8
9
diols were known to direct alkylation /acylation and sily-
1
0
lation to the C3 hydroxyl group, we decided to use the
,3-O-cis-stannylene acetal 15 to try to switch the regiose-
Scheme 5. Approach to Cleistrioside-6
2
lectivity of the Pd-catalyzed glycosylation. In practice, we
treated diol 14 with a slight excess of the in situ generated
Bu Sn(OMe) before proceeding with our normal Pd-
2 2
catalyzed glycosylation procedure. To our delight, exposure
of the stannylene acetal complex 15 and pyranone 11 to our
typical conditions gave the desired glycosylation product 17
in 76% yield (1:7, 16/17). Subsequent chloroacetylation of
the C2-hydroxyl group using chloroacetic anhydride in the
presence of catalytic amount of DMAP in pyridine provided
9
in excellent yield (97%).
With access to the key intermediate 9 for our proposed
divergent synthesis, we embarked on the synthesis of the
two cleistriosides (1 and 2) via postglycosylation/deprotection
sequences (Schemes 4 and 5). As before, a sequential Luche
switching a chloroacetylation for acetylation step in the
postglycosylation sequence of 9 gave 20 (66% yield, 3 steps).
A subsequent per-acetylation (21 in 97%) and similar
deprotection sequence generated the target cleistrioside-6
Scheme 4. Approach to Cleistrioside-5
(89% yield, 2 steps).
We believed that the key intermediate 9 from these two
syntheses could also be used for the further divergent
synthesis of the desired cleistetrosides (3-8). This would
require a further branching point at the above trisaccharides
1
9 and 20, which vary by an acetyl vs chloroacetyl group at
C4 in the third sugar (Schemes 6 and 7).
We first turned our attention to the synthesis of the five
required protected cleistetrosides (22-26) from the pivotal
intermediate 19 (Scheme 6). Sequential Pd-catalyzed gly-
4
cosylation, NaBH reduction and Upjohn dihydroxylation of
1
9 afforded the desired triol 22 (64% yield, three steps),
which was then peracetylated to give 23 (96% yield). By
incorporating an acylation step in the synthesis of 22
tetrasaccharide 25 was prepared from 19 (60% yield, four
steps). Whereas, the incorporation of two additional steps
(chloroacylation at C4 and orthoester mediated acylation of
the axial alcohol at C2) gave the tetrasaccharide 24 (44%
yield, 5 steps). Once again, using orthoester chemistry
(CH C(OCH ) /TsOH; AcOH/H O) on 25 allowed for the
reduction, acetylation and Upjohn dihydroxylation installed
the rhamno-stereochemistry producing diol 18 in 77% yield
(
for 3 steps). Selective acetylation of the C2 axial hydroxyl
group of diol 18 was successfully achieved using orthoester
chemistry forming 19 (CH C(OCH /p-TsOH then 90%
O, 96%). Removal of chloroacetyl group using
thiourea (3 equiv) in the presence of NaHCO (3.3 equiv.)
NI, followed by deprotection of the
3
3 3
)
1
1
AcOH/H
2
3
3 3
2
3
installation of a C2 acetyl group affording the desired C2/
C4 diacetate 26 in good yield (93%).
1
2
and catalytic Bu
acetonide group using 80% AcOH/H
4
2a
2
O furnished the target
We then turned our attention to the synthesis of the final
required protected cleistetroside (27) from the remaining
pivotal intermediate 20 (Scheme 7). As before, a selective
acetylation of the C2 hydroxyl group of diol 20 using
orthoester chemistry followed by sequential Pd-catalyzed
cleistrioside-5 (75% yield, two steps).
The same intermediate 9 was used to synthesize the other
trisaccharide, cleistrioside-6 (Scheme 5). For example,
(
8) (a) David, S.; Thieffry, A.; Veyrieres, A. J. Chem. Soc., Perkin Trans.
1981, 1796–1801. (b) Fernandex, P.; Jimenez-Barbero, J.; Martin-Lomas,
M. Carbohydr. Res. 1994, 254, 61–79.
9) (a) Ogawa, T.; Nozaki, M.; Matsui, M. Carbohydr. Res. 1978, 60,
4
glycosylation, NaBH reduction, and Upjohn dihydroxylation
generated triol 27 (58%, 4 steps).
1
(
C7–C10. Ogawa, T.; Matsui, M. Carbohydr. Res. 1977, 56, C1–C6. Ogawa,
T.; Matsui, M. Tetrahedron 1981, 37, 2363–2369. (b) Roelens, S. J. Org.
Chem. 1996, 61, 5257–5263. (c) Bredenkamp, M. W.; Spies, H. S. C.
Tetrahedron Lett. 2000, 41, 543–546. Bredenkamp, M. W.; Spies, H. S. C.;
van der Merwe, M. J. Tetrahedron Lett. 2000, 41, 547–550.
(11) (a) King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754–1769.
(b) Lowary, T. L.; Hindsgaul, O. Carbohydr. Res. 1994, 251, 33–67. (c)
Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem. 1999, 64,
2982–2983. (d) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.;
O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17–36.
(
10) Glen, A.; Leigh, D. A.; Martin, R. P.; Smart, J. P.; Truscello, A. M.
(12) (a) Clausen, M. H.; Madsen, R. Chem.sEur. J. 2003, 9, 3821–
3832. (b) Naruto, M.; Ohno, K.; Takeuchi, N. Tetrahedron Lett. 1979, 251.
Carbohydr. Res. 1993, 248, 365–369.
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