346
E.G. Dennis et al. / Tetrahedron 68 (2012) 340e348
temperature in the cold bath over 3 h. The mixture was poured into
satd aq NaHCO3 (10 mL)/EtOAc (20 mL) and stirred vigorously for
10 min. The phases were separated and the organic phase was se-
quentially washed with water (20 mL) and brine (20 mL), then
dried (Na2SO4), filtered and concentrated. The residue was then
purified by silica gel chromatography (EtOAc/hexanes 1:4) to pro-
vide title compound 13 (190 mg, 90%) as a white foamy solid after
solvent removal. 1H NMR (600 MHz, CDCl3) 90:10 mixture of major
added dropwise over 5 min. The resulting mixture was allowed to
stir at ꢁ78 ꢀC for 1 h, before being slowly warmed to 0 ꢀC in the cold
bath over 4 h. Water (5 mL) was then added dropwise over 10 min
with stirring and the resulting mixture was poured into EtOAc
(100 mL)/ice (ca. 50 g) and allowed to warm to room temperature
with stirring over 30 min. The phases were separated and the or-
ganic layer was washed sequentially with water (25 mL) and brine
(25 mL), then dried (Na2SO4), filtered and concentrated. Purifica-
tion of the orange residue by gradient silica chromatography
(EtOAc/hexanes 1:4 to 1:2) provided boronic acid 17 (1.30 g, 65%) as
a white, foamy solid after solvent removal. 1H NMR (400 MHz,
and minor product.
d (major product only) 7.51e7.24 (m, 19H),
7.18e7.08 (m, 4H), 7.01 (d, 1H, J¼8.3 Hz), 6.97 (m, 2H), 6.70 (d, 2H,
J¼7 Hz), 6.14 (s, 1H, C6eH), 6.04 (br s, 1H, TMB CeH), 5.98 (br s, 1H,
TMB CeH), 5.25 (s, 2H, OeCH2ePh), 5.17 (q, 2H, J¼12 Hz,
OeCH2ePh), 5.06 (d, 1H, J¼12 Hz, OeCH2ePh), 5.04 (d, 1H, J¼12 Hz,
OeCH2ePh) 4.85 (d, 1H, J¼8.2 Hz, C4eH), 4.78 (d, 1H, J¼11.5 Hz,
OeCH2ePh), 4.68 (d, 1H, J¼9.72 Hz, C2eH), 4.55 (d, 1H, J¼11.5 Hz,
OeCH2ePh), 3.95 (dd, 1H, J¼9.7 and 8.2 Hz, C3eH), 3.82 (s, 3H,
TMBeOMe), 3.72 (d, 1H, J¼6 Hz, OeCH2ePh), 3.59 (d, 1H, J¼6 Hz,
OCH2Ph), 3.47 (br s, 3H, TMBeOMe), 3.36 (br s, 3H, TMBeOMe).
CDCl3) d 7.31e7.22 (m, 23H), 7.05e6.93 (m, 7H), 6.27 (s, 1H, C6eH),
5.19 (s, 2H), 5.11e5.07 (m, 6H), 4.85 (d, 1H, J¼8.04 Hz, C2eH), 4.28
(d, 1H, J¼12 Hz, C3eOeCH2ePh), 4.14 (d, 1H, J¼12 Hz,
C3eOeCH2ePh), 3.73 (m, 1H, C3eH), 3.03 (dd, 1H, J¼16.6 and
5.6 Hz, C4eH), 2.70 (dd, 1H, J¼16.6 and 8.7 Hz, C4eH). 13C NMR
(100 MHz, CDCl3) d164.1, 160.4, 159.6, 149.1, 149.0, 137.7, 137.1, 137.0,
136.3, 135.5, 131.2, 130e125 (Benzyl AreH), 120.2, 115.0, 113.4,
103.4, 91.3 (C6), 80.7 (C2), 73.8 (C3), 71.6, 71.3 (x2), 71.2, 70.0, 26.1
13C NMR (125 MHz, CDCl3)
d (major product only) 159.3
(TMBeCqeOMe), 159.2 (TMBeCqeOMe), 158.3 (TMBeCqeOMe),
156.0, 153.9, 153.7, 148.56, 148.51, 137.8, 137.33, 137.24, 136.8, 136.6,
132.4, 129e126 (Benzyl AreH), 120.6, 114.7, 114.2, 113.5, 111.3, 94.5
(C8), 92.7 (C6), 91.7 (TMBeCeH), 90.9 (TMBeCeH), 81.4
(OeCH2ePh), 81.3 (C2), 73.9 (C3), 71.3 (OeCH2ePh), 71.07
(OeCH2ePh), 71.00 (OeCH2ePh), 70.3 (OeCH2ePh), 36.4 (C4).
HRMS (ESI) calculated for C59H5379BrO9 [MþNaþ],1007.2765; found
1007.2767. FTIR (thin film): 3062, 3031, 2935, 2876, 2836, 1599,
1513, 1496, 1454, 1415, 1338, 1203, 1120, 1027, 811, 736, 698.
(C4). 11B NMR (126 MHz, CD3CN)
d 29.1. HRMS (ESI) calculated for
C50H4511BO8 [MþNHþ4 ], 802.3546; found, 802.3553. FTIR (thin
film): 3519, 3063, 3032, 2928, 2871, 1600, 1580, 1515, 1497, 1454,
1426, 1302, 1265, 1174, 1098, 1027, 763, 697.
4.4.8. 8-Bromo-3,5,7,30,40-penta-O-benzyl-catechin-4
a/8-
3,5,7,30,40-penta-O-benzyl-catechin (5). To a stirring solution of 6
(0.65 g, 0.71 mmol) and 17 (0.66 g, 0.89 mmol) in THF (7 mL) at
ꢁ78 ꢀC, neat TMSOTf (140
mL, 7.7 mmol) was added dropwise and
stirring was continued at ꢁ78 ꢀC for 1 h. The reaction was then
allowed to warm to room temperature in the cold bath over 3 h. The
mixture was poured into satd aq NaHCO3 (10 mL)/EtOAc (30 mL)
and stirred vigorously for 10 min. The phases were separated and
the organic phase was sequentially washed with water (20 mL) and
brine (20 mL), then dried (Na2SO4), filtered and concentrated. The
residue was then purified by silica gel chromatography to provide
dimer 5 (1.05 g, 95%) as a white foamy solid after solvent removal.
1H NMR (600 MHz, CDCl3, two rotamers: maj/min w75:25)
4.4.5. 3,5,7,30,40-Penta-O-benzyl-(þ)-catechin (4). The title com-
pound was prepared by an adaption of the procedure described
above for 5,7,30,40-tetra-O-benzyl-(þ)-catechin (9).
NaH (4.67 g, 117 mmol, 60% dispersion in mineral oil, 6 equiv)
and BnCl (15.6 mL, 135 mmol, 7 equiv) were added to a solution of
(þ)-catechin 8 (5.61 g, 19.3 mmol) in DMF (120 mL) at ꢁ78 ꢀC. The
resulting mixture was stirred at ꢁ78 ꢀC for 15 min, then warmed to
room temperature and stirred for a further 24 h. The mixture was
then quenched and extracted using the same procedure as for that
of 9. Filtration of the residue over SiO2 (CH2Cl2/hexane 1:1 eluted
mineral oil and excess BnCl, then CH2Cl2 eluted product) afforded
pentabenzylcatechin 4 (13.0 g, 91%) as a white foamy solid after
solvent removal. 1H and 13C NMR spectra of the product matched
that reported by Kikuchi et al. for the title compound 4.26
d
7.61e6.86 (m, AreH, B, E-ring-H, maj and min) 6.79e6.74 (m, B, E-
ring-H, maj and min), 6.65 (d, J¼7.2 Hz), 6.58 (d, J¼7.2 Hz) 6.43 (m,
maj and min), 6.37 (s, D6eH, min), 6.31 (s, D6eH, maj), 6.22 (s,
A6eH, maj), 6.15 (s, A6eH, min), 5.30e4.52 (m, OeCH2ePh, maj
and min), 4.89 (d, J¼8.2 Hz, C4eH, maj), 4.65 (d, J¼9.3 Hz, C2eH,
maj and min), 4.26 (d, J¼12 Hz, OeCH2ePh, maj), 4.18 (d, J¼12 Hz,
OeCH2ePh, maj), 4.08 (dd, J¼9.3 and 8.2 Hz, C3eH, maj), 4.03e3.94
(m, C3eH, min and OeCH2ePh, min), 3.83 (d, J¼11.52 Hz,
C3eOeCH2ePh, maj), 3.74 (d, J¼9.2 Hz, F2eH, maj), 3.59 (d,
J¼11.52 Hz, C3eOeCH2ePh, maj), 3.51e3.42 (m), 3.35 (d,
J¼10.6 Hz), 3.26 (dd, J¼15.9 and 5.8 Hz, F4eH, maj), 3.21 (dd, J¼15.9
and 5.8 Hz, F4eH, min), 2.68 (dd, J¼16.4 and 10.1 Hz, F4eH, min),
2.54 (dd, J¼16.4 and 10.1 Hz, F4eH, min) 13C NMR (125 MHz, CDCl3)
4.4.6. 8-Bromo-3,5,7,30,40-penta-O-benzyl-catechin (15). The title
compound was prepared by an adaption of the procedure for the
same compound reported by Kozikowski et al.16
To a stirring solution of 4 (4.98 g, 6.7 mmol) in CH2Cl2 (100 mL)
at 0 ꢀC, NBS (1.32 g, 7.4 mmol) was added as a solid. The mixture
was then allowed to slowly warm to room temperature in the ice
bath with continuous stirring for 4 h. The reaction was quenched by
the addition of aq Na2S2O3$5H2O (1 g in 30 mL water) and the
resulting mixture was vigorously stirred at room temperature for
10 min. The phases were separated and the aqueous phase was
extracted with CH2Cl2 (2ꢂ20 mL). The combined organic extracts
were dried (Na2SO4), filtered and concentrated. Filtration of the
residue over SiO2 (CH2Cl2) provided the desired product (5.27 g,
96%) as a white foamy solid after solvent removal. 1H and 13C NMR
spectra of the product matched that reported by Kozikowski et al.
for the title compound 15.16
(major isomer only)
d
157e153, 149e148 (CeB30, CeB40, CeE30,
CeE40, maj and min), 138.5e133.6 (Bn CqPh, maj and min), 133.1,
132.6, 132.1, 131.6, 130e127 (Benzyl AreH, maj and min), 121.2,
120.53, 120.45, 119.6, 115.3, 114.8, 114.5, 114.3, 113.8, 113.1, 112.6,
112.0 (CeD8, min), 112.0 (CeD8, maj), 110.9, 110.8, 93.39 (CeA8,
maj), 93.94 (CeA8, min), 93.28e93.27 (CeA6, maj and min), 93.10
(CeD6, min), 90.88 (CeD6, maj), 81.6 (CeC2, maj), 81.1 (CeC2, min),
80.8 (CeF2, maj), 79.6 (CeF2, min), 79.2, 78.4, 75.5, 75.1, 74.4, 72.7,
72.4, 72e69 (Bn OeCH2ePh), 36.52 (CeC4, min), 36.51 (CeC4, maj),
27.8 (CeF4, min), 27.5 (CeF4, maj). HRMS (ESI) calculated for
C100H8579BrO12 [MþNH4þ], 1574.5563; found, 1574.5579. FTIR (thin
film): 3062, 3030, 2930, 2870, 1601, 1514, 1498, 1454, 1418, 1380,
1213, 1171, 1117, 1027, 735, 697.
4.4.7. 3,5,7,30,40-Penta-O-benzyl-catechin-8-boronic acid (16). To
a stirring solution of 16 (2.09 g, 2.56 mmol) in THF (25 mL) at
ꢁ78 ꢀC, n-BuLi (2.10 mL, 1.35 M in hexanes, 2.84 mmol) was added
dropwise over 2 min. The resulting deep yellow solution was stirred
4.4.9. (þ)-Catechin-4
a
/8-(þ)-catechin (1). Using the conditions
at ꢁ78 ꢀC for 15 min, then neat B(OMe)3 (600
mL, 5.38 mmol) was
specified by Tarascou et al.,13 compound 5 (0.20 g, 0.13 mmol),