A Convenient Route to O-Glycosyl Lactates via Conjugate Addition to 2-Nitroglycals: Ring Closure to Novel Pyrano[2.3-b][1,4]-oxazines

Article abstract of DOI:10.1055/s-2003-42494

Lactate esters D-2a, L-2a, and D-2b could be readily added to 3,4,6-tri-O-benzyl-2-nitro-galactal (1) and 3,4,6-tri-O-benzyl-2-nitro-glucal (4), affording exclusively a- and β-anomers with galacto- and gluco-configuration, respectively. Nitro group reduct

Full text of DOI:10.1055/s-2003-42494

PAPER
53
A Convenient Route to O-Glycosyl Lactates via Conjugate Addition to 2-Nitro-
glycals: Ring Closure to Novel Pyrano[2.3-b][1,4]-oxazines
O-Glycosyl
Lactat
h
es via Conju
m
gate
A
ddition to 2-N
e
itroglycalsd I. Khodair,b Kandasamy Pachamuthu,a Richard R. Schmidt*a
a
Fachbereich Chemie, Universität Konstanz, Fach M 725, 78457 Konstanz, Germany
Fax +49(7531)883135; E-mail: Richard.Schmidt@uni-konstanz.de
b
On leave from the Chemistry Department, Faculty of Education, Tanta University, Kafr El-Sheikh Branch, Kafr El-Sheikh, Egypt
Received 26 June 2003; revised 9 October 2003
Dedicated to Professor Dr. Wolfgang Steglich on the occasion of his 70th birthday.
Abstract: Lactate esters D-2a, L-2a, and D-2b could be readily add-
ed to 3,4,6-tri-O-benzyl-2-nitro-galactal (1) and 3,4,6-tri-O-benzyl-
2-nitro-glucal (4), affording exclusively - and -anomers with ga-
lacto- and gluco-configuration, respectively. Nitro group reduction
to the amino group and ester cleavage led to compounds 6a, 6b, and
7, which can be regarded as dipeptide mimetics. For these com-
pounds the bicyclic pyrano[2.3-b][1,4]-oxazines 8–10 were pre-
pared via ring closure.
Key words: glycal, nitroolefin, Michael additions, glycosides, pep-
tide mimetic, bicyclic systems, azadioxadecalines
Glycosylation of -hydroxycarboxylic acid with glycosyl
donors derived from -aminosugars should lead to a vari-
ety of interesting compounds, which can be regarded as a
new type of dipeptide mimetics.1 Possibly, due to the de-
creased nucleophilicity of the -hydroxy group, these
compounds have gained little attention thus far.2 How-
ever, the successful direct base-catalysed addition of O-,
Scheme 2 Synthesis of 3a and 3a .
N-, and C-nucleophiles to 2-nitroglycals (Scheme 1), as
recently introduced by us,3–5 made these type of com-
pounds readily available. Hence, we performed an explor-
atory study with alkyl lactates as nucleophiles. The
liberation of the underlying dipeptide mimetics and ring
closure to a novel bicyclic system was also investigated.
J2,3 = 10.7 Hz; D-3a : J1,2 = 8.1Hz; J2,3 = 9.4 Hz]. The
same reaction with the L-isomer L-2a led to a 1.2:1 ratio
of L-3a and L-3a , thus indicating that the / ratio de-
pends not only on the chirality of the sugar moiety but also
on the stereochemistry of lactate. Inspection of the plausi-
ble transition state of this reaction, as shown for D-2a in
Scheme 3, exhibits that formation of D-3a via transition
state D-3a is sterically favoured over formation of D-
3a via transition state D-3a whereas the opposite is true
for the formation of the L-isomers.
Scheme 1 Base-catalysed addition of nucleophiles to 2-nitrogalac-
tals.
3,4,6-Tri-O-benzyl-2-nitro-D-galactal (1), which is readi-
ly available via nitration of the corresponding galactal de-
rivative,3a,6 furnished with methyl D-lactate (D-2a) in the
presence of potassium tert-butoxide as base and toluene as
solvent, D-3a together with some -anomer D-3a ( : =
9:2) in good yield (Scheme 2).
Scheme 3 Possible transition states.
The two compounds could be readily separated and struc-
turally assigned by their NMR data (D-3a ): J1,2 = 4.1 Hz,
Hence, together with the stereoelectronically favoured -
side attack, there should be, as is observed, a clear prefer-
ence for D-3a formation. This effect is also exhibited in
the addition of L-threonine esters, in which the carbon
connected to the hydroxy group, has D-configuration;
SYNTHESIS 2004, No. 1, pp 0053–0058
x
x
.
x
x
.2
0
0
3
Advanced online publication: 19.11.2003
DOI: 10.1055/s-2003-42494; Art ID: T05803SS.pdf
© Georg Thieme Verlag Stuttgart · New York

54
A. I. Khodair et al.
PAPER
therefore, mainly or exclusively the -anomer was ob- group of L-5a and D-5b in the presence of platinized
tained.3b–d
Raney-nickel10 as catalyst afforded dipeptide mimetics L-
6a and D-6b , respectively. Ensuing hydrogenolytic O-
debenzylation, for instance, of L-6a with Pd/C as catalyst
and then N- and O-acetylation furnished L-11a . Treat-
ment of D-6b with trifluoroacetic acid (TFA) readily led
to the removal of the tert-butyl group, thus furnishing D-
7 with deprotection of the peptide mimetic part. Obvi-
ously, this type of compounds can be readily ring closed.
For instance, treatment with diphenyl phosphoryl azide as
condensing agent11 in the presence of Et3N as base, af-
fords the novel bicyclic system D-8 . Hydrogenolytic O-
debenzylation in the presence of Pd/C as catalyst ( D-
9 ) and then O-acetylation with acetic anhydride in pyri-
dine afforded O-acetyl protected D-10 . The reaction se-
quence from 5 to 8 could also be performed without
isolation of intermediates 6 and 7 as shown for D-5b
which gave D-8 in 55% overall yield.
Extension of this reaction to the corresponding 3,4,6-tri-
O-benzyl-2-nitro-D-glucal7,8 (4, Scheme 4) furnished less
stereocontrol than with the galacto-isomer 1.
In conclusion, base catalysed -hydroxycarboxylate addi-
tion to 2-nitroglycals readily provides the corresponding
- and -glycosides with generation of two new stereo-
genic centres, of which one is highly stereoselectively
formed. Transformation of these compounds gives access
to dipeptide mimetics and to novel bicyclic pyrano[2.3-b]
[1.4]-oxazines.
Solvents were removed under reduced pressure while the water bath
temperature was maintained below 40 °C. Solvents for chromatog-
raphy were distilled prior to use. Petroleum ether (bp 35–80 °C) was
used. Chromatography was performed on silica gel for flash chro-
matography (40 m; J. T. Baker) at a pressure of 3 bar. For TLC,
TLC plastic sheets (60 F254 silica gel) were used and the compounds
were viewed by illumination under UV light at 253 nm and by treat-
ment with 5% (NH4)2MoO4, 0.1% Ce(SO4)2 in 10% H2SO4 and
heating to 160 °C. Optical rotations were measured at 25 °C with a
Perkin-Elmer 241/MS polarimeter at the sodium D line. NMR spec-
tra were measured on Bruker AC-250 Cryospec, Bruker DR-600
spectrometers. TMS or the solvent residual peaks were used as in-
ternal standard. 3JC,H couplings were observed in gradient-selected
heteronuclear multi-bond correlations (HMBC). For MALDI-MS,
Kratos Kompact Maldi 1 and 2,5-dihydroxybenzoic acid (as matrix)
were used. FAB–MS was measured on Finnigan MAT 312/AMD-
5000 instrument at 790 eV and 70 °C. Calculated yields are based
on consumed starting material where its recovery is stated.
Methyl O-(3,4,6-tri-O-benzyl-2-deoxy-2-nitro- -D-galactopyra-
nosyl)-L-lactate (L-3a ) and Methyl O-(3,4,6-tri-O-benzyl-2-
deoxy-2-nitro- -D-galactopyranosyl)-L-lactate (L-3a )
Methyl L-lactate L-2a (0.45 g, 4.34 mmol) and 2-nitrogalactal 1
(1.00 g, 2.17 mmol) were dried under high vacuum and dissolved in
anhyd toluene (30 mL) under Ar. Freshly activated molecular sieves
(3 Å, 1.50 g) were introduced and the mixture stirred for 1 h. Then
1 M t-BuOK solution in THF (0.20 mL, 0.20 mmol) was added and
stirring was continued for 12 h at r.t. HOAc (0.20 mL) was used to
acidify the reaction mixture, the molecular sieves were filtered off
and the solvents removed under reduced pressure. The residue was
purified by column chromatography (petroleum ether–EtOAc, 9:1)
to furnish L-3a (0.45 g, 37%) and L-3a (0.38 g, 31%) as colorless
oils.
Scheme 4 Reagents and conditions: (a) t-BuOK, Tol, r.t. (b) Raney
Ni (T4), H2, EtOH, r.t. (c) TFA, CH2Cl2, r.t. (d) DPPA, NEt3, DMF,
r.t. (e) Pd/C, H2, MeOH–HOAc, r.t. (f) Ac2O, Pyr. (g) Pd/C, H2,
MeOH–HOAc; Ac2O, Pyr. r.t.
Similar observations were previously made with simple
alcohols,7–9 and also an inspection of the corresponding
transition states as shown for 1 in Scheme 3, supports
these results. Thus, with L-2a, L-5a and L-5a were ob-
tained in an approximately 1:1 ratio (NMR: L-5a , J1,2
=
3.4 Hz, L-5a , J1,2 = 8.0 Hz). For the D-isomer D-2b the -
isomer D-5b was even the major isomer ( : ca. 1:2).
The diastereomers could be readily separated and further
reactions were investigated. Thus, reduction of the nitro
L-3a
Rf 0.58 (petroleum ether–EOAc, 8:2); [ ]D +60.25 (c 0.79, CHCl3).
Synthesis 2004, No. 1, 53–58 © Thieme Stuttgart · New York

PAPER
O-Glycosyl Lactates via Conjugate Addition to 2-Nitroglycals
55
3
1H NMR (250 MHz, CDCl3): = 1.36 (d, J = 6.8 Hz, 3 H,
-
127.8, 127.9, 128.1, 128.2, 128.3, 128.5, 128.6, 136.5, 137.5, 137.8
(C-Ar), 171.9 (COOMe).
,
CH3), 3.46 (dd, 3J6,5 = 5.7 Hz, 2J6,6 = 9.1 Hz, 1 H, 6-H), 3.60 (m,
1 H, 6 -H), 3.65 (s, 3 H, OMe), 4.11 (m, 2 H, 4-H, 5-H), 4.37 (q,
MS (MALDI): m/z = 588 [MNa+].
3J = 6.8 Hz, 1 H, -CH), 4.49–4.58 (m, 4 H, 2 × OCH2Ph), 4.78
,
2
2
Anal. Calcd for C31H35NO9 (565.6): C, 65.83; H, 6.24; N, 2.48.
Found: C, 65.99; H, 6.35; N, 2.23.
(d, J = 11.3 Hz, 2 H, OCH2Ph), 4.88 (d, J = 11.2 Hz, 1 H,
OCH2Ph), 5.06 (dd, 3J2,1 = 4.3 Hz, 3J2,3 = 10.7 Hz, 1 H, 2-H), 5.39
(d, 3J1,2 = 4.3 Hz, 1 H, 1-H), 7.23–7.41 (m, 15 H, Ar-H).
Methyl O-(3,4,6-tri-O-benzyl-2-deoxy-2-nitro- -D-glucopyra-
nosyl)-L-lactate (L-5a ) and Methyl O-(3,4,6-tri-O-benzyl-2-
deoxy-2-nitro- -D-glucopyranosyl)-L-lactate (L-5a )
13C NMR (62.8 MHz, CDCl3): = 17.67 ( -CH3), 51.88 (OCH3),
67.77 ( -CH), 69.97 (C-6), 72.83 (C-5), 73.07 (C-4), 73.20
(OCH2Ph), 74.56 (OCH2Ph), 74.92 (C-3), 74.99 (OCH2Ph), 84.18
(C-2), 97.13 (C-1), 127.54, 127.66, 127.90, 127.98, 128.03, 128.20,
128.27, 128.37, 128.40,.137.31, 137.77, 137.96 (C-Ar), 172.21
(COOMe).
L-5a and L-5a were obtained as described for L-3a and L-3a .
L-5a
Yield: 0.53 g (43%); white foam.
EI–MS: m/z = 565 [M+].
Rf 0.50 (petroleum ether–EtOAc, 8:2); [ ]D +47.5 (c 0.32, CHCl3).
Anal. Calcd for C31H35NO9 (565.6): C, 65.83; H, 6.24; N, 2.48.
Found: C, 66.28; H, 6.02; N, 2.64.
3
1H NMR (250 MHz, CDCl3): = 1.38 (d, J = 6.8 Hz, 3 H,
-
,
CH3), 3.62 (dd, 3J6,5 = 2.0 Hz, 2J6,6 = 10.9 Hz, 1 H, 6-H), 3.70 (s, 3
H, OCH3), 3.81–3.87 (m, 2 H, 6 -H, 5-H), 4.15 (q, 3J = 6.8 Hz, 1
,
L-3a
H, -CH), 4.27 (d, 3J4,3 = 10.3 Hz, 1 H, 4-H), 4.48–4.67 (m, 5 H, 2
× OCH2Ph, 3-H), 4.85 (d, 2J = 10.9 Hz, 1 H, OCH2Ph), 4.95 (s, 2 H,
OCH2Ph, 2-H), 5.42 (dd, 3J1,2 = 3.4 Hz, 1 H, 1-H), 7.21–7.40 (m, 15
H, Ar-H).
Rf 0.508 (petroleum ether–EtOAc, 8:2); [ ]D –7.32 (c 0.41, CHCl3).
3
1H NMR (250 MHz, CDCl3): = 1.40 (d, J = 6.9 Hz, 3 H,
-
,
CH3), 3.55–3.65 (m, 3 H, 6-H, 6 -H, 5-H), 3.68 (s, 3 H, OCH3), 3.73
(d, 3J4,3 = 5.8 Hz, 1 H, 4-H), 4.04 (m, 1 H, -CH), 4.40–4.61 (m, 7
H, 5 OCH2Ph, 3-H, 2-H), 4.82–4.88 (m, 2 H, OCH2Ph, 1-H), 7.22–
7.40 (m, 15 H, Ar-H).
13C NMR (62.8 MHz, CDCl3): = 17.16 ( -CH3), 51.53 (OCH3),
67.01 ( -CH), 70.74 (C-6), 72.92 (C-5), 74.46 (C-4, OCH2Ph),
75.20 (OCH2Ph), 76.47 (C-3, OCH2Ph), 86.09 (C-2), 96.61 (C-1),
127.04, 127.26, 127.34, 127.83, 137.01, 137.20, 137.25 (C-Ar),
171.54 (COOMe).
EI–MS: m/z = 565 [M+].
Anal. Calcd for C31H35NO9 (565.6): C, 65.83; H, 6.24; N, 2.48.
Found: C, 65.66; H, 6.15; N, 2.31.
EI–MS: m/z = 565 [M+].
Anal. Calcd for C31H35NO9 (565.6): C, 65.83; H, 6.24; N, 2.48.
Found: C, 65.67; H, 6.10; N, 2.48.
Methyl O-(3,4,6-tri-O-benzyl-2-deoxy-2-nitro- -D-galactopyra-
nosyl)-D-lactate (D-3a ) and Methyl O-(3,4,6-tri-O-benzyl-2-
deoxy-2-nitro- -D-galactopyranosyl)-D-lactate (D-3a )
L-5a
D-3a and D-3a were obtained as described for L-3a and L-3a .
Yield: 0.45 g (37%): white foam.
Rf 0.48 (petroleum ether–EtOAc, 8:2); [ ]D –19.12 (c 0.34, CHCl3).
D-3a
3
1H NMR (250 MHz, CDCl3): = 1.45 (d, J = 7.0 Hz, 3 H,
-
Yield: 587 mg (48%).
,
CH3), 3.53 (m, 1 H, 6-H), 3.66–3.74 (m, 6 H, 6 -H, 5 -H, OCH3, 4-
H), 4.25 (dd, 3J3,2 = 8.8 Hz, 2J3,4 = 10.3 Hz, 1 H, 3-H), 4.42–4.62 (m,
7 H, -CH, 3 × OCH2Ph), 4.78 (dd, 3J2,3 = 8.8 Hz, 1 H, 2-H), 4.92
(d, 3J2,1 = 8.0 Hz, 3J2,3 = 8.7 Hz, 1 H, 1-H), 7.14–7.33 (m, 15 H, Ar-
H).
13C NMR (62.8 Hz, CDCl3): = 18.42 ( -CH3), 52.06 (OCH3),
67.77 ( -CH), 72.57 (C-6), 73.52 (C-5, OCH2Ph), 75.09 (C-4),
75.30 (OCH2Ph), 75.48 (C-3), 81.36 (OCH2Ph), 89.66 (C-2), 98.35
(C-1), 127.81, 127.98, 128.04, 128.45, 136.98, 137.49, 137.71 (C-
Ar), 171.92 (COOMe).
Rf 0.78 (petroleum ether–EtOAc, 8:2); [ ]D +112.0 (c 1, CHCl3).
3
1H NMR (250 MHz, CDCl3): = 1.44 (d, J = 6.9 Hz, 3 H,
-
,
CH3), 3.55 (d, 3J6,5 = 6.5 Hz, 2 H, 6-H, 6 -H), 3.71 (s, 3 H, OMe),
4.03–4.27 (m, 2 H, 4-H, 5-H), 4.32 (q, 3J = 6.9 Hz, 1 H, -CH),
,
3
4.35–4.88 (m, 7 H, 3-H, 3 × OCH2Ph), 5.03 (dd, J2,1 = 4.1 Hz,
3J2,3 = 10.7 Hz, 1 H, 2-H), 5.45 (d, 3J1,2 = 4.1 Hz, 1 H, 1-H), 7.09–
7.37 (m, 15 H, Ar-H).
13C NMR (62.8 MHz, CDCl3): = 18.3 ( -CH3), 52.1 (OCH3), 68.3
( -CH), 70.2 (C-6), 71.5 (C-5), 73.1 (C-4), 73.13 (OCH2Ph), 73.5
(OCH2Ph), 75.0 (C-3), 75.1 (OCH2Ph), 83.9 (C-2), 95.5 (C-1),
127.7, 127.8, 127.9, 128.0, 128.1, 128.3, 128.5, 137.3, 137.6, 137.8
(C-Ar), 171.7 (COOMe).
EI–MS: m/z = 565 [M+].
Anal. Calcd for C31H35NO9 (565.6): C, 65.83; H, 6.24; N, 2.48.
Found: C, 65.56; H, 6.22; N, 2.51.
MS (MALDI): m/z = 588 [MNa+].
Anal. Calcd for C31H35NO9 (565.6): C, 65.83; H, 6.24; N, 2.48.
Found: C, 65.76; H, 6.27; N, 2.67.
tert-Butyl O-(3,4,6-tri-O-benzyl-2-deoxy-2-nitro- -D-glucopyr-
anosyl)-D-lactate (D-5b ) and tert-Butyl O-(3,4,6-tri-O-benzyl-
2-deoxy-2-nitro- -D-glucopyranosyl)-D-lactate (D-5b )
tert-Butyl-D-lactate D-2b (317 mg, 2.17 mmol) and 2-nitroglucal 4
(1.00 g, 2.17 mmol) were dried under high vacuum and dissolved in
anhyd toluene (30 mL) under Ar. The reaction was carried out as de-
scribed for the synthesis of L-3a to furnish D-5b (0.30 g, 23%) and
D-5b (0.50 g, 38%) as white foams.
D-3a
Yield: 136 mg (11%).
Rf 0.70 (petroleum ether–EtOAc, 8:2); [ ]D = +20.8 (c 1, CHCl3).
3
1H NMR (250 MHz, CDCl3): = 1.35 (d, J = 6.8 Hz, 3 H,
-
,
CH3), 3.52–3.67 (m, 3 H, 6-H, 6 -H, 5-H), 3.68 (s, 3 H, OMe), 3.99–
4.19 (m, 2 H, 3-H, 4-H), 4.18 (q, 3J = 6.8 Hz, 1 H, -CH), 4.43–
,
D-5b
4.63 (m, 5 H, 2 × OCH2Ph, 1-H), 4.82–4.94 (m, 3 H, 2-H,
OCH2Ph), 7.23–7.36 (m, 15 H, Ar-H).
13C NMR (62.8 MHz, CDCl3): = 17.6 ( -CH3), 52.1 (OCH3), 67.9
( -CH), 71.4 (C-6), 72.3 (C-5), 73.6 (C-4), 74.0 (OCH2Ph), 74.8
(OCH2Ph), 75.2 (C-3), 79.4 (OCH2Ph), 87.1 (C-2), 99.7 (C-1),
Rf 0.56 (petroleum ether–EtOAc, 8:2); [ ]D +77.39 (c 0.23, CHCl3).
3
1H NMR (250 MHz, CDCl3): = 1.40 (d, J = 6.9 Hz, 3 H,
-
,
CH3), 1.47 (s, 9 H, CMe3), 3.62–3.90 (m, 4 H, 6-H, 6 -H, 5-H, 4-H),
4.21 (q, 3J = 6.8 Hz, 1 H, -CH), 4.49–4.66 (m, 5 H, 3-H,
,
Synthesis 2004, No. 1, 53–58 © Thieme Stuttgart · New York

56
A. I. Khodair et al.
PAPER
OCH2Ph, 2-H), 4.84 (d, 2J = 10.7 Hz, 1 H, OCH2Ph), 4.92 (s, 2 H,
(310 mg, 94%) as a colorless oil which was immediately used in the
next step; Rf 0.36 (CH2Cl2–MeOH, 95:5); [ ]D +43.33 (c 0.18,
OCH2Ph), 5.50 (d, 3J1,2 = 3.0 Hz, 1 H, 1-H), 7.17–7.36 (m, 15 H, Ar-
H).
CHCl3).
3
13C NMR (62.8 MHz, CDCl3): = 18.19 ( -CH3), 27.82 (CMe3),
67.76 ( -CH), 71.26 (C-6), 71.57 (C-5), 73.56 (C-4), 75.20
(OCH2Ph), 75.81 (C-3), 77.16 (OCH2Ph), 78.12 (OCH2Ph), 82.17
(CMe3), 86.47 (C-2), 95.01 (C-1), 127.76, 127.81, 127.94, 128.36,
128.40, 128.46, 137.53, 137.75 (C-Ar), 170.16 (C=O).
1H NMR (250 MHz, CDCl3): = 1.35 (d, J = 7.0 Hz, 3 H,
-
,
CH3), 1.44 (s, 9 H, CMe3), 3.49 (m, 1 H, 6-H), 3.63–3.75 (m, 5 H,
6 -H, 5-H, NH2, 4-H), 4.96 (m, 1 H, 3-H), 4.25 (q, 3J = 7.0 Hz, 1
,
H, -CH), 4.41–4.91 (m, 8 H, 2-H, OCH2Ph, 1-H), 7.11–7.34 (m,
15 H, Ar-H).
MS (MALDI): m/z = 630 [MNa+], 646 [MK+].
MS (MALDI): m/z = 579 [MH+], 601 [MNa+].
Anal. Calcd for C34H41NO9 (607.7): C, 67.20; H, 6.80; N, 2.30.
Found: C, 67.16; H, 6.79; N, 2.52.
Anal. Calcd for C34H43NO7 (577.7): C, 70.69; H, 7.50; N, 2.42.
Found: C, 70.94; H, 7.50; N, 2.45.
D-5b
O-(2-Amino-3,4,6-tri-O-benzyl-2-deoxy- -D-glucopyranosyl)-D-
lactic Acid (D-7 )
Rf 0.48 (petroleum ether–EtOAc, 8:2). [ ]D –12.80 (c 0.18, CHCl3).
Aminoglycoside D-6b (0.30 g, 0.52 mmol) was dissolved in a mix-
ture of trifluoroacetic acid and CH2Cl2 (20 mL, 1:1) and the solution
stirred at r.t. for 12 h. Then all the solvents were evaporated under
reduced pressure. The residue was dissolved in CH2Cl2 followed by
addition of sat. aq NaHCO3 with vigorous stirring. The layers were
separated and the aq phase was extracted with CH2Cl2. The com-
bined organic phases were dried (MgSO4), filtered, concentrated
under reduced pressure, and purified by column chromatography
(CH2Cl2–MeOH, 95:5) to furnish D-7 (0.26 g, 96%) as a white
foam which, was immediately used in the next step; Rf 0.40
(CH2Cl2–MeOH, 95:5); [ ]D +49.09 (c 0.33, CHCl3).
3
3
1H NMR (250 MHz, CDCl3): = 1.30 (d, J = 6.9 Hz, 3 H,
-
,
CH3), 1.42 (s, 9 H, CMe3), 3.66–3.74 (m, 4 H, 6-H, 6 -H, 5-H, 4-H),
4.03 (q, 3J = 6.8 Hz, 1 H, -CH), 4.20 (dd, 3J3,2 = 8.3 Hz, 3J3,4
=
,
8.2 Hz, 1 H, 3-H), 4.42–4.58 (m, 5 H, OCH2Ph), 4.70 (dd, 3J2,1 = 8.0
Hz, 3J2,3 = 8.2 Hz, 1 H, 2-H), 4.76 (d, 2J = 10.5 Hz, 1 H, OCH2Ph),
4.86 (d, 3J1,2 = 8.0 Hz, 1 H, 1-H), 7.13–7.33 (m, 15 H, Ar-H).
13C NMR (62.8 MHz, CDCl3): = 17.79 ( -CH3), 27.88 (CMe3),
53.38 ( -CH), 68.21 (C-6), 73.52 (C-5), 75.12 (C-4), 75.30
(OCH2Ph), 75.61 (C-3), 75.84 (OCH2Ph), 77.40 (OCH2Ph), 81.42
(CMe3), 89.52 (C-2), 99.53 (C-1), 127.69, 127.73, 127.84, 127.90,
127.96, 128.06, 128.08, 128.23, 128.37, 128.43, 128.46, 128.58,
136.95, 137.53, 137.83 (C-Ar), 170.62 (C=O).
1H NMR (250 MHz, CDCl3): = 1.32 (d, J = 7.0 Hz, 3 H,
-
,
CH3), 3.52 (d, 3J6,6 = 10.6 Hz, 1 H, 6-H), 3.66–3.80 (m, 5 H, 6 -H,
MS (MALDI): m/z = 631 [MNa+].
3
3
5-H, NH2, 4-H), 4.01 (t, J3,4 = J3,2 = 9.7 Hz, 1 H, 3-H), 4.28 (q,
3J = 6.9 Hz, 1 H, -CH), 4.31–4.91 (m, 8 H, 2-H, OCH2Ph, 1-H),
Anal. Calcd for C34H41NO9 (607.7): C, 67.20; H, 6.80; N, 2.30.
Found: C, 67.56; H, 7.27; N, 2.24.
,
5.17 (br s, 1 H, COOH), 7.04–7.38 (m, 15 H, Ar-H).
MS (MALDI): m/z = 523 [MH+], 545 [MNa+], 561 [MK+].
Methyl O-(2-Amino-3,4,6-tri-O-benzyl-2-deoxy- -D-glucopyra-
nosyl)-L-lactate (L-6a )
Anal. Calcd for C30H35NO7 (521.6): C, 69.08; H, 6.76; N, 2.69.
Found: C, 69.78; H, 7.09; N, 2.26.
Nitroglycoside L-5a (0.13 g, 0.23 mmol) was dissolved in EtOH (5
mL), and transferred to a hydrogen vessel. Platinized Raney Ni T4
catalyst was freshly prepared as described in ref.10 and the material
obtained from 2 g of Raney Ni/Al alloy was suspended in EtOH (15
mL). From a homogeneous suspension of this catalyst 10 mL was
added to the reaction vessel and the suspension shaken under H2 for
48 h at ambient temperature and pressure. The catalyst was filtered
off and the solvent evaporated. The residue was purified by column
chromatography (CH2Cl2–MeOH, 98:2) to furnish L-6a (96 mg,
78%) as a colorless oil; Rf 0.52 (CH2Cl2–MeOH, 95:5); [ ]D 31.58
(c 0.28, CHCl3).
(3R,4aS,6R,7S,8R,8aR)-7,8-Bis-benzyloxy-6-benzyloxymethyl-
3-methyl-hexahydro-pyrano[2,3-b][1,4]-oxazin-2-one (D-8 )
To a solution of the aminoglycoside D-7 (0.30 g, 0.57 mmol) in
DMF (10 mL) was added Et3N (0.25 mL, 1.80 mmol). After being
stirred for 10 min, diphenyl phosphoryl azide (DPPA) (0.36 mL,
1.80 mmol) was added and the resulting reaction mixture was fur-
ther stirred at r.t. for 1.5 h. The reaction mixture was quenched with
sat. aq NaCl (20 mL) and extracted with Et2O (3 × 10 mL). The ex-
tract was dried over MgSO4 and concentrated under reduced pres-
sure. The residue was purified by column chromatography
(petroleum ether–EtOAc, 8:2) to furnish D-8 (0.20 g, 77%) as a
colorless oil; Rf 0.60 (petroleum ether–EtOAc, 6:4); [ ]D –5.20 (c
0.25, CHCl3).
1H NMR (600 MHz, CDCl3): = 1.51 (d, 3JMe,3 = 6.9 Hz, 3 H, CH3),
3.72–3.81 (m, 5 H, 8a-H, 1 a-H, 1 b-H, 7-H, 8-H), 4.29 (m, 2 H,
OCH2Ph, 3-H), 4.27–4.50 (m, 4 H, OCH2Ph, 6-H), 4.52 (d, 2J = 12.0
Hz, 1 H, OCH2Ph), 4.60 (d, 2J = 12.0 Hz, 1 H, OCH2Ph), 4.95 (d,
3J4a,8a = 7.7 Hz, 1 H, 4a-H), 6.12 (s, 1 H, NH), 7.15–7.35 (m, 15 H,
Ar-H).
3
1H NMR (250 MHz, CDCl3): = 1.41 (d, J = 6.6 Hz, 3 H,
-
,
CH3), 2.53 (br s, 2 H, NH2), 3.52–7.79 (m, 7 H, 6-H, 6 -H, OMe, 5-
3
H, 4-H), 4.02 (m, 1 H, 3-H), 4.18 (q, J = 6.6 Hz, 1 H, -CH),
,
4.45–4.99 (m, 8 H, 2-H, 3 × OCH2Ph, 1-H), 7.18–7.33 (m, 15 H,
Ar-H).
13C NMR (62.8 MHz, CDCl3): = 17.92 ( -CH3), 51.80 (OCH3),
68.77 (C-6), 69.02 ( -CH), 71.45 (C-5), 73.31 (C-4), 73.64
(OCH2Ph), 74.44 (OCH2Ph), 75.01 (C-3), 75.42 (OCH2Ph), 78.46
(C-2), 99.86 (C-1), 127.51, 127.56, 127.62, 127.77, 128.19, 128.35,
137.75, 138.05, 138.38 (C-Ar), 172.97 (COOMe).
13C NMR (150.8 MHz, CDCl3): = 17.71 (CH3), 53.22 (C-8a),
67.67 (C-1 ), 71.13 (C-8), 71.60 (OCH2Ph), 72.74 (OCH2Ph), 73.18
(OCH2Ph), 73.34 (C-3), 75.09 (C-7), 76.17 (C-6), 91.41 (C-4a),
127.60, 127.71, 127.86, 127.95, 128.15, 128.36, 128.46, 128.54,
129.67, 137.04, 137.32, 137.86 (C-Ar), 172.01 (CO).
MS (MALDI): m/z = 536 [MH+], 558 [MNa+], 574 [MK+].
Anal. Calcd for C31H37NO7·1.25 H2O (558.1): C, 66.65; H, 6.98; N,
2.51. Found: C, 66.52; H, 6.86; N, 2.50.
MS (MALDI): m/z = 505 [MH+], 527 [MNa+], 543 [MK+].
tert-Butyl O-(2-amino-3,4,6-tri-O-benzyl-2-deoxy- -D-glucopy-
ranosyl)-D-lactate (D-6b )
Nitroglycoside D-5b (0.35 g, 0.57 mmol) was dissolved in EtOH
(10 mL), and transferred to a hydrogen vessel. The reaction was car-
ried out as described for the synthesis of L-6a to furnish D-6b
Anal. Calcd for C30H33NO6 (503.59): C, 71.55; H, 6.61; N, 2.78.
Found: C, 71.36; H, 6.33; N, 2.67.
Synthesis 2004, No. 1, 53–58 © Thieme Stuttgart · New York

PAPER
O-Glycosyl Lactates via Conjugate Addition to 2-Nitroglycals
57
(3S,4aS,6R,7S,8R,8aR)-7,8-Diacetoxy-3-methyl-2-oxo-hexahy-
dro-pyrano[2,3-b][1,4]-oxazin-6-ylmethyl acetate (D-10 )
Compound D-8 (50 mg, 0.10 mmol) was dissolved in MeOH–
HOAc (1:1, 4 mL) and Pd/C (50 mg, 10% Pd) was suspended in the
solution. This mixture was stirred for 24 h under H2 at r.t. After
complete disappearance of the starting material (TLC, CH2Cl2–
MeOH, 9:1), the catalyst was filtered off and all the solvents were
removed under reduced pressure. The residue of O-unprotected ma-
terial D-9 {MS (MALDI): m/z calcd 233 + 23 [Na]: 256; found:
256 [M + Na]+} was treated with pyridine–acetic anhydride (3:2, 6
mL) and stirred at r.t. for 12 h. All volatiles were evaporated and the
residue was purified by flash column chromatography (CH2Cl2–
MeOH, 98:2) to furnish D-10 (30 mg, 83%) as a white foam.
2J = 11.0 Hz, 1 H, OCH2Ph), 5.20 (d, 3J4a,8a = 2.9 Hz, 1 H, 4a-H),
6.07 (br d, 3JNH,8a = 3.7 Hz, 1 H, NH), 7.18–7.35 (m, 15 H, Ar-H).
13C NMR (150.8 MHz, CDCl3): = 17.52 (CH3), 55.91 (C-8a),
67.80 (C-1 ), 73.09 (C-6), 73.27 (C-3), 73.63 (OCH2Ph), 74.91
(OCH2Ph), 75.78 (OCH2Ph), 77.40 (C-7), 83.06 (C-8), 93.15 (C-
4a), 127.82, 127.85, 127.97, 128.16, 128.44, 128.50, 128.68, 137.64
(C-Ar), 169.75 (CO).
MS (MALDI): m/z = 505 [MH+], 527 [MNa+].
Anal. Calcd for C30H33NO6·0.5 H2O (512.6): C, 70.23; H, 6.43; N,
2.73. Found: C, 70.60; H, 6.87; N, 2.76.
Methyl O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy- -D-glu-
copyranosyl)-L-lactate (L-11a )
D-10
Aminoglycoside L-6a (53.5 mg, 0.1 mmol) was dissolved in
MeOH–HOAc (2:1, 6 mL) and Pd/C (50 mg, 10% Pd) was suspend-
ed in the solution. This mixture was stirred for 24 h under H2 at r.t.
After complete disappearance of the starting material (TLC:
CH2Cl2–MeOH, 9:1), the catalyst was filtered off and all the sol-
vents were removed under reduced pressure. The residue was treat-
ed with pyridine–acetic anhydride (3:2, 6 mL) and stirred at r.t. for
12 h. All volatiles were evaporated and the residue was purified by
flash column chromatography (petroleum ether–EtOAc, 6:4) to fur-
nish L-11a (40 mg, 92%) as a colorless oil; Rf 0.56 (petroleum
ether–EtOAc, 50:50); [ ]D +60.83 (c 0.24, CHCl3).
Rf 0.42 (CH2Cl2–MeOH, 95:5); [ ]D +3.33 (c 0.12, CHCl3).
1H NMR (600 MHz, CDCl3): = 1.53 (d, 3JMe,3 = 6.9 Hz, 3 H, Me),
3
2.11, 2.13, 2.17 (3 × s, 9 H, 3 × Ac), 3.83 (dd, J8a,8 = 2.9 Hz,
3
3
3J8a,NH = 7.8 Hz, 1 H, 8a-H), 4.23 (dd, J1 a,6 = 5.5 Hz, J1 a,1 b
=
3
3
11.7 Hz, 1 H, 1 a-H), 4.38 (dd, J6,1 a = 5.7 Hz, J6,7 = 8.4 Hz, 1
H, 6-H), 4.42 (q, 3J3,Me = 6.9 Hz, 1 H, 3-H), 4.65 (dd, 3J1 b,6 = 8.8
Hz, 3J1 b,1 = 11.8 Hz, 1 H, 1 b-H), 4.88 (d, 3J7,8 = 2.2 Hz, 1 H, 7-H),
5.06 (d, 3J4a,8a = 7.8 Hz, 1 H, 4a-H), 5.28 (m, 1 H, 8-H), 5.99 (s, 1
H, NH).
13C NMR (150.8 MHz, CDCl3): = 17.60 (Me), 20.75, 20.80 (3Ac),
52.95 (C-8a), 59.99 (C-1 ), 66.86 (C-7), 67.61 (C-8), 73.80 (C-3),
75.93 (C-6), 90.62 (C-4a), 169.24, 170.10, 170.82 (3 × Ac), 170.60
(CO).
3
1H NMR (250 MHz, CDCl3): = 1.39 (d, J = 6.9 Hz, 3 H,
-
,
CH3), 1.92, 1.99, 2.00, 2.05 (4 × s, 12 H, 4 × Ac), 3.71 (s, 3 H,
OMe), 3.98 (m, 1 H, 6-H), 4.06–4.34 (m, 3 H, 6 -H, 5-H, 4-H), 4.33
3
(dd, 3J3,4 = 9.3 Hz, 1 H, 3-H), 4.90 (q, J = 6.9 Hz, 1 H, -CH),
,
MS (MALDI): m/z = 360 [MH+], 382 [MNa+], 398 [MK+].
5.10 (dd, 3J2,3 = 9.6 Hz, 3J2,1 = 9.8 Hz, 1 H, 2-H), 5.20 (d, 3J1,2 = 9.8
Anal. Calcd for C15H21NO9 (359.3): C, 50.14; H, 5.89; N, 3.90.
Found: C, 50.15; H, 6.04; N, 3.97.
Hz, 1 H, 1-H), 5.86 (d, 3JNH,2 = 9.2 Hz, 1 H, NH).
13C NMR (62.8 MHz, CDCl3): = 17.60 ( -CH3), 23.97, 26.38,
26.49 (4 × Ac), 51.92 (OCH3), 52.92 ( -CH), 61.64 (C-6), 67.60
(C-5), 67.82 (C-4), 71.12 (C-3), 74.01 (C-2), 97.55 (C-1), 169.28
(COOMe), 169.97, 170.68, 171.37, 172.42 (4 Ac).
(3S,4aR,6R,7S,8R,8aR)-7,8-Bis-benzyloxy-6-benzyloxymethyl-
3-methyl-decahydro-pyrano[2,3-b][1,4]oxazin-2-one (D-8 )
Nitroglycoside D-5b (50 mg, 0.09 mmol) was dissolved in EtOH
(3 mL), and transferred to a hydrogenation vessel. Platinized Raney
Ni T4 catalyst was freshly prepared as described in ref.10 and the
material obtained from 1 g of Raney Ni/Al alloy was suspended in
EtOH (5 mL). From a homogeneous suspension of this catalyst 3
mL was added to the reaction vessel and the suspension shaken un-
MS (MALDI): m/z = 434 [MH+], 456 [MNa+], 472 [MK+].
Anal. Calcd for C18H27NO11 (433.4): C, 49.88; H, 6.28; N, 3.23.
Found: C, 49.64; H, 6.26; N, 2.87.
der H2 for 48 h at ambient temperature and pressure. The catalyst Acknowledgment
was filtered off and the solvent evaporated. The residue was imme-
This work was supported by the Deutsche Forschungsgemeinschaft,
diately used in the next step. To a solution of the crude aminoglyco-
side in CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL). After
being stirred for 12 h at r.t., the solvents were evaporated under re-
duced pressure. The residue was dissolved in CH2Cl2 followed by
addition of sat. aq NaHCO3 with vigorous stirring. The layers were
separated and the aq phase was extracted with CH2Cl2. The com-
bined organic phases were dried (MgSO4), filtered, concentrated
under reduced pressure. The residue was immediately used in the
next step. To a solution of the crude free acid in DMF (3 mL) was
added Et3N (70 L, 0.50 mmol). After being stirred for 10 min,
diphenylphosphoryl azide (DPPA) (100 L, 0.50 mmol) was added
and the resulting reaction mixture was further stirred at r.t. for 1.5
h. The reaction mixture was quenched with sat. aq NaCl (6 mL) and
extracted with Et2O (3 × 5 mL). The extract was dried over MgSO4
and concentrated under reduced pressure. The residue was purified
by column chromatography (petroleum ether–EtOAc, 8:2) to fur-
nish D-8 (25 mg, 55%) as a colorless oil; Rf 0.50 (petroleum ether–
EtOAc, 6:4); [ ]D +62.0 (c 0.25, CHCl3).
the European Community (Grant No. HRPN-CT-2000-00001/
GLYCOTRAIN) and the Fonds der Chemischen Industrie. A. I. K.
and K. P. are grateful for the Alexander von Humboldt-Fellowships.
We are grateful to Ms. Anke Friemel for her help in the structural
assignments by NMR experiments.
References
(1) For a review on glycosyl amino acids and carbohydrate
based peptide mimetics see: Schweizer, F. Angew. Chem.
Int. Ed. 2002, 41, 230; Angew. Chem. 2002, 114, 240; and
references therein.
(2) Some related structures have been thus far reported as
degradation products of natural compounds: (a) Stortz, C.
A.; Chermiak, A.; Jones, R. G.; Treber, T. D.; Reinhardt, D.
J. Carbohydr. Res. 1990, 207, 101. (b) Linkhardt, R. J.;
Loganathan, D.; Al-Hakim, A.; Wang, H.-M.; Walenga, J.
M.; Hoppensteadt, D.; Fareed, J. J. Red. Chem. 1990, 33,
1539.
1H NMR (600 MHz, CDCl3): = 1.42 (d, 3JMe,3 = 6.8 Hz, 3 H, CH3),
3.35 (m, 1 H, 8a-H), 3.66–3.81 (m, 4 H, 1 a-H, 1 b-H, 7-H, 8-H),
4.05 (m, 1 H, 6-H), 4.33 (q, 3J3,Me = 6.8 Hz, 1 H, 3-H), 4.49–4.69
(m, 4 H, OCH2Ph), 4.80 (d, 2J = 10.5 Hz, 1 H, OCH2Ph), 4.96 (d,
(3) (a) Das, J.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 1609.
(b) Winterfeld, G. A.; Ito, Y.; Ogawa, T.; Schmidt, R. R.
Eur. J. Org. Chem. 1999, 1167. (c) Winterfeld, G. A.;
Schmidt, R. R. Angew. Chem. Int. Ed. 2001, 40, 2654;
Synthesis 2004, No. 1, 53–58 © Thieme Stuttgart · New York

58
A. I. Khodair et al.
PAPER
Angew. Chem. 2001, 113, 2718. (d) Winterfeld, G. A.;
Khodair, A. I.; Schmidt, R. R. Eur. J. Org. Chem. 2003,
1009. (e) Khodair, A. I.; Winterfeld, G. A.; Schmidt, R. R.
Eur. J. Org. Chem. 2003, 1847. (f) Reddy, B. G.; Vankar,
Y. D. Tetrahedron Lett. 2003, 44, 4765.
(7) Lemieux, R. U.; Nagabushan, T. L.; Gunner, S. W. Can. J.
Chem. 1968, 46, 405.
(8) Holzapfel, C. W.; Marais, C. F.; van Dyk, M. S. Synth.
Commun. 1988, 18, 97.
(9) (a) Takamoto, T.; Sudoh, R.; Nakagawa, T. Carbohydr. Res.
1973, 27, 135. (b) Sakakibara, T.; Tachimori, Y.; Sudoh, R.
Tetrahedron Lett. 1982, 23, 5545.
(4) Winterfeld, G. A.; Das, J.; Schmidt, R. R. Eur. J. Org. Chem.
2000, 3047.
(5) Pachamuthu, K.; Gupta, A.; Das, J.; Schmidt, R. R.; Vankar,
Y. D. Eur. J. Org. Chem. 2002, 1479.
(10) Nishimura, S. Bull. Chem. Soc. Jpn. 1959, 32, 61.
(11) This compound is commercially available.
(6) Bovin, N. V.; Zurabyan, S. E.; Khorlin, A. Y. Carbohydr.
Res. 1981, 87, 25.
Synthesis 2004, No. 1, 53–58 © Thieme Stuttgart · New York