A R T I C L E S
Iimura et al.
Table 1. Diastereoselection in the Conversion of Bromide 27 to
(+)-Guanacastepene N (1) and Epimer 2
added. This solution was then added dropwise to a solution of
Eschenmoser’s salt (16) (2.92 g, 15.8 mmol) and DMF (26 mL) at 0
°C.32 The resulting mixture was stirred at 0 °C for 1 h and then diluted
with EtOAc (100 mL). This solution was washed with saturated aqueous
NaHCO3 solution (310 mL), and then brine, dried over anhydrous Na2-
SO4, and concentrated. The resulting residue was taken up in Et2O (40
mL), and MeI (4.0 mL, 64 mmol) was added. After 12 h at room
temperature, the solution was concentrated and the residue was dissolved
in CH2Cl2 (40 mL). Methanol (10 mL) and aqueous K2CO3 solution
(15%, 30 mL) were added, and the mixture was stirred vigorously for
3 h. The reaction mixture was extracted with CH2Cl2 (2 × 30 mL),
and the combined organic phases were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography (SiO2, Biotage 40M+, 150 × 40 mm, hexanes/EtOAc
entry
conditions
yield (%)
1:2
1
AgOTf, acetone/H2O (9:1),
50
1:5
room temperature, 15 min
2
3
4
AgSbF6, acetone/H2O (9:1),
room temperature, 48 h
Ag2O, acetone/H2O (9:1),
room temperature, 48 h
44
24
47
1:1.8
1:1.5
9:1, flow rate 20 mL/min) to afford 811 mg (57% overall) of dienone
1
17 as a colorless oil: [R]25 -3.8° (c ) 1.0, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 6.00 (s, 1H), 5.58 (ddd, J ) 4.0, 4.0, 10.0 Hz, 1H),
5.31 (d, J ) 10.0 Hz, 1H), 5.07 (s, 1H), 2.43 (dd, J ) 8.5, 19.0 Hz,
1H), 2.16 (dd, J ) 7.0, 18.5 Hz, 1H), 1.93-1.84 (m, 4H), 1.62-1.42
(m, 5H), 1.33 (ddd, J ) 5.5, 5.5, 13.0 Hz, 1H), 1.26-1.20 (m, 2H),
1.12 (s, 3H), 1.11 (m, 1H), 0.98 (d, J ) 6.5 Hz, 3H), 0.91 (s, 3H),
0.77 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 207.7, 154.3,
136.7, 125.9, 115.9, 46.2, 45.5, 39.2, 36.9, 35.0, 34.8, 34.6, 34.2, 28.9,
Bu3SnH, air, toluene, room temperature, 16 h,
10:1
then Ph3P, CHCl3, room temperature, 2 h
N (1) were identical to the corresponding spectra of the natural
product published by Clardy and co-workers.8,47
27.7, 25.3, 22.9, 19.9, 19.4; IR (film) 2958, 2931, 2871, 1727 cm-1
;
Conclusions
HRMS (ESI) m/z calcd for C19H30O6Na (M + Na), 297.2194; found,
297.2196.
The enantioselective total synthesis of (+)-guanacastepene
N (1) was accomplished by a convergent sequence. This
synthesis constitutes the first total synthesis of a guanacastepene
containing a lactone fragment and the second enantioselective
total synthesis in this area.13 The central strategic step in the
synthesis was a high yielding intramolecular 7-endo Heck
reaction to construct the central seven-membered B ring of the
guanacastepene ring system. In the course of this synthetic
endeavor, chiral cyclopentenone and cyclohexene building
blocks constituting the A and C rings of the guanacastepenes
were accessed by short and reliable routes, and linked by a
challenging conjugate addition reaction. The convergent strategy
described herein provides intermediates that may serve as
branching points for accessing other members of the guana-
castepene family, as well as derivatives thereof for a more
detailed evaluation of their pharmacological profile.
Heck Cyclization of Triflate 23. Preparation of (5aS,7aR,8R)-8-
Isopropyl-5a,7a-dimethyl-4,5,5a,6,7,7a,8,9-octahydro-3H-1-oxa-ben-
zo[cd]cyclopenta[h]azulene-2,10-dione (24). A suspension of Pd2-
(dba)3‚CHCl3 (80 mg, 0.078 mmol) and dppb (66 mg, 0.16 mmol) in
dry, deoxygenated N,N-dimethylacetamide (DMA, 1 mL) was stirred
for 30 min at room temperature under N2. A solution of triflate 23
(360 mg, 0.65 mmol) in dry, deoxygenated DMA (5.5 mL) and KOAc
(190 mg, 1.94 mmol) was added to the resulting dark orange solution,
and the mixture was stirred under N2 at 80 °C for 12 h. The resulting
tan solution was poured into a biphasic mixture of EtOAc and brine
(100 mL, 1:1), and the aqueous phase was extracted with EtOAc (50
mL). The combined organic phases were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (SiO2, Biotage 40 M,
40 × 150 mm, toluene/acetone 10:0 f 20:1, flow rate 15 mL/min) to
yield pure 24 (197 mg, 75%) as a colorless oil: [R]26D -162 (c ) 2.7,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.36-7.29 (m, 5H), 7.20 (bs,
1H), 5.15 (d, J ) 12.2 Hz, 1H), 5.12 (d, J ) 12.2 Hz, 1H), 2.53-2.44
(m, 2H), 2.34-2.27 (m, 1H), 2.07 (dd, J ) 13.2, 18.0 Hz, 1H), 1.87
(t, J ) 12.5 Hz, 1H), 1.77-1.42 (m, 8H), 1.03 (s, 3H), 1.02 (d, J )
6.6 Hz, 3H), 0.93 (d, J ) 6.6 Hz, 6H); 13C NMR (125 MHz, toluene-
d8, 363 K)49 δ 202.5, 168.5, 168.0, 145.7, 137.2, 132.2, 131.6, 129.2,
128.9, 128.4, 66.9, 51.1, 46.8, 39.9, 38.5, 38.3, 34.7, 28.8, 28.1, 26.9,
24.5, 22.2, 19.9, 19.1;50 IR (film) 2954, 2925, 2856, 1717, 1636, 1457,
1378, 1277, 1225, 1025, 752 cm-1; HRMS (ESI) m/z calcd for C27H35O3
(M + H), 407.2586; found, 407.2580.
Experimental Section48
(3R,4R)-4-Isopropyl-3-methyl-3-[(S)-1-methylcyclohex-2-en-1-yl)-
ethyl]-2-methylenecyclopentanone (17). A pentane solution of t-BuLi
(1.33 M, 5.8 mL, 7.7 mmol) was added dropwise to a solution of alkyl
iodide 6 (1.94 g, 7.74 mmol) and dry Et2O (5.82 mL) at -78 °C.35
This solution was maintained at -78 °C for 30 min, and then CuCN
(693 mg, 7.74 mmol) was added in one portion with stirring. After 5
min at -78 °C, the solution was allowed to warm to -30 °C and
maintained at this temperature until a color change to yellow or tan
was clearly visible (typically after ∼5-10 min). The reaction was
recooled to -78 °C, and dry THF (5.8 mL) and TMSBr (1.2 g, 7.7
mmol) were added sequentially. Stirring was continued another 5 min,
and then a solution of enone 5 (713 mg, 5.16 mmol) in dry THF (5.8
mL) was slowly added by cannula. After an additional 6 h at -78 °C,
the solution was diluted with hexanes (100 mL), allowed to warm to
room temperature, and washed with a mixture of saturated aqueous
NH4Cl and aqueous NH4OH (9:1), H2O, and brine. After drying over
anhydrous Na2SO4, this solution was concentrated at ambient temper-
ature, and dry DMF (26 mL) and 2,6-lutidine (1.8 mL, 16 mmol) were
(3S,5aR,7aR,8R,9R)-9-Acetoxy-3-bromo-8-isopropyl-5a,7a-dimethyl-
4,5,5a,6,7,7a,8,9-octahydro-3H-1-oxabenzo[cd]cyclopenta[h]azulene-
2,10-dione (27). Triethylsilane (122 mg, 1.05 mmol) and Et3N (28 mg,
0.28 mmol) were added to an orange solution of Pd(OAc)2 (31 mg,
0.14 mmol) in dry CH2Cl2 (1.5 mL).45 The resulting dark solution was
stirred at room temperature for 30 min, and then added to a solution of
ester 25 (32.4 mg, 0.070 mmol) in dry CH2Cl2 (1.5 mL). The reaction
was maintained at room temperature for 2 h, diluted with EtOAc (15
mL), and filtered through Celite. The filtrate was washed with saturated
aqueous NH4Cl, dried over Na2SO4, and concentrated. The residue was
(49) Interpretation of 13C NMR spectra recorded in CDCl3 at room temperature
was complicated by the occurrence of slowly interconverting conformational
isomers of the central seven-membered B ring. Spectra of some intermedi-
ates were therefore recorded at 363 K in toluene-d8.
(47) The assignment of the configuration at C5 of (+)-1 and (+)-2 was further
corroborated by 2D NMR spectroscopy (COSY, HMQC, HMBC, NOESY).
(48) General experimental details are provided in the Supporting Information.
(50) One peak is missing, which we attribute to overlap with the solvent signal.
9
13100 J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006