by the presence of the difficult and sensitive â-mannosyl
phosphate linkage. Here, through the efficient and highly
diastereoselective synthesis of the model phosphoisoprenoid
4, we demonstrate for the first time that such â-mannosyl
phosphates may be readily accessed by adaptation of our
general â-mannoside synthesis.4-6
propensity for anomerization to the R-anomer, the 41% yield
of 8 as an isolable, stable substance was considered very
encouraging.
Commercial phytol, a mixture of isomers, was reduced to
dihydrophytol (9) with hydrogen over Adams’ catalyst
quantitatively. This isomeric mixture was then coupled to
10, itself obtained in 94% yield from commercial 2-cyano-
ethyl N,N-diisopropylchlorophosphoramidite and benzyl
alcohol in the presence of Hunig’s base, and tetrazole to give
11, followed by oxidation to 12 with tert-butyl hydroperoxide
in 96% yield for the two-step sequence (Scheme 2).
Treatment of 12 with tetrabutylammonium hydroxide in a
dichloromethane/water biphasic system then afforded salt 13
quantitatively.
As â-mannosyl phosphates had frustrated the efforts of
several other groups, giving, for example, single digit yields
by the Schmidt trichloroacetimidate method,7 and escaping
others altogether,8,9 we saw fit to begin our investigation with
a model study. To this end dibutylphosphoric acid was
converted to its tetrabutylammonium salt and allowed to
react, at -78 °C, with the mannosyl sulfoxide 5,5 which had
been previously activated with triflic anhydride and, so,10
converted to the R-triflate 6. After workup, a 1/1 mixture of
the anomeric phosphates 7 and 8 was obtained from which
the desired â-isomer was isolated in 41% yield (Scheme 1).
Scheme 2. Synthesis of the Ammonium Phosphate 13
Scheme 1. Synthesis of the Dibutyl Phosphates 7 and 8
Coupling of 13 with preformed 6 in dichloromethane at
-78 °C was slower than the analogous coupling with dibutyl
phosphate and resulted in the isolation of 63% of the
R-anomer 14 and a disappointing 11% of the desired 15.
Nevertheless, 15 was isolable and did not undergo ready
epimerization to 14 unless exposed to acid (Scheme 3). Both
anomers, 14 and 15, were approximately 1/1 mixtures of
The anomeric configuration of 7 and 8 was readily estab-
lished by comparison of the JCH coupling at the anomeric
1
carbons11 (176.7 and 161.4 Hz, respectively), as well as by
the NOE correlation between H’s 1, 3, and 5 in 8. Moreover,
H5 in the 4,6-O-benzylidene-protected â-mannoside 8 was
found to resonate at δ 3.47 in CDCl3, which is a characteristic
feature of â-mannosides with this protecting system.5 Given
the difficulties previously recorded in the literature for the
synthesis of â-mannosyl phosphates, as well as their reported
Scheme 3. Synthesis of the â-Mannosyl Phosphoisoprenoid 4
(4) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
(5) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(6) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435-436.
(7) Schmidt, R. R.; Stumpp, M. Liebigs 1984, 680-691.
(8) Garcia, B. A.; Gin, D. Y. Org. Lett. 2000, 2, 2135-2138.
(9) The â-selective (4/1) phosphorylation of 2,3,4,6-tetra-O-acetyl-
mannopyranose with limiting diphenyl chlorophosphidate has been re-
ported: Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169-185. It is
highly unlikely that this method can be extended to the significantly less
reactive dialkyl chlorophosphidates required for the synthesis of the present
targets. Other groups typically report R-selective phosphorylation of
mannose in this type of process even with diphenyl chlorophosphidate, e.g.,
Boger, D. L.; Teramoto, S.; Zhou, J. J. Am. Chem. Soc. 1995, 117, 7344-
7356.
(10) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
(11) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-
297.
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Org. Lett., Vol. 2, No. 24, 2000