124
M. R. Lefever et al. / Carbohydrate Research 351 (2012) 121–125
M = Sc, B, Strong Lewis Acids
X
H
X
M
X
O
O
O
MX3
ROH
OR
OAc
X
OAc
X
M
X
OAc
OAc
OAc
OAc
M = In – HOAc
Minimally Competent Lewis Acids
Scheme 1. Minimally competent Lewis acids such as InBr3 can dissociate (lower pathway) from the displaced acetate to form acetic acid and regenerate the Lewis acid
catalyst. Stronger Lewis acids remain associated with the acetate (upper pathway) to produce a Brønsted acid, and generally require a full equivalent of the Lewis acid.
2-Acetoxy
O
O
O
Participation
O
O
AcO
O
OAc
COOH
O
O
AcO
O
OAc
InBr3
O
O
O
O
AcO
InBr3
HN Fmoc
OAc
1
O
O
O
AcO
COOH
COOH
O
O
AcO
AcO
COOH
HN Fmoc
O
O
O
O
HN Fmoc
HN Fmoc
OAc
OAc
Ortho
Ester
2
5
Dioxocarbenium
Ion
Desired
⇓-Glycoside
1
OAc
AcO
AcO
AcO
O
COOH
COOH
O
COOH
O
O
AcO
O
O
O
AcO
OAc
HN Fmoc
HN Fmoc
OAc
HN Fmoc
OH
OH
6
3
4
Scheme 2. Participation by the 2-acetoxy group produces an intermediate that largely undergoes desired trans b-glycoside formation. Formation of an orthoester can
decompose in 3 ways, leading to the desired glycoside 1, or acyl transfer to the serine acceptor (cf. 4), which produces a 2-hydroxyl sugar oxonium ion that rapidly
glycosylates another acceptor in situ. Lactose b-peracetate and Fmoc-L-threonine have been used as well to provide 5 and 6 in good yields and without the use of molecular
sieves or chromatography.
The very reactive and non-bulky acceptor CH3OH leads to
cosides (Table 2, entries 1–12), and prolonged heating leads to
higher proportions of the -glycoside, especially in the presence
a-gly-
References
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S.; Bielfeldt, T.; Meldal, M.; Bock, K. Carbohydr. Res. 1995, 268, 17–34.
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a
of the stronger Lewis acid Sc(OTfl)3 that is not ‘minimally compe-
tent,’ requiring a full equivalent of this Lewis acid promotor such
as BF3ÁEt2O, SnCl4, or AgOTfl.1a,10–12 These observations are quite
consistent with what is known about the anomeric effect, and it
is not surprising that the axial glycosides ultimately predominate
as reaction times are extended. Further studies of minimally com-
petent Lewis acid promotors with more complex donors and other
acceptors are probably warranted.
3. Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005,
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4. Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199–6200.
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Acknowledgments
We thank the Office of Naval Research (N00014-05-1-0807 &
N00014-02-1-0471), the National Science Foundation (CHE-
607917) and the National Institutes of Health (NINDS-NS-
052727) for Support.
6. A 250 mL round bottom flask equipped with a magnetic stirrer and a reflux
condenser was charged with 17.8 g (45.6 mMol) b-glucose peracetate, 4.98 g
(15.2 mMol) Fmoc-L-serine, and 808 mg (1.52 mMol) InBr3. Next, 80 mL dry
PhCH3 and 8 mL dry (filtered through a plug of SiO2) CH2Br2 were added, and
the reaction was placed in an oil bath at 65–70 °C for 20 min until the starting
materials had dissolved forming a pink solution. The oil bath was heated to
110 °C and the reaction run for 3–4 h until the Fmoc-serine had disappeared by
TLC. The reaction was cooled, and the solvent evaporated to form a glassy solid,
which was redissolved in 250 mL dry EtOAc, washed 3Â with 75 mL saturated
NaHCO3, then extracted 3Â with 75 mL deionized H2O, alternating between
washing and extracting each time. The neutral extractions were combined, and
Supplementary data
Supplementary data associated with this article can be found, in
Lefever, Mark R.
