New Marine Resorcylic Macrolides
J . Org. Chem., Vol. 67, No. 5, 2002 1565
306 (3.82) nm; IR (KBr) νmax 3419, 1646, 1615, 1575, 1318,
1257, 1204, 1160, 1041, 966 cm-1; MS (ESI-TOF) m/z 365 [M
+ H]+, 347, 288; HRMS (ESI-TOF) m/z [M + H]+ 365.1617
(calcd for C19H25O7, 365.1600); 1H and 13C NMR data, see
Tables 1 and 2.
Hz, H-3′a), 1.57 (1H, ddd, J ) 14.0, 11.6, 8.8 Hz, H-3′b), 1.45
(3H, s, acetonide), 1.42 (3H, s, acetonide), 1.40 (3H, d, J ) 6.5
Hz, 10′-CH3).
Aceton id e 11. Colorless amorphous solid: IR (KBr) νmax
3484, 1723, 1606, 1460, 1261, 1160, 1043 cm-1; HRMS (ESI-
TOF) m/z [M + H]+ 435.2034 (calcd for C23H31O8, 435.2019);
1H NMR (CDCl3, 400 MHz) δ 6.39 (2H, brs, H-3 and H-5), 5.97
(1H, ddd, J ) 16.0, 6.5, 6.1 Hz, H-8′), 5.68 (1H, dd, J ) 16.0,
7.2 Hz, H-7′), 5.41 (1H, m, H-10′), 4.27 (1H, m, H-4′), 4.13 (1H,
dd, J ) 9.5, 7.2 Hz, H-6′), 4.07 (1H, dd, J ) 9.6, 5.0 Hz, H-5′),
3.88 (1H, d, J ) 1.7 Hz, H-1′), 3.81 (3H, s, 2-OCH3 or 4-OCH3),
3.79 (3H, s, 4-OCH3 or 2-OCH3), 2.87 (1H, m, H-2′), 2.68 (1H,
brs, 6′-OH), 2.48 (1H, m, H-9′a), 2.42 (1H, m, H-9′b), 2.02 (1H,
m, H-3′a), 1.98 (1H, m, H-3′b), 1.49 (3H, s, acetonide), 1.39
(3H, d, J ) 6.4 Hz, 10′-CH3), 1.37 (3H, s, acetonide).
Aceton id e 12. Colorless powder: HRMS (ESI-TOF) m/z [M
+ H]+ 419.1724 (calcd for C22H27O8, 419.1706); 1H NMR
(CDCl3, 400 MHz) δ 11.76 (1H, s, 2-OH), 6.96 (1H, ddd, J )
16.4, 7.2, 7.1 Hz, H-8′), 6.50 (1H, d, J ) 2.6 Hz, H-5), 6.42
(1H, d, J ) 2.6 Hz, H-3), 6.27 (1H, d, J ) 16.4 Hz, H-7′), 5.55
(1H, m, H-10′), 4.97 (1H, d, J ) 6.3 Hz, H-5′), 4.54 (1H, ddd,
J ) 6.4, 6.4, 5.4 Hz, H-4′), 4.34 (1H, d, J ) 1.6 Hz, H-1′), 3.80
(3H, s, 4-OCH3), 2.83 (1H, m, H-9′a), 2.66 (1H, m, H-2′), 2.61
(1H, m, H-9′b), 2.14 (1H, m, H-3′a), 1.80 (1H, ddd, J ) 15.1,
7.0, 6.8 Hz, H-3′b), 1.63 (3H, s, acetonide), 1.46 (3H, d, J )
6.5 Hz, 10′-CH3), 1.39 (3H, s, acetonide).
Aceton id e 13. Colorless powder: HRMS (ESI-TOF) m/z [M
+ H]+ 419.2007 (calcd for C23H31O7, 419.1992); 1H NMR
(CDCl3, 400 MHz) δ 6.41 (1H, d, J ) 2.3 Hz, H-3), 6.30 (1H, d,
J ) 2.3 Hz, H-5), 6.01 (1H, ddd, J ) 15.7, 7.3, 4.7 Hz, H-8′),
5.71 (1H, dd, J ) 15.8, 6.7 Hz, H-7′), 5.61 (1H, m, H-10′), 4.01
(1H, dd, J ) 7.5, 7.3 Hz, H-6′), 3.85 (1H, d, J ) 1.7 Hz, H-1′),
3.81 (3H, s, 2-OCH3), 3.79 (3H, s, 4-OCH3), 3.72 (1H, ddd, J )
8.1, 8.1, 4.8 Hz, H-5′), 2.84 (1H, ddd, J ) 6.9, 2.2, 2.1 Hz, H-2′),
2.48 (1H, m, H-9′a), 2.40 (1H, m, H-9′b), 2.17 (1H, m, H-3′a),
1.94 (1H, m, H-4′a), 1.73 (1H, m, H-4′b), 1.55 (1H, m, H-3′b),
1.43 (3H, s, acetonide), 1.41 (3H, s, acetonide), 1.37 (3H, d, J
) 6.3 Hz, 10′-CH3).
Aceton id e 17. Colorless powder: HRMS (ESI-TOF) m/z [M
+ H]+ 403.2126 (calcd for C23H31O6, 403.2120); 1H NMR
(CDCl3, 400 MHz) δ 6.56 (1H, d, J ) 1.9 Hz, H-5), 6.35 (1H, d,
J ) 1.9 Hz, H-3), 6.26 (1H, d, J ) 15.4 Hz, H-1′), 6.14 (1H,
ddd, J ) 15.3, 9.9, 4.2 Hz, H-2′), 5.73 (1H, ddd, J ) 15.2, 9.3,
3.5 Hz, H-8′), 5.59 (1H, ddd, J ) 15.2, 9.6, 1.6 Hz, H-7′), 5.32
(1H, m, H-10′), 4.57 (1H, dd, J ) 9.6, 5.4 Hz, H-6′), 4.19 (1H,
ddd, J ) 11.6, 5.3, 3.1 Hz, H-5′), 3.82 (3H, s, 2-OCH3), 3.79
(3H, s, 4-OCH3), 2.51 (1H, m, H-9′a), 2.47 (1H, m, H-9′b), 2.30
(1H, m, H-3′a), 2.10 (1H, m, H-4′a), 1.82 (1H, m, H-3′a), 1.53
(1H, m, H-4′b), 1.47 (3H, s, acetonide), 1.36 (3H, d, J ) 6.1
Hz, 10′-CH3), 1.35 (3H, s, acetonide).
Aceton id e 18. Colorless powder: HRMS (ESI-TOF) m/z [M
+ H]+ 403.2134 (calcd for C23H31O6, 403.2120); 1H NMR
(CDCl3, 400 MHz) δ 6.47 (1H, d, J ) 11.5 Hz, H-1′), 6.36 (1H,
d, J ) 2.0 Hz, H-3), 6.29 (1H, d, J ) 1.8 Hz, H-5), 5.74 (1H,
ddd, J ) 11.1, 11.0, 5.5 Hz, H-2′), 5.57 (1H, ddd, J ) 15.4, 9.8,
3.9 Hz, H-8′), 5.43 (1H, ddd, J ) 15.3, 9.1, 1.0 Hz, H-7′), 5.20
(1H, m, H-10′), 4.49 (1H, dd, J ) 9.0, 5.8 Hz, H-6′), 4.15 (1H,
ddd, J ) 8.0, 5.5, 4.3 Hz, H-5′), 3.81 (6H, s, 2-OCH3 and
4-OCH3), 2.63 (1H, m, H-3′a), 2.42 (1H, m, H-9′a), 2.33 (1H,
m, H-9′b), 1.96 (1H, m, H-3′b), 1.64 (1H, m, H-4′a), 1.55 (1H,
m, H-4′b), 1.43 (3H, s, acetonide), 1.37 (3H, d, J ) 6.3 Hz, 10′-
CH3), 1.35 (3H, s, acetonide).
Syn th esis of Com p ou n d 16. To a solution of aigialomycin
C (4; 3.0 mg) in pyridine (0.3 mL) was added excess p-
bromobenzoyl chloride (10 mg), and the mixture was stirred
at room temperature for 2 days. After the usual aqueous
workup, the crude mixture was subjected to preparative HPLC
(reversed-phase column; MeCN/H2O ) 80:20, then 100:0) to
obtain the triester 14 (4.6 mg). This product was treated in
aq K2CO3 (0.2 mL)/dioxane (0.4 mL)/MeOH (0.2 mL) for 6 h
and then concentrated in vacuo. Standard aqueous workup and
purification by column chromatography on silica gel (CH2Cl2)
afforded compound 15 (3.0 mg). A portion of 15 (1.0 mg) was
treated with 3,5-dinitrobenzoyl chloride (10 mg) in pyridine
(0.15 mL) for 2 days. The usual aqueous workup and subse-
Aigia lom ycin D (5). Colorless crystals: mp 83-85 °C;
[R]24 -19 (c 0.24, MeOH); UV (MeOH) λmax (log ꢀ) 238 (4.42),
D
275 (4.05), 314 (3.71) nm; IR (KBr) νmax 3336, 1640, 1602, 1315,
1262, 1165, 1013, 968 cm-1; MS (EI) m/z 334 [M]+, 316, 237,
219, 208, 189, 175, 163; HRMS (ESI-TOF) m/z [M + H]+
335.1499 (calcd for C18H23O6, 335.1494); 1H and 13C NMR data,
see Tables 1 and 2.
Aigia lom ycin E (6). Colorless amorphous solid: mp 91-
94 °C; [R]24 +14 (c 0.28, MeOH); UV (MeOH) λmax (log ꢀ) 226
D
(4.31), 268 (4.00), 307 (3.69) nm; IR (KBr) νmax 3401, 1646,
1615, 1318, 1261, 1163, 1021, 969 cm-1; MS (EI) m/z 334 [M]+,
316, 237, 219, 189, 175; HRMS (ESI-TOF) m/z [M + H]+
335.1498 (calcd for C18H23O6, 335.1494); 1H and 13C NMR data,
see Tables 1 and 2.
Hyd r ogen a tion of 1. To a solution of hypothemycin (1, 30
mg) in EtOAc (4 mL) was added 10% Pd/C (20 mg), and the
mixture was stirred under hydrogen for 26 h. The suspension
was filtered by suction, and the filtrate was concentrated and
subjected to column chromatography on silica gel (MeOH/
CH2Cl2) to obtain dihydrohypothemycin 7 (25.4 mg, 84%).
Recrystallization from MeOH gave colorless crystals. Hydro-
genation of compound 2 (20 mg) under the same reaction
conditions gave a compound (13.5 mg, 67%) whose spectral
data were identical to 7.
Dih yd r oh yp oth em ycin (7). Colorless crystals: mp 175-
177 °C; [R]26D -16 (c 0.17, CHCl3); UV (MeOH) λmax (log ꢀ) 218
(4.44), 265 (4.14), 305 (3.81) nm; IR (KBr) νmax 3404, 1698,
1650, 1618, 1256, 1159, 1051, 1023 cm-1; HRMS (ESI-TOF)
m/z [M + H]+ 381.1541 (calcd for C19H25O8, 381.1549); 1H NMR
(CDCl3, 400 MHz) δ 11.98 (1H, s, 2-OH), 6.50 (1H, d, J ) 2.6
Hz, H-5), 6.41 (1H, d, J ) 2.5 Hz, H-3), 5.26 (1H, m, H-10′),
4.52 (1H, brs, H-5′), 4.42 (1H, d, J ) 1.4 Hz, H-1′), 4.22 (1H,
brd, J ) 10.5 Hz, H-4′), 3.81 (3H, s, 4-OCH3), 3.58 (1H, brs,
5′-OH), 2.98 (1H, d, J ) 8.5 Hz, H-2′), 2.82 (1H, m, H-7′a),
2.42 (1H, m, H-7′b), 2.38 (1H, brs, 4′-OH), 2.16 (1H, dd, J )
15.4, 10.9 Hz, H-3′a), 1.80-1.64 (4H, m, H-8′ and H-9′), 1.39
(3H, d, J ) 6.3 Hz, 10′-CH3), 1.20 (1H, dd, J ) 15.5, 8.5 Hz,
H-3′b); 13C NMR (CDCl3, 100 MHz) δ 208.3 (s, C-6′), 170.9 (s,
-COO-), 165.9 (s, C-4), 165.1 (s, C-2), 142.0 (s, C-6), 104.0 (s,
C-1), 103.9 (d, C-5), 101.0 (d, C-3), 82.2 (d, C-5′), 73.0 (d, C-10′),
69.7 (d, C-4′), 61.1 (d, C-2′), 58.3 (d, C-1′), 55.5 (q, 4-OCH3),
38.5 (t, C-7′), 34.6 (t, C-3′), 34.5 (t, C-9′), 21.2 (t, C-8′), 20.5 (q,
10′-CH3).
P r ep a r a tion of Aceton id es 10 a n d 11. To a solution of
aigialomycin B (3; 6.0 mg) in 2,2-dimethoxypropane (1 mL)
was added a very small amount of p-TsOH‚H2O. After stirring
at room temperature for 3 h, saturated aq NaHCO3 was added
and extracted with EtOAc. The organic layer was dried over
MgSO4 and concentrated in vacuo to obtain an acetonide
mixture (8 and 9; 7.3 mg). The crude acetonide mixture was
dissolved in 2-butanone (0.3 mL), MeI (50 µL) and K2CO3 (s)
(50 mg) were added, and the mixture was stirred for 34 h. After
standard aqueous workup, the crude product (7.9 mg) was
subjected to preparative reversed-phase HPLC (40 × 100 mm;
MeCN/H2O ) 35:65; 20 mL/min) to obtain compounds 10 (4.2
mg; tR 22 min) and 11 (2.3 mg; tR 16 min).
Aceton id e 10. Colorless amorphous solid: IR (KBr) νmax
3486, 1722, 1605, 1460, 1262, 1161, 1045 cm-1; HRMS (ESI-
TOF) m/z [M + H]+ 435.2032 (calcd for C23H31O8, 435.2019);
1H NMR (CDCl3, 400 MHz) selected signals, δ 4.52 (1H, dd, J
) 7.7, 7.7 Hz, H-6′), 4.18 (1H, brd, J ) ca 12 Hz, H-4′), 3.84
(1H, m, H-5′), 1.45 (6H, s, acetonide CH3 × 2); 1H NMR
(methanol-d4, 400 MHz) δ 6.58 (1H, d, J ) 2.2 Hz, H-3), 6.37
(1H, d, J ) 2.2 Hz, H-5), 6.02 (1H, ddd, J ) 15.7, 6.4, 5.5 Hz,
H-8′), 5.74 (1H, dd, J ) 15.7, 7.4 Hz, H-7′), 5.61 (1H, m, H-10′),
4.53 (1H, dd, J ) 7.7, 7.7 Hz, H-6′), 4.19 (1H, ddd, J ) 11.5,
3.8, 1.5 Hz, H-4′), 3.94 (1H, d, J ) 1.6 Hz, H-1′), 3.85 (3H, s,
2-OCH3 or 4-OCH3), 3.84 (3H, s, 4-OCH3 or 2-OCH3), 3.76 (1H,
dd, J ) 8.0, 1.6 Hz, H-5′), 2.88 (1H, m, H-2′), 2.57 (1H, m,
H-9′a), 2.47 (1H, m, H-9′b), 2.28 (1H, ddd, J ) 14.2, 3.5, 3.3