Communication
anomeric Bn protecting group was performed by Pd-
C catalyzed hydrogenation reaction to afford a mix-
ture of a/b-anomers, which were subjected to a-se-
lective phosphite formation using dibenzyl N,N-diiso-
propylphosphoramidite and 5-(ethylthio)-1H-tetra-
zole. The generated a-phosphite intermediate was
oxidized with tBuO2H to afford the a-phosphate 10
in 70% overall yield for three steps. Deprotection of
the 2-(phenylsulfonyl)ethanol protecting group of 10
was achieved by treatment with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to furnish the a-phosphoryl
GlcNAc-MurNAc-monopeptide derivative. The tetra-
peptide,
HCl·H-l-Ala-g-d-Glu(OMe)-l-Lys(COCF3)-d-
Ala-d-Ala-OMe (11) was synthesized in water media
with water-soluble reagents (glyceroacetonide-
Oxyma (12), EDCI, and NaHCO3; see Supporting Infor-
mation).[11] Coupling of the free carboxylic acid a-
phosphoryl GlcNAc-MurNAc-monopeptide with the
tetrapeptide 11 under mild conditions (12, EDCI, and
NaHCO3) in H2O yielded the a-phosphoryl GlcNAc-
MurNAc-pentapeptide 13 in over 90% overall yield
from 10. Conveniently, all reagents and excess tetra-
peptide used in this step could be removed with
a basic water work-up. Hydrogenolytic debenzyla-
tions of 10 followed by the treatment with Et3N re-
sulted in the corresponding monotriethylammonium
Scheme 1. One-pot protection–glycosylation to synthesize GlcNAc-MurNAc-peptide 7.
PS=polystyrene, MS=molecular sieves.
6a in 75–85% yield in a one-pot two-step strategy (Scheme 1).
It is worth mentioning that the (2,6-dichloro-4-methoxyphen-
yl)(2,4-dichlorophenyl)methyl ether protecting group possesses
a characteristic UV absorption, and isolation of the disaccharide
7d from the crude reaction mixture with chromatography was
relatively simple compared to 7c (Entry 2 in Table 1).
phosphate 14 in quantitative yield, whose structure was estab-
lished by 1H NMR analysis. Triethylammonium phosphate 14
was then applied to a carbonyldiimidazole (CDI) promoted di-
phosphate-formation reaction.[4e,f] Triethylammonium a-phos-
phoryl GlcNAc-MurNAc-pentapeptide 14 was first activated
with CDI and the excess CDI was quenched with MeOH to
afford 1H-imidazole-1-carboxylic (phosphoric) anhydride and
methyl 1H-imidazole-1-carboxylate, which was not reactive
against the phosphate nucleophiles. All volatiles were exten-
sively removed and the resulting mixture was subjected to the
cross-coupling reaction with the ammonium undecaprenyl
phosphate (15) or neryl phosphate (16). Progress in the cou-
pling reactions was monitored with reverse-phase HPLC
(0.05m NH4HCO3:MeOH to MeOH for lipid II). The reaction mix-
ture was lyophilized and the fully protected product was sub-
jected to global deprotection reactions with aq. LiOH. Lipid II
(1) was synthesized in 45% overall yield from 13 after purifica-
tion with reverse-phase HPLC. The structure of 1 was con-
In order to further facilitate the synthesis of the key inter-
mediate iv in Figure 2, (2,6-dichloro-4-alkoxyphenyl)(2,4-di-
chlorophenyl)methyl trichloroacetimidate linker resin 4 was ap-
plied to a one-pot two-step strategy for the synthesis of iii
(Figure 2).[10] Loading of the diol 6a onto the linker resin 4 was
completed with BF3·OEt2 (5 equivalents) at room temperature
in 1 h; in this step, progress of the reaction was monitored by
measuring the consumption of 6a with LC-MS. Once the load-
ing step was completed, the imidate 5a was added into the
reaction mixture to afford the desired b-glycoside resin 7e in
65–80% yield which was determined based on the isolated 7a
(Table 1) after the cleavage of 7e with 30% trifluoroacetic acid
(TFA) in CH2Cl2 for 1 h. Accordingly, convenient synthetic pro-
cedures for 7d and 7e for the syntheses of lipid II analogues
were accomplished. The other convenient feature of (2,6-di-
chloro-4-alkoxyphenyl)(2,4-dichlorophenyl)methyl ether pro-
tecting group and linker is that they can be deprotected or
cleaved simultaneously when the N-Troc group is removed
under reductive conditions. The N-Troc and C6-ether protect-
ing group or linker of 7d or 7e were deprotected with Zn in
30% TFA-AcOH to furnish the amino alcohol 8 (Scheme 2).
Acetylations of the free amine and alcohol of 8 afforded 9 in
85–90% yield from 7d or 7e. a-Phosphorylation and diphos-
phate ester formation of 9 were carried out using established
protocols with minor modifications. Deprotection of the
1
firmed by H NMR, negative ESI-TOF-MS spectroscopy, and re-
tention time in HPLC analysis.[4e] Similarly, neryl-lipid II ana-
logue (2) could be synthesized in 75% overall yield by using
excess ammonium neryl phosphate (16). The dansyl group was
conjugated to the Ne-lysine moiety of 2 with 4-(dansylamino)-
phenyl isothiocyanate to furnish neryl-lipid II Ne-dansylthiourea,
2-Ne-dansylthiourea, in greater than 90% yield.
In conclusion, chemical syntheses of lipid II and neryl-lipid II
analogues were accomplished with one-pot protection–glyco-
sylation protocols. (2,6-Dichloro-4-methoxyphenyl)(2,4-dichlor-
ophenyl)methyl trichloroacetimidate (3) and its linker resin 4
were demonstrated to be useful temporary protecting groups
for the primary alcohol of the diol 6a that could be compatible
Chem. Eur. J. 2014, 20, 1 – 6
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