Antitumour Agents
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10.2, ꢀ3.0, ꢀ3.4, ꢀ3.5, ꢀ3.9 ppm (CH3); IR: n˜ =1786, 1704 cmꢀ1 (C=O);
HR-EIMS m/z (%): calcd for C50H79NO6Si3ꢀtBu: 816.4611; found:
816.4601 (100) [MꢀtBu]+, 684 (12), 639 (15), 290 (42); elemental analy-
sis: calcd (%) for C50H79NO6Si3: C 68.68, H 9.11; found: C 68.60, H 9.01.
7.70–7.65 (m, 4H), 7.45–7.35 (brm, 6H), 3.89 (dd, J=5.5, 1.5 Hz, 1H),
3.84 (quint, Jꢃ6.0 Hz, 1H), 3.68 (m, 1H), 3.53 (dd, J=9.8, 5.7 Hz, 1H),
3.48 (dd, J=9.8, 6.0 Hz, 1H), 2.20 (brs, 1H; OH), 1.80 (m, 1H), 1.65–
1.45 (brm, 6H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (s, 9H), 0.98 (d, J=7.0 Hz,
3H), 0.95 (d, J=6.6 Hz, 3H), 0.93 (s, 9H, overlapping one methyl dou-
blet), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.06 (s, 3H), 0.05 ppm (s,
3H); 13C NMR: d=134.0 (2), 19.3, 18.3, 18.2 (C), 135.6 (4), 129.5
(2), 127.6 (4), 76.9, 73.8, 72.2, 43.0, 41.6, 36.3 (CH), 69.0, 33.0, 28.2
(CH2), 26.9 (3), 26.1
(3), 26.0 (3), 21.2, 16.9, 10.6, 8.4, ꢀ3.2, ꢀ3.3, ꢀ4.1 ꢀ4.4 ppm (CH3);
IR: n˜ =3450 cmꢀ1 (br, OH); HR-EIMS m/z (%): calcd for
C41H74O4Si3ꢀtBu: 657.4190; found: 657.4168 (1) [MꢀtBu]+, 525 (2), 469
(7), 199 (14), 135 (18), 73 (100); elemental analysis: calcd (%) for
C41H74O4Si3: C 68.85, H 10.43; found: C 68.98, H 10.25.
(2S,3R,4R,5S,8S)-3,5-bis(tert-Butyldimethylsilyloxy)-9-(tert-butyldiphe-
nylsilyloxy)-N-methoxy-2,4,8-N-tetramethylnonanamide (16): A solution
of compound 15 (3.59 g, 4.1 mmol) in THF/H2O 3:1 (20 mL) was cooled
to 08C and treated with 30% H2O2 (2.5 mL, approximately 22 mmol)
and LiOH monohydrate (345 mg, 8.2 mmol). The mixture was stirred for
2 h at 08C and then overnight at room temperature. After addition of
Na2SO3 (2.8 g dissolved in 20 mL of water), most of the THF was re-
moved under reduced pressure and the residue was extracted with
CH2Cl2. This gave a crude acid which was used as such in the next reac-
tion.
A solution of the crude acid from above in dry CH2Cl2 (40 mL) was
cooled to 08C and treated with CDI (650 mg, 4 mmol). After stirring for
30 min at 08C, N,O-dimethylhydroxylamine hydrochloride (780 mg,
8 mmol) was added. The reaction mixture was then stirred overnight at
room temperature. Workup (extraction with CH2Cl2) and column chro-
matography on silica gel (hexane/EtOAc 80:20) furnished Weinreb
amide 16 (2.49 g, 80% overall from 15). Colourless oil; [a]D =ꢀ0.7 (c=
1.8 in CHCl3); 1H NMR: d=7.70–7.65 (m, 4H), 7.45–7.35 (brm, 6H),
4.10 (t, J=5.3 Hz, 1H), 3.69 (s, 3H), 3.63 (m, 1H), 3.55 (dd, J=9.8,
5.7 Hz, 1H), 3.48 (dd, J=9.8, 6.4 Hz, 1H), 3.19 (s, 3H), 3.05 (m, 1H),
1.77 (m, 1H), 1.70–1.55 (brm, 4H), 1.45 (m, 1H), 1.16 (d, J=7 Hz, 3H),
1.09 (s, 9H), 0.97 (d, J=6.6 Hz, 3H), 0.94 ppm (brs, 9H, overlapping one
methyl doublet), 0.91 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H),
0.05 ppm (s, 3H); 13C NMR: d=176.6*, 134.1, 134.0, 19.3, 18.3, 18.2 (C),
135.6 (4), 129.5 (2), 127.6 (4), 73.2, 72.7, 43.7, 37.8, 36.4 (CH), 69.3,
32.8, 27.7 (CH2), 61.0, 32.4*, 26.9 (3), 26.1 (3), 26.0 (3), 16.9, 13.4,
11.1, ꢀ3.5, ꢀ3.8, ꢀ4.0, ꢀ4.4 ppm (CH3) (starred peaks are very low and
broad); IR: n˜ =1670 cmꢀ1 (C=O); HR-EIMS m/z (%): calcd for
C42H75NO5Si3ꢀtBu, 700.4248; found: 700.4213 (4) [MꢀtBu]+, 670 (100),
199 (58); elemental analysis: calcd (%) for C42H75NO5Si3: C 66.52, H
9.97; found: C 66.39, H 9.82.
(2S,3R,4S,5R,6S,9S)-4,6-Bis(tert-butyldimethylsilyloxy)-10-(tert-butyldi-
phenylsilyloxy)-2-methoxy-3,5,9-trimethyldecane (5): A solution of alco-
hol 17 (1.29 g, 1.8 mmol) in dry CHCl3 (80 mL) was treated at room tem-
perature with 2,6-di-tert-butylpyridine (8 mL, 36 mmol) and MeOTf
(2 mL, 18 mmol). Both reagents were added in two portions with an in-
terval of 2 h. The reaction mixture was then stirred at reflux until con-
sumption of the starting material (about 2 h, TLC monitoring), and then
quenched by addition of methanol (2 mL) and saturated aqueous
NaHCO3 (6 mL), followed by further stirring for 30 min at room temper-
ature. Workup (extraction with CH2Cl2) and column chromatography on
silica gel (hexane/EtOAc 95:5) gave 5 (1.10 g, 84%). Colourless oil;
[a]D = +4.1 (c=1.7 in CHCl3); 1H NMR: d=7.70–7.65 (m, 4H), 7.45–
7.35 (brm, 6H), 3.82 (brd, J=6.0 Hz, 1H), 3.74 (m, 1H), 3.53 (dd, J=
9.8, 5.7 Hz, 1H), 3.47 (dd, J=9.8, 6.2 Hz, 1H), 3.30 (s, 3H), 3.15 (quint,
J=6.5 Hz, 1H), 1.73 (m, 1H), 1.65–1.50 (brm, 5H), 1.45 (m, 1H), 1.13
(d, J=6.3 Hz, 3H), 1.08 (s, 9H), 0.95 (d, J=6.5 Hz, 3H), 0.94 (d, J=
6.5 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.86 (d, J=7.0 Hz, 3H), 0.10 (s,
3H), 0.07 (s, 6H), 0.05 ppm (s, 3H); 13C NMR: d=134.1, 134.0, 19.3,
18.5, 18.3 (C), 135.6 (4), 129.5 (2), 127.6 (4), 79.8, 73.3, 72.8, 43.3,
41.4, 36.5 (CH), 69.2, 33.0, 28.1 (CH2), 56.5, 26.9 (3), 26.1 (3), 26.0 (
3), 16.9, 16.5, 11.0, 10.5, ꢀ3.2, ꢀ3.4, ꢀ3.9 ꢀ4.0 ppm (CH3); HR-EIMS m/
(3S,4R,5R,6S,9S)-4,6-Bis(tert-butyldimethylsilyloxy)-10-(tert-butyldiphe-
nylsilyloxy)-3,5,9-trimethyldecan-2-one (6): A solution of Weinreb amide
16 (2.43 g, 3.2 mmol) in dry THF (30 mL) was cooled under N2 at ꢀ208C
and treated dropwise with MeMgBr (3m solution in Et2O, 3.7 mL,
11.2 mmol). The reaction mixture was then stirred at 08C for 1 h and
worked up (extraction with CH2Cl2). Column chromatography on silica
gel (hexane/EtOAc 95:5) afforded ketone 6 (1.6 g, 70%). Colourless oil;
[a]D =+14.6 (c=1.2 in CHCl3); 1H NMR: d=7.70–7.65 (m, 4H), 7.45–
7.35 (brm, 6H), 4.27 (dd, J=6.7, 2.3 Hz, 1H), 3.80 (dt, J=7.2, 4.0 Hz,
1H), 3.52 (dd, J=9.8, 5.8 Hz, 1H), 3.49 (dd, J=9.8, 6.0 Hz, 1H), 2.60
(qd, J=7.0, 2.3 Hz, 1H), 2.17 (s, 3H), 1.70 (m, 1H), 1.65–1.40 (brm, 5H),
1.13 (d, J=7.0 Hz, 3H), 1.08 (s, 9H), 0.96 (d, J=6.8 Hz, 3H), 0.90 (s,
9H), 0.89 (s, 9H), 0.87 (d, J=7.0 Hz, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08
(s, 3H), 0.01 ppm (s, 3H); 13C NMR: d=210.8, 134.0 (2), 19.3, 18.3, 18.2
(C), 135.6 (4), 129.5 (2), 127.6 (4), 73.1, 72.7, 50.2, 43.0, 36.3 (CH),
68.9, 33.3, 28.5 (CH2), 28.6, 26.9 (3), 26.1 (3), 26.0 (3), 16.9, 10.3,
10.2, ꢀ3.3, ꢀ3.9, ꢀ4.0 (2) (CH3); IR: n˜ =1716 cmꢀ1 (C=O); HR-EIMS
m/z (%): calcd for C41H72O4Si3ꢀtBu, 655.4034; found: 655.4038 (12)
[MꢀtBu]+, 483 (27), 469 (33), 199 (44), 135 (73), 73 (100); elemental
analysis: calcd (%) for C41H72O4Si3: C 69.04, H 10.17; found: C 69.19, H
10.00.
z
(%): calcd for C42H76O4Si3ꢀtBu: 671.4347; found: 671.4293 (7)
[MꢀtBu]+, 539 (6), 469 (23), 199 (18), 135 (22), 73 (51), 59 (100); ele-
mental analysis: calcd (%) for C42H76O4Si3: C 69.17, H 10.50; found: C
69.00, H 10.65.
(2S,5S,6R,7S,8R,9S)-5,7-Bis(tert-butyldimethylsilyloxy)-9-methoxy-2,6,8-
trimethyldecanol (18): A solution of compound 5 (1.1 g, approximately
1.5 mmol) in 10% NaOH/MeOH (40 mL) was stirred at reflux for 30 h.
Workup (extraction with CH2Cl2) and column chromatography on silica
gel (hexane/EtOAc 90:10) gave 18 (618 mg, 84%). Colourless oil; [a]D =
1
+4.9 (c=1.7 in CHCl3); H NMR: d=3.82 (dd, J=5.8, 1.5 Hz, 1H), 3.68
(brq, J= ꢃ5.0 Hz, 1H), 3.51 (dd, J=10.5, 5.8 Hz, 1H), 3.47 (dd, J=10.5,
6.6 Hz, 1H), 3.30 (s, 3H), 3.14 (quint, J=6.5 Hz, 1H), 1.73 (m, 1H),
1.70–1.55 (brm, 4H), 1.50–1.45 (m, 2H), 1.40 (brs, 1H; OH), 1.13 (d, J=
6.0 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 0.90 (s,
9H), 0.89 (s, 9H), 0.88 (d, J=7.0 Hz, 3H), 0.09 (s, 3H), 0.07 (s, 3H),
0.06 ppm (s, 6H); 13C NMR: d=18.5, 18.3 (C), 80.1, 73.3, 72.4, 43.4, 41.0,
36.2 (CH), 68.2, 32.3, 27.5 (CH2), 56.5, 26.1 (3), 26.0 (3), 16.6, 16.3,
11.3, 10.7, ꢀ3.3, ꢀ3.6, ꢀ4.1 ppm (2) (CH3); IR: n˜ =3360 cmꢀ1 (br, OH);
HR-EIMS m/z (%): calcd for C26H58O4Si2ꢀMeCHOMe: 431.3371; found:
431.3321 (2) [MꢀMeCHOMe]+, 231 (48), 75 (100), 59 (65); elemental
analysis: calcd (%) for C26H58O4Si2: C 63.61, H 11.91; found: C 63.74, H
11.75.
(2S,3R,4S,5R,6S,9S)-4,6-Bis(tert-butyldimethylsilyloxy)-10-(tert-butyldi-
phenylsilyloxy)-3,5,9-trimethyldecan-2-ol (17): Ketone
6
(1.57 g,
(4S,5S,8S,9R,10S,11R,12S)-8,10-Bis(tert-butyldimethylsilyloxy)-12-meth-
oxy-5,9,11-trimethyltridec-1-en-4-ol (20): Oxalyl chloride (130 mL,
2.2 mmol) was dissolved at ꢀ788C in dry CH2Cl2 (25 mL) and treated
with Me2AlCl (2m solution in hexane, 5.5 mL, 5.5 mmol). The reaction
mixture was stirred for 5 min at ꢀ788C, then cooled to ꢀ908C and treat-
ed with nBu3SnH (675 mL, 2.5 mmol). After stirring for 1 h at ꢀ908C, the
cooling bath was removed, saturated aq NaHCO3 (10 mL) was added
and the mixture was further stirred at room temperature for 30 min.
Workup (extraction with CH2Cl2) provided a 92:8 mixture of diastereo-
isomeric alcohols (1.43 g, 91%), which was carefully purified by means of
flash column chromatography on silica gel (hexane/EtOAc 95:5) to yield
pure 17. Colourless oil; [a]D =ꢀ2.6 (c=2.2 in CHCl3); 1H NMR: d=
1.5 mmol) was added dropwise at ꢀ788C to
a solution of DMSO
(210 mL, 3 mmol) in dry CH2Cl2 (3 mL). The mixture was stirred for
5 min at this temperature. A solution of alcohol 18 (614 mg, 1.25 mmol)
in dry CH2Cl2 (1 mL) was then added via syringe. The reaction mixture
was stirred for 15 min at ꢀ788C. After addition of Et3N(840 mL,
6 mmol), the mixture was stirred for 15 min at ꢀ788C and then for
20 min at 08C. Workup (extraction with CH2Cl2) gave crude aldehyde 19
which was used as such in the next reaction.
Chem. Eur. J. 2007, 13, 5060 – 5074
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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