Duvall et al.
extracted with CH2Cl2. The combined CH2Cl2 extracts were dried
over MgSO4 and concentrated to give 44.
2E-enoyl chloride (38d), which was used immediately: 1H NMR
(CDCl3) 6.98 (d, 1, J ) 8.6), 5.73 (dq, 1, J ) 8.6, 6.7), 4.06 (s, 2),
3.46 (s, 3), 2.00 (s, 3), 1.42 (d, 3, J ) 6.7).
A solution of crude 44 in 25 mL of MeOH was stirred with
10% Pd/C (170 mg, 0.16 mmol) under 1 atm of H2 at 25 °C for 2
h. The mixture was filtered through Celite and concentrated to give
crude 45, which cyclized on standing for 24 h at 25 °C to give
crude 26. Flash chromatography on silica gel (95:5 EtOAc/MeOH)
Jenamidines A1/A2 (8), Jenamidines A1/A2 4′-Methoxyacetate
(39d), and 3-Amino-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one
(14b). Vinylogous urea 26 (106 mg, 0.44 mmol) and NaH (60%
dispersion in mineral oil, 45 mg, 1.1 mmol) were stirred in 10 mL
of dry THF under N2 for 10 min. Acid chloride 38d (0.96 mmol)
in 3 mL of dry THF was added, and the resulting solution was
stirred for 2 h, quenched with brine, and extracted with CH2Cl2.
The combined organic extracts were dried over MgSO4 and
concentrated to give 196 mg of a mixture of mono- and bis-acylated
products. A solution of the mixture in 10 mL of 9:1 CH2Cl2/TFA
was stirred for 15 h, neutralized with saturated sodium bicarbonate
solution, saturated with NaCl, and extracted with EtOAc. The
combined organic extracts were dried over MgSO4 and concentrated
to afford jenamidines A1/A2 4′-methoxyacetate (39d) as the major
product and no jenamidines A1/A2 (8), as expected. Flash chroma-
tography on silica gel (97:3 CH2Cl2/MeOH to 90:10 CH2Cl2/MeOH)
gave 55 mg (39%) of 39d, followed by 20 mg (18%) of a mixture
of 8 and other decomposition products.
A solution of a second batch of crude 39d (prepared as before
from 96 mg (0.40 mmol) of 26, 42 mg (1.0 mmol) of NaH, and
0.96 mmol of 38d followed by TFA hydrolysis) was stirred in 10
mL of MeOH containing 10 drops of H2O and 200 mg of Na2CO3
at 0 °C for 24 h. The mixture was filtered through silica gel and
concentrated to give a 4:1:1 mixture of 8, 39d, and 14d. Flash
chromatography on silica gel (95:5 CH2Cl2/MeOH) gave 14 mg
(11% from 26) of 39d and 45 mg (45% from 26) of 8, while 14b
was recovered along with a complex mixture of products upon
flushing the silica gel with MeOH.
gave 190 mg (50%) of 26: mp 200-203 °C; [R]22 -62.2 (c )
D
1.1, MeOH); UV (MeOH) λmax nm (log ꢀ) 211(4.17), 241 (4.21),
1
264 (4.11); H NMR (CDCl3) 8.00 (br, 1, NH), 5.42 (br, 1, NH),
3.87 (dd, 1, J ) 6.7, 9.8), 3.34-3.42 (m, 1), 3.20-3.28 (m, 1),
2.06-2.26 (m, 3), 1.54-1.60 (m, 1), 1.55 (s, 9); 13C NMR (CDCl3)
193.1, 174.0, 164.9, 90.5, 79.9, 69.7, 46.6, 28.5 (3 C), 27.6, 26.7;
IR (KBr) 3475, 3077, 1714, 1638; HRMS (DEI) calcd for
C12H18N2O3 (M+) 238.1317, found 238.1315.
tert-Butyl (4S)-4-[[(tert-Butyl)dimethylsilyl]oxy]-2-methylpent-
2E-enoate (34). A solution of (1-tert-butoxycarbonylethylidene)-
triphenylphosphorane (32)22 (1.9 g, 4.7 mmol) in 18 mL of dry
CH2Cl2 was added to 2-[[(tert-butyl)dimethylsilyl]oxy]propanal
(33)23 (730 mg, 3.8 mmol) in 8 mL of dry CH2Cl2. The mixture
was stirred at 25 °C for 2 h and quenched with 25 mL of H2O. The
layers were separated, and the organic layer was dried over MgSO4
and concentrated. Flash chromatography on silica gel (98:2 hexanes/
EtOAc) yielded 770 mg (67%) of 34: 1H NMR (CDCl3) 6.57 (br
d, 1, J ) 8.5), 4.59 (dq, 1, J ) 8.5, 6.7), 1.78 (d, 3, J ) 1.2), 1.49
(s, 9), 1.22 (d, 3, J ) 6.7), 0.88 (s, 9), 0.05 (s, 3), 0.04 (s, 3); 13C
NMR (CDCl3) 167.3, 144.7, 126.8, 80.1, 66.0, 28.0 (3 C), 25.8 (3
C), 23.4, 18.1, 12.5, -4.7, -4.8; IR (neat) 1710; HRMS (DCI/
NH3) calcd for C16H36NO3Si (MNH4+) 318.2464, found 318.2455.
tert-Butyl (S)-4-Hydroxy-2-methylpent-2E-enoate (35). Silyl
ether 34 (300 mg, 1.0 mmol) in 2 mL of THF was added to 18 mL
of a 1.4 M solution of pyridine‚HF (5 mL of pyridine‚(HF)x, 20
mL of THF, 20 mL of pyridine). The mixture was stirred for 4 h
in an Eppendorf tube, slowly quenched with saturated sodium
bicarbonate solution, and extracted with EtOAc. The combined
organic extracts were dried over MgSO4 and concentrated to yield
185 mg (99%) of pure 35: 1H NMR (CDCl3) 6.58 (br d, 1, J )
8.3), 4.67 (dq, 1, J ) 8.3, 6.1), 1.83 (d, 3, J ) 1.5), 1.49 (s, 9),
1.31 (d, 3, J ) 6.1); 13C NMR (CDCl3) 167.2, 143.0, 129.0, 80.5,
64.9, 28.0 (3 C), 22.6, 12.6; IR (neat) 3421, 1707; HRMS (DCI/
NH3) calcd for C10H22NO3 (MNH4+) 204.1600, found 204.1606.
tert-Butyl (S)-4-Methoxyacetoxy-2-methylpent-2E-enoate (36d).
Methoxyacetyl chloride (0.15 mL, 1.6 mmol) was added slowly to
a solution of alcohol 35 (185 mg, 0.99 mmol), pyridine (0.17 mL,
2.12 mmol), and DMAP (12 mg, 0.1 mmol) in 15 mL of dry THF
under N2, resulting in a white precipitate. The mixture was stirred
for 2 h at 25 °C, filtered, diluted with EtOAc, washed successively
with 2 M HCl, water, saturated sodium bicarbonate solution, and
water, dried over MgSO4, and concentrated to give 255 mg (99%)
of pure 36d: 1H NMR (CDCl3) 6.51 (br d, 1, J ) 8.9), 5.73 (dq,
1, J ) 8.9, 6.1), 4.03 (s, 2), 3.45 (s, 3), 1.88 (d, 3, J ) 1.5), 1.49
(s, 9), 1.36 (d, 3, J ) 6.1); 13C (CDCl3) 169.4, 166.6, 137.6, 131.3,
80.7, 69.8, 68.2, 59.3, 27.9 (3 C), 19.7, 12.8; IR (neat) 1756, 1709;
HRMS (DCI/NH3) calcd for C13H26NO5 (MNH4+) 276.1811, found
276.1809.
Data for 39d as a 1:1 mixture of diastereomers: 1H NMR (CD3-
OD) 6.345 (br d, 1 × 0.5, J ) 8.0), 6.340 (br d, 1 × 0.5, J ) 8.0),
5.72-5.80 (m, 1), 5.64 (s, 1), 4.07 (s, 2 × 0.5), 4.06 (s, 2 × 0.5),
3.95 (dd, 1, J ) 8.8, 8.8), 3.40-3.47 (m, 1), 3.42 (s, 3 × 0.5),
3.41 (s, 3 × 0.5), 3.20-3.26 (m, 1), 2.10-2.25 (m, 3), 1.994 (s, 3
× 0.5), 1.991 (s, 3 × 0.5), 1.50-1.60 (m, 1), 1.41 (d, 3 × 0.5, J
) 6.1), 1.40 (d, 3 × 0.5, J ) 6.1); 13C NMR (CD3OD) 204.7, 173.4,
(171.39, 171.37), (169.4, 169.3), (138.04, 138.00), (134.20, 134.18),
93.9, 70.7, 70.5, (69.4, 69.3), (59.54, 59.52), 49.3, 28.8, 27.5, 19.8,
(13.29, 13.26); IR (neat) 1744, 1702, 1636, 1563, 1506; HRMS
(DCI/NH3) calcd for C16H23N2O5 (MH+) 323.1607, found 323.1609.
Data for jenamidines A1/A2 (8) as a 1:1 mixture of diastereo-
mers: [R]22D 4.2 (c ) 0.6, MeOH), lit.1 [R]22D 6.8 (c ) 0.7, MeOH);
MeOH
1
UV λmax
nm (log ꢀ) 240 (4.29), 282 (3.84), 3.26 (4.02); H
NMR (CD3OD) 6.37 (d, 1, J ) 7.9), 5.67 (s, 1 × 0.5), 5.63 (s, 1
× 0.5), 4.67 (dq, 1, J ) 6.5, 7.9), 3.92-3.98 (m, 1), 3.42-3.49
(m, 1), 3.18-3.26 (m, 1), 2.08-2.24 (m, 3), 1.92 (s, 3), 1.50-
1.60 (m, 1), 1.31 (d, 3 × 0.5, J ) 6.5), 1.29 (d, 3 × 0.5, J ) 6.5);
13C NMR (CD3OD) (204.69, 204.57), (173.61, 173.48), (169.84,
169.82), (143.67, 143.65), (131.62, 131.60), (93.82, 93.80, 93.76,
93.75), (70.77, 70.67), (65.31, 65.25), 49.29, 28.80, (27.51, 27.47,
27.40, 27.37), (22.68, 22.64), 12.92; IR (neat) 2973, 1699, 1634,
1557, 1504, 1404, 1244, 1139, 1059; HRMS (DCI/NH3) calcd for
1
C13H19N2O3 (MH+) 251.1396, found 251.1394. The H and 13C
NMR spectra are identical to those of the natural product.1,2a H7a
is approximately 50% exchanged with deuterium. C2 (93.7-93.8)
and C7 (27.3-27.5) absorb as four peaks since the carbon for each
diastereomer absorbs separately for the proton and deuterium
isomers due to the isotope shift.28
(S)-4-Methoxyacetoxy-2-methylpent-2E-enoic acid (37d). A
solution of ester 36d (255 mg, 0.98 mmol) in 5 mL of 9:1 CH2-
Cl2/TFA was stirred for 12 h at 25 °C. The mixture was diluted
with H2O and extracted with CH2Cl2. The combined organic extracts
were dried over MgSO4 and concentrated to give 194 mg (98%)
of pure 37d: 1H NMR (CDCl3) 11.0 (br s, 1, OH), 6.74 (d, 1, J )
8.8), 5.74 (dq, 1, J ) 8.8, 6.4), 4.05 (s, 2), 3.45 (s, 3), 1.93 (s, 3),
1.38 (d, 3, J ) 6.4); 13C NMR (CDCl3) 172.8, 169.5, 141.3, 129.0,
69.7, 68.1, 59.3, 19.4, 12.4; IR (neat) 3187, 1753, 1696; HRMS
(DCI/NH3) calcd for C9H18NO5 (MNH4+) 220.1185, found 220.1189.
Conversion of 37d to the Acid Chloride. A solution of acid
37d (194 mg, 0.96 mmol) in 8 mL of oxalyl chloride was stirred
for 4 h at 25 °C under N2. Excess oxalyl chloride was removed
under reduced pressure to give (S)-4-methoxyacetoxy-2-methylpent-
Pure 39d (30 mg, 0.093 mmol) was stirred in 2 mL of MeOH
containing 5 drops of H2O and 50 mg of Na2CO3 at 0 °C for 6 h.
The mixture was filtered through silica gel and concentrated. Flash
chromatography on silica gel (90:10 CH2Cl2/MeOH) gave 6 mg
(20%) of recovered 39d, followed by 13 mg (56%, 70% based on
recovered 39d) of 8 and 2.5 mg (18%) of 14b.
Data for 14b: 1H NMR (CD3OD) 4.50 (s, 1), 3.90 (dd, 1, J )
6.7, 9.1), 3.28-3.35 (m, 1), 3.12-3.20 (m, 1), 2.05-2.25 (m, 3),
1.40-1.48 (m, 1); 13C NMR (CD3OD) 197.5, 178.5, 72.1, 47.7,
8588 J. Org. Chem., Vol. 71, No. 22, 2006