Total Synthesis of the Plakotenins
FULL PAPER
0.50 (cyclohexane/EtOAc=18:1). Description of major diastereomer (Z):
1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz, CDCl3): d=0.94 (d,
J=6.8 Hz, 3H, EtO2CC=CHCHCH3), 0.95 (d, J=6.4 Hz, 3H,
TrtOCH2CHCH3), 1.01 (t, J=7.2 Hz, 3H, EtO2CCH2CH3), 1.07–1.12 (m,
1H, CHCHAHBCH), 1.24 (t, J=7.2 Hz, 3H, CO2CH2CH3), 1.36–1.44 (m,
1H, CHCHAHBCH), 1.74–1.82 (m, 1H, TrtOCH2CH), 2.23 (q, J=7.2 Hz,
2H, EtO2CCH2CH3), 2.85 (dd, J=6.4, 8.4 Hz, 1H, TrtOCHAHB), 2.94
(dd, J=5.6, 8.4 Hz, 1H, TrtOCHAHB), 2.99–3.07 (m, 1H, C=CHCH),
4.12 (q, J=7.2 Hz, 2H, CO2CH2CH3), 5.57 (d, J=10.0 Hz, 1H, C=CH),
7.20–7.31 (m, 9H, Ar-H), 7.43–7.45 ppm (m, 6H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=13.7 (p), 14.3 (p), 17.6 (p), 20.3 (p), 27.6 (s), 31.0
(t), 31.8 (t), 41.2 (s), 59.9 (s), 68.5 (s), 86.1 (q), 126.8 (t), 126.7 (t), 128.8
(t), 131.9 (q), 144.6 (t), 146.0 (q), 168.3 ppm (q); IR (film): n˜ =3086,
3059, 3023, 2964, 2928, 2871, 1712, 1643, 1597, 1491, 1449, 1373, 1303,
1215, 1158, 1070, 1032, 988, 899, 764, 746, 706, 648, 633 cmÀ1; MS (EI,
70 eV): m/z (%): 470 (0.01) [M+], 440 (0.04), 243 (100), 165 (16), 105 (6),
77 (2); HRMS m/z: calcd for C32H38O3: 470.2821; found: 470.2825.
(m, 1H, TrtOCHAHB), 2.83–2.87 (m, 1H, TrtOCHAHB), 5.17 (d, J=
9.6 Hz, 1H, PhCH=CHC=CH), 6.48 (d, J=16.2 Hz, 1H, PhCH), 6.90 (d,
J=16.2 Hz, 1H, PhCH=CH), 7.12–7.27 (m, 14H, Ar-H), 7.36–7.43 ppm
(m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3): d=13.9 (p), 18.4 (p), 21.6
(p), 26.7 (s), 29.4 (t), 32.0 (t), 42.0 (s), 67.9 (s), 86.1 (q), 125.4 (t), 126.4
(t), 126.9 (t), 127.2 (t), 127.6 (t), 127.7 (t), 128.7 (t), 128.9 (t), 136.4 (q),
137.3 (t), 138.2 (q), 144.7 ppm (q); IR (film): n˜ =3058, 3025, 2961, 2924,
2871, 1627, 1597, 1491, 1448, 1373, 1315, 1219, 1182, 1155, 1069, 1032,
961, 899, 763, 747, 706, 633 cmÀ1
.
Diene 41: Under argon, I2 (10.1 mg, 0.040 mmol) was added to a solution
of compound 39 (200.0 mg, 0.399 mmol) in CHCl3 (4 mL) at RT. After
stirring at RT for 1 h, the reaction mixture was quenched with a saturated
solution of sodium metabisulfite (5 mL). The aqueous layer was extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated to give crude compound 41
(200.0 mg, 0.399 mmol), which was used for the next step without further
purification. Rf =0.56 (cyclohexane/EtOAc 18:1); mixture of 3 diaster-
Alcohol 38: lithium aluminium hydride (24.8 mg, 0.654 mmol) was slowly
added to a solution of ester 37 (280.0 mg, 0.595 mmol) in THF (6 mL) at
08C. The reaction mixture was stirred at RT overnight, after which it was
cooled to 08C and quenched with H2O (5 mL) followed by Rochelleꢄs
salt solution (5 mL) and the reaction mixture stirred at RT for 15 h. The
aqueous layer was extracted with EtOAc (3ꢂ10 mL). The combined or-
ganic extracts were dried (MgSO4) and evaporated under reduced pres-
sure. The crude product was purified by column chromatography on
silica using cyclohexane/ethyl acetate 9:1 to give alcohol 38 (237.1 mg,
0.553 mmol, 93%) as colorless oil. A 5:1 ratio of Z/E products was ob-
tained. Rf =0.24 (cyclohexane/EtOAc 6:1). Description of major diaster-
eomer (Z): 1H NMR (400 MHz, CDCl3): d=0.85 (d, J=6.4 Hz, 3H,
EtO2CC=CHCHCH3), 0.98 (t, J=7.2 Hz, 3H, EtO2CCH2CH3), 1.01 (d,
J=6.4 Hz, 3H, TrtOCH2CHCH3), 1.02–1.06 (m, 1H, CHCHAHBCH),
1.34–1.43 (m, 1H, CHCHAHBCH), 1.72 (sext, J=6.4 Hz, 1H,
TrtOCH2CH), 2.06 (q, J=7.2 Hz, 2H, EtO2CCH2CH3), 2.23–2.36 (m, 1H,
C=CHCH), 2.79 (dd, J=7.2, 8.0 Hz, 1H, TrtOCHAHB), 2.98 (dd, J=4.8,
8.8 Hz, 1H, TrtOCHAHB), 3.86 (dd, J=12,0, 19.2 Hz, 2H, CCH2OH),
4.98 (d, J=9.6 Hz, 1H, C=CH), 7.19–7.30 (m, 9H, Ar-H), 7.43–7.45 ppm
(m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3): d=13.0 (p), 18.6 (p), 22.0
(p), 27.7 (s), 29.4 (t), 31.8 (t), 42.1 (s), 60.5 (s), 67.8 (s), 86.2 (q), 126.9 (t),
127.8 (t), 128.9 (t), 134.0 (t), 138.4 (q), 144.6 ppm (q); IR (film): n˜ =3342,
3086, 3058, 3032, 2961, 2924, 2869, 1597, 1491, 1449, 1384, 1219, 1182,
1155, 1068, 1032, 899, 764, 746, 706, 633 cmÀ1; HRMS m/z: calcd for
C30H36O2: 428.2715; found: 428.2712.
eoisomers: (E,E)/
astereomers (E,E)/AHCTUNGTRENNUNG
G
ACHTUNGTREN(NUNG Z,Z)=6.6/3.3/1; description of the two major di-
(400 MHz, CDCl3): d=0.91 (d, J=6.4 Hz, 3H, C=CHCHCH3, (E,E)),
0.95–1.03 (m, 9H, C=CHCHCH3, (E,Z); TrtOCH2CHCH3, (E,E) and
(E,Z); CCH2CH3, (E,E)), 1.06–1.12 (m, 3H, CHCHAHBCH, (E,E);
CHCHAHBCH, (E,Z); and CCH2CH3, (E,Z)), 1.45–1.52 (m, 1.5H,
CHCHAHBCH, (E,E); and CHCHAHBCH, (E,Z)), 1.71–1.79 (m, 1.5H,
TrtOCH2CH, (E,E); and TrtOCH2CH, (E,Z)), 2.12 (dq, J=3.2, 7.6 Hz,
2H, CCH2CH3, (E,E)), 2.27 (q, J=7.2 Hz, 1H, CCH2CH3, (E,Z)), 2.33–
2.43 (m, 1H, C=CHCH, (E,E)), 2.66–2.73 (m, 0.5H, C=CHCH, (E,Z)),
2.83 (dd, J=6.4, 8.8 Hz, 1H, TrtOCHAHB, (E,E)), 2.87 (dd, J=6.0,
8.4 Hz, 0.5H, TrtOCHAHB, (E,Z)), 2.94 (dd, J=5.2, 8.8 Hz, 1H, TrtO-
CHAHB, (E,Z)), 3.01 (dd, J=4.8, 8.8 Hz, 1H, TrtOCHAHB, (E,E)), 5.19
(d, J=9.6 Hz, 0.5H, PhCH=CHC=CH, (E,Z)), 5.29 (d, J=10.0 Hz, 1H,
PhCH=CHC=CH, (E,E)), 6.41 (d, J=16.2 Hz, 1H, PhCH, (E,E)), 6.50
(d, J=16.0 Hz, 0.5H, PhCH, (E,Z)), 6.62 (d, J=16.2 Hz, 1H, PhCH=CH,
(E,E)), 6.92 (d, J=16.0 Hz, 0.5H, PhCH=CH, (E,Z)), 7.15–7.30 (m, 14H,
Ar-H), 7.36–7.45 ppm (m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3): d=
13.9 (p), 14.2 (p), 18.4 (p), 18.5 (p), 20.1 (s), 21.5 (p), 21.6 (p), 26.7 (s),
29.5 (t), 30.3 (t), 32.0 (t), 41.9 (s), 42.0 (s), 67.8 (s), 67.9 (s), 86.1 (q),
125.3 (t), 125.4 (t), 126.2 (t), 126.4 (t), 126.9 (t), 127.2 (t), 127.7 (t), 127.8
(t), 128.7 (t), 128.9 (t), 132.9 (t), 136.4 (q), 137.3 (t), 138.2 (q), 138.3 (q),
138.4 (q), 140.6 (t), 144.6 (q), 144.7 ppm (q).
Alcohol 42: Camphorsulfonic acid (134 mg, 0.577 mmol) was added in
one portion to a solution of compound 41 (170 mg, 0.340 mmol) in
CH2Cl2/MeOH (16/8 mL) at 08C. The mixture was stirred at RT for 1 h
30 min and was then neutralized by the addition of saturated aqueous
NaHCO3 (10 mL). The layers were separated and the aqueous layer ex-
tracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers were
washed with brine, dried (MgSO4) and then concentrated. The crude
product was then purified by flash chromatography using cyclohexane/
ethyl acetate 6:1 to yield alcohol 42 (39.5 mg, 0.153 mmol, 45%) as color-
less solid. Rf =0.16 (cyclohexane/EtOAc 6:1 [a]2D0 =À31.4 (c=0.14 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=0.96 (d, J=6.8 Hz, 3H,
HOCH2CHCH3), 1.00 (d, J=6.8 Hz, 3H, C=CHCHCH3), 1.11 (t, J=
7.6 Hz, 3H, PhCH=CHCCH2CH3), 1.13–1.17 (m, 1H, CHCHAHBCH),
1.38 (brs, 1H, OH), 1.39–1.46 (m, 1H, CHCHAHBCH), 1.65–1.72 (m,
1H, HOCH2CH), 2.38 (q, J=7.6 Hz, 2H, PhCH=CHCCH2CH3), 2.59–
2.70 (m, 1H, C=CHCH), 3.42 (dd, J=6.4 Hz, J=10.4 Hz, 1H, HO-
CHAHB), 3.53 (dd, J=5.2 Hz, J=10.4 Hz, 1H, HOCHACHB), 5.38 (d, J=
10.0 Hz, 1H, PhCH=CHC=CH), 6.48 (d, J=16.2 Hz, 1H, PhCH), 6.68
(d, J=16.2 Hz, 1H, PhCH=CH), 7.20 (t, J=7.4 Hz, 1H, Ar-H), 7.31 (t,
J=8.0 Hz, 2H, Ar-H), 7.41 ppm (d, J=7.6 Hz, 2H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=14.3 (p), 17.3 (p), 20.2 (s), 21.2 (p), 30.3 (t), 33.7
(t), 41.3 (s), 68.3 (s), 125.6 (t), 126.3 (2 t), 127.0 (t), 128.7 (2 t), 132.7 (t),
138.1 (q), 138.4 (q), 140.3 ppm (t); IR (neat): n˜ =3345, 3026, 2961, 2925,
2872, 1627, 1598, 1493, 1450, 1375, 1030, 961, 749, 693 cmÀ1; MS (EI,
70 eV): m/z (%) 258 ([M+], 33), 185 (72), 169 (100), 145 (39), 129 (48),
99 (60), 91 (61); HRMS m/z: calcd for C18H26O: 258.1984; found:
258.1982.
Diene 40: Dess–Martin periodinane (1.51 mL, 0.698 mmol) was added at
08C to a solution of alcohol 39 (230.0 mg, 0.537 mmol) in CH2Cl2 (5 mL).
After stirring for 2 h at RT, the reaction mixture was quenched by adding
saturated aqueous Na2S2O3 (3 mL) and saturated aqueous NaHCO3
(3 mL). The layers were separated and the aqueous layer extracted with
CH2Cl2 (4ꢂ5 mL). The organic layer was dried (MgSO4) and concentrat-
ed to yield the crude aldehyde 39 (230.0 mg, 0.537 mmol, assumed to be
quantitative) as colorless oil, which was used without further purification
for the following olefination reaction. Lithium bis(trimethylsilyl)amide
(1m in THF, 0.91 mL, 0.91 mmol) was slowly added, at 08C, to a solution
of 5-(benzylsulfonyl)-1-phenyl-1H-tetrazole (B) (282 mg, 0.939 mmol) in
THF (8 mL). After stirring for 20 min at RT, it was cooled to À788C and
a solution of crude aldehyde 39 (230.0 mg, 0.537 mmol) in THF (2 mL)
was added. The reaction mixture was stirred overnight while slowly
warming up to RT. It was diluted with Et2O (5 mL) and the reaction
quenched by addition of saturated aqueous NaHCO3 (5 mL). The aque-
ous layer was extracted with EtOAc (3ꢂ15 mL). The combined organic
extracts were dried (MgSO4) and evaporated under reduced pressure.
The crude product was purified by column chromatography on silica
using cyclohexane/ethyl acetate 50:1 to give compound 40 (209.2 mg,
78%) as colorless oil. Rf =0.36 (cyclohexane/EtOAc 50:1); mixture of 4
diastereoisomers: (E,Z)/ACHTNUGTREN(NNUG E,E)/ACHTUNRTGENN(GUN Z,Z)/ACHTGUNTREN(NUGN E,Z)=25/5.3/3.3/1. Description of
major diastereomer (E,Z): 1H NMR (400 MHz, CDCl3): d=0.93 (d, J=
6.8 Hz, 3H, C=CHCHCH3), 0.98 (d, J=6.8 Hz, 3H, TrtOCH2CHCH3),
1.06 (t, J=7.2 Hz, 3H, CCH2CH3), 1.07–1.12 (m, 1H, CHCHAHBCH),
1.45–1.52 (m, 1H, CHCHAHBCH), 1.71–1.77 (m, 1H, TrtOCH2CH), 2.24
(q, J=7.2 Hz, 2H, CCH2CH3), 2.64–2.71 (m, 1H, C=CHCH), 2.83–2.87
Chem. Eur. J. 2012, 18, 15004 – 15020
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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