Total Synthesis of Branimycin
FULL PAPER
3822, 3676, 3651, 3629, 3448, 2931, 1701, 1513, 1249, 1033, 821 cmꢀ1
;
36.0, 32.4 ppm; IR (Si, film): n˜ = 3400, 2874, 1612, 1514, 1248, 1077,
HRMS (ESI): m/z: calcd for C19H22NaO4 [M+Na]+ 337.1416; found:
671 cmꢀ1
.
337.1412.
Malonate addition to 125
(1R*,4S*,4aS*,5R*,6R*,8aS*)-5-((4-Methoxybenzyl)oxy)-6-(methoxy-
methyl)-1,4,4a,5,6,8a-hexahydro-1,4-epoxynaphthalene (rac-112): To a sus-
pension of NaH (60% in mineral oil, 300 mg, 7.6 mmol) in dry THF
(12 mL) at 08C was added dry DMF (12 mL) and MeI (5.4 g, 2.5 mL,
38 mmol), followed by the abovementioned alcohol (1.2 g, 3.8 mmol) in
dry THF (5 mL). The reaction mixture was stirred at 08C for 12 h. Then
saturated aq. NH4Cl (1 mL) was added carefully and the volatiles were
removed in vacuo at RT (CAUTION: distillate contains MeI, which is
toxic!). The residue was diluted with water (70 mL) and extracted with
toluene (5ꢅ50 mL). The combined organic phase was washed with water
(3ꢅ20 mL), brine (30 mL) and passed through a plug of cotton. The sol-
vents were removed in vacuo and the residue was subjected to column
chromatography (EtOAc/hexane) to yield 1.11 g of rac-112 (89%) as
a colorless oil. 1H NMR (400 MHz): d=7.30 (brd, J=8.8 Hz, 2H), 6.90
(brd, J=8.8 Hz, 2H), 6.38 (dd, J=1.6, 5.8 Hz, 2H), 6.28 (dd, J=1.5,
5.8 Hz, 1H), 5.83 (ddd, J=2.9, 4.6, 9.9 Hz, 1H), 5.71 (dd, J=1.5, 9.9 Hz,
H), 5.14 (brs, 1H), 4.68 (brs, 1H), 4.57 (d, J=11.4 Hz, 1H), 4.50 (d, J=
11.4 Hz, 1H), 3.81 (s, 3H), 3.74 (d, J=6.3, 10.4 Hz, 1H), 3.58 (d, J=4.5,
9.0 Hz, 1H), 3.50 (d, J=3.0, 9.0 Hz, 1H), 3.33 (s, 3H), 2.57–2.49 (m, 1H),
2.29–2.23 (m, 1H), 2.08 ppm (brt, 1H); 13C NMR (100.6 MHz): d=159.3,
137.7, 134.9, 131.2, 130.8, 129.5, 129.1, 113.9, 85.6, 78.2, 76.8, 72.8, 71.4,
59.2, 55.4, 39.4, 39.4, 39.3 ppm; IR (Si, film): n˜ = 2928, 1612, 1513, 1249,
1117, 1079, 822 cmꢀ1; HRMS (ESI): m/z: calcd for C20H24NaO4 [M+Na]+
351.1572; found: 351.1570.
Dimethyl 2-((1S,2R,4aR,5R,6R,7R,8R,8aS)-6,8-bis((tert-butyldimethylsi-
lyl)oxy)-1-((4R,5S,6S,E)-6-((tert-butyldimethylsilyl)oxy)-7-methoxy-5-
(methoxymethoxy)-4-methylhept-2-en-2-yl)-7-(methoxymethyl)-4-oxode-
cahydro-1,5-epoxynaphthalen-2-yl)malonate: To a solution of Na (6 mg,
0.263 mmol) in MeOH (0.8 mL) was added dimethyl malonate (0.18 mL,
1.579 mmol) at RT and the resulting mixture was stirred for 5 min. This
mixture was then cooled to - 218C and a solution of enone 125 (140 mg,
0.175 mmol) in MeOH (0.8 mL) was added. The mixture was warmed to
RT overnight, then diluted with Et2O and quenched with aq. saturated
NH4Cl. The water phase was extracted with Et2O (3ꢅ3 mL). The com-
bined organic layers were washed with brine, dried (MgSO4) and concen-
trated in vacuo to give a residue, which was purified by flash chromatog-
raphy (EtOAc/hexane) on silica gel to afford 144 mg (88%) of the Mi-
chael adduct as an oil. [a]2D0 = +42.4 (c=0.55, CHCl3); 1H NMR
(600 MHz, CDCl3): d=5.88 (d, J=10.0 Hz, 1H), 4.76 (d, J=6.6 Hz, 1H),
4.69 (d,J=6.6 Hz, 1H), 4.02–3.94 (m, 3H), 3.68 (s, 3H), 3.66 (s, 3H), 3.58
(d, J=2.6 Hz, 1H), 3.56 (dd, J=11.2, 2.5 Hz, 1H), 3.51 (dd, J=9.5,
4.7 Hz, 1H), 3.44 (dd, J=4.6, 4.6 Hz, 1H), 3.42 (s, 3H), 3.38 (dd, J=9.5,
6.4 Hz, 1H), 3.34 (s, 3H), 3.32–3.26 (m, 2H), 3.22 (s, 3H), 3.10 (dd, J=
17.4, 7.2 Hz, 1H), 3.04 (s, 1H), 2.94–2.87 (m, 2H), 2.87–2.80 (m, 1H),
2.56 (dd, J=17.4, 8.7 Hz, 1H), 2.42 (d, J=2.4 Hz, 1H), 1.71 (d, J=
1.1 Hz, 1H), 1.04 (d, J=7.0 Hz, 1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s,
9H), 0.08 (s, 3H), 0.06 (s, 3H), 0.04 (s, 6H), 0.03 (s, 3H), 0.00 ppm (s,
3H); 13C NMR (150.9 MHz, CDCl3): d=208.5, 169.6, 169.2, 133.0, 129.6,
100.1, 98.4, 89.8, 83.0, 80.9, 75.0, 73.3, 71.4, 69.9, 68.8, 58.9, 58.6, 55.9,
53.4, 52.8, 52.0, 49.6, 49.4, 42.2, 41.1, 37.1, 33.3, 26.3, 26.1, 26.0, 18.4, 18.3,
18.2, 16.7, 15.9, ꢀ3.2, ꢀ4.2, ꢀ4.4, ꢀ4.5, ꢀ5.3 ppm; IR (Si, film): n˜ = 2928,
2851, 1792, 1735, 1539, 1473, 1307, 1254, 1177, 1118, 1060, 1028, 949, 837,
794, 777, 676, 420, 418, 416, 403 cmꢀ1; HRMS (ESI): m/z: calcd for
C46H86O13Si3Na [M+Na]+: 953.5274; found: 953.5291.
(1S,4aS,7R,8R,8aR)-8-((4-Methoxybenzyl)oxy)-7-(methoxymethyl)-
1,2,4a,7,8,8a-hexahydronaphthalen-1-ol (113) and (1R,4aS,5S,6R,8aS)-5-
((4-methoxybenzyl)oxy)-6-(methoxymethyl)-1,2,4a,5,6,8a-hexahydronaph-
thalen-1-ol (114): A solution of [NiACHTNUTRGNENG(U cod)2] (420 mg, 1.52 mmol) in toluene
(dry and degassed; 25 mL) was added to (R)-BINAP (1.43 g, 2.29 mmol)
and the mixture was stirred at RT for 4 h. (NOTE: the solution became
dark burgundy red. Green or brown colors indicate presumably a partial
oxidation of Ni0 species and may result in lower selectivity.) To this bur-
gundy red solution a solution of rac-112 (2.50 g, 7.62 mmol) in toluene
(43 mL) was added (the color stayed dark burgundy red, but a weak
green-brown shade appeared) and the mixture was stirred for 30 min
Then DIBAL-H (1.0m in hexanes, 8.8 mL, 8.8 mmol) was added over 6 h
at 228C via a syringe pump. The reaction was allowed to stir for 1 h, then
saturated aq. sodium potassium tartrate (100 mL) was added and the
mixture was stirred for 30 min The organic phase was separated and the
water phase was extracted with Et2O (4ꢅ50 mL). The combined organic
phase was washed with brine, passed through a plug of cotton and the
solvents were removed in vacuo. The solid residue was triturated with
MeOH (50 mL), the solution was filtered to remove undissolved BINAP
and its oxides, and the filtrate was concentrated in vacuo. The residue
was subjected to flash column chromatography (EtOAc/hexane) to
obtain 114 (1.16 g, 46%) as yellowish crystals and a mixture of 113 with
(R)-BINAP monooxide. The latter mixture was resubjected to flash
column chromatography (EtOAc/toluene) to yield 113 (1.13 g, 45%) as
Macrolactonization of seco-acids 133a and b
(3R,4S,7R,7aR,9aR,10R,11R,12R,13R,13aS,13bS,E)-11,13-Bis((tert-butyl-
dimethylsilyl)oxy)-4-((S)-1-((tert-butyldimethylsilyl)oxy)-2-methoxyeth-
yl)-7,12-bis(methoxymethyl)-1,3-dimethyl-7,7a,9a,10,11,12,13,13a-octahy-
dro-3H-10,13b-epoxynaphthoACTHNUGRTENUNG[2,1-d]oxonin-6(4H)-one (134b): To seco-
acid 133a (6 mg, 0.007 mmol) was added a solution of 2,2’-dithiodipyri-
dine (0.43m in toluene, 150 mL, 0.064 mmol) and a solution of PPh3
(0.43m in toluene, 150 mL, 0.064 mmol), and the mixture was stirred at
RT for 14 h. The resulting mixture was diluted by toluene (5 mL) and
added via syringe pump to a solution of AgClO4 (44 mg, 0.214 mmol) in
toluene (15 mL) at 858C over 2 h. The resulting mixture was filtrated
through a pad of celite and the filtrate was concentrated in vacuo. The
residue was subjected to column chromatography (EtOAc/hexanes) to
obtain lactone 134a (2.4 mg, 40%). In the same manner 134b was pre-
pared from 133b.
134a: [a]2D0 = +173.3 (c=0.05, CHCl3); 1H NMR (400 MHz, CDCl3): d=
5.98 (ddd, J=9.2, 7.0, 2.0 Hz, 1H), 5.66 (dd, J=7.5, 1.0 Hz, 1H), 5.38
(dd, J=9.8, 2.5 Hz, 1H), 4.95 (dd, J=9.2, 6.2 Hz, 1H), 4.13 (ddd, J=8.9,
7.1, 2.0 Hz, 1H), 4.03–3.97 (m, 2H), 3.69 (dd, J=11.2, 1.8 Hz, 1H), 3.58–
3.51 (m, 2H), 3.46 (dd, J=8.6, 5.1 Hz, 1H), 3.41–3.33 (m, 2H), 3.33–3.25
(m, 1H), 3.31 (s, 3H), 3.29 (s, 3H), 3.24 (s, 3H), 3.07 (dm, J=9.5 Hz,
1H), 3.03–2.94 (m, 1H), 2.85–2.77 (m, 1H), 2.69 (d, J=7.0 Hz, 1H),
2.60–2.51 (m, 1H), 2.27 (s, 1H), 1.68 (s, 3H), 1.21 (d, J=6.9 Hz, 3H),
0.90 (s, 18H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H), 0.06 (s, 3H), 0.05 (s,
3H), 0.03 ppm (s, 6H); 13C NMR (150.9 MHz, CDCl3): d=177.9, 138.5,
134.2, 131.2, 127.1, 89.1, 84.2, 80.7, 76.0, 73.7, 72.5, 71.1, 70.3, 69.2, 59.2,
58.7, 58.4, 52.4, 50.0, 46.3, 41.1, 40.1, 32.3, 29.9, 26.4, 26.3, 26.0, 18.6, 18.5,
18.2, 17.4, 15.8, ꢀ3.5, ꢀ3.6, ꢀ4.3, ꢀ4.9, ꢀ5.1, ꢀ5.2 ppm; IR (Si, film): n˜ =
2955, 2929, 2857, 1721, 1472, 1389, 1361, 1252, 1211, 1116, 1084, 1057,
1031, 866, 837, 777, 668, 418, 404 cmꢀ1; HRMS (ESI): m/z: calcd for
C43H80O9Si3Na [M+Na]+: 847.5008; found: 847.5018.
1
a colorless oil. [a]2D0 = +146.2 (c=1.10, CHCl3); H NMR (400 MHz): d=
7.29 (brd, J=8.9 Hz, 2H), 6.88 (brd, J=8.9 Hz, 2H), 5.80–5.74 (m, 1H),
5.69–5.58 (m, 3H), 4.58 (d, J=11.4 Hz, 1H), 4.43 (d, J=11.4 Hz, 1H),
4.45–4.39 (m, 1H), 3.81 (dd, J=5.3, 9.7 Hz, 1H), 3.81 (s, 3H), 3.53–3.46
(m, 2H), 3.30 (s, 3H), 3.06–2.98 (m, 1H), 2.98–2.91 (m, 1H), 2.39–2.34
(m, 1H), 2.26–2.22 (m, 2H), 1.90 ppm (d, J=10.3 Hz, 1H, OH);
13C NMR (100.6 MHz): d=159.3, 131.0, 129.5, 128.8, 128.7, 128.5, 123.6,
113.9, 75.5, 73.3, 70.9, 64.2, 59.1, 55.4, 40.5, 37.5, 35.2, 34.8 ppm; IR (Si,
film): n˜ = 3480, 2890, 1513, 1247, 772 cmꢀ1; HRMS (ESI): m/z: calcd for
C20H26NaO4 [M+Na]+: 353.1729; found: 353.1733.
114: m.p. 104–1068C; [a]2D0 =ꢀ151.3 (c
=
1.6, CHCl3); 1H NMR
(400 MHz): d=7.25 (brd, J=8.7 Hz, 2H), 6.87 (brd, J=8.7 Hz, H), 5.79–
5.74 (m, 1H), 5.72–5.66 (m, 2H), 5.64–5.59 (m, 1H), 4.56 (d, J=11.3 Hz,
1H), 4.47 (d, J=11.3 Hz, 1H), 4.00–3.94 (m, 1H), 3.79 (s, 3H), 3.69 (dd,
J=3.6, 6.5 Hz, 1H), 3.45–3.33 (m, 2H), 3.31 (s, 3H), 2.91–2.84 (m, 1H),
2.69–2.63 (m, 1H), 2.26–2.10 (m, 2H); 13C NMR (100.6 MHz): d=159.3,
130.3, 129.6, 128.3, 126.2, 113.9, 75.7, 73.6, 71.2, 67.7, 59.0, 55.4, 40.5, 39.8,
134b:1H NMR (400 MHz, CDCl3): d=5.99 (ddd, J=9.3, 6.8, 2.4 Hz, 1H),
5.74 (dd, J=9.6, 1.0 Hz, 1H), 5.46 (dd, J=9.4, 2.4 Hz, 1H), 4.98 (dd, J=
7.2, 5.1 Hz, 1H), 4.15 (dd, J=10.1, 5.3 Hz, 1H), 4.06–3.98 (m, 2H), 3.95
(dd, J=4.8, 3.9 Hz, 1H), 3.64 (dd, J=11.3, 2.1 Hz, 1H), 3.50–3.47 (m,
Chem. Eur. J. 2012, 18, 9651 – 9668
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9665