2012 J . Org. Chem., Vol. 65, No. 7, 2000
Haney and Curran
1
8E: H NMR (300 MHz, CDCl3) 6.08 (s, 1H), 5.39 (tq, J )
1.5, 6.6 Hz, 1H), 4.69 (d, J ) 17.9 Hz, 2H), 2.59 (t, J ) 7.2 Hz,
2H), 2.49 (s, 3H), 2.37 (m, 6H), 2.15 (s, 3H), 1.75 (s, 3H); 13C
NMR (75 MHz, CDCl3) 200.5, 157.8, 145.2, 133.6, 123.4, 109.9,
104.4, 42.5, 39.4, 34.5, 33.5, 31.8, 22.7, 19.4; IR (cm-1) 3077,
1713, 1689, 1648, 1619; HRMS calcd for C14H21IO 332.0637,
found 332.0628.
needed on what factors control the reversibility in these
types of systems.
Exp er im en ta l P r oced u r es
6-Iod oh ep t-5-en -2-on e (9). NaH (95%, 0.62 g, 24.5 mmol)
was added to dry THF (250 mL), and the mixture was cooled
to 0 °C. Methyl acetoacetate (1.99 mL. 18.3 mmol) was added
slowly with significant evolution of H2 gas. After 30 min, BuLi
(1.6 M, 11.4 mL, 18.3 mmol) was added slowly. The dark
orange solution was cooled to -78 °C, and bromide 11 (4.56 g,
17.5 mmol) was added rapidly. The solution was warmed
slowly to room temperature and allowed to stir for an ad-
ditional 3 h. The reaction mixture was quenched by dropwise
addition of H2O and partitioned between Et2O and H2O. The
aqueous layer was extracted into Et2O. The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated to give a brown oil. The crude oil was purified
by flash chromatography on silica gel eluting with hexanes/
ethyl acetate (5:1) to give 2.30 g of the desired â-keto ester
(45%): 1H NMR (300 MHz, CDCl3) 5.46 (tq, J ) 1.2, 6.6 Hz,
1H), 3.74 (s, 3H), 3.47 (s, 2H), 2.65 (t, J ) 7.2 Hz, 2H), 2.48 (s,
3H), 2.38 (m, 2H); 13C NMR (75 MHz, CDCl3) 201.7, 167.5,
133.1, 102.6, 52.4, 48.9, 41.4, 33.5, 30.4; IR (cm-1) 1754, 1722,
1645. The â-keto ester (2.21 g, 7.5 mmol) was dissolved in a
1:1 THF/H2O mixture (40 mL). LiOH (0.62 g, 15.0 mmol) was
added, and the solution was heated to 50 °C. After 24 h, the
solution was cooled to room temperature and poured into H2O
(50 mL). The aqueous solution was extracted with Et2O. The
combined organic extracts were washed with H2O and brine,
dried over MgSO4, and concentrated. The resulting yellow oil
was purified by flash chromatography on silica gel eluting with
hexanes/ethyl acetate (6:1) to yield 80% of the ketone 9 as a
light yellow oil: 1H NMR (300 MHz, CDCl3) 5.45 (tq, J ) 1.5,
6.7 Hz, 1H), 2.53 (t, J ) 7.3 Hz, 2H), 2.47 (s, 3H), 2.34 (q, J )
7.1 Hz, 2H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3) 215.6,
133.6, 102.3, 42.1, 33.6, 30.9, 29.9; IR (cm-1) 3002, 2954, 1715,
1651; HRMS calcd for C7H11IO 237.9855, found 237.9855.
(5-Meth yl-2-oxoh ex-5-en yl)p h osp h on ic Acid Dieth yl
Ester (10). Diethyl 2-oxopropylphosphonate (8.5 mL, 44 mmol)
was added to dry THF (300 mL) and cooled to 0 °C. BuLi (1.6
M, 58.3 mL, 93 mmol) was added slowly. The dark orange
solution was cooled to -78 °C, and methallyl iodide (8.89 g,
48 mmol) was added rapidly. The solution was warmed slowly
to room temperature and allowed to stir for an additional 3 h.
The reaction mixture was quenched by dropwise addition of
H2O and partitioned between Et2O and H2O. The aqueous
layer was extracted into Et2O. The combined organic layers
were washed with H2O and brine, dried over MgSO4, and
concentrated to give a yellow oil. The crude oil was purified
by flash chromatography on silica gel eluting with hexanes/
ethyl acetate (1:2) to give 7.92 g of the phosphonate 10 as a
clear oil (73%): 1H NMR (300 MHz, CDCl3) 4.72 (d, J ) 18.7
Hz, 2H), 4.17 (m, 4H), 3.13 (d, J ) 22.7 Hz, 2H), 2.78 (t, J )
7.3 Hz, 2H), 2.30 (t, J ) 7.5 Hz, 2H), 1.74 (s, 3H), 1.34 (t, J )
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) 201.4, 144.0, 110.3,
62.5 (2C), 43.2, 42.1, 31.0, 22.6, 16.3 (2C); IR (cm-1) 3076, 2977,
8Z: 1H NMR (300 MHz, CDCl3) 6.10 (s, 1H), 5.47 (tq, J )
1.5, 6.6 Hz, 1H), 4.69 (d, J ) 19.7 Hz, 2H), 2.69 (t, J ) 7.6 Hz,
2H), 2.56 (t, J ) 7.1 Hz, 2H), 2.48 (s, 3H), 2.36 (m, 4H), 1.93
(s, 3H), 1.75 (s, 3H); 13C NMR (75 MHz, CDCl3) 196.5, 157.8,
143.8, 134.6, 124.2, 109.9, 101.4, 42.4, 35.1, 33.4, 32.0, 31.7,
25.5, 22.7; IR (cm-1) 3077, 1713, 1689, 1648, 1619; HRMS calcd
for C14H21IO 332.0637, found 332.0628.
P r ep a r a t ive Cycliza t ion of 8 To F or m 3a ,8,8a -Tr i-
m eth ylocta h yd r o-4,8-m eth a n oa zu len -5-on e (7b), 3a ,8,8a -
Tr im eth yloctah ydr o-4,8-m eth an o-azu len -5-on e (7a), 2-(1,2-
Dim eth ylcyclopen ta-2-en yl)-4-m eth ylcycloh exan on e (12a),
2-(1,2-Dim e t h ylcyclop e n t a -2-e n yl)-4-m e t h ylcycloh e x-
a n on e (12b), a n d 1-(1,2-Dim eth ylcyclop en ta -2-en yl)-5-
m eth yl-h ex-5-en -2-on e (13). Enone 8 (0.07 g, 0.21 mmol) was
dissolved in tert-butyl alcohol (40 mL). Sodium cyanoborohy-
dride (0.020 g, 0.32 mmol) and AIBN (0.007 g, 0.042 mmol)
were added, followed by tin hydride 14 (0.015 g, 0.021 mmol).
The reaction mixture was heated to 80 °C and allowed to stir
for 12 h. After being cooled to room temperature, the mixture
was poured into H2O and diluted with Et2O. The layers were
separated, and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with H2O and brine,
dried over MgSO4, and concentrated. This residue was filtered
through a small plug of fluorous reversed-phase silica gel
rinsing with CH3CN. The CH3CN was removed by rotary
evaporation, and the residue was purified by HPLC eluting
with hexanes/ethyl acetate (97:3) to yield each of the title
compounds.
3a ,8,8a -Tr im e t h yloct a h yd r o-4,8-m e t h a n oa zu le n -5-
on e (7a ): 0.001 g, 2%, white paste; 1H NMR (500 MHz, CDCl3)
2.38 (m, 2H), 2.24 (d, J ) 4.4 Hz, 1H), 2.10 (dt, J ) 3.4, 12.5
Hz, 1H), 1.94 (m, 1H), 1.83 (m, 1H), 1.73 (m, 2H), 1.64 (m,
2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.22 (m, 1H), 1.09 (s, 3H),
1.01 (s, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, CDCl3) 215.4,
62.4, 56.0, 54.4, 43.7, 41.9, 37.9, 37.1, 36.1, 33.7, 27.4, 26.6,
24.9, 23.6; IR (cm-1) 1705; MS (m/e) 206 (10), 191 (10), 188
(20), 163 (10), 149 (5), 137 (20), 121 (20), 109 (50), 95 (100), 81
(50), 67 (40), 55 (50).
3a ,8,8a -Tr im e t h yloct a h yd r o-4,8-m e t h a n oa zu le n -5-
on e (7b): 0.009 g, 20%, white paste; 1H NMR (500 MHz,
CDCl3) 2.31 (dd, J ) 9.0, 18.6 Hz, 1H), 2.26 (d, J ) 5.2 Hz,
1H), 2.20 (dd, J ) 9.0, 18.5 Hz, 1H), 2.05 (dt, J ) 4.1, 12.7 Hz,
1H), 1.84 (qd, J ) 3.7, 9.5 Hz, 1H), 1.67 (m, 1H), 1.59 (m, 2H),
1.51 (m, 2H), 1.45 (m, 1H), 1.35 (m, 1H), 1.26 (m, 1H), 0.96 (s,
3H), 0.92 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3) 214.1,
61.8, 52.7, 51.5, 45.3, 44.0, 42.1, 38.2, 36.1, 34.7, 23.5, 21.6,
20.6, 18.4; IR (cm-1) 1705; HRMS calcd for C14H22O 206.1671,
found 206.1664.
2-(1,2-Dim eth ylcyclop en ta -2-en yl)-4-m eth ylcycloh ex-
a n on e (12a ): 0.005 g, 13%, clear oil; 1H NMR (500 MHz,
CDCl3) 5.30 (s, 1H), 2.59 (dd, J ) 5.5, 11.9 Hz, 1H), 2.48 (dt,
J ) 5.9, 12.7 Hz, 1H), 2.25 (m, 1H), 2.21 (dt, J ) 4.9, 13.5 Hz,
1H), 2.08 (m, 2H), 1.98 (m, 1H), 1.88 (m, 2H), 1.77 (m, 1H),
1.67 (dt, J ) 4.9, 12.1 Hz, 1H), 1.55 (m, 1H), 1.53 (s, 3H), 1.15
(d, J ) 7.0 Hz, 3H), 1.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
213.5, 144.4, 125.2, 51.1, 50.5, 39.9, 35.7, 33.8, 32.9, 30.2, 27.4,
25.1, 18.3, 12.4; IR (cm-1) 3041, 1707, 1658; MS (m/e) 206 (5),
107 (10), 95 (100), 94 (65), 79 (25), 67 (27), 55 (30).
1717, 1648; HRMS calcd for
248.1177.
C
11H21O4P 248.1177, found
11-Iod o-2,7-d im et h yl-d od eca -1,6,10-t r ien -5-on e
(8).
KOtBu (1.68 g, 15.0 mmol) was added to dry toluene (200 mL),
and the suspension was cooled to 0 °C. Phosphonate 10 (3.72
g, 15.0 mmol) was added dropwise, and the bright yellow
solution was stirred for 1 h. Ketone 9 (1.42 g, 6.0 mmol) was
added dropwise, and the solution was heated to 110 °C. After
23 h, the reaction mixture was cooled to room temperature,
diluted with Et2O, and poured into H2O. The layers were
separated, and the aqueous layer was extracted with Et2O.
The organic layers were combined and washed with brine,
dried over MgSO4, and concentrated by rotary evaporation to
give a dark brown oil. The crude oil was purified by flash
chromatography on silica gel eluting with hexanes/ethyl
acetate (12:1) to give 1.43 g of a 2.2:1 mixture of the E and Z
enone 8 (72%) as a light yellow oil along with 0.23 g of
unreacted ketone 9 (16%):
2,2-(1,2-Dim eth ylcyclop en ta -2-en yl)-4-m eth ylcycloh ex-
a n on e (12b): 0.006 g, 14%, clear oil; 1H NMR (500 MHz,
CDCl3) 5.29 (s, 1H), 2.47 (dd, J ) 4.9, 13.3 Hz, 1H), 2.38 (dt,
J ) 5.4, 13.8 Hz, 1H), 2.29 (m, 2H), 2.25 (m, 1H), 2.10 (m,
1H), 2.00 (m, 1H), 1.91 (m, 2H), 1.73 (m, 1H), 1.56 (s, 3H),
1.38 (dq, J ) 3.8, 17.1 Hz, 1H), 1.16 (q, J ) 13.0 Hz, 1H), 1.12
(s, 3H), 0.97 (d, J ) 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
212.9, 144.4, 125.1, 55.6, 50.4, 43.2, 38.5, 36.5, 32.8, 32.6, 30.2,
24.8, 21.4, 12.5; IR (cm-1) 3041, 1707, 1658; MS (m/e) 206 (5),
191 (3), 107 (10), 95 (100), 94 (40), 79 (20), 67 (20), 55 (25).