Angewandte
Chemie
which was confirmed by the characteristic values (3.5 Hz for
23 and 3.6 Hz for 22) for J1’,2’ coupling constants. Clearly, the
2-azido-2-glucose-a-d-glucosyl moiety worked as an addi-
tional powerful chiral auxiliary and facilitated the separation
of d- and l-myo-inositol derivatives.
sn-glyceryl hydrogenphosphonates 7 and 8 were synthesized
starting from commercially available 2,3-O-isopropylidene-
sn-glycerol 30, which was first alkylated with n-hexadecyl
iodide in the presence of NaH followed by acid hydrolysis to
produce 1-O-hexadecyl-sn-glycerol 31 (55%). This com-
pound was then successively silylated at the 3-hydroxy
group with Et3SiCl in pyridine, esterified with oleoyl or
linoleoyl chloride, and desilylated with 3HF·Et3N, thus
providing the 2-O-acylated glycerol derivatives 32 and 33,
respectively. Each of them was converted (almost quantita-
tively) to the corresponding hydrogenphosphonate derivative
(7 and 8, respectively) by reaction with triimidazolylphos-
phine[22] followed by hydrolysis.
For the transformation 23!6, first, the introduction of the
acid-labile 2-trimethylsilylethoxymethyl (SEM) permanent
protecting group at the O3’ position was needed. This was
performed through the mild basic deacetylation of 23
followed by orthoesterification with PhC(OEt)3 in mild
acidic conditions (to form the 4’,6’-orthoester derivative 24)
and reaction with SEM chloride in the presence of N,N-
diisopropylethylamine. Basic cleavage of the (ꢀ)-menthylcar-
bonate gave the 1-hydroxy derivative 25, which was then
successively silylated with TBSOTf/Et3N, hydrolyzed with
0.1% trifluoroacetic acid (TFA)/water in CH2Cl2 (10 min) to
open the orthoester (thus forming a mixture of 4’- and 6’-
acetates), deacetylated (with MeONa in MeOH; !26), and
silylated at the O6’ position with Et3SiCl in pyridine/CH2Cl2.
Thus, the azidoglucose–inositol block 6 was prepared from
compound 23 in seven steps in approximately 50% overall
yield.
The 2-azidoethylphosphonodichloridate 3 was prepared
(Scheme 4) from diethyl 2-bromoethylphosphonate 27
through the azidation reaction with NaN3 (!28) followed
by de-esterification with Me3SiBr and chlorination with oxalyl
chloride in the presence of N,N-dimethylformamide. The 2-
(N-Boc)-aminoethyl hydrogenphosphonate 4 was prepared
by the reaction of N-Boc-ethanolamine 29 with H3PO3 in the
presence of pivaloyl chloride.[21] The 2-O-acyl-1-O-hexadecyl-
With all the principal building blocks in hand, we pursued
the preparation of the target GPIs 1 and 2. First, the glycan–
inositol backbone 34 was prepared (Scheme 5) by the
glycosylation of the glycosyl acceptor 6 with the mannotet-
raose trichloroacetimidate 5 in the presence of TMSOTf and
4- molecular sieves. Subsequent cleavage of the TES group
(the “weakest” of the three silyl protecting groups) with acetic
acid-buffered tetrabutylammonium fluoride (TBAF)
smoothly gave the 6’-hydroxy pseudo-hexasaccharide deriv-
ative 35 (60% from 5), ready to turn to the “P-decoration”
procedures. 1H-Tetrazole-assisted esterification of 35 with the
phosphonodichloridate 3 followed by methanolysis afforded
the phosphonic diester 36 (79%) as a diastereomeric mix-
[
]
*
ture (dP = 28.5, 28.8). It was then a subject of successive
reduction of the azido groups with Ph3P, N protection with
Boc anhydride (!37), and selective cleavage of the primary
TBS ether with 3HF·Et3N, thus cleanly producing the 6’’’’-
hydroxy
glycan–inositol–phosphonate
compound 38 (80%). Furthermore, the
introduction of the ethanolamine phos-
phate moiety was performed by the con-
densation of 38 with the hydrogenphosph-
onate derivative 4 (activated by pivaloyl
chloride)[23] followed by in situ oxidation
with iodine in aqueous pyridine. The
phosphonate–phosphate block 39 was iso-
lated in 88% yield prior to the final
desilylation with TBAF/AcOH (at
558C), which gave the 1-hydroxy glyco-
conjugated derivative 40.
We reported earlier[24] that the pres-
ence of phosphodiester units in a molecule
still allows the next O-phosphorylation
step to be performed effectively by the
hydrogenphosphonate method (that is,
P protection for phosphodiesters is not
required). Indeed, compound 40 (contain-
ing a phosphodiester moiety at the O6’’’’
position) was successfully phospholipi-
Scheme 4. Reagents: a) NaN3, nBu4NHSO4 cat., toluene; b) TMSBr,
[*] The P protection was requiredat this stage to avoidundesired
modifications of the phosphonate moiety during further trans-
formations. Each of the methyl phosphonate derivatives 36–42 was
formedas a mixture of diastereomers at the phosphorus atom (in a
ratio of 1:1), as clearly indicated by the 31P NMR spectra (see
Supporting Information).
MeCN; c) (COCl)2, DMF cat., CH2Cl2; d ) HPO3, pivaloyl chloride,
3
pyridine; e) CH3(CH2)15I, NaH, DMF/THF; f) CF3COOH/water (9:1);
g) TESCl, pyridine, CH2Cl2; h) oleoyl chloride for 32 (or linoleoyl
chloride for 33), Et3N, DMAP, pyridine; i) 3HF·Et3N, MeCN/CH2Cl2;
j) triimidazolylphosphine, MeCN/CH2Cl2; k) Et3NHHCO , water (pH 7).
DMAP=4-dimethylaminopyridine, DMF=N,N-dimethyl3formamide.
Angew. Chem. Int. Ed. 2006, 45, 468 –474
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
471