COMMUNICATIONS
Table 1. Selected physical and spectroscopic data of compounds 35, 44, and
2.
linkage between rings F and G, a challenge that was solved by
applying our recently developed methodology for 1 !1'-
disaccharide construction. Thus, the coupling of tin acetal 7
with trichloroacetimidate 8 (Scheme 5) proceeded smoothly
under the catalytic influence of TMSOTf in CH2Cl2 leading,
after PPTS-induced cleavage of the intermediate TMS ether,
to disaccharide 29 in 74% overall yield. As expected from our
previous findings[3] the 1 !1'-disaccharide linkage was formed
in a completely stereocontrolled fashion, furnishing 29 as a
single isomer. The free hydroxyl group in 29 was methylated
(NaH/MeI, 87% yield) and the benzoyl group at C2 of ring G,
which played a crucial role in directing the stereochemical
outcome of the glycoslylation reaction, was removed by
treatment with NaOH in MeOH to afford alcohol 30 (95%
yield). For strategic reasons, a benzyl group was installed on
the hydroxyl group of 30 (NaH/BnBr/nBu4NI, 90% yield) to
afford 31, and the PMB group of ring F was replaced with a
TIPS group (DDQ, 91% yield; TIPSOTf/2,6-lutidine, 97%
yield) to furnish compound 32. Removal of the allyl protect-
ing groups from 32 required initial treatment with Wilkinsonꢁs
catalyst and DABCO, followed by cleavage of the resulting
enol ethers with OsO4/NMO, to furnish 5 in 81% overall
yield. Despite the nonselective differentiation of the two
hydroxyl groups of 5Ðeven with the tin acetal technology,[5]
which led to hydroxychloroacetate 33 (nBu2SnO/CACl, 97%
yield) and its regioisomer (approximately 1:1 ratio)Ðan
efficient pathway to the next stage was secured. Thus, while
the indicated regioisomer (33) was used directly as a
carbohydrate acceptor in a glycosidation reaction with
glycosyl fluoride 6 (SnCl2, Et2O) to give trisaccharide 34
(92% yield) stereoselectively, its regioisomer required further
manipulation prior to being used in the forward sequence.
Specifically, the C4 regioisomer of 33, was benzoylated (BzCl/
Et3N/4-DMAP, 94%) and the chloroacetate group was re-
moved (Et3N/MeOH (1/3), 90% yield) leading to the C3
benzoate counterpart of 33. This compound was then sub-
jected to the same coupling procedure with 6 to afford the
benzoate analogue of trisaccharide 34 (90% yield). Cleavage
of the ester group from 34 (or its benzoate analogue) with
K2CO3 in MeOH led to alcohol 35 in 98% yield (Table 1),
which was now poised for a SinayÈ orthoester formation.[2]
Thus, having assisted in the construction of the glycoside
bond linking rings G and H, the 2-phenylseleno group was
now utilized to prepare the ground for the formation of the
second C O bond between these two rings. To ensure the
stereochemistry of the expected orthoester bond between
rings G and H, we had to rely on the anomeric effect,[13] which
is maximized in the sequence adopted for the formation of the
two C O bonds (see Figure 3). Extensive model studies
demonstrated that the correct orthoester stereochemistry
could only be obtained by first attaching the H ring to the C4
oxygen atom of ring G and then constructing the second
oxygen bridge (C3), rather than the other way around (which
leads to the opposite orthoester stereochemistry, see Fig-
ure 3). Thus, oxidation of the phenylseleno group with NaIO4
followed by heating the crude selenoxide in a mixture of vinyl
acetate/toluene/diisopropylamine (2/2/1) in a sealed tube at
1408C effected sequential syn-elimination at the anomeric
position and ring closure[2] to furnish orthoester 36 in 81%
35: Rf 0.18 (silica gel, 50% EtOAc in hexanes); aD22
22.7 (c 2.7,
CHCl3); IR (thin film): nÄmax 3451, 3051, 2930, 2863, 1612, 1582, 1513, 1463,
1383, 1357, 1304, 1251, 1110, 1031, 942, 885, 883 cm 1; 1H NMR (600 MHz,
CDCl3): d 7.55 (d, J 7.1, 2H, ArH), 7.39 ± 7.25 (m, 12H, ArH), 7.15 (t,
J 7.8 Hz, 2H, ArH), 7.06 (t, J 7.3 Hz, 1H, ArH), 6.86 (d, J 8.6, 2H,
ArH (PMB)), 5.16 (d, J 1.7, 1H, G-1), 4.87 and 4.69 (AB, J 12.2 Hz, 2H,
CH2Ar), 4.80 (d, J 9.1, 1H, H-1), 4.69 and 4.40 (AB, J 11.1 Hz, 2H,
CH2Ar), 4.66 (s, 1H, F-1), 4.61 and 4.47 (AB, J 12.1 Hz, 2H, CH2Ar), 4.30
(brs, 1H, H-3), 4.01 ± 3.92 (m, 5H, G-4, F-4, H-5, H-5, G-2), 3.83 ± 3.79 (m,
1H, G-3), 3.80 (s, 3H, OMe (PMB)), 3.71 ± 3.68 (m, 2H, G-5, F-6), 3.61 (dd,
J 9.1, 2.7 Hz, 1H, H-2), 3.56 (dd, J 10.5, 6.1 Hz, 1H, F-6), 3.51 (d, J
2.6 Hz, 1H, F-2), 3.47 (s, 3H, OMe (F-2)), 3.33 ± 3.31 (m, 2H, F-3, F-5), 3.32
(s, 3H, OMe (F-6)), 3.22 (brs, 1H, H-4), 3.15 (t, J 10.9 Hz, 1H, G-5),
1.02 ± 0.96 (m, 21H, (iPr)3Si), 0.90 (s, 9H, tBuSi), 0.14 (s, 3H, MeSi), 0.07
(s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d 159.4, 138.4, 138.0, 131.6,
131.6, 129.6, 129.4, 128.5, 128.4, 128.2, 128.1, 127.6, 127.5, 127.4, 127.4, 127.2,
126.0, 113.9, 102.8, 95.6, 95.2, 82.2, 78.9, 77.4, 76.8, 76.3, 74.4, 73.6, 72.9, 71.9,
70.8, 70.5, 70.1, 68.0, 63.4, 61.5, 60.3, 59.0, 55.2, 48.4, 25.7, 18.2, 18.0, 18.0,
18.0, 13.2, 13.0, 4.4, 4.8; HR-MS (FAB), calcd for C61H90O14SeSi2Cs
[M Cs]: 1315.4089, found: 1315.4022
44: Rf 0.34 (silica gel, 50% EtOAc in hexanes); aD22
19.2 (c 0.12,
CHCl3); IR (thin film): nÄmax 3448, 2943, 2861, 1725, 1614, 1514, 1455, 1372,
1
1308, 1255, 1108, 1079, 1032, 843, 779 cm 1; H NMR (600 MHz, CDCl3):
d 8.04 (d, J 7.1, 2H, ArH), 7.61 (t, J 7.4 Hz, 1H, ArH), 7.47 (t, J
7.9 Hz, 2H, ArH), 7.37 ± 7.29 (m, 10H, ArH), 7.12 (d, J 8.6, 2H, PMB),
6.75 (d, J 8.6, 2H, PMB), 5.42 (t, J 9.2 Hz, 1H, H-3), 5.34 (s, 1H, G-1),
4.87 and 4.66 (AB, J 11.6 Hz, 2H, CH2Ar), 4.67 (s, 1H, F-1), 4.63 and 4.56
(AB, J 11.5 Hz, 2H, CH2Ar), 4.53 and 4.50 (AB, J 11.0 Hz, 2H,
CH2Ar), 4.48 (ddd, J 10.5, 10.5, 4.5 Hz, 1H, G-4), 4.33 (brs, 1H, G-2),
4.11 (dd, J 9.6, 4.5 Hz, 1H, G-5), 4.00 (dd, J 10.2, 2.3 Hz, 1H, G-3), 3.90
(dd, J 11.4, 5.4 Hz, 1H, H-5), 3.87 (t, J 9.0 Hz, 1H, F-4), 3.82 ± 3.76 (m,
3H, H-2, H-4, G-5), 3.76 (s, 3H, OMe (PMB)), 3.69 (t, J 10.7 Hz, 1H,
H-5), 3.62 (dd, J 10.4, 1.8 Hz, 1H, F-6), 3.55 (dd, J 10.8, 5.3 Hz, 1H,
F-6), 3.52 (s, 3H, OMe (F-2)), 3.49 (brs, 1H, F-2), 3.33 (s, 3H, OMe (F-6)),
3.29 ± 3.27 (m, 2H, F-3, F-5), 2.49 (d, J 8.3 Hz, 1H, OH), 0.86 (s, 9H,
tBuSi), 0.04 (s, 3H, MeSi), 0.03 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3):
d 167.1, 159.4, 137.9, 137.8, 133.4, 129.9, 129.5, 129.5, 128.4, 128.3, 128.3,
127.8, 127.7, 127.7, 127.6, 119.3, 113.8, 95.7, 82.0, 81.7, 77.1, 76.7, 75.8, 73.6,
73.4, 72.7, 71.9, 71.4, 71.4, 69.7, 67.5, 63.3, 62.5, 61.8, 59.0, 55.2, 29.7, 25.9,
18.1, 3.7, 5.1; HR-MS (FAB), calcd for C53H68O16SiNa [M Na ]:
1011.4174, found: 1011.4205
2: Rf 0.21 (silica gel, 60% EtOAc in hexanes); aD22
5.7 (c 0.14,
CHCl3); IR (thin film): nÄmax 3448, 2955, 2919, 2872, 1725, 1602, 1449, 1378,
1
1255, 1155, 1108, 1049, 932, 738 cm
;
1H NMR (600 MHz, CDCl3): d
7.39 ± 7.23 (m, 20H, ArH), 6.43 (s, 2H, ArH (A2)), 5.44 (ddd, J 9.7, 9.7,
5.5 Hz, 1H, H-4), 5.33 (d, J 0.8 Hz, 1H, G-1), 5.18 (s, 1H, OCH2O), 5.05
(s, 1H, OCH2O), 5.02 (s, 2H, CH2Ar (A2)), 5.00 (s, 2H, CH2Ar (A2)), 4.77
and 4.61 (AB, J 11.7 Hz, 2H, CH2Ar), 4.75 and 4.66 (AB, J 11.9 Hz, 2H,
CH2Ar), 4.69 (s, 1H, F-1), 4.54 (ddd, J 10.5, 10.5, 4.5 Hz, 1H, G-4), 4.29
(brs, 1H, G-2), 4.18 (dd, J 9.7, 4.6 Hz, 1H, G-5), 4.12 (dd, J 11.3, 5.4 Hz,
1H, H-5), 4.05 (dd, J 10.2, 2.4 Hz, 1H, G-3), 3.94 (t, J 9.8 Hz, 1H, H-3),
3.88 (t, J 9.5 Hz, 1H, F-4), 3.82 (dd, J 10.6, 10.6 Hz, 1H, G-5), 3.70 (dd,
J 10.5, 3.7 Hz, 1H, F-6), 3.63 (dd, J 10.5, 5.1 Hz, 1H, F-6), 3.61 ± 3.59
(m, 2H, F-2, H-2), 3.60 (s, 3H, OMe (F-2)), 3.56 (dd, J 11.3, 9.7 Hz, 1H,
H-5), 3.37 (s, 3H, OMe (F-6)), 3.36 ± 3.34 (m, 2H, F-3, F-5), 2.72 (brs, 1H,
OH), 2.32 (s, 3H, Me (A2)); 13C NMR (150 MHz, CDCl3): d 166.8, 160.6,
157.3, 138.7, 137.7, 137.5, 136.3, 136.3, 128.6, 128.4, 128.3, 128.1, 128.0, 127.8,
127.7, 127.5, 127.4, 127.0, 119.1, 115.8, 108.1, 98.2, 96.7, 96.0, 96.0, 81.3, 81.0,
77.4, 75.6, 74.9, 73.2, 72.4, 71.8, 70.3, 70.1, 70.1, 69.6, 67.8, 63.4, 63.4, 61.8,
59.3, 53.8, 29.6, 29.6, 27.7, 20.0, 14.1, 14.0; HR-MS (FAB), calcd for
C55H60O17Cs [M Na ]: 1015.3728, found: 1015.3735
yield and with a diastereoselectivity of approximately 8:1. The
stereochemistry of the orthoester linkage in this series of
compounds was determined by NMR spectroscopic techni-
ques and correlation with a structure of one such isomer
determined unambiguously by X-ray crystallographic analysis
Angew. Chem. Int. Ed. 1999, 38, No. 22
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