Total Synthesis of (+)-Acutiphycin
Stereochemistry is unassigned, dr >10:1. [R]D -16.1 (c 0.4, 21 °C,
(bm, 2H), 1.37 (q, J ) 11.5 Hz, 1H), 1.32-1.20 (bm, 9H), 1.05 (s,
9H), 1.01 (d, J ) 7.0 Hz, 3H), 0.99 (s, 3H), 0.89 (s, 3H), 0.88 (t,
J ) 7.0 Hz, 3H); 13C (125.8 MHz, CDCl3) δ 169.7, 136.4, 136.4,
135.1, 135.0, 132.1, 130.4, 130.3, 128.5, 128.3, 128.3, 126.4, 100.4,
83.4, 80.4, 77.9, 75.3, 75.1, 67.1, 49.6, 44.5, 44.3, 43.7, 39.1, 35.0,
34.4, 32.4, 31.9, 30.4, 27.6, 25.8, 24.6, 23.2, 21.9, 20.7, 19.8, 14.8,
14.7, 13.5, 13.4; HRMS m/z (ESI, M + Na+) calcd 757.4470, found
757.4464.
CHCl3); IR 3365 (bm), 2929 (s), 2857 (s), 2226 (s), 1717 (w), 1654
1
(m), 1471 (m), 1428 (m), 1111 (s), 1008 (s), 703 (s); H NMR
(500 MHz, CDCl3) δ 7.72 (m, 4H), 7.45 (m, 2H), 7.40 (m, 4H),
5.50 (d, J ) 10.5 Hz, 1H), 5.46 (t, J ) 7.0 Hz, 1H), 4.46 (apparent
quint, J ) 5.5 Hz, 1H), 4.25 (q, J ) 7.0, 2H), 4.16 (d, J ) 9.0 Hz,
1H), 3.99 (s, 1H), 3.66 (m, 1H), 3.50 (d, J ) 2.0 Hz, 1H), 3.01
(bs, 1H), 2.82 (dd, J ) 15.0, 7.5 Hz, 1H), 2.72 (dd, J ) 15.0, 6.0
Hz, 1H), 2.65 (m, 1H), 2.48 (d, J ) 2.5 Hz, 1H), 2.23 (t, J ) 7.0
Hz, 2H), 1.75 (m, 1H), 1.69 (s, 3H), 1.50-1.40 (bm, 8H), 1.35-
1.25 (bm, 9H), 1.06 (s, 9H), 0.98 (d, J ) 7.0 Hz, 3H), 0.92 (s,
3H), 0.90 (t, J ) 7.0 Hz, 3H), 0.72 (s, 3H); 13C (125.8 MHz, CDCl3)
δ 185.4, 138.7, 136.2, 136.2, 135.6, 133.5, 133.4, 130.1, 130.1,
127.9, 127.9, 127.0, 125.7, 103.6, 86.9, 84.3, 77.6, 74.0, 71.9, 69.2,
52.2, 45.3, 42.7, 41.3, 37.3, 36.0, 34.1, 32.1, 29.9, 27.1, 25.6, 22.9,
20.6, 19.5, 15.9, 15.2, 14.6, 14.3, 11.9; HRMS m/z (ESI, M + Na+)
calcd 771.4627, found 771.4639.
(+)-Acutiphycin (1). Compound 49 (3.9 mg, 5.4 µmol) was
dissolved in THF (2.1 mL) and treated with 980 µL of TBAF/
HOAc solution (TBAF 1 M THF, 2.5 mL; acetic acid 0.15 mL).
The reaction was stirred at room temperature for 52 h, diluted with
ethyl acetate, washed with sodium bicarbonate (2×) and brine, dried
over magnesium sulfate, filtered, concentrated, and purified by silica
gel chromatography (3:2 diethyl ether/hexanes) to give 1 as a white
solid (2.4 mg, 92%). mp 150-151 °C; [R]D +151.6 (c 0.095, 21 °C,
CH2Cl2); IR (solution in CDCl3) 3608 (m), 3457 (bw), 2985 (s),
2932 (m), 2902 (s), 1702 (m), 1643 (m), 1562 (m), 1298 (m), 1261
(-)-Macrocycle, Hemi-ketal (45). Dry (azeotroped with anhy-
drous toluene) 47 (13 mg, 17.4 µmol) in dry xylenes (24 mL) was
added dropwise over 5 h to refluxing (150 °C) xylenes (48 mL)
and tri-n-butylamine (48 µL, 0.20 mmol). The reaction was stirred
for an additional 20 min after the slow addition was complete, then
poured into a separation funnel containing ice, and diluted with
ethyl acetate. The organic layer was washed with 0.1 M NaHSO4
and brine, dried over magnesium sulfate, filtered, concentrated, and
purified by silica gel chromatography (20:1 hexanes/ethyl acetate
f 4:1 hexanes/ethyl acetate) to give 11.3 mg (90%) of 45 as a
single diastereomer. [R]D -8.1 (c 0.19, 21 °C, CHCl3); IR 3452
(bm), 2929 (s), 2858 (s), 1710 (m), 1428 (m), 1378 (m), 1208 (s),
1
(m), 1216 (s), 1167 (s); H NMR (500 MHz, CDCl3) δ 5.39 (d, J
) 2.4 Hz, 1H), 5.29 (m, 2H), 4.98 (m, 1H), 4.64 (d, J ) 3.8 Hz,
1H), 4.33 (dd, J ) 12.0, 2.1 Hz, 1H), 4.28 (m, 1H), 4.95 (m, 1H),
2.67 (d, J ) 14.6 Hz, 1H), 2.62 (d, J ) 14.6 Hz, 1H), 2.42 (ddd,
J ) 15.1, 10.7, 1.9 Hz, 1H), 2.18 (ddd, J ) 11.9, 4.6, 1.3 Hz, 1H),
2.10 (apparent t, J ) 13.6 Hz, 1H), 1.89 (dt, Jd ) 12.2, Jt ) 2.2
Hz, 1H), 1.78 (d, J ) 1.3 Hz, 3H), 1.67 (s, 3H), 1.61-1.51 (m,
3H), 1.33-1.24 (m, 9H), 1.12 (s, 3H), 1.05 (d, J ) 6.6 Hz, 3H),
1
0.89 (s, 3H), 0.88 (t, J ) 6.9 Hz, 3H); H NMR (500 MHz, 1:1
C6D6/CDCl3) δ 5.37 (bs, 1H), 5.21 (d, J ) 10.4 Hz, 1H0, 5.16 (d,
J ) 11.2 Hz, 1H), 4.91 (m, 1H), 4.52 (s, 1H), 4.18 (d, J ) 11.9
Hz, 1H), 4.01 (tt, J ) 11.1, 4.3 Hz, 1H), 3.87 (m, 1H), 2.42 (d, J
) 14.4 Hz, 1H), 2.29 (d, J ) 14.4 Hz, 1H), 2.20 (ddd, J ) 14.9,
10.7, 1.8 Hz, 1H), 1.97 (d, J ) 12.8 Hz, 1H), 1.91 (m, 1H), 1.63
(s, 3H), 1.54 (m, 1H), 1.44 (s, 3H), 1.30 (m, 1H), 1.22-1.10 (m,
11H), 1.04 (m, 3H), 1.00 (dt, Jd ) 2.2, Jt ) 11.5 Hz, 1H), 0.85 (s,
3H), 0.82 (m, 3H); 13C (125.8 MHz, CDCl3) δ 215.7, 172.6, 135.1,
135.0, 131.1, 126.6, 96.8, 79.9, 76.1, 74.4, 64.7, 52.8, 44.8, 43.9,
43.3, 38.2, 35.5, 32.9, 31.8, 25.8, 25.2, 22.7, 19.3, 16.3, 14.2, 13.1,
11.3; 13C (125.8 MHz, DMSO-d6) δ 214.5, 170.9, 136.2, 134.9,
128.0, 123.6, 96.2, 77.3, 74.1, 73.8, 62.7, 53.1, 45.9, 43.5, 41.3,
38.2, 34.4, 31.7, 31.0, 24.4, 23.3, 22.0, 20.7, 16.7, 13.9, 12.9, 11.9;
HRMS m/z (ESI, M + Na+) calcd 503.2979, found 503.2987.
1
1112 (s), 1058 (s), 998 (s), 702 (s); H NMR (500 MHz, CDCl3)
δ 7.67 (m, 4H), 7.43 (m, 2H), 7.38 (apparent t, J ) 7.5 Hz, 4H),
5.42 (d, J ) 10.5 Hz, 1H), 5.17 (d, J ) 10.0 Hz, 1H) 5.12 (d, J )
2.0 Hz, 1H), 4.92 (m, 1H), 4.29 (apparent sept, J ) 5.0 Hz, 1H),
4.12 (dd, J ) 12.0, 2.0 Hz, 1H), 3.92 (s, 1H), 3.56 (s, 1H), 2.88
(m, 1H), 2.55 (d, J ) 14.0 Hz, 1H), 2.47 (d, J ) 14.0 Hz, 1H),
2.37 (m, 1H), 2.04 (d, J ) 14.0 Hz, 1H), 1.99 (dd, J ) 12.0, 3.5
Hz, 1H), 1.71 (m, 1H), 1.66 (s, 3H), 1.62 (d, J ) 1.0 Hz, 3H),
1.55-1.48 (bm, 2H), 1.40-1.32 (bm, 2H), 1.30-1.23 (bm, 8H),
1.06 (s, 9H), 1.01 (d, J ) 7.0 Hz, 3H), 0.99 (s, 3H), 0.87 (t, J )
7.0 Hz, 3H), 0.64 (s, 3H); 13C (125.8 MHz, CDCl3) δ 172.4, 136.3,
135.9, 134.5, 131.9, 131.4, 129.8, 129.8, 127.8, 127.8, 96.6, 81.2,
79.8, 76.5, 74.4, 66.5, 44.8, 44.2, 43.3, 38.6, 35.8, 34.1, 32.8, 31.8,
27.2, 25.1, 22.7, 22.2, 19.4, 19.4, 18.8, 14.2, 13.0, 11.1; HRMS
m/z (ESI, M + Na+) calcd 743.4314, found 743.4334.
(+)-Macrocycle, Methyl-ketal (43). Compound 45 (11.3 mg,
15.7 µmol), citric acid (3.8 mg, 19.8 µmol), and methanol (30 mL)
were combined in a sealed tube and then heated to 75 °C overnight.
The crude mixture was concentrated and purified by chromatog-
raphy (20:1 hexanes/ethyl acetate f 4:1 hexanes/ethyl acetate) to
give 11.5 mg (100%) of 43. [R]D +15.2 (c 0.083, 22 °C, CHCl3);
IR 3447 (bm), 2926 (s), 2855 (s), 1725 (m), 1462 (m), 1378 (m),
1201 (m), 1113 (s), 1063 (s), 702 (s); 1H NMR (500 MHz, CDCl3)
δ 7.67 (d, J ) 7.0 Hz, 4H), 7.44 (m, 2H), 7.38 (m, 4H), 5.63 (t, J
) 7.0 Hz, 1H), 5.50 (d, J ) 10.5 Hz, 1H), 4.78 (m, 1H), 4.17 (s,
1H), 4.12 (m, 1H), 3.76 (d, J ) 11.5 Hz, 1H), 3.41 (d, J ) 6.5 Hz,
1H), 2.98 (s, 3H), 2.86 (m, 1H), 2.74 (d, J ) 13.5 Hz, 1H), 2.46
(d, J ) 13.5 Hz, 1H), 2.44 (m, 1H), 2.20 (m, 1H), 2.01 (dd, J )
7.5, 4.5 Hz, 1H), 1.77 (m, 1H), 1.71 (s, 3H), 1.66 (m, 3H), 1.49
Acknowledgment. This work was supported by the National
Institute of General Medical Sciences (GM-063755). We thank
Dr. Karen Miller-Moslin for thoughtful discussions on 1,6-enyne
reductive coupling reactions. We are grateful to Dr. Li Li for
obtaining mass spectrometric data for all compounds and to Dr.
Peter Mu¨ller for obtaining crystal structures of 27 and 49.
Supporting Information Available: Experimental procedures
and spectral data for 1, 3, 5, 6, 9, 10, 13, 18, 19, 21-25, 27, 29,
31, 36, 39-41, 45, 47, and 49 as well as all unknown (with the
exception of the diastereomeric mixture of â-hydroxy ketones
resulting from the Reformatsky reaction depicted in Scheme 18)
intermediates en route to the successful total synthesis of 1. X-ray
data (CIF) for 27 and 49. This material is available free of charge
JO701821H
J. Org. Chem, Vol. 72, No. 25, 2007 9745