Total Synthesis of (-)-Ardeemin
) 8.0 Hz, 1H), 7.99 (rotamer B; d, J ) 8.0 Hz, 1H), 8.65 (rotamer
A; s, 1H), 8.91 (rotamer B; s, 1H); 13C NMR (50 MHz, CDCl3; a
mixture of two rotamers in a 1:2 ratio) rotamer B: δ 22.1, 23.1,
29.6, 31.8, 36.5, 41.0, 59.3, 61.1, 78.8, 82.1, 114.8, 117.7, 124.7,
129.2, 133.3, 140.6, 142.6, 162.1, 152.7, 177.4; rotamer A: 22.1,
23.1, 29.6, 31.8, 34.8, 41.0, 59.3, 62.5, 78.3, 83.1, 114.8, 117.7,
125.1, 129.2, 133.3, 140.2, 142.6, 153.1, 161.3, 177.0; HRMS-
ESI calcd for C22H27N2O5 (M - H)- 399.1926, found 399.1920;
HRMS-ESI calcd for C21H27N3O4Na (M + Na)+ 408.1894, found
408.1899; IR (KBr) 1740, 1696, 1464, 1367, 1260, 803 cm-1
.
Amides 23a and 23b. To a mixture of amides 22a and 22b (2.5
mg, 0.006 mmol) in MeOH saturated with ammonia (0.5 mL) at 0
°C was added DMAP (4-dimethylaminopyridine, 0.5 mg, 0.004
mmol). The solution was stirred overnight, allowed to warm to room
temperature, and concentrated. The residue was purified by flash
chromatography (100% EtOAc) to give a mixture of amides 23a
and 23b (2.0 mg, 86% yield). 1H NMR (400 MHz, CDCl3; a mixture
of two rotamers in 1:4 ratio) δ 0.98 (rotamer A; s, 3H), 1.02
(rotamer B; s, 3H), 1.07 (rotamer B; s, 3H), 1.10 (rotamer A; s,
3H), 1.40 (rotamer A and B; d, J ) 6.8 Hz, 3H), 2.18-2.08 (rotamer
A and B; m, 1H), 2.32 (rotamer B; dd, J ) 12.4, 5.6 Hz, 1H), 2.40
(rotamer A; dd, J ) 12.4, 5.6 Hz, 1H), 2.81 (rotamer A and B; s
br, 1H), 3.50 (rotamer A; dd, J ) 10.4, 5.6 Hz, 1H), 3.54 (rotamer
B; dd, J ) 10.4, 5.6 Hz, 1H), 4.44 (rotamer A and B; q, J ) 7.2
Hz, 1H), 5.06 (rotamer A and B; d, J ) 17.2 Hz, 1H), 5.14 (rotamer
A and B; d, J ) 10.8 Hz, 1H), 5.29 (rotamer A and B; s br, 1H),
5.41 (rotamer A; s, 1H), 5.65 (rotamer B; s, 1H), 5.90 (rotamer A;
dd, J ) 17.2, 6.8 Hz, 1H), 5.93 (rotamer B; dd, J ) 17.2, 6.8 Hz,
1H), 6.11 (rotamer A and B; s br, 1H), 7.16-7.08 (rotamer A and
B; m, 2H), 7.27-7.22 (rotamer A and B; m, 1H), 7.35 (rotamer B;
d, J ) 8.0 Hz, 1H), 8.04 (rotamer A; d, J ) 7.6 Hz, 1H), 8.58
(rotamer A; s, 1H), 8.93 (rotamer B; s, 1H).
Diketopiperazines 26a and 26b. To a solution of 22a and 22b
(20 mg, 0.052 mmol) in a 10:1 mixture of MeOH/H2O (5 mL) was
added LiOH (11 mg, 0.268 mmol). After stirring for 4 h, the
reaction was diluted with CH2Cl2 (10 mL), washed with brine (10
mL), dried over Na2SO4, concentrated and purified by flash
chromatography (17% MeOH/CH2Cl2) to give a viscous residue.
To a solution of the above residue in CH2Cl2 (5 mL) were added
Et3N (14 µL, 0.10 mmol) and ClCOOiBu (14 µL, 0.10 mmol) at 0
°C. After stirring at 0 °C for 2 h, the mixture was then quenched
by saturated NaHCO3 (10 mL) and CH2Cl2 (10 mL). The organic
layer was separated, dried over Na2SO4, and concentrated in
vacuum. The residue was purified by column chromatography (50%
EtOAc/petroleum) to yield diketopiperazines 26a (7.0 mg, 36%
IR (KBr) 3460, 1688, 1596, 1367, 1150, 755 cm-1
.
Amides 21a and 21b. To a solution of acids 20a and 20b (50
mg, 0.12 mmol) and Et3N (35 µL, 0.25 mmol) in CH2Cl2 (5 mL)
was added ClCOOiBu (33 µL, 0.25 mmol) at 0 °C by using a
syringe. After stirring for 15 min, to the mixture was added D-Ala-
OMe (methyl D-alaninate, 25.8 mg, 0.25 mmol), and the mixture
was allowed to stir for 1 h at 0 °C. The mixture was then quenched
by saturated NaHCO3 (10 mL) and CH2Cl2 (10 mL). The organic
layer was separated, dried over Na2SO4, and concentrated in
vacuum. The residue was purified by column chromatography (25%
EtOAc/petroleum) to yield a mixture of amides 21a and 21b (49
1
mg, 81% yield), [R]20 ) -135° (c 0.1, CHCl3); H NMR (400
D
MHz, CDCl3; a mixture of two rotamers in a 1:2 ratio) δ 0.98
(rotamer A and B; s, 3H), 1.01 (rotamer A and B; s, 3H), 1.33
(rotamer B; s br, 9H), 1.45-1.39 (rotamer A and B; m, 3H), 1.50
(rotamer A; s br, 9H), 2.48-2.44 (rotamer A and B; m, 2H), 3.75
(rotamer B; s, 3H), 3.76 (rotamer A; s, 3H), 3.77-3.73 (rotamer A
and B; m, 1H), 4.63-4.58 (rotamer A and B; m, 1H), 5.06 (rotamer
A and B; d, J ) 17.2 Hz, 1H), 5.14 (rotamer A and B; d, J ) 10.8
Hz, 1H), 5.70 (rotamer A; s, 1H), 5.86-5.82 (rotamer A and B;
m, 1H), 5.90 (rotamer B; s, 1H), 6.24 (rotamer A and B; s br, 1H),
7.16 (rotamer A and B; t, J ) 7.2 Hz, 1H), 7.28-7.25 (rotamer A
and B; m, 1H), 7.33 (rotamer A and B; t, J ) 7.6 Hz, 1H), 7.89
(rotamer A; s br, 1H), 7.97 (rotamer B; d, J ) 7.2 Hz, 1H), 8.65
(rotamer A; s, 1H), 8.89 (rotamer B; s, 1H); 13C NMR (50 MHz,
CDCl3; a mixture of two rotamers in a 1:2 ratio) rotamer B: δ 18.8,
22.2, 23.0, 28.0, 29.6, 37.3, 40.9, 47.9, 52.5, 61.2, 79.2, 82.2, 114.7,
117.6, 124.7, 129.1, 133.6, 140.9, 142.8, 153.0, 162.0, 170.8, 173.1;
rotamer A: δ 18.6, 22.2, 23.0, 28.0, 29.6, 35.5, 40.9, 47.9, 52.5,
60.8, 79.2, 82.2, 114.7, 117.6, 124.5, 129.1, 133.6, 140.9, 142.8,
153.0, 161.5, 170.4, 173.1; HRMS-ESI calcd for C26H35N3O6Na
(M + Na)+ 508.2418, found 508.2419; IR (KBr) 3322, 1774, 1681,
yield) and 26b (6.0 mg, 35% yield).
1
26a: [R]20 ) -162° (c 0.15, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 0.98 (s, 3H), 1.12 (s, 3H), 1.43 (d, J ) 6.8 Hz, 3H), 2.43
(t, J )12.0 Hz, 1H), 2.65 (dd, J ) 12.8, 6.0 Hz, 1H), 3.93 (q, J )
5.6 Hz, 1H), 4.09-4.03 (m, 1H), 5.11 (d, J ) 17.2 Hz, 1H), 5.16
(d, J ) 10.8 Hz, 1H), 5.87 (dd, J ) 17.2, 10.8 Hz, 1H), 6.13 (s,
1H), 6.26 (s br, 1H), 7.16 (t, J )7.6 Hz, 1H), 7.33 (q, J )7.2 Hz,
2H), 8.06 (d, J ) 8.0 Hz, 1H), 9.04 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 21.3, 22.2, 23.0, 37.4, 41.0, 53.3, 57.7, 60.1, 77.6, 115.5,
117.0, 124.9, 129.5, 132.0, 141.4, 142.4, 161.7, 166.3, 167.6;
HRMS-ESI calcd for C20H23N3O3Na (M + Na)+ 376.1637, found
1460, 1151, 756 cm-1
.
Synthesis of Compounds 26a and 26b. Compounds 22a and
22b. A mixture of amides 21a and 21b (33 mg, 0.068 mmol) was
dissolved in freshly distilled dry MeCN (5 mL), chilled to 0 °C
under N2. To the solution was added TMSI (iodotrimethylsilane,
39 µL, 0.27 mmol) dropwise.6 After 30 min, the reaction mixture
was poured into saturated NaHCO3 (10 mL) and extracted with
CH2Cl2 (10 mL × 3). The combined organic layers were washed
with brine (10 mL), dried over Na2SO4, and concentrated. The
residue was purified by chromatography (50% EtOAc/petroleum)
376.1629; IR (KBr) 3307, 1744, 1674, 1458, 756 cm-1
.
1
26b: [R]20 ) -199° (c 0.15, CHCl3); H NMR (400 MHz,
D
to give a mixture of 22a and 22b (26 mg, 98% yield). [R]20
)
CDCl3) δ 0.99 (s, 3H), 1.13 (s, 3H), 1.48 (d, J ) 6.8 Hz, 3H), 2.47
(t, J )11.2 Hz, 1H), 2.63(dd, J )12.8, 6.0 Hz, 1H), 4.00-3.95
(m, 1H), 4.12 (q, J ) 7.2 Hz, 1H), 5.10 (d, J ) 17.2 Hz, 1H), 5.16
(d, J ) 10.4 Hz, 1H), 5.85 (dd, J ) 17.2, 10.8 Hz, 1H), 6.07 (s,
1H), 6.20 (s br, 1H), 7.16 (t, J )7.6 Hz, 1H), 7.35-7.30 (m, 2H),
8.03 (d, J ) 7.6 Hz, 1H), 9.04 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 16.4, 22.2, 23.0, 36.5, 40.9, 51.2, 59.0, 60.4, 77.3, 115.3, 117.0,
124.9, 129.4, 132.2, 141.3, 142.4, 161.6, 166.1, 168.8; HRMS-
ESI calcd for C20H23N3O3Na (M + Na)+ 376.1637, found 376.1632;
D
1
-47° (c 0.1, CHCl3); H NMR (400 MHz, CDCl3; a mixture of
two rotamers in 1:5 ratio) δ 1.03 (rotamer A; s, 3H), 1.07 (rotamer
B; s, 6H), 1.10 (rotamer A; s, 3H), 1.40 (rotamer A and B; d, J )
7.2 Hz, 3H), 2.05 (rotamer A and B; s br, 1H), 2.33-2.22 (rotamer
A and B; m, 2H), 3.57-3.52 (rotamer A and B; m, 1H), 3.76
(rotamer A and B; s, 3H), 4.61-4.53 (rotamer A and B; m, 1H),
5.06 (rotamer A and B; d, J ) 17.6 Hz, 1H), 5.13 (rotamer A and
B; d, J ) 10.8 Hz, 1H), 5.43 (rotamer A; s, 1H), 5.66 (rotamer B;
s, 1H), 5.90 (rotamer A; dd, J ) 12.0, 10.8 Hz, 1H), 5.94 (rotamer
B; dd, J ) 12.0, 10.8 Hz, 1H), 7.14-7.07 (rotamer A and B; m,
2H), 7.30-7.21 (rotamer A and B; m, 1H), 7.35 (rotamer B; d, J
) 7.6 Hz, 1H), 8.04 (rotamer A; d, J ) 7.6 Hz, 1H), 8.59 (rotamer
IR (KBr) 3307, 1682, 1463, 1375, 1160, 757 cm-1
.
Compounds 27 and 28 from 26a. To a solution of diketopip-
erazine 26a (10.0 mg, 0.028 mmol) in THF (3 mL) at -78 °C
n
under N2 was added BuLi (2.5 M in THF, 22 µL, 0.055 mmol).
A; s, 1H), 8.94 (rotamer B; s, 1H); 13C NMR (50 MHz, CDCl3;
a
After stirring for 20 min at -78 °C, a solution of o-azidobenzoic
anhydride (17 mg, 0.056 mmol) in THF (0.1 mL) was added via a
syringe. After 10 min, the mixture was poured into a biphasic
mixture of saturated NaHCO3 (5 mL) and EtOAc (5 mL). The
aqueous layer was separated and extracted with EtOAc (5 mL ×
3). The combined organic layers were washed with brine, dried
mixture of two rotamers in 1:5 ratio) rotamer B: δ 18.2, 22.5, 23.5,
29.7, 40.4, 47.2, 52.4, 60.0, 62.2, 78.3, 108.4, 114.4, 124.6, 126.5,
128.6, 131.1, 134.3, 143.4, 158.6, 172.6, 173.0; rotamer A: δ 19.1,
22.6, 23.3, 29.2, 39.4, 47.5, 52.4, 60.9, 62.2, 80.4, 108.4, 116.2,
124.9, 126.5, 128.8, 131.1, 134.3, 141.0, 159.4, 172.6, 173.0;
J. Org. Chem. Vol. 74, No. 1, 2009 303