Total Synthesis of (ꢀ)-Blennolide A
FULL PAPER
(1.50 g, 13.9 mmol, 4.00 equiv), carbon monoxide was passed through the
resulting mixture for 2 min before being stirred under a CO atmosphere
(1 atm) at RT for a further 22 h. The solvent was evaporated in vacuo,
and the residue was purified by column chromatography on silica gel (pe-
troleum ether/EtOAc=12:1) to give a crude product, which was dis-
solved in Et2O (150 mL). After washing with an aq solution of NaOH
(1m, 3ꢂ30 mL) and brine (30 mL), the organic layer was dried over
Na2SO4 and concentrated in vacuo. Chroman 11 was obtained as a yellow
oil (912 mg, 2.56 mmol, 74%, 96% ee). Analytical HPLC (Daicel Chiral-
pakꢃ IA, n-hexane/iPrOH=99.5:0.5, flow rate: 0.8 mLminꢀ1, wavelength:
205 nm): tR =17.8 (ꢀ)-(S)-11, 2.2%; 20.1 min, (+)-(R)-11, 97.8%; ee:
96%; a=1.18; Rf =0.47 (petroleum ether/EtOAc=5:1); [a]2D5 = +6.1 (c=
0.49 in CHCl3); 1H NMR (300 MHz, CDCl3): d=2.04 (t, J=6.9 Hz, 2H,
3’-H2), 2.64 (br t, J=6.9 Hz, 2H, 4’-H2), 2.72 (d, J=14.4 Hz, 1H, 2-Ha),
2.84 (d, J=14.4 Hz, 1H, 2-Hb), 3.62 (s, 3H, COOCH3), 3.67 (brs, 2H,
CH2OBn), 3.80 (s, 3H, 5’-OCH3), 4.54 (d, J=12.0 Hz, 1H, OCHaPh),
4.62 (d, J=12.0 Hz, 1H, OCHbPh), 6.41 (d, J=8.4 Hz, 1H, 6’-H), 6.46 (d,
J=8.4 Hz, 1H, 8’-H), 7.05 (t, J=8.4 Hz, 1H, 7’-H), 7.22–7.35 ppm (m,
5H, 5ꢂPh-H); 13C NMR (125 MHz, CDCl3): d=16.1 (C-4’), 26.2 (C-3’),
39.3 (C-2), 51.5 (COOCH3), 55.4 (5’-OCH3), 72.7 (CH2OBn), 73.4
(OCH2Ph), 76.3 (C-2’), 101.8 (C-6’), 110.8, 110.8 (C-8’, C-4a’), 127.0
After addition of water (300 mL), the aqueous layer was extracted with
EtOAc (3ꢂ230 mL), combined organic layers were dried over Na2SO4,
and the solution was concentrated in vacuo. Column chromatography of
the residue on silica gel (petroleum ether/EtOAc=3:2!1:1) furnished a
mixture of the diols syn/anti-13 as a colorless oil (syn/anti=1:2.4, 6.70 g,
19.5 mmol, 95%). Rf =0.37 (petroleum ether/EtOAc=1:1); 1H NMR
(300 MHz, CDCl3, syn/anti=1:2.4): d=1.78–2.20 (m, 4H, 3’-H2syn+anti),
2.38–2.80 (m, 6H, 4’-H2syn+anti, 1-OHsyn+anti), 2.93–3.04 (m, 2H, 2-OHsyn+
), 3.50–3.70 (m, 4H, CH2OBnsyn+anti), 3.71–3.96 (m, 12H, 1-Hsyn+anti, 2-
anti
H2syn+anti, 5’-OCH3syn+anti), 4.43–4.59 (m, 4H, OCH2Phsyn+anti), 6.41 (d, J=
8.1 Hz, 2H, 6’-Hsyn+anti), 6.46 (d, J=8.1 Hz, 1H, 8’-Hanti), 6.47 (d, J=
8.1 Hz, 1H, 8’-Hsyn), 7.04 (t, J=8.1 Hz, 2H, 7’-Hsyn+anti), 7.22–7.37 ppm
(m, 10H, 5ꢂPh-Hsyn+anti); 13C NMR (125 MHz, CDCl3, syn/anti=1:2.4):
d=15.7, 15.7 (C-4’syn, C-4’anti), 23.1 (C-3’syn), 23.5 (C-3’anti), 55.5 (5’-
OCH3syn+anti), 62.0 (C-2anti), 62.3 (C-2syn), 69.0 (C-1syn), 70.2 (C-1anti), 73.9
(OCH2Phsyn), 74.0 (OCH2Phanti), 74.2 (CH2OBnsyn), 75.4 (CH2OBnanti),
77.6 (C-2’anti), 78.2 (C-2’syn), 102.0 (C-6’syn+anti), 109.7, 109.7
(C-8’syn, C-8’anti), 110.3 (C-4a’syn), 110.4 (C-4a’anti), 127.0, 127.0 (C-7’syn, C-
7’anti), 127.6, 127.7, 127.9, 127.9, 128.4 (Ph-Co syn+anti, Ph-Cm syn+anti, Ph-Cp
), 137.1 (Ph-Ci syn), 137.2 (Ph-Ci anti), 153.2 (C-8a’syn), 153.3 (C-8a’anti),
syn+anti
157.5 (C-5’syn), 157.6 ppm (C-5’anti); IR (film): n˜ =3406, 2938, 1592, 1469,
1347, 1251, 1191, 1095, 1028, 909, 771, 737, 699 cmꢀ1; UV (CH3OH): lmax
(lg e)=204.5 (4.716), 271.0 (3.168), 279.0 nm (3.156); MS (ESI): m/z (%):
711.3 (55) [2M+Na]+, 367.1 (100) [M+Na]+; HRMS (ESI): m/z calcd
(%) for C20H24O5 (344.40): 367.1521 [M+Na]+; found: 367.1517.
ACHTUNGTRENNUNG(C-7’), 127.5, 127.5 (Ph-Co, Ph-Cp), 128.2 (Ph-Cm), 138.1 (Ph-Ci), 153.5
(C-8a’), 157.6 (C-5’), 170.6 ppm (COOCH3); IR (film): n˜ =2949, 1737,
1592, 1469, 1439, 1347, 1267, 1249, 1200, 1096, 1018, 902, 772, 738,
699 cmꢀ1
; UV (CH3OH): lmax (lg e)=204.0 (4.716), 271.5 (3.117),
279.0 nm (3.126); MS (ESI): m/z (%): 735.3 (40) [2M+Na]+, 379.2 (100)
[M+Na]+; HRMS (ESI): m/z calcd for C21H24O5 (356.41): 379.1521
[M+Na]+; found: 379.1518.
Methyl (3R,4R)-4-[(R)-2-(benzyloxymethyl)-5-methoxychroman-2-yl)-4-
(tert-butyldimethylsilyloxy)-3-methylbutanoate (18a): MeLi (72.4 mL of
a 1.6m solution in Et2O, 116 mmol, 12.0 equiv) was added to a suspension
of CuBr·Me2S (11.9 g, 57.9 mmol, 6.00 equiv) in THF (80 mL) at ꢀ358C,
and the resulting mixture was stirred for 40 min at ꢀ358C. Then, TMSCl
(7.40 mL, 6.29 g, 57.9 mmol, 6.00 equiv) and a solution of ester (E)-17
(4.95 g, 9.65 mmol, 1.00 equiv) in THF (110 mL) were added and stirring
was continued at ꢀ358C for 60 min. Afterwards, the reaction was
quenched by careful addition of NEt3 (165 mL) and water (400 mL). The
aqueous layer was extracted with tBuOMe (2ꢂ200 mL), and the com-
bined organic layers were washed with water (250 mL), dried over
Na2SO4, and concentrated in vacuo. Column chromatography on silica
gel (petroleum ether/EtOAc=20:1!15:1) provided ester 18a as a color-
less oil (4.62 g, 8.74 mmol, 91%). Rf =0.51 (petroleum ether/tBuOMe=
7:1); [a]2D3 =ꢀ15.1 (c=0.93, CHCl3); 1H NMR (300 MHz, CDCl3): d=
(S)-2-(Benzyloxymethyl)-5-methoxy-2-vinylchroman (6):
A solution of
Pd(OTFA)2 (121 mg, 365 mmol, 10 mol%) and (S,S)-Bn-BOXAX (12)
ACHTUNGTRENNUNG
(209 mg, 365 mmol, 10 mol%) in MeOH (3.6 mL) was stirred at RT for
30 min. After addition of a solution of phenol 7b (E/Z=1:1.7, 1.14 g,
3.65 mmol, 1.00 equiv) in MeOH (5.4 mL) and p-benzoquinone (1.58 g,
14.6 mmol, 4.00 equiv), the mixture was heated at 608C for 24 h and then
cooled to RT. Filtration over a pad of silica gel (15ꢂ6 cm, washing with
petroleum ether/EtOAc=10:1, TLC monitoring), evaporation of the sol-
vent in vacuo, and column chromatography on silica gel (petroleum
ether/EtOAc=30:1) provided vinylchroman 6 as a colorless oil (933 mg,
3.01 mmol, 82%, 85% ee). (Z)-7b and (E)-7b were also transformed
into 6 using the same procedure: for (Z)-7b (79%, 89% ee); for (E)-7b
(81%, 72% ee). Analytical HPLC (Daicel Chiralcelꢃ OD, n-hexane/
iPrOH=99:1, flow rate: 0.8 mLminꢀ1, wavelength: 205 nm): tR =12.0
(ꢀ)-(S)-6, 92.4%; 17.0 min (+)-(R)-6, 7.6%; ee: 85%; a=1.83; Rf =0.35
(petroleum ether/EtOAc=20:1); [a]2D0 =ꢀ52.9 (c=0.52, CHCl3);
1H NMR (300 MHz, CDCl3): d=1.87–2.08 (m, 2H, 3-H2), 2.44 (ddd, J=
17.1, 10.8, 6.6 Hz, 1H, 4-Ha), 2.73 (ddd, J=17.1, 4.8, 3.9 Hz, 1H, 4-Hb),
3.53 (d, J=16.5 Hz, 1H, CHaOBn), 3.57 (d, J=16.5 Hz, 1H, CHbOBn),
3.79 (s, 3H, 5-OCH3), 4.59 (d, J=12.3 Hz, 1H, OCHaPh), 4.63 (d, J=
12.3 Hz, 1H, OCHbPh), 5.17 (dd, J=10.8, 1.5 Hz, 1H, 2’-Ha), 5.25 (dd,
J=17.4, 1.5 Hz, 1H, 2’-Hb), 5.85 (dd, J=17.4, 10.8 Hz, 1H, 1’-H), 6.40 (d,
J=8.1 Hz, 1H, 6-H), 6.58 (d, J=8.1 Hz, 1H, 8-H), 7.06 (t, J=8.1 Hz, 1H,
7-H), 7.23–7.38 ppm (m, 5H, 5ꢂPh-H); 13C NMR (125 MHz, CDCl3): d=
16.4 (C-4), 26.6 (C-3), 55.5 (5-OCH3), 73.7 (OCH2Ph), 75.6 (CH2OBn),
78.8 (C-2), 101.6 (C-6), 109.8 (C-8), 110.8 (C-4a), 116.2 (C-2’), 126.9 (C-
7), 127.5 (Ph-Cp), 127.6 (Ph-Co), 128.3 (Ph-Cm), 137.8 (C-1’), 138.3
ꢀ0.02 (s, 3H, Si
ACHTGNUERTN(NUGN CH3)a), 0.13 (s, 3H, SiAHCTUNRGTENN(GNU CH3)b), 0.85 (s, 9H, SiCACHTUNGTRENNUNG(CH3)3),
1.06 (d, J=6.9 Hz, 3H, 3-CH3), 1.87–2.06 (m, 2H, 3’-H2), 2.15 (dd, J=
15.9, 10.2 Hz, 1H, 2-Ha), 2.30–2.54 (m, 2H, 3-H, 4’-Ha), 2.67 (dd, J=15.9,
2.7 Hz, 1H, 2-Hb), 2.72 (ddd, J=17.1, 5.1, 3.6 Hz, 1H, 4’-Hb), 3.52 (s, 2H,
CH2OBn), 3.59 (s, 3H, COOCH3), 3.79 (s, 3H, 5’-OCH3), 3.94 (d, J=
0.9 Hz, 1H, 4-H), 4.40 (d, J=12.0 Hz, 1H, OCHaPh), 4.50 (d, J=12.0 Hz,
1H, OCHbPh), 6.37 (d, J=8.1 Hz, 1H, 6’-H), 6.43 (d, J=8.1 Hz, 1H,
8’-H), 7.02 (t, J=8.1 Hz, 1H, 7’-H), 7.19–7.33 ppm (m, 5H, 5ꢂPh-H);
13C NMR (125 MHz, CDCl3): d=ꢀ4.8 (Si
(CH3)a), ꢀ3.7 (Si
ACHTUNGTRENNUNG
(C-3), 36.5 (C-2), 51.3 (COOCH3), 55.3 (5’-OCH3), 70.1 (CH2OBn), 73.6
(OCH2Ph), 80.0 (C-4), 81.2 (C-2’), 101.3 (C-6’), 110.2 (C-4a’), 110.3
AHCTNUGTREN(GUNN C-8’), 126.8 (C-7’), 127.4 (Ph-Cp), 127.5 (Ph-Co), 128.2 (Ph-Cm), 138.1
(Ph-Ci), 153.9 (C-8a’), 157.6 (C-5’), 174.4 ppm (COOCH3); IR (neat): n˜ =
2952, 2852, 1738, 1591, 1468, 1251, 1136, 1092, 1037, 1004, 832, 770,
G
738 cmꢀ1
; UV (CH3OH): lmax (lg e)=204.0 (4.732), 273.0 (3.115),
280.0 nm (3.103); MS (ESI): m/z (%): 551.3 (100) [M+Na]+; HRMS
(ESI): m/z calcd for C30H44O6Si (528.75): 551.2805 [M+Na]+; found:
551.2799.
698 cmꢀ1
; UV (CH3OH): lmax (lg e)=204.0 (4.701), 271.5 (3.113),
279.0 nm (3.121); MS (ESI): m/z (%): 643.3 (53) [2M+Na]+, 333.2 (100)
[M+Na]+, 311.2 (25) [M+H]+; HRMS (ESI): m/z calcd for C20H22O3
(310.39): 311.1642 [M+H]+, 333.1461 [M+Na]+; found: 311.1641,
333.1460.
Methyl (3R,4R,4aS)-4-(tert-butyldimethylsilyloxy)-1-hydroxy-8-methoxy-
3-methyl-9-oxo-2,3,4,4a-tetrahydroxanthene-4a-carboxylate (4): A solu-
tion of TiCl4 (2.47 mL of
a 1.0m solution in CH2Cl2, 2.47 mmol,
2-(R/S)-[1-(R)-2-(Benzyloxymethyl)-5-methoxychroman-2-yl]ethane-1,2-
2.60 equiv) was added slowly to a stirred solution of chromanone 19
(456 mg, 949 mmol, 1.00 equiv) and NEt3 (390 mL, 288 mg, 2.85 mmol,
3.00 equiv) in CH2Cl2 (7 mL) at 08C, and stirring was continued at 08C
for 60 min. Then, the reaction was quenched by addition of a saturated
aq solution of NH4Cl (4 mL). Water (60 mL) was added and the aqueous
layer was extracted with EtOAc (3ꢂ60 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. Column chro-
diol (13):
A suspension of AD-mix-a (57.6 g) in tBuOH/H2O (1:1,
180 mL) was stirred at RT for 30 min before addition of a solution of vi-
nylchroman 6 (6.40 g, 20.6 mmol, 1.00 equiv) in n-hexane (25 mL) and
CH3SO2NH2 (1.96 g, 20.6 mmol, 1.00 equiv) at RT. Stirring was continued
at RT for 4 d, then the reaction was quenched by addition of saturated
aq Na2SO3 solution (70 mL) at 08C with stirring for another 60 min.
Chem. Eur. J. 2013, 19, 8610 – 8614
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8613