Protecting group manipulations on glycosyl phosphate triesters

Article abstract of DOI:10.1080/07328300701298204

Glucosyl and mannosyl phosphate triester building blocks were differentially protected by protecting group manipulations on competent glycosyl donors. Dibutyl 3,4-di-O-benzyl-6-O-(fluorenylmethoxycarbonyl)-2-O-pivaloyl - D-glucopyranoside phosphate, not a

Full text of DOI:10.1080/07328300701298204

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20
Protecting Group Manipulations on Glycosyl
Phosphate Triesters
Frédéric R. Carrel & Peter H. Seeberger
To cite this article: Frédéric R. Carrel & Peter H. Seeberger (2007) Protecting Group
Manipulations on Glycosyl Phosphate Triesters, Journal of Carbohydrate Chemistry, 26:2,
125-139, DOI: 10.1080/07328300701298204
To link to this article: http://dx.doi.org/10.1080/07328300701298204
Published online: 09 May 2007.
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Date: 09 June 2016, At: 20:12

Journal of Carbohydrate Chemistry, 26:125–139, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300701298204
Protecting Group
Manipulations on Glycosyl
Phosphate Triesters
´ ´
Frederic R. Carrel and Peter H. Seeberger
Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH), Zu¨rich,
Switzerland
Glucosyl and mannosyl phosphate triester building blocks were differentially protected
by protecting group manipulations on competent glycosyl donors. Dibutyl 3,4-di-O-
benzyl-6-O-(fluorenylmethoxycarbonyl)-2-O-pivaloyl-b-D-glucopyranoside phosphate,
not accessible by other methods, was prepared this way.
Keywords Glycosyl phosphate triester, Protecting group manipulation
INTRODUCTION
Glycosyl phosphate triesters have become an important class of glycosylating
agents for the synthesis of oligosaccharides. Compared to glycosyl trichloroace-
timidates and glycosyl halides, glycosyl phosphates are relatively stable. Most
glycosyl phosphates can be stored for months at 48C and are less prone to
hydrolysis during purification on silica gel. Upon activation with stoichiometric
amounts of TMSOTf, glycosyl phosphates are highly reactive as most glycosy-
lations proceed at low temperatures (b-phosphate: 2608C, a-phosphate:
2308C). Therefore, glycosyl phosphates are attractive glycosylating agents
for solution[1] and solid-phase oligosaccharide synthesis.[2]
Glycosyl phosphate triesters can be synthesized from different precursor
types. Starting from lactols, glycosyl phosphates can be obtained by reaction
with dialkylchlorophosphate,[3] by dehydrative glycosylation,[4] or by triester
phosphite formation followed by oxidation.[5] Regioselective opening of
1,2-orthoesters using dialkylphosphate is an efficient method to afford
glycosyl phosphates.[6] 1,2-Glucals can be converted to glycosyl phosphates
Received December 13, 2006; accepted February 21, 2007.
Address correspondence to Peter H. Seeberger, Laboratory of Organic Chemistry, Swiss
Federal Institute of Technology (ETH), Wolfgang-Pauli-Strasse 10, CH-8093, Zu¨rich,
Switzerland. E-mail: Seeberger@org.chem.ethz.ch
125

F. R. Carrel and P. H. Seeberger
126
via a three-step one-pot procedure: epoxidation of the double bond, followed by
regioselective opening of the epoxide at C(1) using dialkylphosphate, and
finally protection at C(2).[7] Finally, other glycosylating agents such as
glycosyl trichloroacetimidates,[8] glycosyl halides,[5b] pentenyl glycosides,[9] or
MOP-glycosides[10] can be converted to glycosyl phosphates by activation and
trapping of the oxycarbenium intermediate with dialkylphosphate.
Glycosyl phosphate triesters mostly are used directly as glycosylating
agents. To date, few chemical transformations on glycosyl phosphate triesters
have been reported with the phosphate moiety remaining intact. A radical
dehalogenation on sialic acid phosphate,[5b] debenzylation,[8b] and deacetyla-
tion[8a] have been reported. Deacetylation at C(6), followed by formation of
the corresponding triflate and subsequent SN2 displacement, has been disclo-
sed.[8c] The C(2) hydroxyl group of glycosyl phosphates has been benzoyla-
ted,[1b,7a] acetylated,[1b,7d] and pivaloylated.[7b] In addition, triethylsilyl,[7b]
2-(azidomethyl)benzoate,[1a] and p-chlorophenyl carbonate[11] groups have
been placed on glycosyl phosphates. However, most of these C(2)-protecting
group manipulations were part of the three-step one-pot procedure from
1,2-glucals.
Here, we report protecting group manipulations on glycosyl phosphate trie-
sters. Each phosphate was isolated by silica gel flash column chromatography
and for most, no degradation was observed for months upon storage at –188C.
RESULTS AND DISCUSSION
Dibutyl 3,4-di-O-benzyl-2-O-pivaloyl-6-O-triisopropylsilyl-b-D-glucopyranoside
phosphate (1)[7b,12] and dibutyl 2-O-acetyl-3,4-di-O-benzyl-6-O-triisopropylsi-
lyl-a-D-mannopyranoside phosphate (2)[6,13] were synthesized as substrates
for the subsequent studies. Since glycosyl phosphates are generally not
stable under acidic conditions, both glycosyl phosphates 1 and 2 were
desilylated by treatment with TBAF in THF to afford the corresponding C(6)
hydroxyl containing glucosyl phosphate 3 and mannosyl phosphate 4 in good
to excellent yield (Sch. 1).
Placement of esters and carbonates was investigated for the C(6)-protec-
tion of glucosyl phosphate 3. Using 2-azido-2-methylpropanoyl anhydride
(“A-cap anhydride”),[14] 3 was successfully esterified to produce 5 in 67%
yield. A C(6) Fmoc group was introduced by treatment with FmocCl and
pyridine in CH2Cl2 to afford the desired carbonate 6 in 95% yield (Sch. 2).
Mannosyl phosphate 4 can be protected in analogous fashion. Treatment of
4 with the A-cap anhydride afforded the corresponding ester 7 in 93% yield.
Under FmocCl/pyridine conditions, 4 gave the expected carbonate 8 in 94%
yield. Standard silylation conditions using TIPSCl and imidazole in DMF
transformed 4 into the corresponding silylether 2 in 68% yield (Sch. 3).

Glycosyl Phosphate Triesters
127
Scheme 1
The encouraging results for the protection of the C6 hydroxyl group
prompted investigations concerning the protection of the C(2)-hydroxyl
group of glycosyl phosphates. Attempts to cleave the acetyl group of 2
using K2CO3 in MeOH yielded, however, the corresponding C(2)-OH
methyl-a-glycoside 9 (a-selectivity determined by measurement of the
1JC(1)-H(1) ¼ 169 Hz).[15] This finding suggests that the intermediate C(2)-
alkoxide displaced the phosphate moiety to afford the epoxide that was
opened by excess methanol. Similar results were obtained with sodium meth-
oxide in methanol. As expected, an equimolar amount of sodium methoxide
was required to drive the reaction to completion. The lower basicity of the
diester phosphate anion compared to sodium methoxide may explain this
observation (Sch. 4).
We had planned to synthesize 3,4-di-O-benzyl-6-O-(fluorenylmethoxycarbo-
nyl)-2-O-pivaloyl-b-D-glucopyranoside phosphate (6) from 1,2-glucals using the
three-step one-pot procedure.[7b] Treatment of 3,4-di-O-benzyl-D-glucal[2b] with
Scheme 2

F. R. Carrel and P. H. Seeberger
128
Scheme 3
FmocCl in pyridine afforded 10 in quantitative yield. On a 0.2-mmol scale, glucal
10 was epoxidized using dimethyldioxirane, followed by epoxide opening with
dibutylphosphate and pivaloylation at C(2) using PivCl and DMAP to afford
the desired phosphate 6 in 80% yield (b/a selectivity ꢀ10/1) (Sch. 5).
Problems with this reaction were encountered during scale-up. On a
5-mmol scale, phosphate 6 was contaminated with considerable amounts of
the corresponding 2,6-bis-pivaloylated phosphate 11 that was inseparable by
silica gel flash column chromatography. Formation of 11 is caused by DMAP,
which cleaves the Fmoc group at C(6) and allows for further pivaloylation at
this position. The structure of 11, as well as the ratio between 6 and 11
(70%/23%), was determined by addition of 1% triethylamine in the chromato-
graphy eluent. Under these basic conditions, the Fmoc group of 6 was cleaved
to afford a mixture of glycosyl phosphates 3 and 11 (Sch. 6), which were separ-
able by silica gel flash column chromatography.
Several ways to avoid or reduce the formation of 11 were investigated.
Replacement of DMAP by pyridine[7a] did not result in pivaloylated product.
Lowering of the reaction temperature did not yield any success as C(2) protec-
tion started at around 2308C, a temperature at which 11 was concomitantly
formed. The reaction was improved by using equimolar amounts of premixed
DMAP and PivCl. However, more equivalents were required (5 eq. each) and
the protection reaction proceeded quickly only at rt, but the ratio of 6 and 11

Glycosyl Phosphate Triesters
129
Scheme 4
clearly improved. After chromatography, phosphate 6 was recovered pure in
64%, separated from fractions contaminated by 11 (ꢀ24%).
The problems we encountered with this synthesis prompted us to establish
suitable protecting group manipulations on glycosyl phosphate 1 for the
synthesis of 6. The silyl ether of 1 was removed under basic treatment with
TBAF to afford 3 in 83% yield before the hydroxyl group at C(6) was protected
using FmocCl and pyridine to afford 6 in 95% yield.
All glycosyl phosphates triesters that were synthesized here were purified
by silica gel flash column chromatography. Due to the slightly acidic character
Scheme 5

F. R. Carrel and P. H. Seeberger
130
Scheme 6
of the silica gel, precautions were taken during purification. Chromatography
often resulted in small amounts of lactols that were difficult to separate from
the glycosyl phosphates. Neutralization of the silica gel, either by addition of
1% triethylamine or pyridine in the eluent, was required to avoid hydrolysis
of the glycosyl phosphate. Most of the glycosyl phosphates triesters synthesized
here were stable for months at 2188C.
CONCLUSIONS
We demonstrated that protecting group manipulations can be executed on
glycosyl phosphate triesters without affecting the phosphate moiety. Due to
the acid labile character of the phosphate, all deprotection, protection, and
purification maneuvers had to be carried out in basic media.
EXPERIMENTAL
General Methods
All chemicals were reagent grade and were used as supplied unless other-
wise noted. Dichloromethane (CH2Cl2) and tetrahydrofurane (THF) were
purified by a J. C. Meyer Solvent Dispensing System (two packed columns of
neutral alumina). Solvents for chromatography and workup procedures were
distilled from commercially available technical grade solvents. Analytical
thin-layer chromatography was performed on E. Merck silica gel 60 F254
plates (0.25 mm). Compounds were visualized by UV and/or by dipping the
plates in a cerium sulphate-ammonium molybdate solution followed by
heating. Liquid column chromatography was performed using forced flow of
the indicated solvent on Fluka silica gel 60 (40–63 mm). 1H/13C/31P NMR

Glycosyl Phosphate Triesters
131
spectra were recorded on a Varian Mercury XL 300 spectrometer. The 1H NMR
spectra (300 MHz) are expressed in ppm relative to CHCl3 (7.26 ppm) as
internal reference; the coupling constants are reported in Hz. The same is
valid for 13C NMR spectra (75 MHz, internal reference CDCl3: 77.0 ppm). For
31P NMR spectra (121 MHz), the H3PO4 (d ¼ 0 ppm) was used as internal
reference. Optical rotation [a]D was recorded on a Jasco DIP-370 spectrometer
using a sodium lamp (589 nm) at rt, with a 10 cm/1 mL cell. The solvent is
specified as well as the concentration (i.e., C ¼ 1 ¼ 10 mg/mL). IR spectra
were recorded as CHCl3 solutions on a Perkin-Elmer 1600 FT-IR spectrometer
and are expressed in cm21. High-resolution mass spectroscopy (HRMS) was
performed by the MS service at the Laboratory of Organic Chemistry at ETH
Zu¨rich; 2,5-dihydroxybenzoic acid (DHB) was used as matrix.
Dibutyl 2-O-Acetyl-3,4-di-O-benzyl-6-O-triisopropylsilyl-a-D-
mannopyranoside Phosphate (2)
To a stirred solution of 4 (238 mg, 0.40 mmol) in DMF (2 mL) was added
imidazole (82 mg, 1.2 mmol) at rt. The solution was cooled to 08C and
TIPSCl (128 mL, 0.6 mmol) was added. The solution was allowed to warm
to rt overnight. After 21 h, the solution was treated with Et2O (10 mL)
and water (3 mL). The aqueous phase was extracted with Et2O
(3 ꢀ 10 mL). The combined organic phase was dried over MgSO4 and the
solvents were evaporated. The residue was purified by silica gel flash
column chromatography (gradient AcOEt/cyclohexane from (1:9) to (1:4),
eluent with 1% NEt3, Rf [AcOEt/hexane(1:4)] ¼ 0.23) to afford 2 (203 mg,
68%) as colorless oil. Spectral data are consistent with those reported
previously.[6b]
Dibutyl 3,4-Di-O-benzyl-2-O-pivaloyl-b-D-glucopyranoside
Phosphate (3)
To a stirred solution of 1 (2.063 g, 2.6 mmol) in THF (52 mL) was added
TBAF (1 M in THF, 3.9 mL, 3.9 mmol) at rt. After 30 min, the reaction
mixture was dried over MgSO4 and the solvents were evaporated. The
residue was purified by silica gel flash column chromatography (gradient
EtOAc:cyclohexane from (1:2) to (2:1) v/v, eluent with 1% NEt3, Rf
[EtOAc:ratio;cyclohexane(1:1)] ¼ 0.30) to afford 3 (1.276 g, 77%) as white
1
solid. H NMR (CDCl3) d 0.92 (t, 6H, J ¼ 7.3, 2ꢁCH3(Bu)), 1.20 (s, 9H,
3ꢁCH3(Piv)), 1.32–1.46 (m, 4H, 2ꢁCH2(Bu)), 1.58–1.70 (m, 4H, 2ꢁCH2(Bu)),
2.30 (bs, 1H, H(OH)), 3.58 (ddd, 1H, J4,5 ¼ 9.9 Hz, J5,6 ¼ 3.6 Hz,
J5,6 ¼ 2.5 Hz, H-5), 3.72 (dd, 1H, J ¼ 8.8 Hz, J ¼ 8.0 Hz, H-3 or 4), 3.76
(dd, 1H, J6a,6b ¼ 12.4 Hz, J5,6a ¼ 3.8 Hz, H-6a), 3.83–3.91 (m, 2H, H-6b, H-3
or 4), 3.99–4.10 (m, 4H, 2ꢁOCH2(Bu)), 4.73, 4.77 (2d, 2H, J ¼ 11.3 Hz,

F. R. Carrel and P. H. Seeberger
132
CH2(Bn)), 4.68, 4.80 (2d, 2H, J ¼ 11.0 Hz, CH2(Bn)), 5.115 (dd, 1H, J2,3 ¼ 7.4 Hz,
J1,2 ¼ 6.9 Hz, H-2), 5.31 (dd, 1H, J1,2 ¼ 6.9 Hz, J1,P ¼ 6.1 Hz, H-1), 7.23–7.36
13
(m, 10ꢁHAr); C NMR (CDCl3) d 13.4 (2ꢁCH3(Bu)), 18.5, 18.5 (2ꢁCH2(Bu)),
27.0 (3ꢁCH3(Piv)), 32.1, 32.0 (2ꢁCH2(Bu)), 38.7 (Cq(Piv)), 61.2 (C6), 67.9–68.0
(m, 2ꢁOCH2(Bu)), 72.6 (d, J ¼ 10.3 Hz, C2), 74.4, 74.9, 76.0, 76.2, 82.4 (C3,
C4, C5, 2ꢁCH2(Bn)), 96.3 (d, J ¼ 5.4 Hz, C1), 127.3, 127.9 (2ꢁCHAr), 127.6,
128.0, 128.3, 128.4 (4ꢁ2CHAr), 137.6, 137.7 (2ꢁCqAr), 176.7 (COO(Piv)); 31P
NMR (CDCl3) d –2.120; [a]D 2 9.18 (c 1.0, chloroform); IR (chloroform, cm21
)
3386, 3065, 3007, 2965, 2934, 2875, 1738, 1497, 1479, 1455, 1398, 1362,
1275, ꢀ1200, 1136, 1095, 1037, 914, 822; HRMS Calcd for C33H49O10PNa:
659.2956. Found: 659.2945.
Dibutyl 2-O-Acetyl-3,4-di-O-benzyl-a-D-mannopyranoside
Phosphate (4)
To a stirred solution of 2 (2.64 g, 3.51 mmol) in THF (70 mL) was added
TBAF (1 M in THF, 5.3 mL, 5.3 mmol) at rt. After 30 min, the solution was
treated with a saturated aqueous solution of NaHCO3 (25 mL) and the THF
was mostly evaporated. The resulting solution was extracted with CH2Cl2
(4 ꢀ 50 mL). The combined organic phases were dried over MgSO4 and
the solvents evaporated. The residue was purified by silica gel flash
column chromatography (gradient EtOAc:cyclohexane from (2:1) to (2.5:1)
v/v, eluent with 1% NEt3, Rf [EtOAc:hexane(3:1)] ¼ 0.53) to afford 4
(2.00 g, 96%) as colorless oil. 1H NMR (CDCl3) d 0.93, 0.94 (2t, 6H,
J ¼ 7.1 Hz, 2ꢁCH3(Bu)), 1.32–1.47 (m, 4H, 2ꢁCH2(Bu)), 1.60–1.74 (m, 4H,
2ꢁCH2(Bu)), 2.15 (s, 3H, CH3(OAc)), 3.76–3.91 (m, 4H), 3.97–4.10
(m, 5H), 4.55, 4.72 (2d, 2H, J ¼ 11.3 Hz, CH2(Bn)), 4.64, 4.91 (2d, 2H,
J ¼ 10.8 Hz, CH2(Bn)), 5.42 (dd, 1H, J2,3 ¼ 3.0 Hz, J1,2 ¼ 2.2 Hz, H-2),
5.62 (dd, 1H, J1,P ¼ 6.0 Hz, J1,2 ¼ 2.2 Hz, H-1), 7.27–7.39 (m, 10ꢁHAr); 13C
NMR (CDCl3) d 13.5 (2ꢁCH3(Bu)), 18.5 (2ꢁCH2(Bu)), 20.8 (CH3(OAc)),
32.0, 32.1 (2ꢁCH2(Bu)), 61.5 (C6), 67.8–68.2 (m, C2, 2ꢁOCH2(Bu)), 71.9,
73.3, 73.7, 75.2, 77.0 (C3, C4, C5, 2ꢁCH2(Bn)), 95.5 (d, J ¼ 5.4 Hz, C1),
127.8, 128.3 (2ꢁCHAr), 127.9, 128.0, 128.3 (4ꢁ2CHAr), 137.5, 137.9 (2ꢁCqAr),
169.8 (COO(OAc)); 31P NMR (CDCl3) d –2.233; [a]D 26.28 (c 1.0, chloro-
form); IR (chloroform, cm21) 3436, 3008, 2964, 2935, 2876, 1746, 1603,
1497, 1455, 1373, 1261, ꢀ1200, 1168, 1078, 1029, 962; HRMS Calcd for
C30H43O10PNa: 617.2486. Found: 617.2475.
Dibutyl 6-O-(2-Azido-2-methylpropanoyl)-3,4-di-O-benzyl-2-
O-pivaloyl-b-D-glucopyranoside Phosphate (5)
To a stirred solution of 3 (127 mg, 0.2 mmol) in CH2Cl2 (2 mL) were added
successively pyridine (161 mL, 2 mmol), DMAP (6.1 mg, 0.05 mmol), and

Glycosyl Phosphate Triesters
133
2-azido-2-methylpropanoyl anhydride (240 mg, 1 mmol) at rt. After 2 h at rt, the
reaction mixture was diluted with CH2Cl2 (10 mL) and treated with a saturated
aqueous solution of NaHCO3 (3 mL). The aqueous phase was extracted with
CH2Cl2 (3 ꢀ 5 mL). The combined organic phase was dried over MgSO4 and
the solvents were evaporated. The residue was coevaporated with toluene
(10 mL) and then purified by silica gel flash column chromatography (gradient
EtOAc:hexane from (1:3) to (1:2) v/v, eluent with 1% NEt3, Rf [EtOAc/
hexane(1:2.5)] ¼ 0.32) to give 5 (100 mg, 67%) as colorless oil. 1H NMR
(CDCl3) d 0.91 (t, 3H, J ¼ 7.5 Hz, CH3(Bu)), 0.92 (t, 3H, J ¼ 7.5 Hz, CH3(Bu)),
1.20 (s, 9H, 3ꢁCH3(Piv)), 1.30–1.42 (m, 4H, 2ꢁCH2(Bu)), 1.47 (s, 6H, 2ꢁCH3(A-
tag)), 1.56–1.68 (m, 4H, 2ꢁCH2(Bu)), 3.64–4.10 (2 m, 7H, H-3, H-4, H-5,
2ꢁOCH2(Bu)), 4.27 (dd, 1H, J6a,6b ¼ 11.8 Hz, J5,6a ¼ 3.5 Hz, H-6a), 4.58 (bd,
1H, J6a,6b ¼ 11.8 Hz, H-6b), 4.72, 4.78 (2d, 2H, J ¼ 10.9 Hz, CH2(Bn)), 4.57,
4.83 (2d, 2H, J ¼ 10.8 Hz, CH2(Bn)), 5.12 (dd, 1H, J2,3 ¼ 8.4 Hz, J1,2 ¼ 8.1 Hz,
H-2), 5.25 (dd, 1H, J1,2 ¼ 7.8 Hz, J1,P ¼ 6.5 Hz, H-1), 7.21–7.36 (m, 10ꢁHAr);
13C NMR (CDCl3) d 13.6, 13.7 (2ꢁCH3(Bu)), 18.7, 18.7 (2ꢁCH2(Bu)), 24.5
(2ꢁCH3(A-Tag)), 27.2 (3ꢁCH3(Piv)), 32.1–32.2 (m, 2ꢁCH2(Bu)), 38.9 (Cq(Piv)),
63.1, 63.2 (C6, Cq-N3(A-Tag)), 67.8–68.0 (m, 2ꢁOCH2(Bu)), 72.7 (d, J ¼ 9.4 Hz,
C2), 73.5, 75.2, 76.9, 82.7 (C3, C4, C5, 2ꢁCH2(Bn)), 96.4 (d, J ¼ 5.4 Hz, C1),
127.7, 128.9 (2ꢁCHAr), 127.3, 127.9, 128.3, 128.5 (4ꢁ2CHAr), 137.1, 137.4
(2ꢁCqAr), 172.1, 176.5 (COO(Piv) þ COO(A-tag)); 31P NMR (CDCl3) d –2.190;
IR (chloroform, cm21) 3008, 2966, 2936, 2875, 2112, 1740, 1498, 1479, 1455,
1390, 1367, 1275, ꢀ1200, 1137, 1095, 1029, 909, 878; HRMS Calcd for
C37H54N3O11PNa: 770.3388. Found: 770.3375.
Dibutyl 3,4-Di-O-benzyl-6-O-(fluorenylmethoxycarbonyl)-2-
O-pivaloyl-b-D-glucopyranoside Phosphate (6)
Synthesis using Dibutyl 3,4-di-O-benzyl-2-O-pivaloyl-b-D-glucopyranoside
phosphate 3
To a stirred solution of 3 (636 mg, 1 mmol) in CH2Cl2 (10 mL) were added
pyridine (480 mL, 6 mmol) and FmocCl (516 mg, 2 mmol) at rt. After 15 min,
the solvents were evaporated. Residual pyridine was coevaporated with
toluene (2 ꢀ 5 mL). The residue was purified by silica gel flash column
chromatography (gradient acetone/toluene from (1:99) to (5:95) v/v, eluent
with 1% pyridine, Rf [EtOAc:hexane(1:2)] ¼ 0.29) to give 6 (812 mg, 95%) as
colorless oil.
Synthesis using 3,4-di-O-benzyl-6-O-(fluorenylmethoxycarbonyl)-D-glucal 10
To a stirred solution of 10 (110 mg, 0.2 mmol) in CH2Cl2 (2 mL) was added
DMDO (ꢀ0.07 M in acetone, 3.7 mL, 0.26 mmol) at 08C. After 15 min, the
solvents were removed under vacuum at 08C. The residue was diluted with

F. R. Carrel and P. H. Seeberger
134
CH2Cl2 (4 mL) and cooled to 2788C. Dibutylphosphate (44 mL, 0.22 mmol) was
added dropwise over 3 min and the solution was allowed to warm to 08C and
stirred for 7 min. The solution was cooled to 2108C; DMAP (98 mg,
0.8 mmol) and PivCl (49 mL, 0.4 mmol) were added and the solution was
stirred for 90 min at 2108C. The reaction mixture was treated with a
mixture of EtOAc (20 mL) and hexane (60 mL). The white precipitate was
filtered through a pad of silica gel and further eluted (first with EtOAc:hexane
(1:3) þ 1% NEt3 v/v (80 mL); then with EtOAc:hexane (1:2) þ 1% NEt3 v/v
(90 mL)). The solvents were evaporated and the residue was purified by
silica gel flash column chromatography (EtOAc:hexane (1:2) þ 1% NEt3 v/v)
to give 6 (137 mg, a/b ꢀ 1:10, 80%) as colorless oil.
When reaction was run on a 1-mmol scale, we observed formation of the
corresponding 2,6-bis-pivaloylated analog 11, inseparable from 6 by chromato-
graphy on silica gel. On larger scale, we also observed Fmoc cleavage due to the
presence of NEt3 in the chromatography eluent.
1H NMR (CDCl3) d 0.87 (t, 3H, J ¼ 7.5 Hz, CH3(Bu)), 0.93 (t, 3H,
J ¼ 7.5 Hz, CH3(Bu)), 1.23 (s, 9H, 3ꢁCH3(Piv)), 1.31–1.47 (m, 4H,
2ꢁCH2(Bu)), 1.51–1.71 (m, 4H, 2ꢁCH2(Bu)), 3.70–4.54 (m, 12H, H-3, H-4,
H-5, 2ꢁH-6, OCH2(Fmoc), CH(Fmoc), 2ꢁOCH2(Bu)), 4.75, 4.81 (2d, 2H,
J ¼ 11.0 Hz, CH2(Bn)), 4.60, 4.83 (2d, 2H, J ¼ 10.9 Hz, CH2(Bn)), 5.10
(m, 1H, J2,3 ¼ 8.4 Hz, J1,2 ¼ 8.0 Hz, H-2), 5.235 (dd, 1H, J1,2 ¼ 8.0 Hz,
J1,P ¼ 6.9 Hz, H-1), 7.22–7.43 (m, 14H, 10ꢁHAr(Bn) þ 4ꢁHAr(Fmoc)), 7.62
(dm, 2H, J ¼ 7.5 Hz, 2ꢁHAr(Fmoc)), 7.77 (d, 2H, J ¼ 7.5 Hz, 2ꢁHAr(Fmoc));
13C NMR (CDCl3)
d
13.7 (2ꢁCH3(Bu)), 18.8, 18.8 (2ꢁCH2(Bu)), 27.3
(3ꢁCH3(Piv)), 32.2–32.3 (m, 2ꢁCH2(Bu)), 39.1 (Cq(Piv)), 46.9 (CH(Fmoc)), 66.1
(C6), 68.0–68.3 (m, 2ꢁOCH2(Bu)), 72.9 (d, J ¼ 9.5 Hz, C2), 70.2, 73.8, 75.3,
75.4, 76.9, 82.9 (C3, C4, C5, OCH2(Fmoc), 2ꢁCH2(Bn)), 96.6 (d, J ¼ 5.1 Hz,
C1), 120.3–128.7 (8ꢁCHAr(Fmoc) þ 10ꢁCHAr(Bn)); 137.5, 137.9 (2ꢁCq(Bn)),
141.4, 141.5, 143.4, 143.5 (4ꢁCq(Fmoc)), 155.1 (OC(O)O(Fmoc)), 177.0
(COO(Piv)); 31P NMR (CDCl3) d –2.488; [a]D 10.68 (c 1.0, chloroform); IR
(chloroform, cm21) 3008, 2964, 2906, 2876, 1742, 1497, 1478, 1452, 1398,
1363, 1262, 1132, 1096, 916, 820; HRMS Calcd for C48H59O12PNa: 881.3636.
Found: 881.3619.
Dibutyl 2-O-Acetyl-6-O-(2-azido-2-methylpropanoyl)-3,4-di-
O-benzyl-a-D-mannopyranoside Phosphate (7)
To a stirred solution of 4 (83 mg, 0.140 mmol) in CH2Cl2 (1.4 mL) were
added successively at rt pyridine (68 mL, 0.837 mmol), DMAP (4.3 mg,
0.035 mmol), and 2-azido-2-methylpropionic anhydride (100 mg, 0.487 mmol).
After 3 h, the solution was diluted with CH2Cl2 (5 mL) and treated with a
saturated aqueous solution of NaHCO3 (2 mL). The aqueous phase was
extracted with CH2Cl2 (3 ꢀ 5 mL). The combined organic phases were dried

Glycosyl Phosphate Triesters
135
over MgSO4 and the solvents were evaporated. The residue was purified by
silica gel flash column chromatography (eluent EtOAc/hexane (1:2) v/v,
eluent with 1% NEt3, Rf [EtOAc:hexane(1:2)] ¼ 0.34) to afford 7 (91 mg, 93%)
1
as colorless oil. H NMR (CDCl3) d 0.94, 0.94 (2t, 6H, J ¼ 7.2 Hz, 2ꢁCH3(Bu)),
1.34–1.47 (m, 4H, 2ꢁ CH2(Bu)); 1.495, 1.515 (2s, 6H, 2ꢁCH3(A-Tag)), 1.66
(broad quintuplet, 4H, J ¼ 6.6 Hz, 2ꢁCH2(Bu)), 2.13 (s, 3H, CH3(OAc)),
3.90 (dd, 1H, J ¼ 9.9 Hz, J ¼ 9.3 Hz, H-4 or 5), 3.99–4.11 (m, 6H, H-3,
2ꢁOCH2(Bu), H-4 or 5), 4.41 (dd, 1H, J
¼ 11.8 Hz, J5,6a ¼ 3.0 Hz, H-6a),
6a,6b
4.51 (dd, 1H, J6a,6b ¼ 11.8 Hz, J5,6b ¼ 1.9 Hz, H-6b), 4.55, 4.73 (2d, 2H,
J ¼ 11.3 Hz, CH2(Bn)), 4.58, 4.95 (2d, 2H, J ¼ 11.0 Hz, CH2(Bn)), 5.43
(dd, 1H, J2,3 ¼ 2.5 Hz, J1,2 ¼ 1.9 Hz, H-2), 5.60 (dd, 1H, J1,P ¼ 6.3 Hz,
J
¼ 1.9 Hz, H-1), 7.26–7.38 (m, 10ꢁHAr); 13C NMR (CDCl3) d 13.5
1,2
(2ꢁCH3(Bu)), 18.5 (2ꢁCH2(Bu)), 20.6 (CH3(Ac)), 24.3, 24.3 (2ꢁCH3(A-Tag)),
32.0–32.2 (m, 2ꢁCH2(Bu)), 63.0, 63.2 þ 63.0 (C6, Cq-N3(A-Tag)), 67.6–68.0
(m, C2, 2ꢁOCH2(Bu)), 71.3, 71.8, 73.2, 75.4, 77.0 (C3, C4, C5,2ꢁCH2(Bn)),
95.3 (d, J ¼ 4.9 Hz, C1), 127.9–128.4 (10ꢁCHAr), 137.2, 137.7 (2ꢁCqAr)), 169.7
(COO(OAc)), 172.3 (COO(A-Tag)); 31P NMR (CDCl3) d –2.729; [a]D 27.08 (c
1.0, chloroform); IR (chloroform, cm21) 3008, 2965, 2936, 2875, 2113, 1744,
1497, 1454, 1373, 1261, ꢀ1200, 1168, 1145, 1073, 1029, 963, 912, 878; HRMS
Calcd for C34H48N3O11P: 728.2919. Found: 728.2906.
Dibutyl 2-O-Acetyl-3,4-di-O-benzyl-6-O-
(fluorenylmethoxycarbonyl)-a-D-mannopyranoside
Phosphate (8)
To a stirred solution of 4 (810 mg, 1.36 mmol) in CH2Cl2 (13.6 mL) were
added pyridine (657 mL, 8.17 mmol) and FmocCl (702 mg, 2.72 mmo1) at rt.
After 30 min, the solution was diluted with CH2Cl2 (40 mL) and treated with
a saturated aqueous solution of NaHCO3 (20 mL). The aqueous phase was
extracted with CH2Cl2 (3 ꢀ 50 mL). The combined organic phase was dried
over MgSO4 and the solvents were evaporated. The residue was purified by
silica gel flash column chromatography (EtOAc/cyclohexane (1:3) v/v, Rf
[EtOAc:cyclohexane(1:3)] ¼ 0.19) to afford 8 (1048 mg, 94%) as colorless oil.
1H NMR (CDCl3) d 0.93, 0.94 (2t, 6H, J ¼ 7.4 Hz, 2ꢁCH3(Bu)), 1.34–1.48
(m, 4H, 2ꢁCH2(Bu)), 1.61–1.73 (m, 4H, 2ꢁCH2(Bu)), 2.17 (s, 3H, CH3(OAc)),
3.86 (dd, 1H, J ¼ 9.9 Hz, J ¼ 9.6 Hz, H-4), 4.01–4.17 (m, 6H, 2ꢁOCH2(Bu),
H-5, H-3), 4.25 (dd, 1H, J ¼ 7.4 Hz, J ¼ 7.1 Hz, CH(Fmoc)), 4.36–4.50
(m, 4H, 2ꢁH-6, OCH2(Fmoc)), 4.57, 4.75 (2d, 2H, J ¼ 11.3 Hz, CH2(Bn)), 4.59,
4.94 (2d, 2H, J ¼ 10.7 Hz, CH2(Bn)), 5.46 (dd, 1H, J2,3 ¼ 2.8 Hz,
J1,2 ¼ 1.9 Hz, H-2), 5.66 (dd, 1H, J1,P ¼ 6.6 Hz, J1,2 ¼ 1.9 Hz, H-1), 7.27–7.44
(m, 10ꢁHAr(Bn) þ 4ꢁHAr (Fmoc)), 7.60 (m, 2H, 2ꢁHAr (Fmoc)), 7.77 (bd, 2H,
J ¼ 7.4 Hz, 2ꢁHAr(Fmoc)); 13C NMR (CDCl3) d 13.5 (2ꢁCH3(Bu)), 18.5
(2ꢁCH2(Bu)), 20.8 (CH3(OAc)), 32.0–32.2 (m, 2ꢁCH2(Bu)), 46.6 (CH(Fmoc)),

F. R. Carrel and P. H. Seeberger
136
66.3 (C6), 67.8–68.1 (m, C2, 2ꢁOCH2Bu)), 69.9, 71.3, 71.9, 73.2, 75.3, 77.0
(CH2(Fmoc), 2ꢁCH2(Bn), C3, C4, C5), 95.2 (d, J ¼ 5.4 Hz, C1), 120.0–128.4
(8ꢁCHAr(Fmoc) þ 10ꢁCHAr (Bn)), 137.4, 137.7 (2ꢁCqAr(Bn)), 141.4, 143.1,
143.3 (4ꢁCqAr(Fmoc)), 154.9 (OC(O)O (Fmoc)), 169.8 (COO(OAc)); 31P NMR
(121 MHz, CDCl3) d –2.648; [a]D 19.18 (c 1.0, chloroform); IR (chloroform,
cm21) 3007, 2963, 2934, 2875, 1746, 1602, 1496, 1452, 1374, 1261, ꢀ1200,
1168, 1102, 1028, 963; HRMS Calcd for C45H53O12PNa: 839.3167. Found.
839.3173.
Methyl 3,4-Di-O-benzyl-6-O-(triisopropylsilyl)-a-D-
mannopyranoside (9)
Method using K2CO3
To a stirred solution of 2 (150 mg, 0.2 mmol) in MeOH (2 mL) was added
K2CO3 (83 mg, 0.6 mmo1) at rt. After 30 min, the solution was diluted with
CH2Cl2 (10 mL) and treated with H2O (2 mL). The aqueous phase was
extracted with CH2Cl2 (3 ꢀ 5 mL). The combined organic phase was dried
over MgSO4 and the solvents were evaporated.
Method using MeONa
To a stirred solution of 2 (150 mg, 0.2 mmol) in MeOH (2 mL) was added
MeONa (1 mg, 0.02 mmo1) at rt. After 1 h, more MeONa (10 mg, 0.2 mmol)
was added to drive the reaction to completion. The solvents were evaporated
30 min later.
Purification
Both crude products were gathered and purified by silica gel flash column
chromatography (acetone/cyclohexane (1:5) v/v, eluent with 1% NEt3, Rf
[acetone/cyclohexane(1:5)] ¼ 0.20) to afford 9 (171 mg, average yield ¼ 60%)
1
as colorless oil. H NMR (CDCl3) d 1.18–1.06 (m, 21ꢁH(TIPS)), 2.43 (d, 1H,
J ¼ 3.3 Hz, H(OH)), 3.37 (s, 3H, MeO), 3.66 (ddd, 1H, J4,5 ¼ 9.6 Hz,
J5,6a ¼ 5.0 Hz, J5,6b ¼ 1.8 Hz, H-5), 3.80 (dd, 1H, J4,5 ¼ 9.6 Hz, J3,4 ¼ 9.1 Hz,
H-4), 3.87–3.94 (m, 2H, H-6a, H-3), 3.98 (dd, 1H, J6a,6b ¼ 11.0 Hz,
J5,6b ¼ 2.0 Hz, H-6), 4.04 (ddd, J2,3 ¼ 3.6 Hz, J2,OH ¼ 3.3 Hz, J1,2 ¼ 1.7 Hz,
H-2), 4.69, 4.74 (2d, 2H, J ¼ 11.7 Hz, CH2(Bn)), 4.76 (d, 1H, J1,2 ¼ 1.7 Hz,
H-1), 4.67, 4.91 (2d, 2H, J ¼ 11.1 Hz, CH2(Bn)), 7.27–7.42 (m, 10ꢁHAr); 13C
NMR (CDCl3) d11.9 (3ꢁCH(TIPS)), 17.9, 17.9 (6ꢁCH3(TIPS)), 54.4 (MeO), 62.9
(C6), 68.3, 71.9, 72.5, 74.2, 75.0, 80.2 (2ꢁCH2(Bn), C2, C3, C4, C5), 100.0
(C1), 127.6–128.4 (10ꢁCHAr), 137.9, 138.4 (2ꢁCqAr); [a]D 46.58 (c 1.0,
chloroform); IR (chloroform, cm21) 3574, 3067, 3008, 2943, 2867, 1602, 1496,
1454, 1384, 1363, 1260, 1110, 1058, 1028, 883; HRMS Calcd for C30H46O6SiNa:
553.2956. Found: 553.2948.

Glycosyl Phosphate Triesters
137
3,4-Di-O-benzyl-6-O-(fluorenylmethoxycarbonyl)-D-glucal
(10)
To a stirred solution of 3,4-di-O-benzyl-D-glucal (3.26 g, 10 mmol) in
pyridine (100 mL) was added FmocCl (5.16 g, 20 mmol) at rt. After 90 min,
the solution was diluted with CH2Cl2 (300 mL) and treated with a saturated
aqueous solution of NaHCO3 (100 mL). The aqueous phase was extracted
with CH2Cl2 (2 ꢀ 200 mL). The combined organic phases were dried over
MgSO4 and the solvents were evaporated. The residue was purified by silica
gel flash column chromatography (adsorbed silica gel, gradient from acetone/
hexane (1:9) to (1:4) v/v, Rf [acetone/hexane(1:4)] ¼ 0.40) to afford 10
1
(5.431 g, 99%) as yellowish oil. H NMR (CDCl3) d 3.91 (dd, 1H, J4,5 ¼ 8.1 Hz,
J3,4 ¼ 5.6 Hz, H(C4)), 4.21–4.34 (m, 3H, H-3, H-5, CH(Fmoc)), 4.46–4.48
(m, 2H, 2ꢁH-6), 4.57 (d, 2H, J ¼ 4.0 Hz, OCH2(Fmoc)), 4.62, 4.72 (2d, 2H,
J ¼ 9.7 Hz, CH2(Bn)), 4.76, 4.94 (2d, 2H, J ¼ 11.5 Hz, CH2(Bn)), 5.01 (dd, 1H,
J1,2 ¼ 6.2 Hz, J2,3 ¼ 2.8 Hz, H-2), 6.49 (dd, 1H, J1,2 ¼ 6.2 Hz, J1,3 ¼ 0.9 Hz,
H-1), 7.32–7.49 (m, 10ꢁHAr(Bn) þ 4ꢁHAr (Fmoc)), 7.69 (bd, 2H, J ¼ 7.5 Hz,
2ꢁHAr(Fmoc)), 7.82 (d, 2H, J ¼ 7.5 Hz, 2ꢁHAr(Fmoc)); 13C NMR (CDCl3)
d 46.8 (CH(Fmoc)), 66.3 (C6), 70.1, 70.5, 73.7, 73.9, 74.9, 75.1 (OCH2(Fmoc),
2ꢁCH2(Bn), C3, C4, C5), 100.1 (C2), 120.0–128.5 (8ꢁCHAr(Fmoc),
10ꢁCHAr(Bn)), 137.8, 138.1 (2ꢁCq(Bn)), 141.2, 143.3, 143.3 (4ꢁCq(Fmoc)),
144.3 (C1), 154.9 (OC(O)O (Fmoc)); [a]D 5.48 (c 1.0, chloroform); IR (chloroform,
cm21) 3068, 3008, 2956, 2866, 1747, 1648, 1497, 1478, 1452, 1397, 1331, 1262,
ꢀ1200, 1101, 1028, 970; HRMS Calcd for C35H32O6Na: 571.2091. Found:
571.2082.
Dibutyl 3,4-Di-O-benzyl-2,6-di-O-pivaloyl-b-D-
glucopyranoside Phosphate (11)
Byproduct of the large-scale DMDO reaction: Rf [EtOAc: cyclo-
1
hexane(1:3)] ¼ 0.30. H NMR (CDCl3) d 0.91 (t, 6H, 2ꢁCH3(Bu)), 1.20, 1.21
(2s, 18H, 2ꢁ[3ꢁCH3(Piv)]), 1.31–1.45 (m, 4H, 2ꢁCH2(Bu)), 1.56–1.67 (m,
4H, 2ꢁCH2(Bu)), 3.64–3.77 (m, 3H), 3.94–4.08 (m, 4H), 4.19 (dd, 1H,
J6a,6b ¼ 11.5 Hz, J5,6a ¼ 3.1 Hz, H-6a), 4.495 (bd, 1H, J6a,6b ¼ 11.5 Hz, H-6b),
4.71, 4.78 (2d, 2H, J ¼ 11.0 Hz, CH2(Bn)), 4.56, 4.80 (2d, 2H, J ¼ 10.7 Hz,
CH2(Bn)), 5.12 (dd, 1H, J2,3 ¼ 8.2 Hz, J1,2 ¼ 8.2 Hz, H-2), 5.25 (dd, 1H,
J1,2 ¼ 8.0 Hz, J1,P ¼ 6.9 Hz, H(C1)), 7.20–7.36 (m, 10ꢁHAr); 13C NMR (CDCl3)
d 13.4, 13.5 (2ꢁCH3(Bu)), 18.4, 18.5 (2ꢁCH2(Bu)), 27.0, 27.1 (2ꢁ[3ꢁCH3(Piv)]),
31.9–32.0 (m, 2ꢁCH2(Bu)), 38.7 (2ꢁCq(Piv)), 61.9 (C6), 67.6–67.9
(m, 2ꢁOCH2(Bu)), 72.8 (d, J ¼ 9.2 Hz, C2), 73.8, 75.1, 75.2, 77.0, 82.6 (C3, C4,
C5, 2ꢁCH2(Bn)), 96.4 (d, J ¼ 4.9 Hz, C1), 127.7, 128.0 (2ꢁCHAr), 127.3, 127.9,
128.3, 128.5 (4ꢁ2CHAr), 137.7, 137.6 (2ꢁCq(Bn)), 176.7, 177.8 (2ꢁCOO(Piv));
31P NMR (CDCl3) d –2.440; [a]D 2.78 (c 1.0, chloroform); IR (chloroform,

F. R. Carrel and P. H. Seeberger
138
cm21) 3007, 2965, 2935, 2875, 1736, 1603, 1497, 1479, 1456, 1398, 1364, 1277,
1138, 1095, 1036, 906, 821; HRMS Calcd for C38H57O11PNa: 743.3531. Found:
743.3518.
ACKNOWLEDGEMENTS
This research was supported by ETH Zu¨rich and the Swiss National Science
Foundation (SNF Grant 200121-101593).
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