3540 J . Org. Chem., Vol. 61, No. 10, 1996
Decicco and Grover
(5S)-1-[N-Boc-cis-4-(ter t-bu tyldim eth ylsilyl)HyP r o-Ala]-
4-h yd r oxy-5-m eth ylp yr r ol-2(5H)-on e (22). Crude 21 (3.06
g, 5,64 mmol) was dissolved in CH3CN (20 mL) and refluxed
for 2.5 h. The solvent was removed under reduced pressure
(m, 1H), 2.05 (s, 3H), 2.03 (m, 1H), 1.65 (m, 1H), 1.50 (bs, 13H),
1.19 (d, J ) 6.2 Hz, 3H), 0.99 (d, J ) 6.6 Hz, 3H), 0.94 (d, J )
6.6 Hz, 3H), 0.90 (d, J ) 6.2 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H);
MS (CI) m/e 694 (M + H)+; IR (neat) 3424, 2962, 2936, 2872,
to provide 2.41 g (97%) crude pyrrolidine 22: [R]25 -21.2° (c
1732, 1688, 1642, 1388, 1236 cm-1
.
D
0.38, MeOH); 1H NMR (300 MHz, CDCl3) δ 5.17 (m, 1H), 4.92
(m, 1H), 4.40 (m, 1H), 4.23 (m, 1H), 3.61 (m, 1H), 3.31 (s, 1H),
3.20 (m, 1H), 2.53 (m, 1H), 1.43 (m, 1H), 1.35 (s, 12H), 0.81 (s,
9H), -0.06 (s, 6H); MS (CI) m/e 441 (M + H)+; IR (CH2Cl2)
N-HCl-N-Me-Leu -OAc-Th r -N-Me-Val-[(5S)-1-[N-HCl-cis-
4-HyP r o-Ala ]-5-m eth ylp yr r ol-2(5H)-on e] (25). The sub-
strate 24 (70 mg, 0.100 mmol) was treated with 4 N HCl in
dioxane (3 mL) and was allowed to stir for 4 h at 0 °C. After
2932, 1756, 1702, 1620, 1394, 1258, 1166, 776 cm-1
.
4 h, the solvent was removed in vacuo to provide 62.1 mg of
1
crude 25 (98%): [R]25
-82.1° (c 0.14, MeOH); H NMR (300
(5S)-1-[N-Boc-cis-4-(ter t-bu tyldim eth ylsilyl)HyP r o-Ala]-
4-h yd r oxy-5-m eth ylp yr r olid in -2-on e (23). A solution of the
crude pyrrol-2(5H)-one 22 (2.40 g, 5.44 mmol) was dissolved
in a 10% mixture of HOAc/CH2Cl2 (30 mL), cooled in an ice
bath, and stirred vigorously while being treated portionwise
with NaBH4 (0.38g, 10.1 mmol) over 0.5 h. The mixture was
maintained for an additional 4 h at the same temperature. It
was then poured into ice-cold water and the organic layer was
washed with water and dried (MgSO4), and the solvent was
removed in vacuo. The crude oil obtained was chromato-
graphed (SiO2, 42-50% gradient, EtOAc-hexane) to provide
1.63 g (73%) of pure 23: [R]25D -10.6° (c 0.10, MeOH); 1H NMR
(300 MHz, CDCl3) δ 5.10 (m, 1H), 4.41 (m, 2H), 4.28 (m, 1H),
3.68 (m, 1H), 3.25 (m, 2H), 2.68 (m, 2H), 2.51 (m, 1H), 1.72
(m, 1H), 1.36 (s, 9H), 1.29 (m, 3H), 0.79 (s, 9H), 0.00 (s, 6H);
13C NMR (300 MHz, CDCl3) δ 172.8, 172.0, 153.9, 79.8, 69.4,
65.2, 60.0, 56.7, 54.2, 39.5, 38.5, 28.2, 25.5, 17.7; MS (CI) m/e
443 (M + H)+; IR (CH2Cl2) 3444, 2954, 2932, 1744, 1708, 1676,
D
MHz, CDCl3) δ 8.07 (d, J ) 8.8 Hz, 1H), 7.28 (dd, J ) 6.2, 2.2
Hz, 1H), 6.10 (dd, J ) 6.2, 1.4 Hz, 1H), 5.88 (bs, 1H), 5.65 (dd,
J ) 9.9, 2.5 Hz, 1H), 5.28 (m, 2H), 5.07 (dd, J ) 8.4, 4.4 Hz,
1H), 5.04 (d, J ) 11.0 Hz, 1H), 4.81 (qt, J ) 7.0, 1.8 Hz, 1H),
4.39 (bm, 1H), 3.86 (d, J ) 11.7 Hz, 1H), 3.77 (dd, J ) 11.4,
4.4 Hz, 1H), 3.55 (t, J ) 6.2 Hz, 1H), 3.14 (s, 3H), 2.55 (s, 3H),
2.51 (m, 1H), 2.29 (m, 1H), 2.03 (s, 3H), 2.00 (m, 1H), 1.66 (m,
3H), 1.46 (d, J ) 6.6 Hz, 3H), 1.25 (d, J ) 6.2 Hz, 3H), 0.98 (d,
J ) 6.6 Hz, 3H), 0.95 (d, J ) 6.2 Hz, 3H), 0.91 (d, J ) 5.8 Hz,
3H), 0.77 (d, J ) 6.6 Hz, 3H);
13C NMR (400 MHz, CDCl3) δ
175.7, 174.3, 171.5, 170.0, 170.0, 169.8, 168.5, 154.1, 125.2,
71.6, 68.6, 62.1, 59.2, 58.5, 58.0, 56.6, 52.2, 40.9, 36.4, 33.1,
30.5, 27.0, 24.8, 22.4, 22.2, 20.9, 18.7, 18.0, 17.3, 16.8; MS (CI)
m/e 594.6 (M + H)
+; IR (CH2Cl2) 3326, 2962, 2874, 1730, 1642,
1460, 1408, 1374, 1238, 1062 cm-1
.
Micr ocolin A (26d ). Amine hydrochloride 25 (14.0 mg,
0.022 mmol) was dissolved in dry CH2Cl2 (0.5 mL) and was
treated with acid 7d (4.9 mg, 0.029 mmol). To this solution
were added BOP-Cl (7.5 mg, 0.029 mmol) and triethylamine
(6.8 mL, 0.029 mmol). After being stirred overnight at 25 °C,
the reaction mixture was washed with 5 mL each of aqueous
NH4Cl, aqueous NaHCO3, and brine, concentrated in vacuo,
and chromatographed (SiO2, 80-100% gradient, EtOAc-
1408, 1366, 1254, 1202, 1098, 838 cm-1
.
(5S)-1-[N-HCl-cis-4-HyP r o-Ala ]-5-m eth ylp yr r ol-2(5H)-
on e (C). Alcohol 23 (220 mg, 0.49 mmol) was dissolved in
CH2Cl2 (4 mL) and treated with methanesulfonyl chloride
(0.097 mL, 0.845 mmol) followed by triethylamine (0.21 mL,
1.49 mmol) at 25 °C. After 1 h, the reaction mixture was
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.111 mL, 0.74
mmol), and this solution was allowed to stir for an additional
20 min. The solvent was removed in vacuo and chromato-
graphed (SiO2, 42-50% gradient, EtOAc-hexane) to provide
hexane) to provide 9.3 mg (56%) of pure microcolin A: [R]25
D
-132° (c 0.02, EtOH); Lit.10 [R]25 -145.3°(c 0.0026, EtOH):
D
1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J ) 6.0, 2.0 Hz, 1H,
H-3), 7.02 (d, J ) 8.9 Hz, 1H, H-22), 6.09 (dd, J ) 6.0, 1.6 Hz,
1H, H-2), 5.66 (dd, J ) 10.0, 2.4 Hz, 1H, H-8), 5.28 (dd, J
)10.3, 5.6 Hz, 1H, H-28), 5.25 (m, 1H, H-23), 5.02 (d, J ) 11.1
Hz, 1H, H-14), 4.96 (dd, J ) 8.9, 3.0 Hz, 1H, H-21), 4.81 (qt,
J ) 6.8, 1.9 Hz, 1H, H-4), 4.38 (m, 1H, H-10), 3.84 (m, 2H,
H-11), 3.09 (s, 3H, H-19), 2.96 (s, 3H, H-34), 2.85 (m, 1H, H-36),
2.49 (ddd, J ) 14.3, 10.0, 4.8 Hz, 1H, H-9), 2.26 (m, 1H, H-16),
2.02 (m, 1H, H-9), 2.01 (s, 3H, H-26), 1.88 (ddd, J ) 13.3, 9.5,
4.5 Hz, 1H, H-37), 1.73 (ddd, J ) 14.0, 10.5, 4.9 Hz, 1H, H-30),
1.58 (ddd, J ) 14.0, 9.5, 5.7 Hz, 1H, H-30), 1.47 (d, J ) 6.8
Hz, 3H, H-6), 1.44 (m, 1H, H-31), 1.34 (m, 1H, H-38), 1.28 (m,
1H, H-39), 1.28 (m, 2H, H-40), 1.28 (m, 2H, H-41), 1.17 (d, J
) 6.5 Hz, 3H, H-24), 1.13 (d, J ) 6.8 Hz, 3H, H-43), 1.12 (m,
1H, H-37), 1.11 (m, 1H, H-39), 0.99 (d, J ) 6.5 Hz, 3H, H-18),
0.95 (d, J ) 6.6 Hz, 3H, H-33), 0.89 (t, J ) 6.6 Hz, 3H, H-42),
0.87 (d, J ) 6.5 Hz, 3H, H-32), 0.85 (d, J ) 6.5 Hz, 3H, H-44),
190 mg (90%) of the pure unsaturated product: [R]25 -3.3°
D
1
(c 0.15, MeOH); H NMR (300 MHz, CDCl3) δ 7.24 (dd, J )
6.2, 2.2 Hz, 1H), 6.03 (dd, J ) 5.9, 1.5 Hz, 1H), 5.19 (dd, J )
8.8, 6.2 Hz, 1H), 4.72 (dq, J ) 6.6, 1.8 Hz, 1H), 4.31 (m, 1H),
3.79 (dd, J ) 10.6, 6.6 Hz, 1H), 3.26 (d, J ) 4.8 Hz, 1H), 2.62
(m, 1H), 1.74 (m, 1H), 1.45 (d, J ) 6.9 Hz, 3H), 1.33 (s, 9H),
0.79 (s, 9H), 0.00 (s, 6H); MS (CI) m/e 425 (M + H)+; IR
(CH2Cl2) 2954, 2932, 2858, 1708, 1474, 1402, 1366, 1254, 1098,
838 cm-1. Anal. Calcd for C21H36O5SiN2: C, 59.40; H, 8.55.
Found: C, 59.32; H, 8.55.
The protected substrate (160 mg, 0.37 mmol) was treated
with 4 N HCl in dioxane (4 mL) and was allowed to stir for 2
h at 0 °C. After 2 h, the solvent was removed in vacuo to
provide 90.5 mg of crude C (97%) as a white solid: [R]25
D
+33.9° (c 0.06, MeOH); 1H NMR (300 MHz, D2O + MeOH-d4)
δ 7.61 (d, J ) 5.1 Hz, 1H), 6.18 (d, J ) 5.1 Hz, 1H), 5.24 (m,
1H), 4.83 (m, 1H), 4.55 (bs, 1H), 3.52 (bs, 1H), 3.47 (bs, 1H),
2.79 (m, 1H), 2.07 (m, 1H), 1.52 (d, J ) 6.6 Hz, 3H); 13C NMR
(300 MHz, CDCl3) δ 174.2, 171.3, 160.6, 127.7, 72.6, 64.1, 62.7,
57.4, 41.7, 20.3; MS (CI) m/e 211 (M + H)+; IR (KBr) 3342,
0.82 (d, J ) 6.7 Hz, 3H, H-17);
13C NMR (400 MHz, CDCl3) δ
177.9 (C-35), 174.5 (C-7), 171.3 (C-27), 169.8 (C-1), 169.8 (C-
20), 169.8 (C-25), 168.9 (C-13), 154.1 (C-3), 125.3 (C-2), 71.7
(C-10), 68.4 (C-23), 59.2 (C-14), 58.6 (C-8), 58.1 (C-4), 56.9 (C-
11), 53.8 (C-28), 51.8 (C-21), 41.8 (C-37), 37.0 (C-39), 36.6 (C-
9), 35.8 (C-30), 33.7 (C-36), 30.7 (C-38), 30.3 (C-19), 30.3 (C-
34), 29.1 (C-40), 27.1 (C-16), 24.8 (C-31), 23.3 (C-33), 22.8 (C-
41), 21.5 (C-32), 21.0 (C-26), 19.5 (C-44), 18.8 (C-18), 18.4 (C-
17), 18.2 (C-43), 17.3 (C-24), 16.9 (C-6), 14.0 (C-42); MS (CI)
m/e 748.8 (M + H)+. Anal. Calcd for C39H66O9N5: C, 62.54;
H, 8.88. Found C, 62.11; H, 8.77.
3010, 2868, 2724, 1730, 1680, 1574, 1336, 1298, 818 cm-1
.
N-Boc-N-Me-Leu -OAc-Th r -N-Me-Val-[(5S)-1-[N-HCl-cis-
4-HyP r o-Ala ]-5-m eth ylp yr r ol-2(5H)-on e] (24). The acid 7
(77.0 mg, 0.15 mmol) was dissolved in dry CH2Cl2 (2.0 mL),
and was treated with the amine hydrochloride C (38 mg, 0.15
mmol). To this were added Bop-Cl (59.0 mg, 0.23 mmol) and
triethylamine (0.047 mL, 0.34 mmol). After being stirred
overnight at 25 °C, the reaction mixture was washed with 5
mL each of aqueous NH4Cl, aqueous NaHCO3, and brine. The
organic layer was dried (MgSO4), concentrated in vacuo, and
chromatographed (SiO2, 80-100% gradient, EtOAc-hexane)
Da ta for C-36S, C-38S epi-m icr ocolin (26a ): [R]25D -150°
(c 0.02, EtOH); 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J )
6.1, 2.1 Hz, 1H, H-3), 6.81 (d, J ) 8.9 Hz, 1H, H-22), 6.09 (dd,
J ) 6.1, 1.7 Hz, 1H, H-2), 5.67 (dd, J ) 10.0, 2.1 Hz, 1H, H-8),
5.26 (m, 1H, H-23), 5.24 (m, 1H, H-28), 5.02 (d, J ) 11.1 Hz,
1H, H-14), 4.96 (dd, J ) 8.8, 2.8 Hz, 1H, H-21), 4.81 (qdd, J )
6.8, 2.1, 1.7 Hz, 1H, H-4), 4.38 (m, 1H, H-10), 3.87 (dd, J )
11.8, 1.6 Hz, 1H, H-11), 3.80 (dd, J ) 11.8, 4.4 Hz, 1H, H-11),
3.10 (s, 3H, H-19), 2.98 (s, 3H, H-34), 2.86 (m, 1H, H-36), 2.48
(ddd, J ) 14.3, 10.7, 5.2 Hz, 1H, H-9), 2.26 (m, 1H, H-16), 2.00
(m, 1H, H-9), 2.00 (s, 3H, H-26), 1.80 (ddd, J ) 13.6, 8.1, 5.9
Hz, 1H, H-37), 1.67 (m, 2H, H-30), 1.47 (d, J ) 6.8 Hz, 3H,
to provide 52.8 mg (50%) of pure 24: [R]25 -112.9° (c 0.12,
D
1
MeOH); H NMR (300 MHz, CDCl3) δ 7.28 (dd, J ) 6.2, 1.8
Hz, 1H), 6.88 (bs, 1H), 6.73 (bs, 1H), 6.09 (dd, J ) 6.2, 1.5 Hz,
1H), 5.66 (dd, J ) 9.5, 1.8 Hz, 1H), 5.28 (m, 1H), 5.02 (d, J )
11.3 Hz, 1H), 5.00 (dd, J ) 8.8, 3.3 Hz, 1H), 4.81 (qt, J ) 6.6,
1.8 Hz, 1H), 4.61 (m, 2H), 4.38 (bm, 1H), 3.83 (m, 2H), 3.11 (s,
3H), 2.78 (s, 3H), 2.49 (ddd, J ) 14.6, 10.2, 5.1 Hz, 1H), 2.26