Syntheses of Agelasimine-A and -B and Purino-diterpene
J. Am. Chem. Soc., Vol. 118, No. 35, 1996 8255
the reaction mixture was poured into H2O (150 mL), acidified with 2
N aqueous HCl, and extracted with ether. The ethereal extracts were
washed with saturated aqueous NaCl, dried over anhydrous MgSO4,
and concentrated to leave a pale yellow oil. Purification of the oil by
flash chromatography (silica gel, hexane) furnished (()-9 (5.06 g, 93%)
as a colorless oil: 1H NMR (CDCl3) δ 0.71 (3H, s, C1-Me), 0.75 (3H,
d, J ) 6.8 Hz, C2-Me), 1.01 and 1.07 (6H, s each, C5-Me2), 0.94 (1H,
m, C8-H), 1.20 (1H, ddd, J ) 13, 13, 4.5 Hz, C6-H), 1.36-1.66 (5H,
m, C2-H, C6-H, C7-H2, C8-H), 1.74 (1H, dddd, J ) 17.5, 11, 3.5, 2
Hz, C3-H), 1.90 (1H, dddd, J ) 17.5, 6, 5, 2 Hz, C3-H), 1.99 (1H, m,
C8a-H), 4.91 (1H, dd, J ) 17.5, 1.5 Hz, CHdCH2), 5.06 (1H, dd, J )
10.5, 1.5 Hz, CHdCH2), 5.48 (1H, ddd, J ) 6, 2, 2 Hz, C4-H), 5.55
(1H, dd, J ) 17.5, 10.5 Hz, CHdCH2); MS m/z 218 (M+).
d, J ) 1.1 Hz, C3-Me), 4.17 (2H, q, J ) 7 Hz, OCH2Me), 6.33 (1H,
q, J ) 1.1 Hz, C2-H); MS m/z 194 and 192 (M+).
(E)-3-Iodo-2-butenoic Acid Ethyl Ester (15c). The (Z)-isomer14,29
(2.09 g, 8.7 mmol) was heated at 220 °C under argon in a sealed tube
for 4 h. Purification of the resulting brown oil by flash chromatography
(silica gel, 3:2 hexane-CH2Cl2) furnished 15c14 (1.44 g, 69%) as a
colorless oil: bp 96-98 °C (24 mmHg); IR (neat) νmax 1717, 1619
cm-1; 1H NMR (CDCl3) δ 1.28 (3H, t, J ) 7 Hz, OCH2Me), 2.98 (3H,
d, J ) 1.4 Hz, C3-Me), 4.16 (2H, q, J ) 7 Hz, OCH2Me), 6.63 (1H,
q, J ) 1.4 Hz, C2-H); MS m/z 240 (M+).
(()-(E)-5-(3-Cyclohexenyl)-3-methyl-2-pentenoic Acid Ethyl Es-
ter [(()-19]. A Typical Example (Entry 14 in Table 2). To a 0.5
M solution (1.8 mL, 0.9 mmol) of 9-BBN in THF was added dropwise
a solution of (()-16 (32.5 mg, 0.30 mmol) in THF (0.4 mL) over 2
min, and the mixture was stirred at room temperature for 1.5 h. In a
separate flask, a solution of the iodide 15c (79 mg, 0.33 mmol) in DMF
(0.2 mL) was added to a stirred mixture of Cs2CO3 (176 mg, 0.54
mmol), PdCl2(dppf)15 (25 mg, 10 mol %), Ph3As (10 mg, 11 mol %),
and DMF (1 mL). Then, H2O (0.195 mL, 36 equiv mol) and the above
THF solution of the borane were added in that order. After having
been stirred at room temperature for 3.5 h, the reaction mixture was
poured into H2O (10 mL) and extracted with ether. The ethereal extracts
were washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, and concentrated to leave a brown oil. Purification of the oil
by flash chromatography (silica gel, 3:2 hexane-CH2Cl2) provided (()-
(()-(1r,2â,8ar)-2-(1,2,3,5,6,7,8,8a-Octahydro-1,2,5,5-tetramethyl-
1-naphthalenyl)ethanol [(()-14]. A Typical Example (Entry 4 in
Table 1). To a 0.5 M solution (3.0 mL, 1.5 mmol) of 9-BBN in THF
was added dropwise a solution of (()-9 (109 mg, 0.50 mmol) in THF
(0.5 mL) over 2 min, and the mixture was heated under reflux for 2 h.
After cooling, the reaction mixture was treated with EtOH (0.9 mL), 3
N aqueous NaOH (0.6 mL), and 30% aqueous H2O2 (0.6 mL) at 50 °C
for 1 h. The aqueous layer was saturated with K2CO3, separated from
the organic layer, and extracted with ether. The combined organic
layers were washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, and concentrated. Purification of the residue by flash
chromatography (silica gel, 99:1 CHCl3-EtOH) provided (()-14 (97
mg, 82%) as a colorless solid, mp 98.5-103 °C. Recrystallization of
the solid from MeOH-H2O (2:1) gave an analytical sample as colorless
19 (56 mg, 84%) as a colorless oil: IR (neat) νmax 1717, 1651 cm-1
;
1H NMR (CDCl3) δ 1.28 (3H, t, J ) 7 Hz, OCH2Me), 1.20-1.30 (1H,
m), 1.39-1.77 (5H, m), and 2.02-2.20 (5H, m) (C1′-H, C2′-H2, C5′-
H2, C6′-H2, C4-H2, and C5-H2), 2.16 (3H, d, J ) 1.0 Hz, C3-Me),
4.14 (2H, q, J ) 7 Hz, OCH2Me), 5.62-5.69 (3H, m, C3′-H, C4′-H,
and C2-H);30 HRMS m/z calcd for C14H22O2 222.1620, found 222.1610.
1
needles: mp 106-107 °C; H NMR (CDCl3) δ 0.66 (3H, s, C1-Me),
0.87 (3H, d, J ) 6.8 Hz, C2-Me), 0.99 and 1.06 (6H, s each, C5-Me2),
1.05 (1H, m, C8-H), 1.20 (1H, ddd, J ) 13, 13, 4.5 Hz, C6-H), 1.37-
1.64 (5H, m) and 1.69-1.88 (4H, m) (C2-H, C3-H2, C6-H, C7-H2,
C8-H, and C1-CH2), 2.13 (1H, m, C8a-H), 3.69 (2H, dt, J ) 4.5, 8
Hz, CH2OH), 5.43 (1H, ddd, J ) 6, 3, 3 Hz, C4-H); HRMS m/z calcd
for C16H28O 236.2140, found 236.2137. Anal. Calcd for C16H28O:
C, 81.29; H, 11.94. Found: C, 81.26; H, 11.94.
(()-[1r(E),2â,8ar]-3-Methyl-5-(1,2,3,5,6,7,8,8a-octahydro-1,2,5,5-
tetramethyl-1-naphthalenyl)-2-pentenoic Acid Ethyl Ester [(()-10].
To a 0.5 M solution (24 mL, 12 mmol) of 9-BBN in THF was added
dropwise a solution of (()-9 (874 mg, 4.0 mmol) in THF (5 mL) over
5 min, and the mixture was heated under reflux for 2 h. In a separate
flask were placed Cs2CO3 (2.35 g, 7.2 mmol), PdCl2(dppf)15 (327 mg,
10 mol %), Ph3As (123 mg, 10 mol %), the iodide 15c (1.06 g, 4.4
mmol), DMF (17 mL), and H2O (0.86 mL, 12 equiv mol). After
addition of the above THF solution of the borane, the reaction mixture
was stirred at room temperature for 3 h and then worked up in a manner
similar to that described above for (()-19. Purification of the crude
oily product by flash chromatography (silica gel, 3:2 benzene-hexane)
yielded (()-10 (995 mg, 75%) as a colorless oil: IR (neat) νmax 1717,
(()-2-(3-Cyclohexenyl)ethanol [(()-18]. To a 0.5 M solution (5.0
mL, 2.5 mmol) of 9-BBN in THF was added dropwise a solution of
(()-4-vinyl-1-cyclohexene [(()-16] (270 mg, 2.5 mmol) in THF (1.5
mL) over 3 min, and the mixture was stirred at room temperature for
1.5 h. After having been treated with EtOH (1.5 mL), 6 N aqueous
NaOH (0.5 mL), and 30% aqueous H2O2 (1.0 mL) at 50 °C for 1 h,
the reaction mixture was worked up as described above for (()-14.
Purification of the crude oily product by flash chromatography (silica
gel, 3:1 hexane-EtOAc) afforded (()-1816 (294 mg, 93%) as a colorless
oil. The 1H and 13C NMR and IR spectral data for this sample were in
agreement with those reported in the literature.16b
(E)-3-[[(Trifluoromethyl)sulfonyl]oxy]-2-butenoic Acid Ethyl Es-
ter (15a). According to the procedure of Keenan et al.,28 this compound
was prepared as follows. To a stirred suspension of NaH (60% oil
dispersion, 300 mg, 7.5 mmol) in DMF (5 mL) at room temperature
was added dropwise a solution of ethyl acetoacetate (651 mg, 5.0 mmol)
in DMF (5 mL), and stirring was continued for 30 min. After addition
of N-phenyltrifluoromethanesulfonimide (2.68 g, 7.5 mmol), the reaction
mixture was stirred for a further 2 h, then diluted with ether, washed
successively with saturated aqueous NH4Cl, H2O, and saturated aqueous
NaCl, and concentrated in Vacuo. Purification of the residual brown
oil by flash chromatography (silica gel, 4:1 hexane-CHCl3) provided
15a17 (661 mg, 50%) as a colorless oil: IR (neat) νmax 1730, 1674
cm-1; 1H NMR (CDCl3) δ 1.31 (3H, t, J ) 7 Hz, OCH2Me), 2.51 (3H,
d, J ) 0.9 Hz, C3-Me), 4.22 (2H, q, J ) 7 Hz, OCH2Me), 5.95 (1H,
q, J ) 0.9 Hz, C2-H); MS m/z 262 (M+).
1
1647 cm-1; H NMR (CDCl3) δ 0.64 (3H, s, C1′-Me), 0.82 (3H, d, J
) 6.8 Hz, C2′-Me), 1.01 and 1.07 (6H, s each, C5′-Me2), 1.04 (1H, m,
C8′-H), 1.20 (1H, ddd, J ) 13, 13, 4.5 Hz, C6′-H), 1.28 (3H, t, J ) 7
Hz, OCH2Me), 1.36-2.20 (12H, m, C2′-H, C3′-H2, C6′-H, C7′-H2, C8′-
H, C8′a-H, C4-H2, and C5-H2), 2.19 (3H, s, C3-Me), 4.15 (2H, q, J )
7 Hz, OCH2Me), 5.44 (1H, ddd, J ) 5.5, 3, 2.5 Hz, C4′-H), 5.69 (1H,
br s, C2-H);30 MS m/z 332 (M+).
(()-[1r(E),2â,4â,4aâ,8ar]-5-(Decahydro-4,4a-epoxy-1,2,5,5-tet-
ramethyl-1-naphthalenyl)-3-methyl-2-pentenoic Acid Ethyl Ester
[(()-11]. A solution of (()-10 (389 mg, 1.17 mmol) and MCPBA
(ca. 70% purity, 345 mg, 1.4 mmol) in CH2Cl2 (12 mL) was stirred at
0 °C for 2 h. The reaction mixture was then washed successively with
10% aqueous Na2SO3, saturated aqueous NaHCO3, and saturated
aqueous NaCl, dried over anhydrous MgSO4, and concentrated in Vacuo.
Purification of the residual oil by flash chromatography (silica gel, 3:2
CH2Cl2-hexane) furnished (()-11 (346 mg, 85%) as a colorless oil:
1
IR (neat) νmax 1717, 1647 cm-1; H NMR (CDCl3) δ 0.69, 0.74, and
(E)-3-Bromo-2-butenoic Acid Ethyl Ester (15b). The (Z)-isomer18
(2.18 g, 11.3 mmol) was heated at 220 °C under argon in a sealed tube
for 5 h. The resulting brown oil was purified by flash chromatography
(silica gel, 20:1 hexane-EtOAc) to afford 15b18 (1.26 g, 58%) as a
colorless oil: bp 83.5-84.5 °C (28 mmHg); IR (neat) νmax 1720, 1634
cm-1; 1H NMR (CDCl3) δ 1.28 (3H, t, J ) 7 Hz, OCH2Me), 2.78 (3H,
1.07 (3H each, s, C1′-Me and C5′-Me2), 0.76 (3H, d, J ) 6.8 Hz, C2′-
Me), 1.24-1.73 (9H, m, C2′-H, C6′-H2, C7′-H2, C8′-H2, and C5-H2),
1.28 (3H, t, J ) 7 Hz, OCH2Me), 1.66 (1H, dd, J ) 15.5, 12.5 Hz,
C3′-H), 1.80 (1H, ddd, J ) 15.5, 6, 6 Hz, C3′-H), 1.88 (1H, dd, J )
12.5, 3 Hz, C8′a-H), 1.98 (2H, dd, J ) 9, 8.5 Hz, C4-H2), 2.17 (3H, d,
J ) 1.5 Hz, C3-Me), 3.16 (1H, d, J ) 6 Hz, C4′-H), 4.15 (2H, q, J )
(28) Keenan, R. M.; Weinstock, J.; Finkelstein, J. A.; Franz, R. G.;
Gaitanopoulos, D. E.; Girard, G. R.; Hill, D. T.; Morgan, T. M.; Samanen,
J. M.; Hempel, J.; Eggleston, D. S.; Aiyar, N.; Griffin, E.; Ohlstein, E. H.;
Stack, E. J.; Weidley, E. F.; Edwards, R. J. Med. Chem. 1992, 35, 3858-
3872.
(29) Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994,
72, 1816-1819.
(30) For convenience, each position of the cyclohexene or naphthalene
ring is indicated by a primed number.