The Journal of Organic Chemistry
Article
Synthesis of Ketoaldehyde 83. (3S,4aS,6aS,7S,10aR,10bS)-7-
(Hydroxymethyl)-3-(2-hydroxypropan-2-yl)-6a,7,10b-trimethylde-
cahydro-1H-benzo[f ]chromen-8(4aH)-one (S6). A 50 mL round-
bottomed flask was charged with acetate 78 (0.71 g, 1.18 mmol, 1.00
equiv) and 2 M HCl(aq)/MeOH/THF/acetone (10:10:10:1, 12 mL).
The mixture was warmed to 85 °C and stirred until full convergence to
a single product was observed by TLC analysis, typically 5 h. The
mixture was cooled to rt and concentrated on a rotary evaporator, and
the residue was taken up into H2O (15 mL) and CH2Cl2 (15 mL) and
partitioned in a separatory funnel. The mixture was extracted with
CH2Cl2 (3 × 10 mL), and the combined organic extracts were dried
with magnesium sulfate and concentrated in vacuo. The product was
purified via flash chromatography (60:40 EtOAc:hexanes) to afford
hydroxy ketone S6 (0.28 g, 71% yield) as a reddish-brown, viscous oil.
Analytical data: [α]D −159.6 (c = 0.30, CHCl3); H NMR (600
MHz, CDCl3) δ 4.12 (dd, J = 8.4, 3.0 Hz, 1H), 3.22 (m, 2H), 3.02 (dd,
J = 6.0, 3.0 Hz, 1H), 2.64 (dd, J = 7.2, 3.0 Hz, 1H), 2.59 (br s, 1H),
2.55 (m, 1H), 2.29 (m, 1H), 1.89−1.86 (m, 2H), 1.80 (m, 1H), 1.70−
1.60 (m, 6H), 1.46 (m, 1H), 1.40 (dt, J = 6.0, 3.6 Hz, 1H), 1.31 (s,
3H), 1.23 (m, 1H), 1.18 (s, 3H), 1.15 (s, 3H), 0.99 (s, 3H), 0.91 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 219.3, 85.0, 84.6, 71.8, 63.6,
57.4, 45.3, 42.1, 37.9, 37.6. 36.4, 30.7, 26.1, 23.9, 23.7, 21.7, 21.2, 18.2,
16.9, 13.5; HRMS (ESI+) calcd for C20H34O4+Na, 361.2355; found
361.2360; IR (thin film, cm−1) 3450, 2950, 1692, 1425, 1166, 1102,
735, 685; TLC (60:40 hexanes/EtOAc) Rf = 0.12.
separatory funnel, diluted with H2O (15 mL) and extracted with Et2O
(3 × 15 mL). The combined organic extracts were washed with
saturated NaHCO3(aq) (10 mL), dried with magnesium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (80:20 to 70:30 to 60:40 hexanes/EtOAc) to afford
an inseparable 2.6:1 mixture of diol diastereomers 84 (0.14 g, 99%
yield) as a pale white, viscous foam. Analytical data: [α]D28 −182.8 (c =
1
0.25, CHCl3); H NMR (600 MHz, CDCl3) δ 6.30 (dd, J = 10.8, 6.0
Hz, 1H), 6.14 (m, 1H), 5.24 (d, J = 17.4 Hz, 1H), 5.08 (d, J = 10.8 Hz,
1H), 5.03−4.99 (m, 2H), 4.40 (d, J = 8.4 Hz, 1H), 3.16 (m, 1H), 2.88
(m, 1H), 1.83 (m, 3H), 1.72 (m, 2H), 1.59 (m, 3H), 1.53 (s, 3H),
1.45−1.36 (m, 5H), 1.15 (s, 3H), 1.14 (s, 3H), 1.03 (m, 1H), 0.90 (s,
3H), 0.87 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 145.8, 140.7,
116.4, 112.6, 85.7, 84.5, 80.0, 79.6, 72.0, 49.4, 47.3, 43.1, 38.0, 36.3,
35.9, 32.4, 26.0, 24.3, 23.6, 21.9, 19.5, 18.6, 17.0, 13.3; HRMS (ESI+)
calcd for C24H40O4+Na, 415.2825; found 415.2829; IR (thin film,
cm−1) 3303, 2949, 2877, 1621, 1461, 1301, 1089, 920, 737; TLC
(60:40 hexanes/EtOAc) Rf = 0.32.
(2S,4aS,4bR,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-4a,9a,9b-
trimethyl-3,4,4a,4b,5,6,9,9a,9b,10,11,11a-dodecahydroindeno[5,4-
f ]chromene-6a,9(2H)-diol (85). A flame-dried, 20 mL scintillation vial
was charged with Grubbs’ second generation catalyst (0.99 g, 0.12
mmol, 0.20 equiv) and a stir bar in a nitrogen-filled glovebox. The vial
was removed from the glovebox and charged with CH2Cl2 (12 mL)
under an atmosphere of N2. Diol 84 (0.23 g, 0.59 mmol, 1.00 equiv)
was added as a solution in CH2Cl2 (3 mL), and the mixture was
allowed to stir at rt until complete conversion of the starting material
was observed by TLC analysis, typically 3 h. The reaction mixture was
concentrated in vacuo, and the product was purified via flash
chromatography (80:20 to 70:30 to 60:40 hexanes/EtOAc) to afford
allylic alcohol 85 (0.16 g, 73% yield) as a pale-brown viscous foam.
Analytical data: [α]D28 −62.8 (c = 0.75, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 6.22 (d, J = 5.4 Hz, 1H), 6.14 (dd, J = 3.0, 2.4 Hz, 1H), 4.42
(br s, 1H), 3.18 (dd, J = 9.0, 3.0 Hz, 1H), 2.95 (dd, J = 7.8, 3.6 Hz,
1H), 2.69 (br s, 1H), 2.26 (d, J = 5.4 Hz, 1H), 2.22 (br s, 1H), 1.83−
1.75 (m, 8H), 1.63 (s, 3H), 1.56−1.54 (m, 3H), 1.42 (m, 2H), 1.17 (s,
3H), 1.16 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 143.2, 137.2, 87.3, 86.0, 84.6, 83.3, 71.9, 52.5, 47.9, 41.8,
38.3, 36.3, 32.9, 30.4, 26.8, 26.1, 23.9, 23.6, 21.9, 20.2, 17.7, 13.2;
HRMS (ESI+) calcd for C22H36O4+Na, 387.2512; found 387.2519; IR
(thin film, cm−1) 3400, 2951, 2675, 1729, 1449, 1384, 1256, 1097,
1023, 910, 754; TLC (60:40 hexanes/EtOAc) Rf = 0.25.
(2S,4aS,4bR,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-4a,9a,9b-
trimethyl-3,4,4a,4b,5,6,8,9a,9b,10,11,11a-dodecahydroindeno[5,4-
f ]chromen-9(2H)-one (86). A flame-dried, 20 mL scintillation vial was
charged with diol 85 (0.15 g, 0.40 mmol, 1.00 equiv) and CH2Cl2 (9
mL) under and atmosphere of N2. The mixture was cooled to 0 °C,
and TFA (0.15 mL, 2.02 mmol, 5.00 equiv) was added. The reaction
mixture was warmed to rt and allowed to stir until complete
conversion of the starting material was observed by TLC analysis,
typically 30 min. The reaction was quenched with saturated
NaHCO3(aq) (5 mL), and the mixture was partitioned in a separatory
funnel. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL), and
the combined organic extracts were dried with Na2SO4 and
concentrated in vacuo. The product was purified via flash
chromatography (90:10 to 80:20 to 70:30 hexanes/EtOAc) to afford
the nonconjugated enone 86 (0.10 g, 71% yield) as a pale brown,
viscous oil. Analytical Data: [α]D28 −77.7 (c = 0.50, CHCl3); 1H NMR
(600 MHz, CDCl3) δ 5.64 (m, 1H), 3.17 (dd, J = 9.0, 2.4 Hz, 1H),
2.95 (dd, J = 5.4, 4.8 Hz, 1H), 2.83 (m, 1H), 2.69 (m, 1H), 2.61 (br
s,1H), 2.40 (m, 1H), 2.10 (br s, 1H), 1.84 (m, 2H), 1.64 (m, 3H), 1.55
(m, 2H), 1.43−1.33 (m, 3H), 1.16 (s, 3H), 1.13 (br s, 4H), 1.12 (s,
3H), 0.91 (s, 3H), 0.83 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
223.0, 148.2, 116.3, 85.5, 84.4, 71.8, 59.3, 46.6, 43.0, 41.1, 37.9, 36.5,
30.9, 27.6, 26.1, 24.0, 23.7, 21.8, 21.7, 17.6, 17.4, 13.4; HRMS (ESI+)
calcd for C22H34O3+Na, 369.2406; found 369.2398; IR (thin film,
cm−1) 3053, 2979, 2977, 1734, 1558, 1472, 1373, 1265, 1139, 1086,
971, 921, 704; TLC (80:20 hexanes/EtOAc) Rf = 0.23.
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(3S,4aS,6aS,7S,10aR,10bS)-3-(2-Hydroxypropan-2-yl)-6a,7,10b-
trimethyl-8-oxododecahydro-1H-benzo[f ]chromene-7-carbalde-
hyde (83). A 20 mL scintillation vial was charged with alcohol S6 (0.29
g, 0.84 mmol, 1.00 equiv) and CH2Cl2 (8 mL). Dess-Martin
periodinane (0.71 g, 1.68 mmol, 2.00 equiv) was added at rt with
stirring. The reaction mixture was allowed to stir at room temperature
until TLC analysis confirmed complete conversion of the starting
material, typically 20 min. The mixture was then quenched via a 1:1
solution of saturated NaHCO3(aq) and saturated Na2S2O3(aq) (10 mL),
and the mixture was stirred 5 min. The reaction mixture was then
diluted with Et2O (15 mL) and partitioned in a separatory funnel. The
aqueous layer was extracted with Et2O (3 × 10 mL), and the
combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo. The product was purified via flash
chromatography (60:40 to 50:50 hexanes/EtOAc) to afford the
ketoaldehyde 83 (0.28 g, 99% yield) as a pale white powder. Analytical
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data: mp 121−125 °C; [α]D −223.7 (c = 0.50, CHCl3); H NMR
(600 MHz, CDCl3) δ 10.06 (s, 1H), 3.22 (dd, J = 9.0, 3.0 Hz, 1H),
3.02 (dd, J = 6.0, 2.4 Hz, 1H), 2.52−2.46 (m, 2H), 1.94−1.82 (m,
3H), 1.57−1.70 (m, 5H), 1.47 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H),
1.22 (m, 1H), 1.18 (s, 3H), 1.15 (s, 3H), 0.94 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 214.0, 204.2, 84.9, 84.6, 71.9, 64.7, 45.1, 43.4, 37.8,
37.6, 36.5, 31.6, 26.1, 23.7, 23.5, 21.6, 20.9, 19.5, 14.8, 13.6; HRMS
(ESI+) calcd for C20H32O4+Na, 359.2199; found 359.2198; IR (thin
film, cm−1) 3019, 2955, 2857, 2400, 1721, 1388, 1265, 1215, 1098;
TLC (60:40 hexanes/EtOAc) Rf = 0.24.
(3S,4aS,6aS,7S,10aR,10bS)-7-(1-Hydroxyallyl)-3-(2-hydroxypro-
pan-2-yl)-6a,7,10b-trimethyl-8-vinyldodecahydro-1H-benzo[f ]-
chromen-8-ol (84). A flame-dried, 20 mL scintillation vial was charged
with LiCl (0.30 g, 7.13 mmol, 20.00 equiv equiv), anhydrous CeCl3
(0.88 g, 3.57 mmol, 10.00 equiv), and a stir bar in a nitrogen-filled
glovebox. The vial was removed from the glovebox and placed under
an N2 atmosphere. THF (5 mL) was added, and this mixture was
stirred at rt for 2.5 h. A separate flame-dried, 20 mL scintillation vial
was charged with aldehyde 83 (0.12 g, 0.36 mmol, 1.00 equiv) and
THF (2 mL) under an atmosphere of N2. The CeCl3·2LiCl suspension
was added to the solution of 83 at rt, and the resulting mixture was
stirred 2.5 h. The reaction was subsequently cooled to −78 °C, and
vinylmagnesium bromide (1 M in THF, 3.57 mL, 3.57 mmol, 10
equiv) was added. The reaction mixture was allowed to stir at this
temperature until TLC analysis confirmed complete consumption of
the starting material, typically 20 min. The reaction was quenched with
MeOH (3 mL), and the mixture was immediately warmed to rt upon
which 5% AcOH(aq) (2 mL) and Et2O (2 mL) were added with
stirring. Once the vial had reached rt, the solution was transferred to a
(2S,4aS,4bR,6aR,9aS,9bS,11aS)-2-(2-Hydroxypropan-2-yl)-
4a,9a,9b-trimethyltetradecahydroindeno[5,4-f ]chromen-9(2H)-one
X
J. Org. Chem. XXXX, XXX, XXX−XXX