+
+
Asymmetric Total Synthesis of (+)-Milbemycin D
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7527
were added to a solution of diol 71 (1.25 g, 1.31 mmol) and 2.5 g of
4 Å powdered sieves in 30 mL of CH2Cl2. The black mixture was
stirred at room temperature for 3 h, filtered through a pad of silica gel
using EtOAc, and concentrated in vacuo. Purification of the residue
by column chromatography on silica gel (5-10% EtOAc-hexanes)
the flask and syringe containing the substrate were washed by more
chloroform (2 × 2 mL) and these solutions were delivered by syringe
pump over a period of 1 h. The reaction mixture was cooled to room
temperature, and excess DCC was consumed by adding MeOH (0.45
mL) and acetic acid (0.11 mL). The resulting solution was stirred at
room temperature for 2 h, concentrated in vacuo, and purified by column
chromatography on silica gel (0-10% EtOAc-hexanes) to afford
macrolactone 75 (0.125 g, 53%) as a white foam. [R]25D ) +90.8° (c
) 1.05, CHCl3). 1H NMR (250 MHz, CDCl3): δ 0.78-0.76 (d, 3 H,
J ) 5.8 Hz), 0.83-0.81 (d, 3 H, J ) 6.6 Hz), 1.03-0.95 (m, 9 H),
1.07 (s, 21 H), 2.47-1.15 (m, 21 H), 2.55-2.49 (dd, 1 H, J ) 12.8,
2.9 Hz), 3.06-3.0 (bdd, 1 H, J ) 9.2, 1.5 Hz), 3.62-3.5 (m, 1 H),
3.63 (s, 1 H), 3.71-3.7 (d, 1 H, J ) 2.2 Hz), 4.15-4.10 (m, 1 H),
4.57 (s, 2 H), 4.98-4.92 (bt, 1 H, J ) 7.5 Hz), 5.25-5.1 (m, 1 H),
5.36-5.27 (dd, 1 H, J ) 12, 10 Hz), 5.85-5.65 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ 173.0, 142.0, 140.2, 137.0, 123.7, 121.0, 120.3,
97.5, 82.7, 78.2, 76.0, 71.5, 67.9, 67.8, 67.5, 48.5, 47.6, 41.6, 36.5,
36.0, 35.7, 34.6, 32.4, 31.6, 28.3, 28.1, 25.6, 22.4, 20.9, 18.2, 17.9,
17.4, 15.5, 14.1, 13.0. IR (film): 3480, 2960, 2880, 1710, 1460, 1380
cm-1. HRMS: calcd for C42H70O7Si 714.4891, found 714.4846.
provided aldehyde 72 (1.0 g, 80%) as a white foam. [R]25 ) +2.4°
D
(c ) 0.88, CHCl3). 1H NMR (250 MHz, CDCl3): δ 0.71-0.63 (m, 9
H), 0.91-0.88 (d, 3 H, J ) 6.6 Hz), 1.04 (s, 12 H), 1.09 (s, 21 H),
2.4-1.2 (m, 21 H), 2.5-2.46 (dd, 1 H, J ) 12, 4 Hz), 2.9-2.86 (bdd,
1 H, J ) 9.8, 1.8 Hz), 3.08 (s, 1 H), 3.35-3.25 (m, 1 H), 3.67-3.66
(d, 1 H, J ) 2.9 Hz), 4.2-4.05 (m, 2 H), 4.63-4.56 (dd, 1 H, J ) 14,
2 Hz), 4.72-4.66 (dd, 1 H, J ) 14, 2 Hz), 5.14-5.09 (bt, 1 H, J ) 6.5
Hz), 5.73-5.64 (dd, 1 H, J ) 15, 6 Hz), 5.89-5.78 (dd, 1 H, J ) 15,
10 Hz), 6.13-6.02 (m, 1 H), 7.7-7.3 (m, 10 H), 9.9 (s, 1 H). 13C
NMR (63 MHz, CDCl3): δ 203.6, 143.1, 140.2, 135.7, 134.7, 134.6,
134.4, 129.4, 127.5, 122.9, 122.7, 121.4, 97.2, 82.9, 77.7, 52.7, 47.2,
45.3, 41.0, 35.7, 34.8, 34.4, 31.5, 31.2, 28.2, 27.0, 22.9, 20.6, 19.2,
19.1, 18.3, 18.2, 18.1, 17.4, 16.3, 14.0, 12.9. IR (film): 3540, 2920,
2860, 1720, 1440, 1410, 1370 cm-1
.
Acid 74. tert-Butyl alcohol (26 mL) and H2O (26 mL) were added
to aldehyde 72 (0.826 g, 0.864 mmol), and the mixture was cooled to
0 °C. 2-Methyl-2-butene (26 mL), followed by NaClO2 (0.637 g, 7.04
mmol) and NaH2PO4‚H2O (1.074 g, 7.78 mmol), were also added
consecutively. After the mixture was warmed to room temperature
and stirred vigorously for 4 h, it was quenched with a pH 4 buffer
solution (20 mL). The aqueous layer was extracted with ether (5 ×
20 mL), and the combined organic extracts were dried over MgSO4,
filtered, and concentrated. Column chromatography on silica gel (10-
240% EtOAc-hexanes) afforded acid 73 (0.517 g, 61%) as a white
Alcohol 76. Tetrabutylammonium fluoride (0.23 mL, 0.23 mmol),
as a 1 M solution in THF, was added to a solution of macrolactone 75
(0.054 g, 0.075 mmol) in 1.0 mL of THF. The resulting solution was
stirred overnight at room temperature, concentrated in vacuo, and
purified by column chromatography on silica gel (10-50% EtOAc-
hexanes) to afford diol 76 (0.040 g, 95%) as a white foam. [R]25
)
D
+154.5° (c ) 1.15, CHCl3). 1H NMR (250 MHz, CDCl3): δ 0.79-
0.76 (d, 3 H, J ) 5.8 Hz), 0.84-0.81 (d, 3 H, J ) 7 Hz), 1.05-0.96
(m, 9 H), 1.95-1.2 (m, 17 H), 2.25-2.1 (m, 3 H), 2.45-2.3 (m, 1 H),
2.6-2.5 (m, 2 H), 3.07-3.03 (bdd, 1 H, J ) 9.5, 1.8 Hz), 3.65-3.5
(m, 1 H), 3.75-3.74 (d, 1 H, J ) 2.6 Hz), 3.90-3.80 (m, 1 H), 4.56
(s, 2 H), 4.93-4.87 (bt, 1 H, J ) 7.5 Hz), 5.08 (s, 1 H), 5.45-5.25
(m, 2 H), 5.75-5.6 (m, 2 H). 13C NMR (63 MHz, CDCl3): δ 175.0,
142.6, 140.0, 136.8, 123.4, 120.8, 119.7, 97.4, 80.7, 78.4, 76.2, 70.2,
68.5, 68.0, 67.3, 48.5, 47.0, 41.1, 37.0, 36.0, 35.8, 34.8, 32.2, 31.6,
28.3, 28.1, 25.8, 22.3, 21.0, 17.4, 17.1, 15.5, 14.2. IR (film): 3460,
2960, 2940, 2860, 1710, 1460, 1380 cm-1. HRMS: calcd for C33H50O7
559.3635, found 559.3546.
foam. [R]25 ) +32.6° (c ) 1.45, CHCl3). 1H NMR (250 MHz,
D
CDCl3): δ 0.72-0.64 (m, 9 H), 0.9-0.87 (d, 3 H, J ) 6.6 Hz), 1.05
(s, 13 H), 1.11 (s, 20 H), 2.45-1.15 (m, 21 H), 2.71-2.65 (bdd, 1 H,
J ) 12.4, 3.6 Hz), 2.91-2.86 (dd, 1 H, J ) 9.5, 1.8 Hz), 3.38-3.22
(m, 1 H), 3.74-3.73 (d, 1 H, J ) 2.9 Hz), 4.25-4.0 (m, 3 H), 4.59-
4.53 (dd, 1 H, J ) 14, 2 Hz), 4.68-4.61 (dd, 1 H, J ) 14, 2 Hz),
5.13-5.07 (bt, 1 H, J ) 6.5 Hz), 5.85-5.6 (m, 2 H), 6.07-5.95 (m,
1 H), 7.7-7.3 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ 175.6, 143.2,
139.2, 135.7, 134.5, 134.4, 129.4, 127.5, 122.8, 122.6, 120.8, 97.1,
82.2, 77.7, 75.6, 71.9, 68.3, 68.1, 66.8, 47.6, 47.1, 45.2, 40.9, 35.6,
34.7, 34.3, 32.1, 31.5, 28.1, 27.0, 20.6, 19.1, 19.0, 18.2, 18.1, 17.8,
17.4, 16.2, 13.9, 12.9. IR (film): 3460, 3080, 2940, 2860, 1710, 1460,
Ketone 77. Tetrapropylammonium perruthenate (0.002 g, 0.0057
mmol) and anhydrous N-methylmorpholine N-oxide (0.006 g, 0.0512
mmol) were added to a solution of diol 76 (0.016 g, 0.0268 mmol)
and 0.20 g of 4 Å powdered sieves in 0.8 mL of CH2Cl2. The black
mixture was stirred at room temperature for 4 h, filtered through a pad
of Celite using CH2Cl2, and concentrated in vacuo. Purification of the
black residue by column chromatography on silica gel (5-25%
EtOAc-hexanes) afforded ketone 77 (0.011 g, 79%) as a white foam
1430, 1370 cm-1
.
Tetrabutylammonium fluoride (0.24 mL, 0.24 mmol), as a 1 M
solution in THF, was added to a solution of acid 73 (0.24 g, 0.25 mmol)
in 5.0 mL of THF. The resulting solution was stirred for 3 days at
room temperature, and more TBAF (0.12 mL, 0.12 mmol) was added.
Following an additional 1 day of stirring the solution was concentrated
in vacuo and purified by column chromatography on silica gel (25-
50% EtOAc-hexanes and then 10-30% MeOH-hexanes) to provide
hydroxy acid 74 (0.123 g, 68%) as a white foam. [R]25D ) +61.8° (c
) 0.677, CHCl3). 1H NMR (250 MHz, CDCl3): δ 0.77-0.75 (d, 3 H,
J ) 5.9 Hz), 0.98-0.93 (m, 6 H), 0.82-0.79 (d, 3 H, J ) 7.4 Hz),
1.03-1.0 (d, 3 H, J ) 6.6 Hz), 1.08 (s, 21 H), 2.5-1.2 (m, 23 H),
2.62-2.56 (bdd, 1 H, J ) 12.5, 3.7 Hz), 3.04-2.99 (bdd, 1 H, J )
9.5, 1.5 Hz), 3.6-3.45 (m, 1 H), 3.71-3.7 (d, 1 H, J ) 2.2 Hz), 4.25-
4.05 (m, 2 H), 4.58 (s, 2 H), 4.97-4.92 (bt, 1 H, J ) 6.5 Hz), 5.5-
5.41 (dd, 1 H, J ) 15, 8 Hz), 5.8-5.69 (dd, 1 H, J ) 15, 11 Hz),
6.0-5.9 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ 176.3, 141.5, 140.6,
135.7, 124.1, 121.4, 120.4, 97.2, 82.8, 78.1, 75.5, 71.5, 68.1, 68.0, 65.8,
47.6, 47.2, 44.7, 38.9, 35.7, 35.0, 34.4, 32.4, 31.6, 28.2, 28.1, 26.6,
21.9, 20.8, 18.2, 17.9, 17.3, 16.1, 14.1, 13.0. IR (film): 3470, 2960,
2860, 1705, 1460, 1380 cm-1. HRMS: calcd for C42H72O8Si 732.4996,
found 732.5010.
Macrolactone 75. A solution of N,N-dicyclohexylcarbodiimide
(DCC; 0.138 g, 0.67 mmol), 4-(dimethylamino)pyridine (0.122 g, 1.0
mmol), and DMAP‚HCl (0.106 g, 0.67 mmol) in 350 mL of dry
(ethanol-free) CHCl3 was heated to reflux. Hydroxy acid 74 (0.240 g,
0.33 mmol) in 20 mL of dry (ethanol-free) CHCl3 was added to the
refluxing solution via a syringe pump over a period of 16 h. The long
needle was inserted through the condenser and placed directly over
the refluxing solution such that the refluxing chloroform washed the
substrate droplets forming at its tip. Upon completion of the addition,
and recovered alcohol 76 (0.002 g). [R]25 ) +138.9° (c ) 0.764,
D
CHCl3). 1H NMR (250 MHz, CDCl3): δ 0.79-0.77 (d, 3 H, J ) 6.2
Hz), 0.84-0.81 (d, 3 H, J ) 7 Hz), 0.99-0.96 (d, 3 H, J ) 6.6 Hz),
1.03-1.0 (d, 3 H, J ) 6.9 Hz), 1.09-1.06 (d, 3 H, J ) 6.6 Hz), 2.5-
2.3 (m, 1 H), 2.25-1.2 (m, 19 H), 2.87-2.7 (m, 1 H), 3.08-2.95 (m,
2 H), 3.74 (s, 1 H), 3.65-3.5 (m, 1 H), 4.62 (s, 1 H), 4.66-4.59 (dd,
1 H, J ) 14, 2 Hz), 4.78-4.71 (dd, 1 H, J ) 14, 2 Hz), 4.95-4.89 (bt,
1 H, J ) 7.5 Hz), 5.48-5.32 (m, 2 H), 5.8-5.6 (m, 2 H). 13C NMR
(75 MHz, CDCl3): δ 206.7, 174.0, 143.5, 138.5, 136.8, 123.3, 120.7,
120.2, 97.4, 84.3, 82.4, 78.3, 69.7, 68.4, 67.3, 48.4, 46.6, 41.3, 41.1,
36.9, 36.0, 35.7, 34.7, 33.0, 31.6, 28.2, 28.0, 22.2, 20.9, 17.3, 15.5,
14.1, 13.8. IR (film): 3480, 2980, 2940, 2880, 1740, 1720, 1470, 1400
cm-1. HRMS: calcd for C33H48O7 556.3400, found 556.3391.
Selenides 78a,b. To a solution of ketone 77 (0.037 g, 0.066 mmol)
in 0.8 mL of CH2Cl2 at 0 °C was added triethylamine (0.40 mL, 2.86
mmol) followed by (TMS)OTf (0.22 mL, 1.13 mmol), and the resulting
solution was stirred at 0 °C for 8 h. The reaction mixture was quenched
slowly with saturated aqueous NaHCO3 (1.0 mL) and stirred an
additional 20 min at 0 °C. The aqueous layer was then extracted with
CH2Cl2 (3 × 2 mL); the extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. Without further purification, the crude silyl
enol ether was dissolved in CH2Cl2 (2.0 mL) and the solution cooled
to -78 °C. Phenylselenenyl chloride (0.019 g, 0.099 mmol) was added
in small portions, and the solution was maintained at -78 °C for another
1 h. The reaction was quenched while at -78 °C with saturated
aqueous NaHCO3 (2.0 mL) and warmed to room temperature. The