Total Synthesis of Sordaricin
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-1-hydroxymethyl-
1-[2′-(1′′-hydroxymethylvinyl)-5′-methylcyclopentyl-
methyl]-3-isopropyl-3a,4,7,7a-tetrahydro-1H-4,7-methano-
indene-2-carboxylate (34). A solution of the MOM ether (200
mg, 0.4 mmol), MgBr2‚Et2O (823 mg, 3.2 mmol), and 1-bu-
tanethiol (299 µL, 2.8 mmol) in diethyl ether (10 mL) was
stirred at room temperature for 24 h. A further portion of
reagents was added and the mixture stirred a further 24 h.
The resulting solution was then diluted with 1.0 M HCl (50
mL) and extracted three times with ethyl acetate (50 mL). The
combined organic extracts were washed with brine (50 mL),
dried (MgSO4) and the solvent removed in vacuo. The residue
was subjected to flash chromatography on a column of silica
gel using 20%, increasing to 70% ethyl acetate in hexanes as
Sordaricin (3) and iso-Sordaricin (iso-3). Freshly dis-
tilled propanethiol (700 µL, 7.72 mmol) was added to a stirred
suspension of hexane-washed NaH (240 mg, 10 mmol) in
HMPA (5.0 mL) at room temperature under a nitrogen
atmosphere. The solution was stirred for 2 h and then allowed
to stand for 1 h to give a 1.35 M solution of propanethiolate.
To a dried flask containing a 1:1 mixture of 30 and iso-30 (70
mg, 0.2 mmol) and a stirrer bar was added a solution
propanethiolate/HMPA (1.35 M, 2.5 mL, 3.4 mmol) and the
solution stirred under a nitrogen atmosphere for 48 h. The
reaction mixture was diluted with ethyl acetate (15 mL) and
washed twice with water (50 mL). The combined aqueous
extracts were extracted twice with ethyl acetate (15 mL), then
the combined organic extracts were washed with brine (20 mL)
and dried (MgSO4). Concentration in vacuo followed by flash
chromatography on a column of silica gel using 20% ethyl
acetate in hexanes and then 60% ethyl acetate in hexane as
the eluant afforded a mixture of sordaricin (3) and isosorda-
ricin (iso-3, 50 mg combined). The mixture was dissolved in
HPLC grade acetonitrile (3 mL) and 50:50:0.05 water/aceto-
nitrile/acetic acid (5 drops) and subjected to semipreparative
HPLC separation using a mixture of 55% acetonitrile (contain-
ing 0.005% acetic acid) and 45% water (containing 0.005%
acetic acid), at a flow rate of 5.0 mL/min. The compounds were
detected at 210 nm. Concentration of the fractions containing
the first eluting compound afforded isosordaricin (iso-3, 17 mg,
25% from mixture of esters). Concentration of the fractions
containing the second eluting compound afforded sordaricin
(3, 25 mg, 38%), which was identical in all respects to an
authentic sample. Isosordaricin (iso-3). [R]20D: -35.7 (c 0.23
CHCl3). IR (film) ν: 3413, 2956, 1703, 1649, 1465, 1255, 1096,
1017, 800 cm-1. 1H NMR (d5-pyridine) δ: 0.73 (d, 3 H, J ) 7.0
Hz, H20), 1.07, 1.09 (2 × d, 2 × 3 H, J ) 6.7 Hz, H15 + H16),
1.11 (obscured m, 2 H), 1.40 (m, 1 H), 1.55 (m, 1 H), 1.75-
2.08 (m, 6 H), 2.39 (d, 1 H, J ) 12.7 Hz), 2.49 (d, 1 H, J ) 12.7
Hz, exo-H5), 2.84 (d, 1 H, J ) 12.7 Hz, endo-H5), 2.95 (m, 1 H,
H14), 3.50 (d, 1 H, J ) 3.2 Hz, H3), 4.26, 4.41 (2 × AB d, 2 ×
1 H, J ) 10.5 Hz, H19,19′), 5.68 (br s, 1 H, H2), 6.85 (variable
br s, 1 H, CO2H), 9.80 (s, 1 H, H17). 13C NMR (d5-pyridine) δ:
17.7 (Me, C20), 20.9, 22.1 (2 × Me, C15 + C16), 26.2 (CH2),
28.4 (CH, C14), 28.6 (CH2), 29.8 (CH, C10), 34.3 (CH2), 37.8
(C, C6), 46.3 (CH), 46.4 (CH2, C5), 46.8 (CH), 49.6 (CH), 58.3
(C, C4), 65.3 (CH2, C19), 69.5 (C, C7), 121.3 (CH, C2), 158.4
(C, C1), 175.8 (C, C18), 203.9 (CH, C17). MS m/z: 332 (M+‚,
7), 314 (25), 302 (72), 284 (100), 274 (44), 256 (40), 241 (34),
227 (25), 166 (51), 147 (62), 133 (37), 105 (50), 91 (66). HRMS:
calcd for C20H28O4 332.1988, found 332.1985.
the eluant, to afford 34 (153 mg, 92%) as a colorless oil. [R]20
:
D
-78.6 (c 0.59 CHCl3). IR (film) ν: 3429, 2955, 1765, 1702, 1436,
1
1252, 1121, 1042 cm-1. H NMR δ: 0.88 (d, 1 H, J ) 7.0 Hz,
CHMe), 1.05 (d, 3 H, J ) 7.0 Hz, CHMe2), 1.13 (d, 3 H, J ) 7.0
Hz, CHMe2′), 1.26 (d, 1 H, J ) 8.1 Hz), 1.38 (m, 2 H), 1.50 (d,
1 H, J ) 8.1 Hz), 1.60-1.90 (m, 5 H), 2.20 (m, 2 H), 2.43 (dd,
1 H, J ) 8.4, 3.8 Hz, H7a), 2.97, 3.07 (br s, 2 × 1 H, H4 + H7),
3.23 (sep, 1 H, J ) 6.9 Hz, CHMe2), 3.39 (dd, 1 H, J ) 8.4, 4.5
Hz, H3a), 3.56 (d, 1 H, J ) 11.3 Hz, CH2OH), 3.66 (s, 3 H,
OMe), 3.75 (d, 1 H, J ) 11.3 Hz, CH2OH′), 3.98 (AB d, 2 H, J
) 14.4 Hz, dCCH2OH), 4.78, 5.03 (br s, 2 × 1 H, dCH2), 5.73
(dd, 1 H, J ) 5.7, 2.9 Hz), 6.04 (dd, 1 H, J ) 5.7, 2.9 Hz). 13C
NMR δ: 16.2 (Me), 21.6 (Me), 21.8 (Me), 28.0, 28.9 (CH), 33.6,
35.7, 36.5 (CH), 42.4 (CH), 45.3 (CH), 47.8 (CH), 48.5 (2 × CH),
51.4 (CH), 52.5 (CH2), 52.8 (Me), 54.6 (CH2), 64.0 (CH2), 66.9
(CH2), 109.4 (dCH2), 132.0 (C), 134.1, 134.3 (2 × dCH), 151.9
(dC), 165.0 (C), 168.1 (CO2Me). MS m/z: 382 ([M - MeOH]+‚,
17), 357 (13), 287 (26), 244 (83), 215 (42), 197 (48), 121 (50),
109 (75), 91 (100), 66 (75). HRMS: calcd for ([M - MeOH]+‚
C25H34O3 382.2508, found 382.2505.
(1S,3aR,4S,7R,7aS,1′R,2′R,5′R)-Methyl-1-[2′-(1′′-formylvi-
nyl)-5′-methylcyclopentylmethyl]-1-hydroxymethyl-3-
isopropyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene-2-
carboxylate (8). Manganese dioxide (600 mg) was added to
a solution of diol 34 (120 mg, 29.0 mmol) in diethyl ether (3
mL) at room temperature. After 30 min, the solution was
filtered through a pad of Celite and the solvent removed in
vacuo to afford pure 8 (120 mg, 100%). [R]20D: -133.8 (c 0.50
CHCl3). IR (film) ν: 3467, 2957, 1694, 1601, 1466, 1434, 1345,
1
1233, 1122, 1016 cm-1. H NMR δ: 0.90 (d, 3 H, J ) 7.0 Hz,
CHMe), 1.04 (d, 3 H, J ) 7.0 Hz, CHMe2), 1.13 (d, 3 H, J ) 7.0
Hz, CHMe2′), 1.23 (d, 1 H, J ) 7.2 Hz), 1.40-1.52 (m, 4 H),
1.73 (dd, 1 H, J ) 14.4, 8.4 Hz), 1.80-1.98 (m, 3 H), 2.24 (m,
1 H), 2.37 (dd, 1 H, J ) 8.5, 3.8 Hz, H7a), 2.58 (m, 1 H), 2.91,
3.06 (br s, 2 × 1 H, H4 + H7), 3.20 (sep, 1 H, J ) 7.0 Hz,
CHMe2), 3.28 (br s, 1 H, OH), 3.36 (dd, 1 H, J ) 8.4, 4.4 Hz,
H3a), 3.49 (br d, 1 H, CH2OH), 3.64 (s, 3 H, OMe), 3.70 (d, 1
H, J ) 11.3 Hz, CH2OH′), 5.71 (dd, 1 H, J ) 5.7, 2.9 Hz), 5.88,
6.12 (br s, 2 × 1 H, dCH2), 6.00 (dd, 1 H, J ) 5.6, 2.9 Hz),
9.43 (s, 1 H, CHO). 13C NMR δ: 15.8 (Me), 21.5 (Me), 21.8
(Me), 28.7 (CH2), 28.9 (CH), 29.7, 33.6, 35.9 (2 × CH2 + C),
37.1 (CH), 43.4 (CH), 43.5 (CH), 45.1 (CH), 47.9 (CH), 48.4
(CH), 51.2 (CH), 52.5 (CH2), 52.6 (OMe), 54.4 (CH2), 66.6 (CH2),
132.1 (dCH2), 134.1 (2 × dCH), 153.5 (C, dCCHO), 165.6 (C),
167.8 (CO2Me), 194.3 (CHO). MS m/z: 412 (M+‚, <1), 380 (5),
346 (9), 328 (45), 284 (100), 256 (30), 180 (35), 147 (55), 119
(50), 91 (52), 66 (56). HRMS: calcd for C26H36O4 412.2614,
found 412.2615.
Methyl 17,19-Dihydroxysodaric-1-en-18-oate (33). A
solution of diol 34 (15 mg, 36 µmol) in 1,2-dichlorobenzene (1.0
mL) was heated at 180 °C under a stream of nitrogen gas from
a cylinder for 3 h. After being cooled to room temperature, the
mixture was subjected to flash chromatography on a column
of silica gel using 100% hexanes then 30%, increasing to 50%,
ethyl acetate in hexanes as the eluant to afford diol 33 (8 mg,
64%) as a white solid. [R]20D: -70.4 (c 0.27 CHCl3). IR (film)
1
ν: 3400, 2953, 1718, 1697, 1435, 1295, 1270, 1028 cm-1. H
NMR δ: 0.21 (d, 1 H, J ) 12.5 Hz, H4R), 0.76 (d, 3 H, J ) 6.7
Hz, H20), 0.87, 1.12 (d, 2 × 3 H, J ) 6.6 Hz, H15 + H16), 1.20
(obscured m, 3 H), 1.60-2.10 (m, 9 H), 2.47 (sep, 1 H, J ) 6.6
Hz, H14), 2.55 (t, 1 H, J ) 4.3 Hz, H3), 3.24, 3.37 (AB d, 2 ×
1 H, J ) 12.2 Hz, H17), 3.67, 3.72 (AB d, 2 × 1 H, H19), 3.78
(s, 3 H, OMe), 5.95 (d, 1 H, J ) 2.2 Hz, H2). 13C NMR δ: 17.5
(Me, C20), 20.9, 22.4 (2 × Me, C15 + C16), 26.2 (CH2, C11),
27.7 (CH, C14), 28.9 (CH2, C12), 31.8 (CH, C10), 31.9, 32.2
(2× CH2, C4 + C8), 41.5, 42.5, 45.0 (3 × CH, C3, C9 + C13),
50.4 (C, C5), 52.2 (OMe), 67.1, 67.2, 68.4, 71.4 (2 × C + 2 ×
CH2, C6, C7, C17 + C19), 128.7 (CH, C2), 149.0 (C, C1), 176.7
(C, C18). MS m/z: 348 (M+‚, 5), 330 (70), 317 (46), 299 (59),
285 (100), 257 (40), 225 (26), 197 (32), 147 (70), 119 (78), 105
(70), 91 (86), 81 (75). HRMS: calcd for C21H32O4 348.2301,
found 348.2298.
Methyl 19-Hydroxy-17-oxo-sordaric-1-en-18-oate (33)
and Isomethyl 19-Hydroxy-17-oxosordaric-1-en-18-oate
(iso-30). A solution of aldehyde 8 (30 mg, 73 µmol) in
dichlorobenzene (1.0 mL) was heated at 180 °C under a stream
of nitrogen gas from a cylinder for 1 h. After being cooled to
room temperature, the mixture was subjected to flash chro-
matography on a column of silica gel using 100% hexanes then
15% ethyl acetate in hexanes as the eluant, to afford an
inseparable 4:1 mixture of 30 and iso-30 (19 mg, 76%) as a
white solid. The mixture was then used in the next reaction.
J. Org. Chem, Vol. 70, No. 5, 2005 1669