 6H, OCH2CH3), 0.98 (d, J¼7.0 Hz, 3H, H20); 13C NMR
(75.4 MHz, CDCl3) d
176.7 (Cq, C500), 173.8 (Cq, C300), 168.3 and 168.2
(2Cq, CO2Et), 95.2 (CH, C400), 61.6 (2C, CH2, OCH2CH3), 59.2 (CH,
C200), 58.4 (CH3, OMe), 53.5 (CH, C2), 34.9 (CH, C10), 14.0 (2C,
OCH2CH3), 12.2 (CH3, C20). Anal. Calcd for C14H21NO6: C, 56.18; H,
7.07; N, 4.68. Found: C, 56.01; H, 7.18; N, 4.50. The presence of
minor isomer syn-15 evidenced by 1H NMR analysis of the crude
reaction product could no longer be detected after column chro-
matography purification. Data for syn-15 (taken from the reaction
1176 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 9.02 (br s, 1H, NH), 5.21 (d,
J¼1.5 Hz, 1H, H40), 4.23 (q, J¼7.1 Hz, 2H, OCH2CH3), 4.15 (q, J¼7.1 Hz,
2H, OCH2CH3), 3.81 (s, 3H, OMe), 3.47 (s, 2H, H3), 1.30 (t, J¼7.1 Hz,
3H, OCH2CH3), 1.24 (t, J¼7.1 Hz, 3H, OCH2CH3); 13C NMR (75.4 MHz,
CDCl3)
d
171.4 and 169.0 (2C, Cq, C30 and C50), 167.2 and 165.9 (2C,
Cq, CO2Et), 136.1 (C20), 108.1 (C2), 95.1 (C40), 61.4 (2C, CH2,
OCH2CH3), 58.5 (CH3, OMe), 35.9 (CH2, C3), 14.0 and 13.9 (2C, CH3,
OCH2CH3). Anal. Calcd for C13H17NO6: C, 55.12; H, 6.05; N, 4.94.
Found: C, 55.24; H, 5.94; N, 4.79.
mixture): 1H NMR (300 MHz, CDCl3)
d 5.90 (br s, 1H, NH), 5.07 (br s,
1H, H400), 4.10–4.30 (m, 5H, OCH2CH3 and H200), 3.82 (s, 3H, OMe),
3.38 (d, J¼8.2 Hz, 1H, H2), 2.70–2.85 (m, 1H, H10), 1.25–1.35 (m, 6H,
OCH2CH3), 0.83 (d, J¼6.8 Hz, 3H, H20).
4.3.8. (2E)-Diethyl 2-[1-(4-methoxybenzyl)-3-methoxy-5-oxo-1H-
pyrrol-2(5H)-ylidene]succinate (18) (Table 2, entry 7)
Prepared according to the representative VMMAR procedure
and utilizing diethyl but-2-ynedioate (7) in place of 2 and pyrroli-
none 1e in place of 1c. Reaction conditions: pyrrolinone 1e (62 mg,
4.3.6. Diethyl 2-{(R
methoxy-5-oxo-1H-pyrrol-2-yl]ethyl}malonate (anti-16) and
diethyl 2-{(S )-1-[(R )-1-(4-methoxybenzyl)-2,5-dihydro-3-
*
)-1-[(R )-1-(4-methoxybenzyl)-2,5-dihydro-3-
*
*
*
methoxy-5-oxo-1H-pyrrol-2-yl]ethyl}malonate (syn-16) (Table 2,
entry 5)
Prepared according to the representative VMMAR procedure
and utilizing diethyl 2-ethylidenemalonate (6) in place of 2 and
pyrrolinone 1e in place of 1c. Reaction conditions: pyrrolinone 1e
1.0 equiv), alkyne 7 (85 mL, 2.0 equiv), TMSOTf (96 mL, 2.0 equiv),
Et3N (74
m
L, 2.0 equiv), reaction temperature ꢀ70 ꢁC, reaction time
4 h. Silica gel flash chromatographic purification (hexane/EtOAc
40:60) afforded compound 18 (42.4 mg, 37% yield), along with the
expected VMMAR products (maleate isomer, 12%; fumarate isomer,
18%), as well as recovered pyrrolinone 1e (13%). Data for 18: IR
(60 mg, 1.0 equiv), malonate 6 (94 mL, 2.0 equiv), TMSOTf (94 mL,
2.0 equiv), Et3N (72
m
L, 2.0 equiv), reaction temperature ꢀ78 ꢁC,
reaction time 12 h. 1H NMR analysis of the crude reaction mixture
revealed a 2:1 anti/syn diastereomeric ratio. Silica gel flash chro-
matographic purification (hexane/EtOAc 40:60) afforded anti-16 as
a colourless glassy solid (49.6 mg, 43% yield) and syn-16 as a pale
yellow glassy solid (24.2 mg, 21% yield). Data for anti-16: IR (neat)
(neat) nmax 2981, 2937, 1731, 1707, 1612,1514,1336, 1246,1174 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.08 (d, J¼8.8 Hz, 2H, Ar), 6.86 (br d,
J¼8.7 Hz, 2H, Ar), 5.32 (s, 1H, H40), 4.92 (s, 2H, CH2Ar), 4.23 (q,
J¼7.2 Hz, 2H, OCH2CH3), 4.16 (q, J¼7.2 Hz, 2H, OCH2CH3), 3.85 (s, 3H,
OMe), 3.80 (s, 3H, OMe), 3.32 (s, 2H, H3), 1.32 (t, J¼7.2 Hz, 3H,
OCH2CH3), 1.26 (t, J¼7.2 Hz, 3H, OCH2CH3); 13C NMR (75.4 MHz,
nmax 2979, 2937, 1753, 1732, 1687, 1628, 1512, 1246 cmꢀ1
(300 MHz, CDCl3)
;
1H NMR
d
7.12 (d, J¼8.6 Hz, 2H, Ar), 6.84 (br d, J¼8.7 Hz,
CDCl3) d
170.7 and 169.3 (2C, Cq, C30 and C50), 168.8 and 166.1 (2C,
2H, Ar), 5.15 (s, 1H, H400), 5.11 (1/2ABq, J¼15.6 Hz, 1H, CH2Ar), 4.00–
4.20 (m, 4H, OCH2CH3), 3.90 (1/2ABq, J¼15.3 Hz, 1H, CH2Ar), 3.87
(br s, 1H, H200), 3.80 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.28 (d,
J¼9.9 Hz, 1H, H2), 2.94 (dqd, J¼9.8, 7.3, 2.6 Hz, 1H, H10), 1.27 (t,
J¼7.1 Hz, 3H, OCH2CH3), 1.23 (t, J¼7.0 Hz, 3H, OCH2CH3), 0.98 (d,
Cq, CO2Et), 158.8 (Cq, Ar), 136.9 (C20), 129.9 (Cq, Ar), 128.0 (2C, CH,
Ar), 114.3 (2C, CH, Ar), 108.8 (C2), 93.2 (C40), 61.5 and 61.4 (2C, CH2,
OCH2CH3), 58.6 (CH3, OMe), 55.3 (CH3, OMe), 43.9 (CH2, NCH2Ar),
35.9 (CH2, C3), 14.1 and 14.0 (2C, CH3, OCH2CH3). Anal. Calcd for
C21H25NO7: C, 62.52; H, 6.25; N, 3.47. Found: C, 62.39; H, 6.37; N,
J¼7.2 Hz, 3H, H20); 13C NMR (75.4 MHz, CDCl3)
d
175.1 (Cq, C500),
3.40. Data for diethyl 2-[(2R
methoxy-5-oxo-1H-pyrrol-2-yl]maleate (not shown): 1H NMR
(300 MHz, CDCl3)
*
)-1-(4-methoxybenzyl)-2,5-dihydro-3-
172.3 (Cq, C300), 168.0 (2C, Cq, CO2Et), 158.9 (Cq, Ar), 129.3 (Cq, Ar),
129.1 (2C, CH, Ar), 114.1 (2C, CH, Ar), 95.1 (CH, C400), 61.9 (CH, C200),
61.6 and 61.5 (2C, CH2, OCH2CH3), 58.2 (CH3, OMe), 55.2 (CH3, OMe),
53.5 (CH, C2), 43.2 (CH2, NCH2Ar), 33.0 (CH, C10), 14.0 and 13.9 (2C,
CH3, OCH2CH3), 12.9 (CH3, C20). Anal. Calcd for C22H29NO7: C, 62.99;
H, 6.97; N, 3.34. Found: C, 63.11; H, 7.08; N, 3.14. Data for syn-16: IR
(neat) nmax 2977, 2934, 1755, 1732, 1689, 1626, 1511, 1240 cmꢀ1; 1H
d
7.16 (d, J¼8.5 Hz, 2H, Ar), 6.86 (br d, J¼8.6 Hz,
2H, Ar), 5.97 (d, J¼0.5 Hz, 1H, H3), 5.18 (1/2ABq, J¼15.0 Hz, 1H,
CH2Ar), 5.11 (d, J¼0.5 Hz, 1H, H40), 4.41 (br s, 1H, H20), 4.10–4.40 (m,
4H, OCH2CH3), 3.80 (s, 3H, OMe), 3.79 (1/2ABq, J¼14.9 Hz, 1H,
CH2Ar), 3.78 (s, 3H, OMe), 1.25–1.35 (m, 6H, OCH2CH3); 13C NMR
(75.4 MHz, CDCl3)
d
173.2 (Cq, C500), 171.3 (Cq, C300), 164.8 (Cq,
NMR (300 MHz, CDCl3)
d
7.30 (d, J¼8.6 Hz, 2H, Ar), 6.84 (br d,
CO2Et),163.8 (Cq, CO2Et),159.1 (Cq, Ar),143.1 (Cq, C2),129.7 (2C, CH,
Ar), 129.0 (Cq, Ar),125.5 (CH, C3), 114.1 (2C, CH, Ar), 94.4 (CH, C40),
62.0 and 61.8 (2C, CH2, OCH2CH3), 61.4 (CH, C20), 58.6 (CH3, OMe),
55.3 (CH3, OMe), 42.7 (CH2, NCH2Ar), 14.0 (2C, CH3, OCH2CH3). Data
J¼8.7 Hz, 2H, Ar), 5.12 (s, 1H, H400), 5.01 (1/2ABq, J¼15.1 Hz, 1H,
CH2Ar), 4.00–4.20 (m, 4H, OCH2CH3), 4.02 (1/2ABq, J¼15.1 Hz, 1H,
CH2Ar), 3.96 (d, J¼2.4 Hz, 1H, H200), 3.80 (s, 3H, OMe), 3.79 (s, 3H,
OMe), 3.70 (d, J¼11.4 Hz, 1H, H2), 2.85 (dqd, J¼11.0, 7.0, 2.4 Hz, 1H,
H10), 1.27 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.20 (t, J¼7.0 Hz, 3H,
OCH2CH3), 0.73 (d, J¼6.9 Hz, 3H, H20); 13C NMR (75.4 MHz, CDCl3)
for diethyl 2-[(2R
oxo-1H-pyrrol-2-yl]fumarate (not shown): 1H NMR (300 MHz,
DMSO-d6, 85 ꢁC)
*
)-1-(4-methoxybenzyl)-2,5-dihydro-3-methoxy-5-
d
7.02 (d, J¼8.6 Hz, 2H, Ar), 6.82 (d, J¼8.6 Hz, 2H,
d
175.0 (Cq, C500),171.9 (Cq, C300),168.2 (Cq, CO2Et),168.0 (Cq, CO2Et),
Ar), 6.80 (s, 1H, H3), 5.70 (br s, 1H, H20), 5.25 (s, 1H, H40), 4.56 (1/
2ABq, J¼15.3 Hz, 1H, CH2Ar), 4.10 (m, 4H, OCH2CH3), 3.97 (1/2ABq,
J¼15.3 Hz, 1H, CH2Ar), 3.75 (s, 3H, OMe), 3.72 (s, 3H, OMe), 1.18 (m,
6H, OCH2CH3).
158.9 (Cq, Ar), 129.8 (Cq, Ar), 129.7 (2C, CH, Ar), 113.8 (2C, CH, Ar),
95.5 (CH, C400), 61.6 and 61.5 (2C, CH2, OCH2CH3), 60.3 (CH, C200),
58.2 (CH3, OMe), 55.2 (CH3, OMe), 54.2 (CH, C2), 43.6 (CH2,
NCH2Ar), 32.2 (CH, C10), 14.0 and 13.9 (2C, CH3, OCH2CH3), 10.2
(CH3, C20). Anal. Calcd for C22H29NO7: C, 62.99; H, 6.97; N, 3.34.
Found: C, 62.82; H, 7.05; N, 3.50.
4.3.9. (R
oxocyclohexyl]-1H-pyrrol-2(5H)-one (anti-19) and (R
methoxybenzyl)-4-methoxy-5-[(S )-3-oxocyclohexyl]-1H-pyrrol-
*
)-1-(4-Methoxybenzyl)-4-methoxy-5-[(R
*
)-3-
*
)-1-(4-
*
4.3.7. (2E)-Diethyl 2-[3-methoxy-5-oxo-1H-pyrrol-2(5H)-
ylidene]succinate (17) (Table 2, entry 6)
Prepared according to the representative VMMAR procedure
and utilizing diethyl but-2-ynedioate (7) in place of 2. Reaction
2(5H)-one (syn-19) (Table 2, entry 12)
Prepared according to the representative VMMAR procedure
and utilizing cyclohex-2-enone (11) in place of 2 and pyrrolinone 1e
in place of 1c. Reaction conditions: pyrrolinone 1e (60 mg,
conditions: pyrrolinone 1c (30 mg, 1.0 equiv), alkyne 7 (85
mL,
1.0 equiv), ketone 11 (50 mL, 2.0 equiv), TMSOTf (94 mL, 2.0 equiv),