Total Synthesis of Spinosyn A
J. Am. Chem. Soc., Vol. 120, No. 11, 1998 2561
C), 113.7 (2 C), 75.4, 74.8, 73.2, 72.2, 68.4, 55.2, 49.9, 47.7, 46.8,
46.6, 45.6, 41.2, 38.4, 37.3, 37.2, 36.4, 35.1, 34.0, 29.6, 27.1 (3 C),
27.0 (3 C), 25.9 (3 C), 20.7, 19.5, 18.1, 13.5, 9.5, -4.4, -4.5; FAB
FAB MS m/z (M+) calcd 724.42, obsd 724.47; [R]22 -59.0 (c 0.80,
CH2Cl2). Anal. Calcd for C45H60O6Si: C, 74.55; H, 8.34. Found:
C, 74.37; H, 8.41.
D
MS m/z (M+ + H) calcd 963.60, obsd 963.66; [R]22 -35.3 (c 1.3,
(2R,3S,3aR,5aS,7R,8aR,8bS)-2-[(2R,3S,7S)-3-(tert-Butyldiphenyl-
siloxy)-7-hydroxy-2-methylnonanoyl]-1,2,3,3a,5a,6,7,8,8a, 8b-decahy-
dro-7-hydroxy-as-indacene-3-acetic Acid K-Lactone (38). A mixture
of 37 (27 mg, 0.04 mmol) and potassium carbonate (6 mg, 0.04 mmol)
in methanol (4.0 mL) was refluxed for 2 days, freed of solvent, and
triturated with ether (5 mL). The concentrated extract was purified by
chromatography on silica gel (elution with 3:1 hexanes/ethyl acetate)
to give 38 (15 mg, 63%) as a colorless oil; IR (film, cm-1) 3410, 1721,
1659, 1610; 1H NMR (300 MHz, CHCl3) δ 7.71-7.66 (m, 4 H), 7.44-
7.34 (m, 6 H), 6.87 (s, 1 H), 5.87 (d, J ) 9.8 Hz, 1 H), 5.77 (dt, J )
9.8, 2.6 Hz, 1 H), 4.61-4.53 (m, 1 H), 4.47-4.41 (m, 1 H), 4.00-
3.96 (m, 1 H), 3.52-3.45 (m, 1 H), 3.37-3.27 (m, 1 H), 3.06-2.86
(m, 3 H), 2.41-2.20 (m, 3 H), 1.86 (dd, J ) 13.3, 6.8 Hz, 1 H), 1.56
(br s, 1 H), 1.54-1.18 (m, 9 H), 1.15 (d, J ) 6.9 Hz, 3 H), 1.07 (s, 9
H), 1.02-0.84 (m, 2 H), 0.75 (t, J ) 7.5 Hz, 3 H) (OH not observed);
13C NMR (75 MHz, CHCl3) ppm 203.0, 172.5, 147.5, 143.6, 136.0 (2
C), 135.9 (2 C), 134.5, 133.9, 129.6, 129.5, 129.4, 129.0, 127.5 (2 C),
127.4 (2 C), 75.6, 75.5, 72.4, 49.5, 48.7, 47.6, 47.0, 41.6, 41.0, 40.7,
40.0, 35.8, 34.4, 30.8, 27.9, 27.1 (3 C), 19.7, 19.6, 18.3, 9.4; MS m/z
D
CH2Cl2). Anal. Calcd for C59H86O7Si2: C, 73.55; H, 9.00. Found:
C, 73.44; H, 9.09.
(3S,3aR,5aS,7R,8aR,8bS)-2-[(2R,3S,7S)-7-(tert-Butyldimethylsiloxy)-
3-(tert-butyldiphenylsiloxy)-2-methylnonanoyl]-3,3a,5a,6,7,8,8a,8b-
octahydro-7-hydroxy-as-indacene-3-acetic Acid Pivalate (36).
A
solution of 35 (0.28 g, 0.29 mmol) in cold (0 °C) CH2Cl2 (45 mL) was
treated sequentially with pH 7.0 phosphate buffer solution (4.5 mL of
0.05 M) and DDQ (220 mg, 0.97 mmol). The mixture was stirred for
2 h and poured into a mixture of ethyl acetate (400 mL) and the same
phosphate buffer (20 mL). The separated organic phase was washed
with phosphate buffer (5 × 20 mL), dried, and concentrated. Flash
chromatography of the residue on silica gel (elution with 1:4 ethyl
acetate/hexanes) provided an inseparable mixture of the primary alcohol
and p-anisaldehyde (280 mg) which was taken up in acetone (6 mL),
cooled to 0 °C, and treated dropwise with precooled (0 °C) Jones reagent
(0.51 mL). The reaction mixture was stirred for 1.5 h and poured into
ethyl acetate (150 mL) and the phosphate buffer (20 mL). The organic
layer was washed with phosphate buffer until the washings were at pH
7, dried, and concentrated. Purification of the product by chromatog-
raphy on silica gel (gradient elution with 1:4 f 1:2 ethyl acetate/
hexanes) gave 36 (0.16 g, 64% for two steps) as a colorless oil; IR
(film, cm-1) 3244, 1728, 1713, 1665, 1613; 1H NMR (300 MHz, C6D6)
δ 7.84-7.74 (m, 4 H), 7.30-7.19 (m, 6 H), 6.37 (s, 1 H), 5.85 (dt, J
) 9.7, 2.5 Hz, 1 H), 5.69 (d, J ) 9.7 Hz, 1 H), 5.14-5.07 (m, 1 H),
4.40-4.35 (m, 1 H), 3.47-3.34 (m, 2 H), 3.29-3.24 (m, 1 H), 3.16-
3.05 (m, 1 H), 2.56-2.39 (m, 3 H), 2.21-2.12 (m, 1 H), 2.01-1.91
(m, 1 H), 1.80 (dd, J ) 13.7, 6.7 Hz, 1 H), 1.67-1.50 (m, 2 H), 1.42-
1.03 (m, 7 H), 1.33 (d, J ) 6.9 Hz, 3 H), 1.21 (s, 9 H), 1.18 (s, 9 H),
0.99 (s, 9 H), 0.89-0.78 (m, 1 H), 0.83 (t, J ) 7.4 Hz, 3 H), 0.62-
0.55 (m, 1 H), 0.07 (s, 6 H) (OH not observed); 13C NMR (75 MHz,
C6D6) ppm 201.4, 177.5, 177.3, 144.9, 144.6, 136.4 (2 C), 136.3 (2
C), 135.1, 134.2, 130.1, 130.0, 129.8, 129.3, 128.2 (2 C), 127.9 (2 C),
75.8, 75.0, 73.7, 50.0, 47.0, 46.9, 46.1, 46.0, 41.6, 38.5, 38.3, 37.8,
37.2, 36.6, 35.7, 30.1, 27.4 (3 C), 27.2 (3 C), 26.2 (3 C), 21.0, 19.8,
18.4, 14.2, 9.7, -4.1, -4.3; FAB MS m/z (M+) calcd 856.51, obsd
(M+) calcd 640.3584, obsd 640.3632; [R]22 -50.6 (c 0.33, CH2Cl2).
D
Anal. Calcd for C40H52O5Si‚0.5 H2O: C, 73.92; H, 8.22. Found: C,
73.89; H, 8.26.
(3S,3aR,5aS,7S,8aR,8bS)-2-[(2R,3S,7S)-3-(tert-Butyldiphenylsiloxy)-
7-hydroxy-2-methylnonanoyl]-7-[(6-deoxy-2,3,4-tri-O-methyl-r-L-
mannopyranosyl)oxy]-3,3a,5a,6,7,8,8a,8b-octahydro-as-indacene-3-
acetic Acid K-Lactone (39). To a solution of 38 (40 mg, 0.06 mmol)
and acetylated R-glycoside (23 mg, 0.9 mmol) in anhydrous toluene
(4 mL) at 0 °C under N2 was added trityl perchlorate36 (2 mg, 0.006
mmol). The reaction mixture was stirred at 0 °C for 10 min and at
room temperature for 3 h and poured onto a mixture of ether (25 mL)
and saturated NaHCO3 solution (10 mL). The separated organic layer
was dried and concentrated to leave a residue that was purified by
chromatography on silica gel (elution with ethyl acetate/hexanes 1:3)
to give 39 (44 mg, 85%) as a white solid followed by unreacted 38 (4
mg, 9%). The â-isomer was not detected.
For 39: mp 82-85 °C; IR (film, cm-1) 1720, 1660; 1H NMR (300
MHz, CHCl3) δ 7.71-7.66 (m, 4 H), 7.44-7.33 (m, 6 H), 6.84 (s, 1
H), 5.85 (d, J ) 9.7 Hz, 1 H), 5.75 (dt, J ) 9.7, 2.6 Hz, 1 H), 4.84 (d,
J ) 1.4 Hz, 1 H), 4.60-4.52 (m, 1 H), 4.34-4.27 (m, 1 H), 4.00-
3.95 (m, 1 H), 3.60-3.44 (m, 4 H), 3.56 (s, 3 H), 3.50 (s, 3 H), 3.49
(s, 3 H), 3.36-3.25 (m, 1 H), 3.12 (t, J ) 9.2 Hz, 1 H), 3.05-2.90 (m,
2 H), 2.89-2.83 (m, 1 H), 2.40-2.35 (m, 1 H), 2.33-2.22 (m, 1 H),
2.21-2.10 (m, 1 H), 1.91 (dd, J ) 13.3, 7.0 Hz, 1 H), 1.50-1.26 (m,
9 H), 1.28 (d, J ) 6.2 Hz, 3 H), 1.14 (d, J ) 6.8 Hz, 3 H), 1.07 (s, 9
H), 0.97-0.79 (m, 2 H), 0.75 (t, J ) 7.5 Hz, 3 H); 13C NMR (75
MHz, CHCl3) ppm 203.0, 172.5, 147.2, 143.6, 136.0 (2 C), 135.9 (2
C), 134.4, 133.9, 129.6, 129.5, 129.2, 129.0, 127.5 (2 C), 127.4 (2 C),
95.5, 82.3, 81.0, 77.7, 76.2, 75.5 (2 C), 67.9, 60.9, 59.0, 57.6, 49.4,
48.6, 47.6, 46.3, 41.6, 41.1, 37.5, 36.4, 35.8, 34.4, 30.8, 27.8, 27.1 (3
C), 19.7, 19.6, 18.3, 17.8, 9.3; FAB MS m/z (M+) calcd 829.46, obsd
856.59; [R]22 -24.6 (c 2.1, ethyl acetate).
D
(3S,3aR,5aS,7R,8aR,8bS)-2-[(2R,3S,7S)-3-(tert-Butyldiphenylsiloxy)-
7-hydroxy-2-methylnonanoyl]-3,3a,5,a6,7,8,8a,8b-octahydro-7-hy-
droxy-as-indacene-3-acetic Acid K-Lactone Pivalate (37). A solution
of 36 (22 mg, 0.03 mmol) in a mixture of THF:H2O:AcOH (1:1:3, 4.0
mL) was stirred for 15 min at 0 °C and 24 h at room temperature,
diluted with ethyl acetate (25 mL), dried, concentrated, and azeotro-
pically dried with benzene (2 × 10 mL) to give the corresponding seco
acid, which was dissolved in dry benzene (50 mL), treated with
triethylamine (273 µL, 1.9 mmol), 2,4,6-trichlorobenzoyl chloride (160
µL, 1.0 mmol), and DMAP (31 mg, 0.26 mmol), and stirred vigorously
under N2. After 1.5 h, an additional 31 mg of DMAP was introduced,
and the cloudy white solution was stirred overnight. On the following
day, 31 mg more of DMAP was added and after 3 h the reaction mixture
was diluted with CH2Cl2 (100 mL) and washed with 0.1 M KHSO4
solution. The aqueous layer was extracted with CH2Cl2 (2 × 50 mL),
and the combined organic layers were washed with saturated NaHCO3
solution (30 mL), dried, and concentrated in vacuo. The residue was
purified by chromatography on silica gel (elution with 1:12 ethyl acetate/
hexanes) to furnish 37 as a white solid, mp 162-164 °C (11.0 mg,
59% for two steps); IR (film, cm-1) 1714, 1658; 1H NMR (300 MHz,
CHCl3) δ 7.70-7.65 (m 4 H), 7.44-7.34 (m 6 H), 6.85 (s, 1 H), 5.88
(d, J ) 9.8 Hz, 1 H), 5.78 (dt, J ) 9.8, 2.5 Hz, 1 H), 5.19-5.12 (m,
1 H), 4.61-4.53 (m, 1 H), 4.00-3.96 (m, 1 H), 3.53-3.47 (m, 1 H),
3.35-3.25 (m, 1 H), 3.06-2.96 (m, 2 H), 2.92-2.85 (m, 1 H), 2.48-
2.35 (m, 2 H), 2.23-2.13 (m, 1 H), 1.93 (dd, J ) 13.7, 6.7 Hz, 1 H),
1.57-1.20 (m, 9 H), 1.19 (s, 9 H), 1.14 (d, J ) 6.9 Hz, 3 H), 1.07 (s,
9 H), 1.05-0.84 (m, 2 H), 0.76 (t, J ) 7.5 Hz, 3 H); 13C NMR (75
MHz, CHCl3) ppm 203.0, 178.2, 172.5, 147.1, 143.7, 136.0 (2 C), 135.9
(2 C), 134.4, 133.9, 129.6, 129.5, 129.3, 129.0, 127.5 (2 C), 127.4 (2
C), 75.6 (2 C), 74.8, 49.5, 48.7, 47.6, 46.6, 41.7, 41.4, 38.4, 37.2, 37.1,
35.8, 34.5, 30.8, 27.8, 27.1 (3 C), 27.0 (3 C), 19.7, 19.6, 18.2, 9.4;
829.47; [R]22 -107 (c 0.9, CH2Cl2). Anal. Calcd for C49H68O9Si:
D
C, 70.98; H, 8.27. Found: C, 70.75; H, 8.21.
(3S,3aR,5aS,7R,8aR,8bS)-7-[(6-Deoxy-2,3,4-tri-O-methyl-r-L-man-
nopyranosyl)oxy]-2-[(2R,3S,7S)-3,7-dihydroxy-2-methylnonanoyl]-
3,3a,5a,6,7,8,8a,8b-octahydro-as-indacene-3-acetic Acid K-Lactone
(3). To a solution of 39 (44 mg, 0.05 mmol) in acetonitrile (3.0 mL)
was added 49% aqueous hydrofluoric acid (0.53 mL). The reaction
mixture was stirred for 24 h and diluted with ethyl acetate (25 mL).
The organic phase was washed with saturated NaHCO3 solution (2 ×
10 mL), dried, and concentrated. The residue was purified by
chromatography on silica gel (elution with ethyl acetate/hexanes 1:1)
to give 3 (29 mg, 91%) as a white solid, mp 168-169 °C; [R]22D -163
(c 0.43, CH2Cl2). This material was identical in all respects to authentic
3 described earlier, mp 168.5-170 °C; [R]22D -170 (c 0.45, CH2Cl2).
Spinosyn A (1). A cold (-50 °C), magnetically stirred solution of
triphenylphosphine (2.03 g, 7.7 mmol) in anhydrous THF (10 mL) was
(36) Dauben, H. J., Jr.; Honnen, L. R.; Harmon, K. M. J. Org. Chem.
1960, 25, 1442.