Total Syntheses of Amphidinolides
FULL PAPER
Enyne metathesis reactions and elaboration of the macrocyclic cores
(30), 359 (18), 279 (11), 267 (11), 251 (20), 233 (15), 207 (13), 183 (27),
159 (19), 131 (24), 117 (14), 89 (15), 75 (58), 73 (100); HRMS (ESI): m/z:
calcd for C30H52O5Si2Na [M++Na]: 571.3249, found: 571.3246; elemental
analysis calcd (%) for C30H52O5Si2 (548.90): C 65.64, H 9.55; found: C
65.48, H 9.60.
(1S,4R,13R,14R)-13-(tert-Butyldimethylsilyloxy)-4-((tert-butyldimethylsi-
lyloxy)methyl)-2,9,10,12-tetramethylene-5,15-dioxabicyclo-
ACHTUNGTRENNUNG[12.1.0]pentadecan-6-one (29): A solution of 27 (484 mg, 0.929 mmol)
and catalyst 28 (79 mg, 0.092 mmol) in toluene (16 mL) was stirred at
458C under an atmosphere of ethylene (1.8 atm) for 14 h. Ethyl vinyl
ether (4 drops) was added and the mixture stirred for 10 min before the
solvent was evaporated. Purification of the residue by flash chromatogra-
phy (hexanes/ethyl acetate 70:1) furnished product 29 as a colorless oil
(356 mg, 70%). [a]D20 =+5 (CHCl3, c=0.27); 1H NMR (CDCl3,
400 MHz): d=0.02 (s, 3H), 0.03 (s, 3H), 0.09 (s, 3H), 0.16 (s, 3H), 0.87
(s, 9H), 0.96 (s, 9H), 2.34 (dd, J=2.8, 14.4 Hz, 1H), 2.43–2.46 (m, 2H),
2.52 (dd, J=6.1, 14.6 Hz, 1H), 2.56–2.63 (m, 1H), 2.71–2.77 (m, 1H),
2.75 (dd, J=2.1, 7.5 Hz, 1H), 3.03 (d, J=16.6 Hz, 1H), 3.21 (d, J=
16.6 Hz, 1H), 3.34 (d, J=1.3 Hz, 1H), 3.55 (dd, J=6.6, 10.4 Hz, 1H),
3.62 (dd, J=5.9, 10.3 Hz, 1H), 3.88 (d, J=7.5 Hz, 1H), 4.94 (s, 1H), 4.98
(s, 1H), 5.00–5.05 (m, 1H), 5.03 (s, 1H), 5.10 (s, 1H), 5.12 (s, 1H), 5.13
(s, 1H), 5.21 (s, 1H), 5.48 ppm (s, 1H); 13C NMR (CDCl3, 100.6 MHz):
d=ꢀ5.4 (CH3), ꢀ5.4 (CH3), ꢀ4.9 (CH3), ꢀ4.4 (CH3), 18.1 (C), 18.3 (C),
25.7 (CH3), 25.8 (CH3), 30.7 (CH2), 33.7 (CH2), 35.5 (CH2), 38.7 (CH2),
57.3 (CH), 62.5 (CH2), 64.1 (CH), 73.6 (CH), 74.8 (CH), 112.7 (CH2),
114.2 (CH2), 114.6 (CH2), 115.4 (CH2), 140.7 (C), 142.7 (C), 144.6 (C),
145.0 (C), 172.1 ppm (C); IR (film): n˜ =2954, 2929, 2857, 1741, 1648,
1598, 1472, 1463, 1436, 1389, 1361, 1251, 1156, 1102, 1059, 1004, 910, 834,
775, 669 cmꢀ1; MS (EI): m/z (%): 548 (2) [M+], 491 (18), 359 (17), 267
(10), 251 (17), 233 (12), 227 (11), 207 (14), 183 (28), 159 (18), 147 (10),
131 (26), 117 (16), 91 (10), 89 (15), 75 (64), 73 (100); HRMS (ESI): m/z:
calcd for C30H52O5Si2Na [M++Na]: 571.3246, found: 571.3245.
(1R,4S,13R,14S)-13-(tert-Butyldimethylsilyloxy)-4-((tert-butyldimethylsi-
lyloxy)methyl)-2,9,10,12-tetramethylene-5,15-dioxabicyclo-
AHCTUNGERTG[NNUN 12.1.0]pentadecan-6-one (54): Prepared analogously from 53 (0.252 g,
0.483 mmol) as a colorless oil (0.193 g, 73%). [a]2D0 =ꢀ56 (CHCl3, c=
0.5); 1H NMR (400 MHz, CDCl3): d=0.03 (s, 3H), 0.03 (s, 3H), 0.04 (s,
3H), 0.06 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 2.30–2.49 (m, 6H), 2.85 (t,
J=2.0 Hz, 1H), 2.93 (d, J=17.2 Hz, 1H), 3.08 (d, J=16.8 Hz, 1H), 3.45
(d, J=1.8 Hz, 1H), 3.57 (dd, J=6.1, 10.4 Hz, 1H), 3.65 (dd, J=5.2,
10.5 Hz, 1H), 4.33 (m, 1H), 4.89–4.97 (m, 1H), 4.89 (s, 2H), 4.97 (s, 1H),
4.98 (s, 1H), 5.03 (s, 1H), 5.15 (s, 1H), 5.20 (s, 1H), 5.24 ppm (s, 1H);
13C NMR (100.6 MHz, CDCl3): d=ꢀ5.4 (CH3), ꢀ5.3 (CH3), ꢀ5.0 (CH3),
18.1 (C), 18.2 (C), 25.7 (CH3), 25.7 (CH3), 30.3 (CH2), 33.5 (CH2), 33.8
(CH2), 36.7 (CH2), 55.9 (CH), 63.2 (CH2), 63.2 (CH), 74.0 (CH), 74.2
(CH), 112.9 (CH2), 114.7 (CH2), 114.9 (CH2), 115.2 (CH2), 141.4 (C),
144.9 (C), 146.1 (C), 147.2 (C), 172.3 ppm (C); IR (film): n˜ =2954, 2929,
2857, 1739, 1646, 1472, 1463, 1361, 1251, 1122, 1101, 1005, 902, 833, 774,
671 cmꢀ1; MS (EI): m/z (%): 548 (2) [M+], 491 (14), 359 (11), 207 (12),
183 (20), 159 (12), 131 (16), 117 (16), 89 (15), 75 (60), 73 (100); HRMS
(ESI): m/z: calcd for C30H52O5Si2Na [M++Na]: 571.3246; found:
571.3252; elemental analysis calcd (%) for C30H52O5Si2 (548.3): C 65.64,
H 9.55; found: C 65.56, H 9.50.
(1S,4R,13R,14R)-13-(tert-Butyldimethylsilyloxy)-4-(hydroxymethyl)-
2,9,10,12-tetramethylene-5,15-dioxabicycloACTHNUTRGNEU[GN 12.1.0]pentadecan-6-one (30):
(1S,4S,13R,14R)-13-(tert-Butyldimethylsilyloxy)-4-((tert-butyldimethylsi-
lyloxy)methyl)-2,9,10,12-tetramethylene-5,15-dioxabicyclo-
ACHTUNGTRENNUNG[12.1.0]pentadecan-6-one (38): Prepared analogously from 37 (0.13 g,
PPTS (91 mg, 0.364 mmol) was added to a solution of 29 (100 mg,
0.182 mmol) in MeOH (9 mL) at 08C and the resulting mixture was
stirred for 20 h. Triethylamine (4 drops) was introduced before all vola-
tile materials were evaporated (308C) and the residue was purified by
flash chromatography (hexanes/ethyl acetate 8:1) to give alcohol 30 as a
colorless oil (62 mg, 78%) as well as a second fraction consisting of un-
reacted started material 30 (9 mg). [a]2D0 =ꢀ10 (CHCl3, c=0.26);
1H NMR (CDCl3, 400 MHz): d=0.09 (s, 3H), 0.15 (s, 3H), 0.95 (s, 9H),
1.90 (brs, 1H), 2.38 (dd, J=2.7, 14.6 Hz, 1H), 2.46–2.64 (m, 4H), 2.74–
2.79 (m, 1H), 2.75 (dd, J=2.1, 7.6 Hz, 1H), 3.02 (d, J=16.6 Hz, 1H),
3.21 (d, J=16.6 Hz, 1H), 3.36 (d, J=1.3 Hz, 1H), 3.67 (brs, 2H), 3.87 (d,
J=7.6 Hz, 1H), 4.94 (s, 1H), 4.99 (s, 1H), 5.02 (s, 1H), 5.05–5.11 (m,
1H), 5.11 (s, 1H), 5.13 (s, 1H), 5.14 (s, 1H), 5.22 (s, 1H), 5.49 ppm (s,
1H); 13C NMR (CDCl3, 100.6 MHz): d=ꢀ4.9 (CH3), ꢀ4.4 (CH3), 18.3
(C), 25.8 (CH3), 30.7 (CH2), 33.7 (CH2), 36.0 (CH2), 38.6 (CH2), 57.1
(CH), 63.8 (CH2), 64.1 (CH), 74.4 (CH), 75.0 (CH), 112.8 (CH2), 114.1
(CH2), 114.7 (CH2), 115.6 (CH2), 140.9 (C), 142.5 (C), 144.5 (C), 145.0
(C), 173.1 ppm (C); IR (film): n˜ =3456, 2954, 2929, 2857, 1735, 1648,
1597, 1471, 1463, 1388, 1361, 1249, 1157, 1111, 1057, 1005, 906, 835, 776,
671 cmꢀ1; MS (EI): m/z (%): 434 (<1) [M+], 251 (17), 233 (15), 207 (12),
183 (31), 177 (19), 159 (22), 131 (41), 117 (15), 113 (12), 109 (13), 105
(13), 91 (19), 81 (16), 79 (12), 75 (100), 73 (50), 59 (10), 57 (15), 55 (11),
43 (11); HRMS (ESI): m/z: calcd for C24H38O5SiNa [M++Na]: 457.2382,
found: 457.2380.
0.25 mmol) as a colorless oil (0.132 g, 96%). [a]2D0 =ꢀ55 (CHCl3, c=
0.65); 1H NMR (400 MHz, CDCl3): d=0.03 (s, 3H), 0.04 (s, 3H), 0.07 (s,
3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.93 (s, 9H), 2.01 (dd, J=11.7, 15.3 Hz,
1H), 2.14 (d, J=15.3 Hz, 1H), 2.27–2.38 (m, 4H), 3.04 (s, 2H), 3.16 (dd,
J=2.0, 7.3 Hz, 1H), 3.21 (d, J=2.0 Hz, 1H), 3.57–3.65 (m, 2H), 3.73 (d,
J=7.3 Hz, 1H), 4.81 (s, 1H), 4.88 (s, 1H), 4.99 (s, 1H), 5.04–5.10 (m,
1H), 5.07 (s, 1H), 5.18 (s, 1H), 5.24 (s, 1H), 5.33 ppm (s, 2H); 13C NMR
(100.6 MHz, CDCl3): d=ꢀ5.4 (CH3), ꢀ5.0 (CH3), ꢀ4.7 (CH3), 18.1 (C),
18.2 (C), 25.7 (CH3), 25.7 (CH3), 27.7 (CH2), 30.5 (CH2), 34.5 (CH2), 36.7
(CH2), 59.5 (CH), 59.7 (CH), 64.1 (CH2), 74.1 (CH), 80.1 (CH), 112.4
(CH2), 113.0 (CH2), 115.8 (CH2), 117.4 (CH2), 141.1 (C), 144.4 (C), 146.5
(C), 146.7 (C), 172.4 ppm (C); IR (film): n˜ =3083, 2955, 2929, 2895, 2857,
1739, 1643, 1598, 1472, 1463, 1443, 1389, 1361, 1257, 1129, 1092, 1061,
902, 838, 778, 669 cmꢀ1; MS (EI): m/z (%): 548 (2) [M+], 492 (12), 491
(30), 359 (18), 279 (11), 267 (11), 251 (20), 233 (15), 207 (13), 183 (27),
159 (19), 131 (24), 117 (14), 89 (15), 75 (58), 73 (100); HRMS (ESI): m/z:
calcd for C30H52O5Si2Na [M++Na]: 571.3246, found: 571.3246; elemental
analysis calcd (%) for C30H52O5Si2 (548.90): C 65.64, H 9.55; found: C
65.48, H 9.47.
(1S,4S,13S,14R)-13-(tert-Butyldimethylsilyloxy)-4-((tert-butyldimethylsi-
lyloxy)methyl)-2,9,10,12-tetramethylene-5,15-dioxabicyclo-
A
(1S,4S,13R,14R)-13-(tert-Butyldimethylsilyloxy)-4-(hydroxymethyl)-
0.33 mmol) as a colorless oil (0.166 g, 92%). [a]2D0 =+19.2 (CHCl3, c=
0.6); 1H NMR (400 MHz, CDCl3): d=0.02 (s, 3H), 0.03 (s, 3H), 0.05 (s,
3H), 0.07 (s, 3H), 0.87 (s, 9H), 0.89 (s, 9H), 1.99 (ddd, J=1.5, 11.7,
15.3 Hz, 1H), 2.16 (ddt, J=2.0, 3.0, 15.3 Hz, 1H), 2.28–2.35 (m, 4H), 2.93
(s, 2H), 3.03 (dd, J=2.0, 1.6 Hz, 1H), 3.57 (dd, J=5.4, 10.5 Hz, 1H), 3.58
(d, J=2.1 Hz, 1H), 3.63 (dd, J=4.6, 10.5 Hz, 1H), 4.53 (s, 1H), 4.78 (s,
1H), 4.91 (s, 1H), 4.94 (s, 1H), 5.02–5.07 (m, 1H), 5.13 (s, 1H), 5.19 (s,
1H), 5.24 (s, 1H), 5.32 (s, 1H), 5.40 ppm (s, 1H); 13C NMR (100.6 MHz,
CDCl3): d=ꢀ5.4 (CH3), ꢀ5.4 (CH3), ꢀ5.1 (CH3), ꢀ5.0 (CH3), 18.1 (C),
18.3 (C), 25.7 (CH3), 25.7 (CH3), 27.7 (CH2), 29.9 (CH2), 34.0 (CH2), 36.1
(CH2), 56.1 (CH), 58.2 (CH), 64.2 (CH2), 73.4 (CH), 74.4 (CH), 111.7
(CH2), 113.1 (CH2), 115.5 (CH2), 117.3 (CH2), 141.8 (C), 145.1 (C), 146.3
(C), 146.9 (C), 172.4 ppm (C); IR (film): n˜ =3083, 2955, 2929, 2895, 2857,
1739, 1643, 1598, 1472, 1463, 1443, 1389, 1361, 1257, 1129, 1092, 1061,
902, 838, 778, 669 cmꢀ1; MS (EI): m/z (%): 548 (2) [M+], 492 (12), 491
2,9,10,12-tetramethylene-5,15-dioxabicycloACTHNGUTERN[UNG 12.1.0]pentadecan-6-one (39):
Prepared analogously from 38 (85 mg, 0.155 mmol) as a colorless oil
(43 mg, 64%). [a]2D0 =ꢀ35.2 (CHCl3, c=0.7); 1H NMR (400 MHz,
CDCl3): d=0.07 (s, 3H), 0.12 (s, 3H), 0.93 (s, 9H), 1.98 (dd, J=11.6,
15.4 Hz, 1H), 2.13 (d, J=15.6 Hz, 1H), 2.29–2.43 (m, 4H), 3.04 (s, 2H),
3.14 (dd, J=2.1, 7.3 Hz, 1H), 3.23 (d, J=2.1 Hz, 1H), 3.60–3.65 (m, 1H),
3.70–3.75 (m, 1H), 3.74 (d, J=7.3 Hz, 1H), 4.82 (s, 1H), 4.89 (s, 1H),
5.00 (s, 1H), 5.09–5.15 (m, 1H), 5.10 (s, 1H), 5.19 (s, 1H), 5.25 (s, 1H),
5.33 (s, 1H), 5.36 ppm (s, 1H); 13C NMR (100.6 MHz, CDCl3): d=ꢀ5.0
(CH3), ꢀ4.6 (CH3), 18.3 (C), 25.8 (CH3), 28.2 (CH2), 30.5 (CH2), 34.4
(CH2), 36.8 (CH2), 59.5 (CH), 59.6 (CH), 65.1 (CH2), 75.4 (CH), 79.8
(CH), 112.5 (CH2), 113.2 (CH2), 115.9 (CH2), 117.6 (CH2), 140.7 (C),
144.3 (C), 146.3 (C), 146.5 (C), 173.4 ppm (C); IR (film): n˜ =3456, 3082,
2954, 2929, 2895, 2857, 1736, 1641, 1598, 1472, 1462, 1443, 1389, 1361,
1252, 1093, 1060, 901, 838, 779, 670 cmꢀ1; MS (EI): m/z (%): 377 (5), 279
Chem. Eur. J. 2009, 15, 4011 – 4029
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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