Regioselective acylation of 3,4-OH free D-glucosamines: A rapid access to orthogonally functionalized building blocks

Article abstract of DOI:10.1055/s-0030-1258200

A method for the regioselective O-acylation of 3,4-OH free D-glucosamines via stannylene acetal methodology was developed. From fully acetylated 2-N-trichloroacetyl-D-glucosamine, 4-OH free D-glucosamine derivatives bearing orthogonal protecting group patterns were prepared. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258200

PAPER
3481
Regioselective Acylation of 3,4-OH Free D-Glucosamines: A Rapid Access to
Orthogonally Functionalized Building Blocks
Regioselective
Acylati
a
onof 3,4-O
r
HFree
D
k
-Glucosamin
u
es s Sebastian Ehret, Mickael Virlouvet, Moritz Bosse Biskup*
Karlsruher Institut für Technologie (KIT), Institut für Organische Chemie, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6085637; E-mail: biskup@kit.edu
Received 6 April 2010; revised 21 June 2010
Within our current research, we required an easy access to
Abstract: A method for the regioselective O-acylation of 3,4-OH
D-glucosamine building blocks for such motifs. At first
these units should function as glycosyl acceptors, while
free D-glucosamines via stannylene acetal methodology was devel-
oped. From fully acetylated 2-N-trichloroacetyl-D-glucosamine, 4-
allowing rapid conversion into glycosyl donors at a later
stage to access 1,2-trans-configured linkages. Ideally the
installed protecting group pattern should also allow for the
selective liberation of the hydroxy groups at C3 and C6
later on. These requirements can be consolidated into a
general structure 2 (Figure 1) with the following features:
(i) an N-protecting group at C2 that can participate as a
neighboring group during subsequent glycosylations, (ii)
the free 4-OH group functions as glycosyl acceptor, and
(iii) a set of orthogonal protecting groups on the hydroxy
groups at C1, C3, and C6 has been installed.
OH free D-glucosamine derivatives bearing orthogonal protecting
group patterns were prepared.
Key words: carbohydrates, protecting groups, regioselectivity,
stannylene acetals, glycosylaminoglycans
Carbohydrate-based structures, glycans, have been recog-
nized as key elements in a plethora of recognition events
at the cellular level1 and in numerous interactions of
pathogens with an infected host.2 While the relevance of
these interactions is indisputable, their study still is se-
verely hampered by the lack of sufficient material for in-
depth studies of the underlying mechanisms at the molec-
ular level. The rapid synthesis of complex carbohydrate
structures requires not only high-yielding and stereoselec-
tive glycosylation reactions, but also an efficient and inex-
pensive access to the required monosaccharidic building
blocks. The work presented here is focused on an efficient
preparation of building blocks for the →4)-2-acetamido-
2-deoxy-b-D-glucopyranosyl-(1→ motif [abbreviated as
→4)-GlcNAcb(1→; structure 1 in Figure 1]. Such 1,4-
linked D-glucosamines appear as structural motifs in a va-
riety of biologically relevant glycan structures. For exam-
ple, 1,4-linked N-acyl-D-glucosamine derivatives appear
as the carbohydrate repeating unit in bacterial
peptidoglycan3 or within the neutral core region of gly-
cosphingolipids (e.g., in the neolacto-series).4 In eukary-
otic organisms the core region of N-glycosylated
glycoproteins contains an N-acetyl-D-glucosamine dimer
linked to asparagine,5 and the glycosaminoglycan keratan
In our case the trichloroacetyl (TCA) group was used as
an N-protecting group; this electron-withdrawing group is
able to participate in glycosylation reactions at later stages
(→1,2-trans-linked glycosides).7 While the 4-OH group
stayed unprotected, an orthogonal set of O-protecting
groups for the remaining hydroxy groups was chosen.
This consisted of the O-allyl group at the reducing end, an
O-silyl ether at C6, and an O-acyl based group at C3 (2 in
Figure 1 with PG = TCA, R1 = All, R2 = acyl, R3 = TBS).
To obtain the desired 4-OH free substitution pattern, we
decided to follow an approach based on the stannylene
acetal methodology.8 The differentiation between the 3-
and 4-OH groups results from the regioselective opening
of a trans-fused stannylene acetal spanning the 3- and 4-
positions of the carbohydrate ring with an electrophile
(EX). This approach markedly differs from the sequence
usually employed to access 4-OH free building blocks
OAc
O
OAc
O
sulfate
is
composed
of
repetitive
→4)-
a)
GlcNAcb(1→3)Galb(→ dimers.6
AcO
AcO
AcO
AcO
OAc
OAll
76%
NTCA
NTCA
OH
OR3
H
H
O
O
O
4
3
HO
R2O
O
OR1
HO
OTBS
O
NAc
H
b)
NH
PG
2
HO
HO
OAll
77%
NTCA
1
H
Figure 1 Structures of the 1,4-linked N-acetylglucosamine motif 1
and the desired building blocks of type 2
5
Scheme 1 Synthesis of the partially protected diol 5 from the fully
acylated precursor 3. Reaction conditions: (a) FeCl3, drierite, allyl al-
cohol, MeCN, r.t., overnight, 76%; (b) 1. NaOMe (~0.02 M), MeOH,
r.t., 2 h; 2. TBSCl, imidazole, DMF, 0 °C to r.t., overnight, 77% over
two steps.
SYNTHESIS 2010, No. 20, pp 3481–3485
Advanced online publication: 05.08.2010
DOI: 10.1055/s-0030-1258200; Art ID: T08510SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

3482
M. S. Ehret et al.
PAPER
Table 1 Regioselective O-Acetylation of Diol 5a
Entry EX (equiv) Yield (%)
from 3,4,6-OH free triols9 and, to our knowledge, this use
of the stannylene acetal method on D-glucosamine deriv-
atives has no literature precedent.
Regioselectivityd
2a + 6ab,c 7ab 2a/6a
Our synthesis of the 4-OH free glucosamine derivatives 2
started from known, fully protected N-trichloroacetyl de-
rivative 3 (Scheme 1).7a,c,10 Compound 3 was transformed
into the known O-allyl glycoside 47d by the action of
iron(III) chloride in the presence of allyl alcohol.11
1e,f
AcCl (1.0), Et3N (1.0), 54
overnight
6
2g
3
AcCl (1.0), 1 h
AcCl (1.0), 1 h
AcCl (1.5), 1 h
Ac2O (1.0), 1 h
72
71
80
94
10
12 >9:1
Afterwards fully protected 4 was partially deprotected un-
der Zemplén conditions12 and the primary alcohol (6-OH
group) in the resultant triol was immediately O-silylated
to afford the diol 5 in 58% overall yield from 3
(Scheme 1).
4
–
–
5
a Stannylene acetal formation: Bu2SnO (1.02 equiv), reflux, overnight
(entry 2) or 1.5 h (entries 3–5).
With diol 5 available in sufficient amounts, we explored
the formation and the regioselective opening of the 3,4-
stannylene acetal with electrophiles (Scheme 2). In a first
series of experiments, different conditions for forming the
stannylene acetal and different acetylating agents were in-
vestigated.
b Yield after chromatography.
c Yield for both diastereoisomers.
d Determined by 1H NMR.
e Acetylation performed without addition of Bu2SnO.
f Starting material (29%) recovered.
g Starting material (8%) recovered.
Based on these promising results, the scope of the reaction
with regard to the electrophile employed in the stannylene
acetal opening was investigated in a second series of ex-
periments (Table 2).
OTBS
O
OTBS
O
HO
HO
a)
O
OAll
OAll
O
Bu2Sn
NTCA
NTCA
H
H
5
Table 2 Regioselective O-Acylation of Diol 5a
b)
OTBS
OTBS
O
Entry EX (equiv)
Yield (%)
Regioselectivityd
HO
R1O
R2O
R1O
O
2 + 6b,c
7b
2/6
OAll
OAll
NTCA
NTCA
1e
2
CA2Of (1.0), 1 h
68
–
~9:1
>9:1
~9:1
~3:1g
H
H
2b R1 = CA
2a R1 = Ac
(50–85%)
6a R1 = H, R2 = Ac
(up to 17%)
7a R1 = R2 = Ac
(up to 12%)
Lev2Of (2.5), 1.5 h 74
–
–
–
2c R1 = Lev
3
PivClf (1.0), 1 h
BzClf (1.0), 1 h
58
Scheme 2 Regioselective acylation of diol 5 using the stannylene
acetal method. Reaction conditions: (a) Bu2SnO, benzene, reflux, 1 h;
(b) EX, benzene, r.t., 1 h.
2d R1 = Piv
4
68
2e R1 = Bz
The direct treatment of 5 with acetyl chloride without ad-
dition of the tin reagent afforded the monoacetylated
product in 54% yield (Table 1, entry 1). When the stan-
a Stannylene acetal formation: Bu2SnO (1.02 equiv), reflux, 1 h.
b Yield after chromatography.
c Yield for both diastereoisomers.
nylene acetal was formed, the monoacetylation, leading to d Determined by 1H NMR.
e Starting material (31%) recovered.
2a and 6a, proceeded in good to excellent yields under all
conditions studied (Table 1, entries 2–5). The formation
of the acetal proceeded rapidly and usually was finished
after one hour. The best yield (94%) was obtained using
stoichiometric amounts of acetic anhydride as the acety-
lating agent. In all experiments high regioselectivity
(>9:1) was observed. The regioselective acetylation of the
diol 5 in the tin-free experiment can perhaps be explained
by the differing nucleophilicity of the 3- and 4-OH groups
of D-glucosamine.9c,13 Other regioselective preparations
of 4-OH free D-glucosamine derivatives by selective pro-
tection of the 3-OH group have been previously report-
ed.14
f CA = chloroacetyl; Lev = levulinoyl (4-oxopentanoyl);
Piv = pivaloyl; Bz = benzoyl.
g Regioisomers not separated.
To our delight, all electrophiles investigated were readily
incorporated and afforded the acylated compounds in syn-
thetically useful yields (Table 2, entries 1–4). However,
the high 3-OH/4-OH regioselectivity already observed for
the formation of 2a was not retained in all cases. Although
the formation of the bulky monopivaloyl derivatives af-
forded essentially the 4-OH free compound 2d, albeit ob-
tained with the lowest yield (entry 3), the sterically less
encumbered benzoyl derivative 2e was only formed as a
3:1 mixture of the regioisomers (entry 4). Especially note-
Synthesis 2010, No. 20, 3481–3485 © Thieme Stuttgart · New York

PAPER
Regioselective Acylation of 3,4-OH Free D-Glucosamines
3483
2
4
3
worthy is the introduction of the 3-O-chloroacetyl15 and
the 3-O-levulinoyl16 residues (entries 1 and 2), as they are
5.23 (dq, J ≈ J = 1.6 Hz, J = 17.2 Hz, 1 H, OAll), 5.79 (dddd,
3J = 17.2, 10.5, 6.2, 4.9 Hz, 1 H, OAll), 7.02 (d, 3J = 9.1 Hz, NH).
susceptible to cleavage reactions distinctive from the usu- 13C NMR (100 MHz, CDCl3): d = –5.3 (2 C, OTBS), 18.4 (OTBS),
21.1 (OAc), 26.0 (OTBS), 55.7 (C2), 64.8 (C6), 70.1 (OAll), 71.7
(C4), 74.4 (C5), 74.7 (C3), 92.7 (CCl3), 99.8 (C1), 118.0 (OAll),
133.6 (OAll), 162.3, 172.1.
al nucleophilic cleavage of O-acyl protecting groups.
Thus an additional orthogonal dimension could be in-
stalled in the protecting group schemes of 2b and 2c.
MS (FAB): m/z (%) = 546 (22) [35Cl37Cl2M + Na]+, 544 (61)
In conclusion, we have developed an efficient access to
highly functionalized D-glucosamine derivatives of the
general structure 2 in five steps, with three purifications
required, from known starting material 3. The key step in
this sequence, electrophilic opening of the trans-fused
3,4-O-stannylene acetal, proceeds with high regioselec-
tivity to afford the 4-OH free compounds. The versatile
incorporation of different 3-O-acyl groups permits the in-
stallation of fully orthogonal sets of protecting groups.
[35Cl237ClM + Na]+, 542 (57) [35Cl3M + Na]+, 466 (15) [35Cl37Cl2M
– OAll]+, 464 (43) [35Cl237ClM – OAll]+, 462 (41) [35Cl3M – OAll]+,
406 (12) [35Cl37Cl2M – OAll – AcOH]+, 404 (28) [35Cl237ClM –
OAll – AcOH]+, 402 (19) [35Cl3M – OAll – AcOH]+, 117 (100);
C19H32Cl3NO7Si (520.9).
HRMS (FAB): m/z [35Cl3M + Na]+ calcd for C19H3235Cl3NNaO7Si:
542.0911; found: 542.0913.
Allyl 6-O-tert-Butyldimethylsilyl-3-O-chloroacetyl-2-deoxy-2-
trichloroacetamido-b-D-glucopyranoside (2b)
Compound 2b was prepared according to the general procedure
from diol 5 and chloroacetic anhydride (71 mg, 0.42 mmol); stirring
was continued for 1 h. The product was obtained as a colorless oil
(158 mg, 0.28 mmol, 68%; 2b/6b ~9:1); some starting material (62
mg, 0.13 mmol, 31%) was recovered.
All moisture-sensitive reactions were carried out under O2-free ar-
gon or N2 using oven-dried glassware and a vacuum line. Flash col-
umn chromatography used Merck silica gel 60 (230–400 mesh) and
TLC used commercially available Merck F254 pre-coated sheets. 1H
and 13C NMR spectra were recorded with a Bruker Cryospek WM-
250 or an AM 400 with reported relative residual solvent protons or
TMS as internal standard. Assignments of proton and carbon chem-
ical shifts were carried out with the aid of 2D NMR experiments:
COSY or HMQC. Multiplicities are reported as they appear in the
spectra. FAB and HRMS (FAB from 3-NBA) were recorded with a
Finnigan MAT-90 machine. Optical rotations were recorded with a
Perkin-Elmer 241 polarimeter (NaD line at 589 nm), and specific
optical rotations [a]D20 are given in units of 10–1 deg cm2 g–1.
Rf = 0.51 (silica gel; hexanes–EtOAc, 2:1).
[a]D20 –42.2 (c 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): d = 0.06 (s, 3 H, OTBS), 0.07 (s, 3 H,
OTBS), 0.86 (s, 9 H, OTBS), 3.45 (dt, 3J = 9.9, 5.0 Hz, 1 H, 5-H),
3.71–4.13 (m, 7 H, 2 OCA, 4-OH, 6-Ha/b, 2-H, OAll), 3.76 (dd,
2
3
3J = 9.2, 9.9 Hz, 1 H, 4-H), 4.28 (ddt, J = 13.1 Hz, J = 5.0 Hz,
4J = 1.5 Hz, 1 H, OAll), 4.64 (d, 3J = 8.3 Hz, 1 H, 1-H), 5.13 (dq, 2J
≈ 4J = 1.4 Hz, 3J = 10.5 Hz, 1 H, OAll), 5.22 (dq, 2J ≈ 4J = 1.6 Hz,
3J = 17.2 Hz, 1 H, OAll), 5.44 (dd, 3J = 10.7, 9.2 Hz, 1 H, 3-H), 5.82
(dddd, 3J = 17.2, 10.5, 6.0, 5.0 Hz, 1 H, OAll), 7.23 (d, 3J = 9.3 Hz,
1 H, NH).
Regioselective Protection of 3,4-OH Free Glucosamine Deriva-
tives; General Procedure
Diol 5 (800 mg, 1.67 mmol, 1.0 equiv) was dissolved in benzene (20
mL) and Bu2SnO (426 mg, 1.71 mmol, 1.02 equiv) was added. The
mixture was heated to reflux for 1.5 h using a Dean–Stark appara-
tus, solvent (3 × 3 mL) was removed from the Dean–Stark trap. Af-
ter cooling to r.t., the obtained suspension was transferred into a
graduated cylinder, diluted with benzene to 16 mL and divided into
four aliquots. The appropriate acylating agent was added to each
flask and the mixture was stirred at r.t. The reaction was monitored
by TLC (silica gel; hexanes–EtOAc, 1:1) and upon complete con-
version the solvent was removed under reduced pressure. The resi-
due was purified by flash chromatography (silica gel; hexanes–
EtOAc, 3:1 to 1:1) to afford mixtures of the diastereoisomers con-
taining primarily the 3-O-monoacylated compound.
13C NMR (62.5 MHz, CDCl3): d = –5.3 (2 C, OTBS), 18.4 (OTBS),
26.0 (OTBS), 41.0 (OCA), 55.8 (C2), 64.2 (C6), 70.3 (OAll), 71.1
(C4), 74.5 (C5), 76.9 (C3), 92.5 (CCl3), 99.4 (C1), 118.0 (OAll),
133.5 (OAll), 162.7, 168.7.
MS (FAB): m/z (%) = 578 (2) [35Cl337ClM + Na]+, 576 (1) [35Cl4M
+ Na]+, 500 (16) [35Cl237Cl2M – OAll]+, 498 (26) [35Cl337ClM –
OAll]+, 496 (18) [35Cl4M – OAll]+, 442 (12) [35Cl237Cl2M – TBS]+,
440 (21) [35Cl337ClM – TBS]+, 438 (14) [35Cl4M – TBS]+, 406 (8)
[35Cl37Cl2M – OAll – CAOH]+, 404 (26) [35Cl237ClM – OAll – CA-
OH]+, 402 (24) [35Cl3M
C19H31Cl4NO7Si (555.4).
– OAll –
CAOH]+, 117 (100);
HRMS (FAB): m/z [35Cl4M + Na]+ calcd for C19H3135Cl4NNaO7Si:
576.0522; found: 576.0524.
Allyl 3-O-Acetyl-6-O-tert-butyldimethylsilyl-2-deoxy-2-trichlo-
roacetamido-b-D-glucopyranoside (2a)
Compound 2a was prepared according to the general procedure
from diol 5 and Ac2O (39 mL, 43 mg, 0.42 mmol); stirring was con-
tinued for 1 h. The product was obtained as a white solid (205 mg,
0.39 mmol, 94%; 2a/6a >9:1).
Allyl 6-O-tert-Butyldimethylsilyl-2-deoxy-3-O-levulinoyl-2-
trichloroacetamido-b-D-glucopyranoside (2c)
Compound 2c was prepared according to the general procedure
from diol 5 and levulinic anhydride16a (134 mg, 0.63 mmol); stirring
was continued for 1 h. Additional anhydride (89 mg, 0.42 mmol)
was added and stirring was continued for 30 min. The product was
obtained as a colorless oil (179 mg, 0.31 mmol, 74%; 2c/6c >9:1).
Rf = 0.30 (silica gel; hexanes–EtOAc, 2:1).
[a]D20 –42.5 (c 1.1, CHCl3).
Rf = 0.23 (silica gel; hexanes–EtOAc, 2:1).
[a]D20 –32.4 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 3 H, OTBS), 0.08 (s, 3 H,
OTBS), 0.87 (s, 9 H, OTBS), 2.07 (s, 3 H, OAc), 3.43 (bs, 1 H, 4-
OH), 3.45 (ddd, 3J = 9.4, 5.9, 5.0 Hz, 1 H, 5-H), 3.75 (t, 3J = 9.4 Hz,
1 H, 4-H), 3.83 (dd, 2J = 10.5 Hz, 3J = 5.9 Hz, 1 H, 6-Ha), 3.93 (dd,
2J = 10.5 Hz, 3J = 5.0 Hz, 1 H, 6-Hb), 3.96 (ddd, 3J = 10.5, 9.1, 8.3
Hz, 1 H, 2-H), 4.02 (ddt, 2J = 13.1 Hz, 3J = 6.2 Hz, 4J = 1.4 Hz, 1 H,
OAll), 4.29 (ddt, 2J = 13.1 Hz, 3J = 4.9 Hz, 4J = 1.5 Hz, 1 H, OAll),
4.56 (d, 3J = 8.3 Hz, 1 H, 1-H), 5.14 (dq, 2J ≈ 4J = 1.4 Hz, 3J = 10.5
Hz, 4J = 1.3 Hz, 1 H, OAll), 5.22 (dd, 3J = 10.5, 9.4 Hz, 1 H, 3-H),
1H NMR (250 MHz, CDCl3): d = 0.06 (s, 3 H, OTBS), 0.06 (s, 3 H,
OTBS), 0.87 (s, 9 H, OTBS), 2.13 (s, 3 H, OAc), 2.40–2.62 (m, 2
H, 2 OLev), 2.67–2.80 (m, 2 H, OLev), 3.45 (dt, 3J = 9.2, 4.5 Hz, 1
H, 5-H), 3.54 (d, 3J = 3.6 Hz, 1 H, 4-OH), 3.69 (td, 3J = 9.2, 3.6 Hz,
1 H, 4-H), 3.85–3.88 (m, 2 H, 6-Ha/b), 3.93 (m, 1 H, 2-H), 4.02 (ddt,
2J = 13.2 Hz, 3J = 6.0 Hz, 4J = 1.4 Hz, 1 H, OAll), 4.28 (ddt,
2J = 13.1 Hz, 3J = 4.9 Hz, 4J = 1.5 Hz, 1 H, OAll), 4.59 (d, 3J = 8.3
Synthesis 2010, No. 20, 3481–3485 © Thieme Stuttgart · New York

3484
M. S. Ehret et al.
PAPER
Hz, 1 H, 1-H), 5.11 (dq, 2J ≈ 4J = 1.3 Hz, 3J = 10.5 Hz, 1 H, OAll),
5.22 (dq, J ≈ J = 1.7 Hz, J = 17.3 Hz, J = 1.7 Hz, 1 H, OAll),
5.27 (dd, 3J = 10.7, 8.9 Hz, 1 H, 3-H), 5.80 (dddd, 3J = 17.3, 10.5,
5.9, 5.0 Hz, 1 H, OAll), 7.23 (d, 3J = 9.2 Hz, 1 H, NH).
– BzOH]+, 402 (16) [35Cl3M – OAll – BzOH]+, 117 (27), 105 (100);
C24H34Cl3NO7Si (583.0).
HRMS (FAB): m/z [35Cl3M + Na]+ calcd for C24H3435Cl3NNaO7Si:
2
4
3
4
604.1068; found: 604.1063.
13C NMR (62.5 MHz, CDCl3): d = –5.3 (OTBS), –5.2 (OTBS), 18.4
(OTBS), 26.0 (OTBS), 28.4 (OLev), 29.9 (OLev), 38.3 (OLev),
55.6 (C2), 63.7 (C6), 69.9 (OAll), 70.5 (C4), 75.1 (C5), 75.5 (C3),
92.7 (CCl3), 99.5 (C1), 117.6 (OAll), 133.7 (OAll), 162.3, 173.6,
207.6.
MS (FAB): m/z (%) = 600 (2) [35Cl237ClM + Na]+, 598 (1) [35Cl3M
+ Na]+, 522 (8) [35Cl37Cl2M – OAll]+, 520 (21) [35Cl237ClM –
OAll]+, 518 (22) [35Cl3M – OAll]+, 406 (6) [35Cl37Cl2M – OAll –
LevOH]+, 404 (24) [35Cl237ClM – OAll – LevOH]+, 402 (24)
[35Cl3M – OAll – LevOH]+, 117 (43), 99 (100); C22H36Cl3NO8Si
(577.0).
Allyl 6-O-tert-Butyldimethylsilyl-2-deoxy-2-trichloroacetami-
do-b-D-glucopyranoside (5)
Fully protected glucosamine 4 (610 mg, 1.24 mmol) was dissolved
in MeOH (5 mL) and Na (3 mg, 0.12 mmol) was added. The soln
was stirred at r.t. for 2 h. The mixture was neutralized with Lewatite
ion exchange resin (H+ form), the mixture was filtered through
Celite and the volatiles were removed. The resulting residue was
dissolved under an argon atmosphere in anhyd DMF (3 mL) and
cooled in an ice bath. Imidazole (169 mg, 2.49 mmol) and TBSCl
(206 mg, 1.37 mmol) were added, the mixture slowly came to r.t.
and was stirred overnight. The mixture was diluted with H2O (40
mL) and extracted with EtOAc (3 × 30 mL). The combined organic
layers were successively washed with brine, sat. aq NH4Cl, sat. aq
NaHCO3, and brine (40 mL each), dried (Na2SO4) and the solvent
was removed under reduced pressure. The residue was purified by
flash column chromatography (silica gel; hexanes–EtOAc, 1:1) to
afford the product as an off-white solid (464 mg, 0.97 mmol, 77%).
HRMS (FAB): m/z [35Cl3M + Na]+ calcd for C22H3635Cl3NNaO8Si:
598.1173; found: 598.1178.
Allyl 6-O-tert-Butyldimethylsilyl-2-deoxy-3-O-pivaloyl-2-
trichloroacetamido-b-D-glucopyranoside (2d)
Compound 2d was prepared according to the general procedure
from diol 5 and pivaloyl chloride (51 mL, 50 mg, 0.42 mmol); stir-
ring was continued for 2 h. As the reaction had not run to comple-
tion, stirring was continued overnight. The product was obtained as
clear syrup (137 mg, 0.24 mmol, 58%; 2d/6d ~9:1).
Rf = 0.35 (silica gel; hexanes–EtOAc, 1:1).
[a]D20 –37.4 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 3 H, OTBS), 0.08 (s, 3 H,
OTBS), 0.88 (s, 9 H, OTBS), 3.37 (dt, 3J = 9.8, 5.2 Hz, 1 H, 5-H),
3.47 (ddd, 3J = 10.5, 8.3, 7.0 Hz, 1 H, 2-H), 3.52 (dd, 3J = 9.8, 8.6
Hz, 1 H, 4-H), 3.78–3.91 (bs, 2 H, 2 OH), 3.87–3.89 (m, 2 H, 6-Ha/b),
Rf = 0.51 (silica gel; hexanes–EtOAc, 2:1).
[a]D20 –35.3 (c 1.2, CHCl3).
1H NMR (250 MHz, CDCl3): d = 0.08 (s, 3 H, OTBS), 0.09 (s, 3 H,
OTBS), 0.89 (s, 9 H, OTBS), 1.19 (s, 9 H, OPiv), 3.27 (bs, 1 H, 4-
OH), 3.45 (dt, 3J = 9.6, 5.1 Hz, 1 H, 5-H), 3.72 (dd, 3J = 9.2, 9.6 Hz,
1 H, 4-H), 3.87–3.90 (m, 2 H, 6-Ha/b), 3.97–4.10 (m, 2 H, 2-H,
OAll), 4.31 (ddt, 2J = 13.2 Hz, 3J = 4.9 Hz, 4J = 1.5 Hz, 1 H, OAll),
4.59 (d, 3J = 8.3 Hz, 1 H, 1-H), 5.14 (dq, 2J ≈ 4J = 1.5 Hz, 3J = 10.4
Hz, 1 H, OAll), 5.22 (dq, 2J ≈ 4J = 1.7 Hz, 3J = 17.3 Hz, 1 H, OAll),
5.37 (dd, 3J = 10.7, 9.2 Hz, 1 H, 3-H), 5.82 (dddd, 3J = 17.3, 10.4,
6.1, 5.0 Hz, 1 H, OAll), 7.18 (d, 3J = 9.6 Hz, 1 H, NH).
13C NMR (62.5 MHz, CDCl3): d = –5.3 (2 C, OTBS), 18.4 (OTBS),
26.0 (OTBS), 27.2 (OPiv), 39.1 (OPiv), 55.7 (C2), 64.5 (C6), 70.1
(OAll), 71.7 (C4), 74.4 (C3), 74.8 (C5), 92.6 (CCl3), 99.8 (C1),
117.8 (OAll), 133.6 (OAll), 162.2, 179.7.
MS (FAB): m/z (%) = 588 (1) [35Cl37Cl2M + Na]+, 586 (3)
[35Cl237ClM + Na]+, 584 (3) [35Cl3M + Na]+, 508 (22) [35Cl37Cl2M –
OAll]+, 506 (51) [35Cl237ClM – OAll]+, 504 (50) [35Cl3M – OAll]+,
406 (18) [35Cl37Cl2M – OAll – PivOH]+, 404 (49) [35Cl237ClM –
OAll – PivOH]+, 402 (50) [35Cl3M – OAll – PivOH]+, 117 (100);
C22H38Cl3NO7Si (563.0).
3
2
3.98 (dd, J = 10.5, 8.6 Hz, 1 H, 3-H), 4.04 (ddt, J = 12.8 Hz,
3J = 6.4 Hz, 4J = 1.4 Hz, 1 H, OAll), 4.29 (ddt, 2J = 12.8 Hz, 3J = 5.2
4
3
Hz, J = 1.4 Hz, 1 H, OAll), 4.72 (d, J = 8.3 Hz, 1 H, 1-H), 5.16
2
4
3
2
(dq, J ≈ J = 1.3 Hz, J = 10.4 Hz, 1 H, OAll), 5.24 (dq, J ≈
4J = 1.6 Hz, J = 17.2 Hz, J = 1.5 Hz, 1 H, OAll), 5.82 (dddd,
3
4
3J = 17.2, 10.4, 6.4, 5.2 Hz, 1 H, OAll), 7.16 (d, J = 7.0 Hz, 1 H,
3
NH).
13C NMR (100 MHz, CDCl3): d = –5.2 (2 C, OTBS), 18.5 (OTBS),
26.1 (OTBS), 58.8 (C2), 64.5 (C6), 70.3 (OAll), 73.1 (C3), 73.8
(C4), 74.7 (C5), 92.7 (CCl3), 98.8 (C1), 118.4 (OAll), 133.6 (OAll),
162.8.
MS (FAB): m/z (%) = 504 (3) [35Cl37Cl2M + Na]+, 502 (13)
[35Cl237ClM + Na]+, 500 (11) [35Cl3M + Na]+, 424 (22) [35Cl37Cl2M
– OAll]+, 422 (86) [35Cl237ClM – OAll]+, 420 (82) [35Cl3M –
OAll]+, 406 (17) [35Cl37Cl2M – OAll – H2O]+, 404 (40) [35Cl237ClM
– OAll – H2O]+, 402 (35) [35Cl3M – OAll – H2O]+, 366 (9)
[35Cl37Cl2M – TBS]+, 364 (34) [35Cl237ClM – TBS]+, 362 (36)
[35Cl3M – TBS]+, 117 (100); C17H30Cl3NO6Si (478.9).
HRMS (FAB): m/z [35Cl3M]+ calcd for C17H3035Cl3NO6Si:
478.0986; found: 478.0983.
HRMS (FAB): m/z [35Cl3M]+ calcd for C22H3835Cl3NO7Si:
562.1561; found: 562.1564.
Allyl 3-O-Benzoyl-6-O-tert-butyldimethylsilyl-2-deoxy-2-
trichloroacetamido-b-D-glucopyranoside (2e)
Compound 2e was prepared according to the general procedure
from diol 5 and BzCl (48 mL, 59 mg, 0.42 mmol); stirring was con-
tinued for 1 h. After chromatography the product was obtained as a
mixture of the regioisomers (163 mg, 0.28 mmol, 68%; 2e/6e ~3:1),
that was not further purified.
Acknowledgment
This work was supported by the KIT ‘Concept for the Future’
(RG49-1); funding was provided by Germany’s federal ‘Excellence
Initiative’ and the ‘Stiftung Stipendien-Fonds des VCI’ (stipend for
MSE).
Rf = 0.49 (silica gel; hexanes–EtOAc, 2:1).
References
1H NMR (250 MHz, CDCl3): d = 4.71 (d, 3J = 8.3 Hz, 1 H, 1-H 2e),
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MS (FAB): m/z (%) = 608 (1) [35Cl37Cl2M + Na]+, 606 (3)
[35Cl237ClM + Na]+, 604 (3) [35Cl3M + Na]+, 528 (6) [35Cl37Cl2M –
OAll]+, 526 (13) [35Cl237ClM – OAll]+, 524 (12) [35Cl3M – OAll]+,
406 (5) [35Cl37Cl2M – OAll – BzOH]+, 404 (16) [35Cl237ClM – OAll
Synthesis 2010, No. 20, 3481–3485 © Thieme Stuttgart · New York

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Regioselective Acylation of 3,4-OH Free D-Glucosamines
3485
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Synthesis 2010, No. 20, 3481–3485 © Thieme Stuttgart · New York