Stereoselective synthesis of the C-analogue of β-D-glucopyranosyl serine

Article abstract of DOI:10.1039/a703063k

The [2,3]-Wittig sigmatropic rearrangement of an appropriate glucose derivative followed by further chemical modification afforded stereoselectively the C-analogue of β-D-glucopyranosyl serine.

Full text of DOI:10.1039/a703063k

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Stereoselective synthesis of the C-analogue of b-d-glucopyranosyl serine
Luigi Lay,a Morten Meldal,b Francesco Nicotra,a Luigi Panza*a and Giovanni Russoa
a Dipartimento di Chimica Organica e Industriale, Centro per lo Studio delle Sostanze Organiche Naturali del CNR, Universita` di
Milano, via Venezian 21, I-20133 Milano, Italy
b Carlsberg Laboratory, Department of Chemistry, Gamle Carlsberg Vej 10, DK-2500 Valby, Copenhagen, Denmark
The [2,3]-Wittig sigmatropic rearrangement of an appro-
priate glucose derivative followed by further chemical
modification afforded stereoselectively the C-analogue of
b-D-glucopyranosyl serine.
treatment with methyl glycolate (5 equiv.) and BF3·Et2O (1.5
equiv.) in the presence of 4 Å molecular sieves.
Since preliminary attempts to effect silyl trifluoromethane-
sulfonate-mediated Wittig rearrangement6 on 2 were un-
successful, the dianionic [2,3]-Wittig rearrangement7 was
considered. Compound 2 was then hydrolysed with 2% NaOH
in MeOH. The carboxylic acid obtained was treated with excess
LDA (3 equiv.) in THF at 278 °C and the reaction mixture was
allowed to warm to 0 °C. The crude product was then treated
wih CH2N2 in Et2O–MeOH and the a-hydroxy ester 3 was
isolated in 70% yield from 2 (de > 95%). The geometry of the
newly formed double bond was shown to be Z by an NOE
experiment.‡ Compound 3 was hydrogenated with freshly
prepared Raney-Ni in EtOH to give 4 in 80% yield. The
absolute configuration of the stereocentre at C-2 was deter-
mined converting 4 into the (R)- and (S)-MTPA esters by
treatment with (R)- and (S)-MTPA chloride, respectively, in
Protein glycosylation plays fundamental roles in inter- and
intra-cellular recognition.1 Thus, N-linked protein glycosylation
is involved in protein sorting and the ability of the immune
system to recognize and discriminate O-linked tumour asso-
ciated glycoprotein antigens of malignant tissue as foreign
structures has been well documented.1 Furthermore,
O-glycosylation of a peptide or a protein can increase their
solubility and their resistance towards enzymatic degradation,
can modify the conformation of the peptide backbone and
modulate the biological activity. These properties have recently
stimulated great interest in glycopeptides as therapeutic
agents.2
1
One limitation of the use of these compounds as potential
drugs is the sensitivity of the glycosidic linkage between the
sugar and the peptide towards both chemical and enzymatic
deglycosylation.1 For these reasons it is of great interest to have
access to stable analogues of O-glycosylated amino acids, such
as C-glycosyl amino acids, in which the glycosidic oxygen atom
can be substituted with a methylene group or omitted to give nor
analogues. Few examples of the synthesis of C-glycosyl amino
acids as well as their incorporation in biologically active
peptides appear in the literature.3 However, such compounds
are not easily obtainable, particularly by direct carbon–carbon
bond forming reactions between a sugar and an amino acid,4 and
have usually been prepared as diastereoisomeric mixtures at the
a-carbon of the amino acid moiety.3
CH2Cl2–pyridine. The H NMR spectrum of the MTPA esters
showed a Dd value (dS 2 dR) of +0.1 ppm for the signals of the
hydrogen atoms at C-3 and C-4, allowing the assigment of the
absolute configuration R at C-2.8
Moreover, the chemical shift of the hydrogen atom at C-5 of
4, which resonates at d 3.27, suggests the presence of an
equatorial substituent which was confirmed subsequently on
compound 8.
The substitution of the hydroxy group with a nitrogen was
attempted using diphenylphosphoryl azide (DPPA),9 which
should have allowed the direct conversion of an a-hydroxy ester
to the corresponding azide with inversion of configuration.
When compound 4 was treated with DPPA (2.5 equiv.) and
DBU (0.98 equiv.) in toluene at 20 °C, only the intermediate
phosphate 5 was isolated in good yield (Scheme 3). Moreover,
when the reaction mixture was heated, the substitution reaction
with the azide was incomplete even at reflux (110 °C) and gave
many byproducts. However, treatment of the phosphate with
Here we describe the synthesis of the C-analogue of
glucopyranosyl serine using
a [2,3]-Wittig sigmatropic
rearrangement5 in which the chirality of the sugar induces the
stereoselective formation of the amino acid moiety, according
to the retrosynthetic pathway in Scheme 1.
The appropriate precursor 2† for Wittig rearrangement was
prepared in 70% yield (Scheme 2) from known compound 15 by
OBn
O
OBn
8
OH
6
i
2
NH2
7
4O
1
BnO
BnO
BnO
BnO
O
HO
HO
3
5
CO2H
BnO
BnO
OH
O
CO2Me
HO
1
2
OR
O
ii–iv
OBn
10
7
RO
RO
8
9
O
CO2H
BnO
1
5
3
6
BnO
CO2Me
2
RO
OBn
OH
4
v
OH
BnO
OH
O
OR
O
BnO
BnO
3
CO2Me
RO
RO
BnO
4
RO
Scheme 2 Reagents and conditions: i, HOCH2CO2Me, BF3·Et2O, 20 °C,
70%; ii, NaOH, MeOH, room temp.; iii, LDA, THF, 278 ? 0 °C; iv,
CH2N2, Et2O–MeOH, 70% from 2; v, H2, Raney-Ni, MeOH, 80%
O
CO2R′
Scheme 1
Chem. Commun., 1997
1469

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OBn
O
Footnotes
OH
BnO
BnO
* E-mail: panza@imiucca.csi.unimi.it
CO2Me
i
† All new compounds gave satisfactory elemental analysis and specroscopic
data. Selected data: [a]D: 2, 25.3 (c 0.8, CHCl3); 3: 45.6 (c 1.0, CHCl3); 4,
4.5 (c 0.9, CHCl3); 5, 5.4 (c 1.0, CHCl3); 6, 8.9 (c 1.0, CHCl3); 7, 28.1 (c
1.0, MeOH); 8, 16.4 (c 1.0, CHCl3). 1H NMR (CDCl3): 2, 5.96 (dd, 1 H, J
17.5, 10.8 Hz, H-2), 5.60 (dd, 1 H, J 17.5, 1.7 Hz, H-1a), 5.30 (dd, 1 H, J
10.8, 1.7 Hz, H-1b), 4.22 (t, 1 H, J 9.5 Hz, H-5), 4.10 and 4.02 (2 d, 2 H, J
16.1 Hz, CH2CO2Me), 3.72 (s, 3 H, Me), 3.42 (d, 1 H, J 9.5 Hz, H-4); 3, 4.94
(t, 1 H, J 7.4 Hz, H-4), 4.26 (br t, 1 H, J 5.1 Hz, H-2), 3.91 (d, 1 H, J 5.7 Hz,
H-6), 3.71 (s, 3 H, Me), 2.94 (br s, 1 H, OH), 2.67–2.58 (m, 2 H, H-3); 4,
4.18 (dd, 1 H, J 7.5, 4.4 Hz, H-2), 3.72 (s, 3 H, Me), 3.27 (m, 1 H, H-5), 3.04
(br s, 1 H, OH), 2.03 (m, 1 H, H-4a), 1.88 (m, 2 H, H-3), 1.57 (m, 1 H, H-4b);
5, 5.04 (dt, 1 H, J 7.7, 4 Hz, H-2), 3.65 (s, 3 H, Me), 3.18 (m, 1 H, H-5), 2.15
(m, 1 H, H-3a), 1.93 (m, 2 H, H-3b and H-4a), 1.57 (m, 1 H, H-4b); 6, 3.94
(dd, 1 H, J 8.8, 4.6 Hz, H-2), 3.74 (s, 3 H, Me), 3.26 (m, 1 H, H-5), 2.03 (m,
1 H, H-3a), 1.81 (m, 2 H, H-3b and H-4a), 1.56 (m, 1 H, H-4b); 7 (D2O,
50 °C), 4.39 (t, 1 H, J 6.3 Hz, H-2), 4.02 (s, 3 H, Me), 3.48 (m, 1 H, H-5),
2.38 (m, 1 H, H-3a), 2.21 (m, 2 H, H-3b and H-4a), 1.73 (m, 1 H, H-4b); 8,
5.14 (t, 1 H, J 9.5 Hz, H-7), 5.01 (t, 1 H, J 9.5 Hz, H-8), 4.85 (t, 1 H, J 9.5
Hz, H-6), 4.18 (dd, 1 H, J 12.4, 5.2 Hz, H-10a), 4.08 (dd, 1 H, J 12.4, 2.3
Hz, H-10b), 3.89 (dd, 1 H, J 8.8, 4.5 Hz, H-2), 3.77 (s, 3 H, Me), 3.60 (ddd,
1 H, J 9.5, 5.2, 2.3 Hz, H-9), 3.42 (dt, 1 H, J 9.5, 2.4 Hz, H-5), 2.1–1.9 (m,
13 H, H-3a and 4 Ac), 1.8–1.6 (m, 2 H, H-3b and H-4a), 1.57 (m, 1 H,
H-4b).
BnO
O
4
OBn
O
OP(OPh)2
i, ii
BnO
BnO
CO2Me
BnO
ii
OBn
O
5
7
N3
BnO
BnO
CO2Me
iii
OH
O
BnO
6
8
NH2•HCl
CO2Me
HO
HO
iv
OAc
O
HO
N3
AcO
AcO
CO2Me
AcO
Scheme 3 Reagents and conditions: i, DPPA, DBU, toluene; ii, Bu4NN3,
toluene; iii, H2, Pd(OH)2, EtOH, quant.; iv, Ac2O, Me3SiOSO2CF3, 67%
‡ By irradiation of the vinylic hydrogen, an NOE of 4.5% was observed on
the hydrogen atom at C-6 for compound 3.
Bu4NN3 in toluene gave the desired substitution product 6 in
88% yield. The reaction conditions were then modified as
follows to obtain a one-pot transformation: the phosphate ester
was formed as described above, but with heating to 55 °C. Then
a solution of Bu4NN310 (3 equiv., 0.2 m solution in toluene) was
added and the mixture was stirred at the same temperature until
the phosphate ester disappeared on TLC: in this way the desired
azido ester 6 was obtained in 92% yield.§
Reduction of the azido group and contemporary hydro-
genolysis of the benzyl ethers was carried out with Pd(OH)2 in
EtOH containing few drops of 5% aq. HCl to finally afford the
deprotected compound 7 in an almost quantitative yield.
In order to incorporate the obtained analogue into glycopep-
tides using either solution or solid phase synthesis, it would be
useful to maintain the azido group11 and to change the
protecting groups on the sugar moiety. The benzylated analogue
6 was thus submitted to acetolysis12 by treatment with
trimethylsilyl trifluoromethanesulfonate in Ac2O at room
temp. for 40 h to give the acetylated derivative 8 in 67%
yield.
§ 1H and 13C NMR spectra of compounds 6-8 each showed a single set of
peaks indicating the formation of a single diastereoisomer.
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The 1H NMR spectrum of compound 8 showed a signal at d
3.42 due to the hydrogen atom at C-5 in which the coupling
constant with the adjacent ring hydrogen at C-6 (J 9.5 Hz)
clearly confirmed that the equatorial configuration had been
obtained at position 5, corresponding to the b-anomer of the
O-linked analogue.
The reported procedure allows a simple and stereoselective
access to the C-linked analogue of glucopyranosyl serine which
can be incorporated in synthetic peptides. As the sugar moiety
is not directly involved into chemical modifications, the
procedure could be, in principle, applicable to other mono-
saccharides. Work is in progress to extend the scope of the
procedure.
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Part of the present work was supported by the EU-Carenet 2
program (ERB4061PL95-0372).
Received in Cambridge, UK, 6th May 1997; 7/03063K
1470
Chem. Commun., 1997