A convenient synthesis of pyrano[2,3-b][1,5]oxazepines by ring closure of O-glycosyl amino acids

Article abstract of DOI:10.1002/ejoc.201101148

N-Boc-protected serine and threonine esters could be readily added to 2-nitroglycals, affording exclusively α- and β-anomers with galacto- and gluco-configuration, respectively. Nitro group reduction to the amino group and also ester cleavage led to compo

Full text of DOI:10.1002/ejoc.201101148

FULL PAPER
DOI: 10.1002/ejoc.201101148
A Convenient Synthesis of Pyrano[2,3-b][1,5]oxazepines by Ring Closure of
O-Glycosyl Amino Acids
Ahmed I. Khodair*[a] and Richard R. Schmidt[b]
Keywords: Cyclization / Diastereoselectivity / Enantioselectivity / Glycoconjugates / Glycosides / Michael addition
N-Boc-protected serine and threonine esters could be readily
age led to compounds 2, 6, and 11, which can be regarded
added to 2-nitroglycals, affording exclusively α- and β-ano- as dipeptide mimetics. From these compounds, bicyclic pyr-
mers with galacto- and gluco-configuration, respectively. Ni-
ano[2.3-b][1,5]oxazepines 7–14 were prepared by ring clo-
tro group reduction to the amino group and also ester cleav-
sure.
Introduction
Glycans are polyalcohol compounds that exhibit broad
diversity with respect to the presence of regioisomers and
stereoisomers at the anomeric position. In the field of gly-
coscience, many glycochemists have made great efforts to
efficiently construct the O-glycosidic linkage in highly regio/
stereoselective ways.[1–4] 1,4(1,5)-Oxa(thia)zepine derivatives
exhibit strong biological activity and have been extensively
studied.[5] In particular, Sintamil is known as an efficient
antidepressant.[6] Substituted 5,11-dihydrobenzo[b,e][1,4]ox-
azepines, which exhibit lower anticholinergic activity,[7–9]
were also tested as a new generation of calcium antagonists.
Piperazinyldibenzo[b,f][1,4]oxa(thia)zepine derivatives be-
long to a class of novel so-called atypical antipsychotic
drugs that are effective in the treatment of psychoneurologi-
cal disorders such as psychosis, depression, and schizophre-
Scheme 1. Base-catalyzed addition of nucleophiles to 2-nitroglycals.
In this paper, we demonstrate that bicyclic lactams are
readily accessible through this route. Compounds of this
type have been previously obtained essentially as by-prod-
ucts of O-glycosyl-serine or threonine liberation from pro-
tected precursors.[23–26]
Results and Discussion
Addition of N-protected serine ester to 2-nitro-galactal
nia.[10] 2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepine-5-carbox- leads, depending on the type of O-protection and reaction
amide showed high inhibitory activity toward γ-secretase in conditions, to either mainly α-galactoside or to an α/β-
the treatment of Alzheimer disease.[11] O-Glycosylation of anomeric mixture.[13–15] In this way, galactoside 1aα and
β-hydroxycarboxylates and, particularly, of serine and thre- 1bα can be readily obtained from 3,4,6-tri-O-benzyl-2-nitro-
onine, having α-amino groups, with glycosyl donors derived galactal[13] and N-Boc-protected serine tert-butyl and
from 2-amino-2-deoxy sugars leads to versatile building methyl ester, respectively[16] (Scheme 2).
blocks for glycopeptide synthesis and for the generation of
Reduction of the nitro group in the presence of platinized
glycopeptide mimetics, and for various functional group Raney-nickel[27] as catalyst afforded the amino derivative
manipulations.[12] The versatile direct base-catalyzed ad- 2aα,[16] which, on treatment with fluorenylmethyloxycarb-
dition of O-, N-, C-, and S-nucleophiles to 2-nitroglycals onyl chloride (FmocCl) in the presence of triethylamine, af-
(Scheme 1), as recently investigated by us,[13–22] have made forded N,O-protected intermediate 3aα. Acid-catalyzed
these building blocks readily available.
cleavage of the Boc group and of the tert-butyl ester led to
formation of the versatile intermediate 4α; attachment of a
Boc group to the amino group furnished the orthogonally
protected O-glycosyl serine derivative 5α. No undesired ring
closure to the lactam was observed in any of the reactions.
To this end, 5α was treated with morpholine to give, after
Fmoc cleavage, N-deprotected 6α, which, on reaction with
diphenylphophoryl azide (DPPA)[28] in the presence of tri-
[a] Chemistry Department, Faculty of Science, Kafrelsheikh
University,
33516 Kafrelsheikh, Egypt
Fax: +20-473-21-51-75
E-mail: khodair_2005@yahoo.com
[b] Fachbereich Chemie, Universität Konstanz, Fach 725,
78457 Konstanz, Germany
Eur. J. Org. Chem. 2011, 7407–7413
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. I. Khodair, R. R. Schmidt
FULL PAPER
Scheme 3. Reagents and conditions: (a) Ra-Ni (T4), H2, EtOH, r.t.;
(b) LiOH, H2O; NEt3, DPPA, DMF; (c) Pd/C, H2, HOAc, MeOH;
(d) Ac2O, Pyr.
Reduction of the nitro group in 10α and 10β as described
above led to the amino derivatives 11α and 11β as interme-
diates, which, on treatment with diphenylphosphoryl azide
(DPPA) and triethylamine, again afforded the bicyclic lac-
tams 12α and 12β, respectively, in high overall yields. Hy-
drogenolytic O-debenzylation (Ǟ 13α and 13β) and then O-
acetylation furnished O-acetyl protected bicyclic lactams
14α and 14β, again in a very straightforward manner. The
structural assignment of these compounds was fully sup-
ported by the physical data.
Scheme 2. Reagents and conditions: (a) Ra-Ni (T4), H2, EtOH, r.t.;
(b) FmocCl, NEt3, CH2Cl2; (c) TFA, CH2Cl2; (d) BocON, NEt3,
dioxane; (e) morpholine, CH2Cl2; (f) NEt3, DPPA, DMF;
(g) LiOH, H2O; NEt3, DPPA, DMF; (h) Pd/C, H2, HOAc, MeOH;
(i) Ac2O, Pyr.
Conclusions
ethylamine as base, furnished bicyclic lactam 7α in high
yield. Clearly, this compound can be more readily obtained
with the more reactive methyl ester 1bα, which, as well as its
β-anomer 1bβ, is also obtained by N-Boc-protected serine
methyl ester addition to 2-nitrogalactal (1H NMR: 1bα:
In conclusion, base-catalyzed N-Boc-protected serine
and threonine ester addition to 2-nitroglycals readily pro-
vides the corresponding α- and β-glycosides together with
the generation of two new stereogenic centers, of which one
is formed highly stereoselectively. Transformation of these
compounds allows access to dipeptide mimetics and to
novel bicyclic pyrano[2,3-b][1,5]oxazepines.
3
3J1,2 = 4.0 Hz, 1bβ: J1,2 = 8.0 Hz). Reduction of the nitro
group in 1bα as described above (Ǟ 2bα), followed by hy-
drolysis of the methyl ester with lithium hydroxide, and en-
suing lactam formation with DPPA/triethylamine, afforded
7α directly in very good overall yield. Similarly, the dia-
stereoisomer 7β was obtained from 1bβ via 2bβ. Hydro-
Experimental Section
genolytic O-debenzylation of 7α in the presence of palla- General Remarks: Solvents were removed under reduced pressure
with the water bath temperature maintained below 40 °C.
Chromatography was performed on silica gel for flash chromatog-
raphy (40 μm; J. T. Baker) at 3 bar pressure. For thin layer
chromatography, TLC plastic sheets (60 F254 silica gel) were used
and the compounds were viewed by illumination under UV light
at 253 nm and by treatment with 5% [(NH4)2MoO4], 0.1%
Ce(SO4)2 in 10% H2SO4 and heating to 160 °C. Optical rotation
values were measured at 25 °C with a Perkin–Elmer 241/MS polari-
meter at the sodium D line. NMR spectra were recorded with a
Bruker AC-250 Cryospec or Bruker DR-600; TMS or the solvent
residual peak were used as internal standard. 3JC,H couplings were
dium on carbon as catalyst afforded O-unprotected 8α,
which, for further characterization was transformed with
acetic anhydride in pyridine into the per-O-acetylated deriv-
ative 9α. The structural assignment of bicyclic lactams 7α
1
and 7β were confirmed by H NMR spectroscopic analysis.
Addition of N-Boc-protected l-threonine methyl ester to
3,4,6-tri-O-benzyl-2-nitroglucal[18,29–32] afforded a 2:1 mix-
3
ture of α- and β-anomers 10α (1H NMR: J1,2 = 3.5 Hz)
3
and 10β (1H NMR: J1,2 = 8.1 Hz), which could be readily
separated (Scheme 3).
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Eur. J. Org. Chem. 2011, 7407–7413

New Pyrano[2,3-b][1,5]oxazepines
observed in gradient-selected heteronuclear multi-bond correlations
(HMBC). MALDI-MS were measured with a Kratos Kompact
Maldi 1; 2,5-dihydroxybenzoic acid was used as matrix. FAB-MS
were measured with a Finnigan MAT 312/AMD-5000, 790 eV,
70 °C. Calculated yields are based on consumed starting material
where its recovery is stated.
(0.84 mL) and FmocCl (0.49 mL, 2 mmol) were dropped into the
reaction mixture simultaneously. Stirring was continued for 24 h at
room temperature, then the reaction mixture was diluted with
CH2Cl2 (50 mL) washed with 0.5 m HCl (3 ϫ 10 mL) and H2O,
dried (MgSO4), and filtered. The residue was purified by column
chromatography (petroleum ether/ethyl acetate, 90:10) to furnish
3aα (1.24 g, 68%) as a colorless oil. TLC (petroleum ether/ethyl
acetate, 80:20): Rf = 0.35. [α]D = +33.18 (c = 0.22; CHCl3). 1H
NMR (250 MHz, CDCl3): δ = 1.41, 1.43 [2 s, 18 H, 2 C(CH3)3],
3.54–3.58 (m, 3 H, 6-H, 6Ј-H, 5-H), 3.81–4.15 (m, 4 H, β-CH2, 4-
H, Fmoc-CH), 4.29–4.72 (m, 11 H, Fmoc-CH2, 3-H, α-CH,
OCH2Ph, 2-H), 4.82 (d, J1,2 = 3.6 Hz, 1 H, 1-H), 4.95 (d, JNH,α
= 11.6 Hz, 1 H, NHBoc), 5.40 (br. d, 1 H, NHFmoc), 7.18–7.76
(m, 23 H, Ar-H) ppm. MS (MALDI): m/z = 938 [M + Na]+, 954
[M + K]+. C54H62N2O11·1H2O (933.09): calcd. C 69.51, H 6.70, N
3.00; found C 69.28, H 6.99, N 2.85.
O-(3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-α-
(tert-butyloxycarbonyl)- -serine Methyl Ester (1bα) and O-(3,4,6-
Tri-O-benzyl-2-deoxy-2-nitro-β- -galactopyranosyl)-N-(tert-butyl-
oxycarbonyl)- -serine Methyl Ester (1bβ): N-(tert-Butyloxycarb-
D-galactopyranosyl)-N-
L
D
L
onyl)-l-serine methyl ester (1.10 g, 5 mmol) and 3,4,6-tri-O-benzyl-
2-nitrogalactal (2.10 g, 5 mmol) were dried under high vacuum and
dissolved in dry toluene (60 mL) under argon. Freshly activated
molecular sieves (3 Å, 3 g) were introduced and the mixture was
stirred for 1 h at room temperature. Potassium tert-butoxide (1 m
in THF, 0.50 mL, 0.25 mmol) was added and stirring was continued
for 120 min. Acetic acid (0.50 mL) was added to acidify the reac-
tion mixture, the molecular sieves were filtered off and all the sol-
vents were removed. The residue was purified by column
chromatography (petroleum ether/ethyl acetate, 90:10) to furnish
1bα (2.04 g, 60%) as a white foam and the corresponding β-glyco-
side 1bβ (1.02 g, 30%) as a white foam. Data for 1bα: TLC (petro-
leum ether/ethyl acetate, 80:20): Rf = 0.66. [α]D = = +75.50 (c =
3
3
O-[(2-Fluorenyl-9-methyloxycarbonylamino)-3,4,6-tri-O-benzyl-2-de-
oxy-α-D-galactopyranosyl]-N-(tert-butyloxycarbonyl)-L-serine (4α):
Compound 3aα (0.90 g, 0.98 mmol) was dissolved in a mixture of
trifluoroacetic acid and CH2Cl2 (50 mL, 1:1) and the solution was
stirred at room temperature for 12 h. All the solvents were evapo-
rated under reduced pressure and the residue was dissolved in
CH2Cl2 followed by addition of saturated aqueous NaHCO3 with
vigorous stirring. The layers were separated and the aqueous phase
was extracted with CH2Cl2. The combined organic phases were
dried (MgSO4), filtered, concentrated under reduced pressure, and
purified by column chromatography (petroleum ether/ethyl acetate,
80:20) to furnish 4α (0.72 g, 97%) as a white foam, which was im-
mediately used in the next step. TLC (CH2Cl2/MeOH, 95:5): Rf =
0.30. [α]D = = +31.2 (c = 0.17; CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 3.48 (m, 3 H, 6-H, 6Ј-H), 3.67 (m, 1 H, 5-H), 3.70–
4.80 (m, 4 H, β-CH2, 4-H, Fmoc-CH), 3.91–4.53 (m, 11 H, Fmoc-
CH2, 3-H, α-CH, OCH2Ph, 2-H), 4.90 (m, 3 H, 1-H, NH2), 5.40
(br. d, 1 H, NHFmoc), 7.10–7.64 (m, 23 H, Ar-H), 8.42 (br. S,
COOH) ppm. MS (MALDI): m/z = 760 [M + H]+, 782 [M +
Na]+. C45H46N2O9 (758.85): calcd. C 71.22, H 6.11, N 3.69; found
C 71.32, H 5.86, N 3.29.
1.5; CHCl3). 1H NMR (600 MHz, CDCl3): δ = 1.49 [s, 9 H, C(CH3)
3
3], 3.60 (m, 2 H, 6-H, 6Ј-H), 3.80 (s, 3 H, OCH3), 3.90 (dd, Jβ,α
=
2
2
2.8 Hz, Jβ,βЈ = 9.0 Hz, 1 H, β-CH), 3.97 (d, JβЈ,β = 9.1 Hz, 1 H,
βЈ-CH), 4.03 (dd, J5,6 = 6.6 Hz, J5,6Ј = 6.7 Hz, 1 H, 5-H), 4.08
3
3
3
3
(m, 1 H, 4-H), 4.43 (dd, J3,4 = 2.8 Hz, J3,2 = 10.7 Hz, 1 H, 3-H),
4.44–4.55 (m, 4 H, OCH2Ph, α-CH), 4.76 (d, 2J = 3.5 Hz, 2 H,
2
3
OCH2Ph), 4.86 (d, J = 11.1 Hz, 1 H, OCH2Ph), 5.00 (dd, J2,1
=
3
3
4.1 Hz, J2,3 = 10.6 Hz, 1 H, 2-H), 5.30 (d, J1,2 = 4.0 Hz, 1 H, 1-
H), 5.48 (d, JNH,α = 8.0 Hz, 1 H, NH), 7.25–7.39 (m, 15 H, Ar-
3
H) ppm. 13C NMR (150.8 MHz, CDCl3): δ = 28.27 [C(CH3)3],
52.71 (OCH3), 53.72 (α-C), 68.00 (C-6), 69.90 (C-5, β-C), 72.84
(OCH2Ph), 72.98 (C-4), 73.55 (OCH2Ph), 74.93 (C-3), 75.10
(OCH2Ph), 80.19 [C(CH3)3], 84.06 (C-2), 97.01 (C-1), 127.84,
127.89, 128.05, 128.11, 128.13, 128.33, 128.47, 137.21, 137.56,
137.82 (C-Ar), 155.30 (COOCH3), 170.07 (NHBoc) ppm. MS
(MALDI): m/z = 703 [M + Na]+. C36H44N2O11 (680.74): calcd. C
63.52, H 6.51, N 4.12; found C 63.52, H 6.55, N 3.78. Data for
O-[(2-Fluorenyl-9-methyloxycarbonylamino)-3,4,6-tri-O-benzyl-2-de-
oxy-α-D-galactopyranosyl]-N-(tert-butyloxycarbonyl)-L-serine (5α):
To a solution of 4α (0.70 g, 0.09 mmol) in dioxane (10 mL) were
successively added Et3N (0.28 mL, 2 mmol) and 2-(tert-butoxyim-
ino)-2-phenylacetonitrile (0.50 g, 2 mmol). The reaction mixture
was stirred at room temperature for 24 h, then quenched with satu-
rated aqueous NaCl and extracted with AcOEt. The extract was
dried with MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography (CH2Cl2/MeOH,
98:2) to furnish 5α (0.56 g, 72%) as a white foam. TLC (CH2Cl2/
MeOH, 95:5): Rf = 0.40. [α]D = +44.70 (c = 0.34, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 3.53–3.75 (m, 3 H,
6-H, 6Ј-H, 5-H), 3.94–4.12 (m, 5 H, β-CH2, 4-H, Fmoc-CH, 3-H),
4.35–4.60 (m, 10 H, Fmoc-CH2, α-CH, OCH2Ph, 2-H), 4.95 (m, 2
H, 1-H, NHBoc), 6.05 (br. d, 1 H, NHFmoc), 7.03–7.73 (m, 23 H,
Ar-H), 8.06 (br. s, 1 H, COOH) ppm. MS (MALDI): m/z = 882
[M + Na]+, 898 [M + K]+. C50H54N2O11 (858.97): calcd. C 69.91,
H 6.34, N 3.26; found C 69.68, H 5.96, N 3.15.
1bβ: TLC (petroleum ether/ethyl acetate, 80:20): Rf = 0.42. [α]D
=
+26.13 (c = 1.5; CHCl3). 1H NMR (600 MHz, CDCl3): δ = 1.47 [s,
9 H, C(CH3)3], 3.60–3.66 (m, 3 H, 6-H, 6Ј-H, 5-H), 3.74 (s, 3 H,
OCH3), 3.82 (dd, 3Jβ,α = 3.4 Hz, 2Jβ,βЈ = 10.1 Hz, 1 H, β-CH), 4.04
3
3
(m, 1 H, 4-H), 4.07 (dd, J3,4 = 2.6 Hz, J3,2 = 10.6 Hz, 1 H, 3-H),
2
3
4.24 (br. d, JβЈ,β = 10.0 Hz, 1 H, βЈ-CH), 4.42 (dd, Jα,β = 3.6 Hz,
3Jα,NH = 7.8 Hz, 1 H, α-CH), 4.47–4.51 (m, 3 H, OCH2Ph), 4.58
(d, 2J = 11.3 Hz, 1 H, OCH2Ph), 4.64 (d, 2J = 11.5 Hz, 1 H,
3
OCH2Ph), 4.77 (d, J1,2 = 8.0 Hz, 1 H, 1-H), 4.85–4.90 (m, 2 H,
3
OCH2Ph, 2-H), 5.27 (d, JNH,α = 7.8 Hz, 1 H, NH), 7.28–7.40 (m,
15 H, Ar-H) ppm. 13C NMR (150.8 MHz, CDCl3): δ = 28.23
[C(CH3)3], 52.56 (OCH3), 53.64 (α-C), 67.64 (C-6), 69.47 (β-C),
71.38 (C-4), 72.32 (OCH2Ph), 73.57 (OCH2Ph), 73.92 (C-5), 74.85
(OCH2Ph), 79.26 (C-3), 80.05 [C(CH3)3], 86.81 (C-2), 100.29 (C-1),
127.78, 127.89, 127.97, 128.16, 128.20, 128.33, 128.32, 128.49,
128.53, 136.45, 137.70 (C-Ar), 155.26 (COOCH3), 170.15
(NHBoc) ppm. MS (MALDI): m/z = 703 [M + Na]+. C36H44N2O11
(680.74): calcd. C 63.52, H 6.51, N 4.12; found C 63.29, H 6.60, N
3.88.
(3S,5aR,6R,7R,8R,9aS)-3-[N-(tert-Butyloxycarbonyl)amino]-6,7-
bisbenzyloxy-8-benzyloxymethyloctahydropyrano[2,3-b]-1,5-oxaz-
epin-4-one (7α)
O-[(2-Fluorenyl-9-methyloxycarbonylamino)-3,4,6-tri-O-benzyl-2-de- Method A: To a solution of 5α (215 mg, 0.25 mmol) in CH2Cl2
oxy-α-
D
-galactopyranosyl]-N-(tert-butyloxycarbonyl)-
L
-serine tert-
(10 mL) was added morpholine (1 mL). The reaction mixture was
stirred at room temperature for 24 h, then the mixture was
quenched with 0.5 m HCl and extracted with CH2Cl2. The ex-
Butyl Ester (3aα): Compound 2aα[16] (1.38 g, 2 mmol) was sus-
pended in dry CH2Cl2 (100 mL) and cooled to 0 °C. Triethylamine
Eur. J. Org. Chem. 2011, 7407–7413
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A. I. Khodair, R. R. Schmidt
FULL PAPER
tracted was dried with MgSO4 and concentrated under reduced
pressure to give O-(2-amino-3,4,6-tri-O-benzyl-2-deoxy-α-d-galac-
topyranosyl)-N-(tert-butyloxycarbonyl)-l-serine (6α; 150 mg, 94%)
as a white foam, which was immediately used in the next step. To
a solution of 6α (140 mg, 0.22 mmol) in dimethylformamide (5 mL)
was added triethylamine (0.09 mL, 0.66 mmol). After stirring for
10 min, diphenylphosphoryl azide (DPPA; 0.14 mL, 0.66 mmol)
was added and the resulting reaction mixture was further stirred at
room temperature for 1.5 h. The reaction mixture was quenched
with saturated aqueous NaCl and extracted with Et2O. The extract
was dried with MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (CH2Cl2/
MeOH, 99:1) to furnish 7α (0.12 g, 78%) as a white foam. TLC
(CH2Cl2/MeOH, 95:5): Rf = 0.60. [α]D = +123.33 (c = 0.03;
give the crude amino acid 6α. To a solution of the crude material
in DMF (10 mL) was added triethylamine (0.19 mL, 1.39 mmol).
After stirring for 10 min, diphenylphosphoryl azide (DPPA;
0.30 mL, 1.39 mmol) was added and the resulting reaction mixture
was further stirred at room temperature for 1.5 h. The reaction
mixture was quenched with saturated aqueous NaCl and extracted
with Et2O. The extract was dried with MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (CH2Cl2/MeOH, 99:1) to furnish 7α in 86% over-
all yield as a white foam.
(3S,5aR,6R,7R,8R,9aR)-3-[N-(tert-Butyloxycarbonyl)amino]-6,7-
bisbenzyloxy-8-benzyloxymethyloctahydropyrano[2,3-b]-1,5-oxaz-
epin-4-one (7β): β-Nitroglycoside 1bβ (0.51 g, 0.75 mmol) was dis-
solved in ethanol (7.5 mL) and transferred to a hydrogen vessel.
Platinized Raney nickel T4 catalyst was freshly prepared as de-
scribed[11] and the material obtained from 1 g of Raney nickel/alu-
minum alloy was suspended in ethanol (7.5 mL). From a homogen-
eous suspension of this catalyst, 7.5 mL was added to the reaction
vessel and the suspension was shaken under H2 for 48 h at ambient
temperature and pressure. The catalyst was filtered off and the sol-
vent evaporated. The residue was purified by column chromatog-
raphy (CH2Cl2/MeOH, 95:5) to furnish O-(2-amino-3,4,6-tri-O-
benzyl-2-deoxy-α-d-galactopyranosyl)-N-(tert-butoxycarbonyl)-l-ser-
ine methyl ester (2bβ; 0.40 g, 82%) as a colorless oil, which was
immediately used in the next step {TLC (CH2Cl2/MeOH, 90:10):
Rf = 0.30}. To a solution of 2-aminoglycoside 2bβ (0.30 g,
0.46 mmol) in water (3 mL) was added lithium hydroxide (17 mg,
0.70 mmol). The reaction mixture was stirred at room temperature
for 24 h, and then concentrated under reduced pressure to give the
crude amino acid. To a solution of the crude material in dimethyl-
formamide (10 mL) was added triethylamine (0.19 mL, 1.39 mmol).
After stirring for 10 min, diphenylphosphoryl azide (DPPA;
0.30 mL, 1.39 mmol) was added and the resulting reaction mixture
was further stirred at room temperature for 1.5 h. The reaction
mixture was quenched with saturated aqueous NaCl and extracted
with Et2O. The extract was dried with MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (CH2Cl2/MeOH, 99:1) to furnish 7β in 83% over-
all yield as a white foam. TLC (CH2Cl2/MeOH, 95:5): Rf = 0.48.
1
CHCl3). H NMR (600 MHz, CDCl3): δ = 1.43 [s, 9 H, C(CH3)3],
2
3
3.58 (d, J10a,10b = 6.6 Hz, 2 H, 10a-H, 10b-H), 3.64 (dd, J2a,3
=
2
3
6.6 Hz, J2a,2b = 10.8 Hz, 1 H, 2a-H), 3.72 (d, J6,5a = 10.3 Hz, 1
H, 6-H), 3.90 (m, 1 H, 5a-H), 4.02 (br. s, 1 H, 7-H), 4.11 (dd, 3J8,10a
3
2
= 6.9 Hz, J8,10b = 6.6 Hz, 1 H, 8-H), 4.22 (dd, J2b,2a = 10.8 Hz,
3J2b,3 = 6.6 Hz, 1 H, 2b-H), 4.42–4.57 (m, 4 H, OCH2Ph), 4.70 (m,
1 H, 3-H), 4.72 (d, 2J = 9.1 Hz, 1 H, OCH2Ph), 4.80 (d, 2J =
11.4 Hz, 1 H, OCH2Ph), 5.42 (br. d, 3JNH,3 = 5.5 Hz, 1 H, NHBoc),
5.54 (br. s, 1 H, 9a-H), 6.12 (br. s, 1 H, NH), 7.26–7.36 (m, 15 H,
Ar-H) ppm. 13C NMR (150.8 MHz, CDCl3): δ = 28.27 [C(CH3)3],
52.60 (C-3), 53.77 (C-5a), 67.88 (C-2), 68.10 (C-10), 71.17 (C-7),
71.41 (C-8), 71.78 (OCH2Ph), 73.55 (OCH2Ph), 74.52 (OCH2Ph),
77.00 [C-9, C(CH3)3], 94.18 (C-9a), 127.81, 127.90, 127.98, 128.03,
128.38, 128.46, 128.76, 136.90, 137.97 (C-Ar), 156.20 (C-4), 170.24
(Boc-CO) ppm. MS (MALDI): m/z = 642 [M + Na]+, 658 [M +
K]+. C35H42N2O8·0.5H2O (627.73): calcd. C 66.97, H 6.74, N 4.46;
found C 66.78, H 6.84, N 4.27.
Method B: α-Nitroglycoside 1bα (1.02 g, 1.50 mmol) was dissolved
in ethanol (15 mL) and transferred to a hydrogen vessel. Platinized
Raney nickel T4 catalyst was freshly prepared as described[11] and
the material obtained from 2 g of Raney nickel/aluminum alloy was
suspended in ethanol (15 mL). From a homogeneous suspension of
this catalyst, 15 mL was added to the reaction vessel and the sus-
pension was shaken under H2 for 48 h at ambient temperature and
pressure. The catalyst was filtered off and the solvent was evapo-
rated. The residue was purified by column chromatography
(CH2Cl2/MeOH, 95:5) to furnish O-(2-amino-3,4,6-tri-O-benzyl-2-
deoxy-α-d-galactopyranosyl)-N-(tert-butoxycarbonyl)-l-serine
methyl ester (2bα; 0.82 g, 84%) as a colorless oil, which was imme-
diately used in the next step. TLC (CH2Cl2/MeOH, 90:10): Rf =
0.32. [α]D = +70.67 (c = 0.30; CHCl3). 1H NMR (250 MHz,
1
[α]D = +57.33 (c = 0.15; CHCl3). H NMR (600 MHz, CDCl3): δ
2
3
= 1.43 [s, 9 H, C(CH3)3], 3.32 (dd, J2a,2b = 11.4 Hz, J2a,3
=
11.0 Hz, 1 H, 2a-H), 3.52–3.85 (m, 3 H, 10a-H, 10b-H, 3-H), 3.73
3
3
3
(ddd, J5a,6 = 2.4 Hz, J5a,NH = 8.2 Hz, J5a,9a = 10.6 Hz, 1 H, 5a-
H), 4.03–4.08 (m, 3 H, 2b-H, 7-H, 6-H), 4.26 (dd, 3J8,10a = 6.7 Hz,
3J8,10b = 6.8 Hz, 1 H, 8-H), 4.43 (d, J = 12.1 Hz, 1 H, OCH2Ph),
2
2
2
4.44 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.52 (d, J = 12.1 Hz, 1 H,
3
3
CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 3.30 (dd, J6,5 = 3.5 Hz, J6,6ЈЈ
OCH2Ph), 4.60 (d, 2J = 11.2 Hz, 1 H, OCH2Ph), 4.75 (d, 2J =
3
3
= 10.5 Hz, 1 H, 6-H), 3.44 (dd, J6Ј,5 = 2.4 Hz, J6Ј,6Ј = 10.5 Hz, 1
H, 6Ј-H), 3.57–3.67 (m, 3 H, 5-H, 4-H, β-CH), 3.72 (s, 3 H, OCH3),
3.74 (m, 1 H, βЈ-CH), 3.90 (m, 3 H, 3-H, NH2), 4.01 (m, 1 H, α-
CH), 4.41–4.57 (m, 5 H, OCH2Ph), 4.75 (d, 2J = 11.5 Hz, 1 H,
3
12.1 Hz, 1 H, OCH2Ph), 4.87 (s, 1 H, OCH2Ph), 4.88 (d, J9a,5a
9.2 Hz, 1 H, 9a-H), 5.54 (d, JNH,3 = 2.6 Hz, 1 H, NHBoc), 6.07
(d, JNH,5a = 8.0 Hz, 1 H, NH), 7.25–7.38 (m, 15 H, Ar-H) ppm.
=
3
3
13C NMR (150.8 MHz, CDCl3): δ = 28.32 [C(CH3)3], 53.96 (C-5a),
55.37 (C-3), 67.01 (C-2), 68.23 (C-10), 71.03 (OCH2Ph), 71.51 (C-
8), 73.04 (C-7), 73.42 (C-6), 74.99 (2 OCH2Ph), 79.82 [C(CH3)3],
98.95 (C-9a), 127.82, 127.89, 127.98, 128.03, 128.11, 128.22, 128.36,
128.43, 128.53, 128.76, 136.97, 137.79, 138.11 (C-Ar), 154.85 (C-
4), 173.84 (Boc-CO) ppm. MS (MALDI): m/z = 642 [M + Na]+,
658 [M + K]+. C35H42N2O8·2H2O (654.76): calcd. C 64.20, H 6.46,
N 4.28; found C 63.93, H 6.46, N 4.14.
3
OCH2Ph), 4.84 (m, 2 H, 2-H, 1-H), 5.54 (d, JNH,α = 9.0 Hz, 1 H,
NHBoc), 7.25–7.37 (m, 15 H, Ar-H) ppm. 13C NMR (62.8 MHz,
CDCl3): δ = 28.29 [C(CH3)3], 51.08 (OCH3), 52.46 (α-C), 54.05 (C-
2), 68.81 (C-6), 70.24 (C-5, β-C), 71.80 (C-4), 72.41 (C-3), 73.54
(OCH2Ph), 74.53 (OCH2Ph), 80.00 [C(CH3)3], 80.91 (OCH2Ph),
101.24 (C-1), 127.57, 127.71, 127.74, 127.85, 128.01, 128.23, 128.40,
128.50, 137.91, 137.96, 138.51 (C-Ar), 156.25 (COOCH3), 170.96
(Boc-CO) ppm. MS (MALDI): m/z = 651 [M + H]+, 673 [M +
Na]+. C36H46N2O9 (650.76): calcd. C 66.44, H 7.12, N 4.30; found
C 66.28, H 7.42, N 4.13. To a solution of 2-aminoglycoside 2bα
(0.30 g, 0.46 mmol) in water (3 mL) was added lithium hydroxide
(17 mg, 0.70 mmol). The reaction mixture was stirred at room tem-
perature for 24 h, and then concentrated under reduced pressure to
(3S,5aR,6R,7R,8R,9aS)-3-[N-(tert-Butyloxycarbonyl)amino]-6,7-di-
hydroxy-8-hydroxymethyloctahydropyrano[2,3-b]-1,5-oxazepin-4-one
(8α): Compound 7α (0.10 g, 0.16 mmol) was dissolved in methanol/
acetic acid (9:1, 10 mL) and Pd/C (0.05 g, 10% Pd) was suspended
in the solution. This mixture was stirred for 24 h under H2 at room
7410
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7407–7413

New Pyrano[2,3-b][1,5]oxazepines
temperature. After complete disappearance of the starting material
(TLC: CH2Cl2/MeOH, 90:10), the catalyst was filtered off and all
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (CH2Cl2/MeOH, 95:5)
to furnish 8α (0.05 g, 90%) as a white solid. M.p. 136–138 °C. TLC
(CH2Cl2/MeOH, 90:10): Rf = 0.20. [α]D = +105.00 (c = 0.06;
H), 7.14–7.34 (m, 15 H, Ar-H) ppm. 13C NMR (62.8 MHz,
CDCl3): δ = 18.70 (γ-CH3), 28.20 [C(CH3)3], 52.68 (OCH3), 57.92
(α-C), 67.67 (C-6), 71.11 (C-5), 73.56 (β-C), 75.27 (C-4), 75.77 (C-
3), 77.07 (OCH2Ph), 78.05 (OCH2Ph), 78.12 (OCH2Ph), 80.13
[C(CH3)3], 86.66 (C-2), 97.48 (C-1), 127.77, 127.99, 128.36, 128.48,
137.36, 137.48, 137.64 (C-Ar), 155.96 (COOCH3), 170.29
MeOH). 1H NMR (250 MHz, CD3OD): δ = 1.51 [s, 9 H, (NHBoc) ppm. MS (MALDI): m/z = 717 [M + Na]+, 733 [M +
C(CH3)3], 3.62–4.60 (m, 9 H, 10a-H, 10b-H, 5a-H, 6-H, 7-H, 8-H, K]+. C37H46O11·1H2O (712.79): calcd. C 62.34, H 6.50, N 3.93;
2a-H, 2b-H, 3-H), 5.54 (br. s, 1 H, 9a-H) ppm. 13C NMR found C 62.02, H 6.51, N 3.74.
(68.8 MHz, CD3OD): δ = 28.64 [C(CH3)3], 56.13 (C-3), 56.80 (C-
5a), 62.44 (C-2), 67.62 (C-10), 69.87 (C-7), 71.16 (C-8), 74.80 (C-
Compound 10β: TLC (petroleum ether/ethyl acetate, 80:20): Rf =
0.24. [α]D = +4.00 (c = 0.25; CHCl3). 1H NMR (250 MHz, CDCl3):
6), 81.13 [C(CH3)3], 98.04 (C-9a), 157.55 (C-4), 174.20 (Boc-
3
δ = 1.13 (d, Jγ,β = 6.4 Hz, 3 H, γ-CH3), 1.43 [s, 9 H, C(CH3)3],
CO) ppm. MS (MALDI): m/z = 371 [M + Na]+, 387 [M + K]+.
2
3.46 (d, J6,6Ј = 9.7 Hz, 1 H, 6-H), 3.62 (s, 3 H, OCH3), 3.64–3.75
C14H23N2O8·1H2O (366.37): calcd. C 45.89, H 6.60, N 7.64; found
C 45.46, H 6.95, N 7.84.
3
3
(m, 3 H, 6Ј-H, 5-H, 4-H), 4.17 (dd, J3,4 = 9.9 Hz, J3,2 = 10.3 Hz,
3
2
1 H, 3-H), 4.30 (dd, Jα,β = 2.2 Hz, Jα,NH = 9.5 Hz, 1 H, α-CH),
4.36–4.58 (m, 7 H, β-CH, OCH2Ph), 4.69 (m, 3 H, 2-H, OCH2Ph),
(3S,5aR,6R,7R,8R,9aS)-3-[N-(tert-Butyloxycarbonyl)amino]-6,7-
bisacetoxy-8-acetoxymethyloctahydropyrano[2,3-b]-1,5-oxazepin-4-
one (9α): Compound 8α was treated with pyridine/acetic anhydride
(3:2, 6 mL) and stirred at room temperature for 12 h. All volatiles
were evaporated and the residue was purified by flash column
chromatography (CH2Cl2/MeOH, 99:1) to furnish 9α (57 mg, 86%)
3
3
4.76 (d, J1,2 = 8.12 Hz, 1 H, 1-H), 5.20 (d, JNH,α = 9.5 Hz, 1 H,
NHBoc), 7.14–7.34 (m, 15 H, Ar-H) ppm. 13C NMR (62.8 MHz,
CDCl3): δ = 18.62 (γ-CH3), 28.26 [C(CH3)3], 52.26 (OCH3), 57.91
(α-C), 68.01 (C-6), 73.62 (C-5, OCH2Ph), 75.14 (β-C), 75.23 (C-4),
75.26 (C-3), 77.22 (OCH2Ph), 80.07 [C(CH3)3], 81.18 (OCH2Ph),
89.53 (C-2), 97.98 (C-1), 127.75, 127.83, 128.03, 128.12, 128.44,
128.48, 136.88, 137.46, 137.65 (C-Ar), 156.07 (COOCH3), 170.72
(NHBoc) ppm. MS (MALDI): m/z = 717 [M + Na]+, 733 [M +
K]+. C37H46O11·0.25H2O (699.27): calcd. C 63.55, H 6.63, N 4.01;
found C 63.16, H 6.58, N 4.04.
as a white foam. TLC (CH2Cl2/MeOH, 95:5): Rf = 0.50. [α]D
=
1
+59.74 (c = 0.39; CHCl3). H NMR (600 MHz, CDCl3): δ = 1.44
3
[s, 9 H, C(CH3)3], 2.05, 2.14 (2 s, 9 H, 3 Ac), 3.70 (dd, J5a,9a
=
3
3.1 Hz, J5a,6 = 7.2 Hz, 1 H, 5a-H), 3.94 (m, 1 H, 2a-H), 4.04 (m,
1 H, 2b-H), 4.07 (dd, 3J10a,8 = 7.0 Hz, 2J10a,10b = 11.4 Hz, 1 H, 10a-
3
2
H), 4.12 (dd, J10b,7 = 6.2 Hz, J10b,10a = 11.4 Hz, 1 H, 10b-H),
(3R,2S,5aR,6R,7S,8R,9aS)-3-[N-(tert-Butyloxycarbonyl)amino]-
6,7-bisbenzyloxy-8-benzyloxymethyl-4-methyloctahydropyrano[2,3-
b]-1,5-oxazepin-4-one (12α): Compound 10α (0.69 g, 1.00 mmol)
was dissolved in ethanol (10 mL) and transferred to a hydrogen
vessel. Platinized Raney nickel T4 catalyst was freshly prepared as
described[11] and the material obtained from 2 g of Raney nickel/
aluminum alloy was suspended in ethanol (10 mL). From a homo-
geneous suspension of this catalyst, 10 mL was added to the reac-
tion vessel and the suspension was 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, 95:5) to furnish O-(2-amino-
3,4,6-tri-O-benzyl-2-deoxy-α-d-glucopyranosyl)-N-(tert-butoxycarb-
onyl)-l-threonine methyl ester (11α; 0.60 g, 90%) as a colorless oil,
which was immediately used in the next step. TLC (CH2Cl2/MeOH,
90:10): Rf = 0.30. [α]D = +34.33 (c = 0.30; CHCl3). MS (MALDI):
m/z = 665 [M + H]+, 687 [M + Na]+, 703 [M + K]+. To a solution
of 2-aminoglycoside 11α (0.50 g, 0.75 mmol) in water (3 mL) was
added lithium hydroxide (28 mg, 1.16 mmol). The reaction mixture
was stirred at room temperature for 24 h, and then concentrated
under reduced pressure to give the crude amino acid. To a solution
of the crude material in dimethylformamide (15 mL) was added
triethylamine (0.32 mL, 2.31 mmol). After stirring for 10 min, di-
phenylphosphoryl azide (DPPA; 0.50 mL, 2.31 mmol) was added
and the resulting reaction mixture was further stirred at room tem-
perature for 1.5 h. The reaction mixture was quenched with satu-
rated aqueous NaCl and extracted with Et2O. The extract was dried
with MgSO4 and concentrated under reduced pressure. The residue
was purified by column chromatography (CH2Cl2/MeOH, 99:1) to
furnish 12α in 82% overall yield as a white foam. TLC (CH2Cl2/
MeOH, 95:5): Rf = 0.62. [α]D = +45.26 (c = 0.38; CHCl3). 1H NMR
3
3
4.48 (dd, J8,10a = 6.3 Hz, J8,10b = 6.4 Hz, 1 H, 8-H), 4.58 (br. s, 1
H, 3-H), 5.33 (d, J6,7 = 9.5 Hz, 1 H, 6-H), 5.42 (m, 2 H, 9a-H, 7-
3
H), 5.84 (br. s, 1 H, NHBoc), 6.56 (br. s, 1 H, NH) ppm. 13C NMR
(150.8 MHz, CDCl3): δ = 20.63, 20.66, 20.68 (3 Ac), 28.25
[C(CH3)3], 52.71 (C-5a), 55.39 (C-3), 61.58 (C-10), 67.05 (C-7),
67.31 (C-2), 68.70 (C-8), 70.01 (C-6), 80.34 [C(CH3)3], 96.45 (C-
9a), 155.32 (C-4), 169.91, 170.45, 170.50, 171.58 (3 Ac, Boc-
CO) ppm. MS (MALDI): m/z = 497 [M + Na]+. C20H30N2O11
(474.46): calcd. C 50.63, H 6.37, N 5.90; found C 50.33, H 6.58, N
5.51.
O-(3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-α-
butyloxycarbonyl)-l-threonine Methyl Ester (10α) and O-(3,4,6-Tri-
O-benzyl-2-deoxy-2-nitro-β- -glucopyranosyl)-N-(tert-butyloxycarb-
onyl)- -threonine Methyl Ester (10β): N-(tert-Butyloxycarbonyl)-l-
D-glucopyranosyl)-N-(tert-
D
L
threonine methyl ester (1.17 g, 5 mmol) and 3,4,6-tri-O-benzyl-2-
nitroglucal (2.10 g, 5 mmol) were dried under high vacuum and
dissolved in dry toluene (60 mL) under argon. Freshly activated
molecular sieve (3 Å, 3 g) was introduced and the mixture stirred
for 1 h at room temperature. Potassium tert-butoxide (1 m in THF,
0.50 mL, 0.25 mmol) was added and stirring was continued for
120 min. Acetic acid (0.50 mL) was added to acidify the reaction
mixture, the molecular sieve was filtered off and all the solvents
were removed. The residue was purified by column chromatog-
raphy (petroleum ether/ethyl acetate, 90:10) to furnish 10α (1.8 g,
52 %) as a colorless oil and the corresponding β-glycoside 10β
(0.83 g, 24%) as a colorless oil.
Compound 10α: TLC (petroleum ether/ethyl acetate, 80:20): Rf =
0.30. [α]D = +52.82 (c = 0.39; CHCl3). 1H NMR (250 MHz,
3
CDCl3): δ = 1.31 (d, Jγ,β = 6.3 Hz, 3 H, γ-CH3), 1.47 [s, 9 H,
C(CH3)3], 3.65 (dd, 3J6,5 = 1.6 Hz, 2J6,6Ј = 10.7 Hz, 1 H, 6-H), 3.70–
(600 MHz, CDCl3): δ = 1.16 (d, JMe,2 = 5.6 Hz, 3 H, CH3), 1.44
3
3
3.80 (m, 6 H, 6Ј-H, OCH3, 5-H, 4-H), 3.90 (dd, Jα,β = 6.5 Hz,
[s, 9 H, C(CH3)3], 3.60 (m, 1 H, 5a-H), 3.66 (m, 2 H, 10a-H, 10b-
H), 3.70 (m, 1 H, 7-H), 3.76 (m, 1 H, 6-H), 3.99 (m, 1 H, 8-H),
3Jα,NH = 9.8 Hz, 1 H, α-CH), 4.27–4.35 (m, 2 H, 3-H, β-CH), 4.46–
4.55 (m, 3 H, OCH2Ph, 2-H), 4.63 (d, 2J = 12.0 Hz, 1 H, OCH2Ph),
3
3
2
4.34 (dd, J3,NH = 5.7 Hz, J3,2 = 5.6 Hz, 1 H, 3-H), 4.48 (d, J =
4.80 (d, 2J = 10.6 Hz, 1 H, OCH2Ph), 4.87 (s, 2 H, OCH2Ph), 5.04 11.1 Hz, 1 H, OCH2Ph), 4.52 (d, 2J = 12.1 Hz, 1 H, OCH2Ph), 4.60
3
3
(d, JNH,α = 9.8 Hz, 1 H, NHBoc), 5.36 (d, J1,2 = 3.5 Hz, 1 H, 1-
(d, 2J = 12.1 Hz, 1 H, OCH2Ph), 4.64 (d, 2J = 11.6 Hz, 2 H,
Eur. J. Org. Chem. 2011, 7407–7413
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7411

A. I. Khodair, R. R. Schmidt
FULL PAPER
OCH2Ph), 4.74 (dd, 3J2,Me = 5.6 Hz, 3J2,3 = 5.6 Hz, 1 H, 2-H), 4.83
duced pressure. The residue was purified by flash column
chromatography (CH2Cl2/MeOH, 95:5) to furnish 13α (50 mg,
87%) as a white foam. TLC (CH2Cl2/MeOH, 90:10): Rf = 0.15.
3
(d, 2J = 11.5 Hz, 1 H, OCH2Ph), 5.51 (d, J9a,5a = 3.3 Hz, 1 H, 9a-
3
3
H), 5.55 (d, JNH,3 = 5.7 Hz, 1 H, NHBoc), 6.02 (d, JNH,5a
=
2.9 Hz, 1 H, NH), 7.13–7.38 (m, 15 H, Ar-H) ppm. 13C NMR [α]D = +67.27 (c = 0.11; MeOH). 1H NMR (600 MHz, [D6]-
3
(150.8 MHz, CDCl3): δ = 16.17 (CH3), 28.28 [C(CH3)3], 55.17 (C- DMSO): δ = 1.05 (d, JMe,2 = 6.0 Hz, 3 H, CH3), 1.40 [s, 9 H,
2), 56.02 (C-5a), 68.45 (C-10), 72.03 (C-3), 72.32 (C-8), 73.49
(OCH2Ph), 73.91 (OCH2Ph), 74.33 (OCH2Ph), 76.26 (C-7), 79.40
(C-6), 80.13 [C(CH3)3], 93.38 (C-9a), 127.75, 127.93, 127.98,
128.04, 128.17, 128.23, 128.40, 128.52, 128.88, 137.29, 137.77 (C-
Ar), 155.18 (C-4), 169.41 (Boc-CO) ppm. MS (MALDI): m/z = 655
[M + Na]+. C36H44N2O8 (632.74): calcd. C 68.34, H 7.01, N 4.43;
found C 67.98, H 7.27, N 4.27.
C(CH3)3], 3.01 (dd, 3J3,2 = 3.9 Hz, 3J3,NH = 5.7 Hz, 1 H, 3-H), 3.11
(m, 1 H, 7-H), 3.45 (m, 1 H, 10a-H), 3.54 (m, 1 H, 5a-H), 3.58 (m,
1 H, 10b-H), 3.72 (m 1 H, 6-H), 3.94 (m, 1 H, 2-H), 4.11 (dd,
3
3J8,10a = 4.0 Hz, J8,10b = 6.0 Hz, 1 H, 8-H), 4.53 (m, 2 H, 10-OH,
7-OH), 5.05 (br. s, 1 H, 6-OH), 5.32 (br. s, 1 H, 9a-H), 5.36 (br. s,
1 H, NHBoc), 7.14 (s, 1 H, NH) ppm. 13C NMR (150.8 MHz, [D6]-
DMSO): δ = 17.34 (Me), 28.08 [C(CH3)3], 57.91 (C-3), 60.74 (C-
5a), 61.48 (C-2), 69.42 (C-10), 71.75 (C-7), 73.01 (C-8), 74.88 (C-
6), 78.76 [C(CH3)3], 95.34 (C-9a), 155.36 (C-4), 169.92 (Boc-
CO) ppm. MS (MALDI): m/z = 385 [M + Na]+, 401 [M + K]+.
C15H26N2O8 (362.38): calcd. C 49.72, H 7.23, N 7.73; found C
49.40, H 7.61, N 7.52.
(3R,2S,5aR,6R,7S,8R,9aR)-3-[N-(tert-Butyloxycarbonyl)amino]-
6,7-bisbenzyloxy-8-benzyloxymethyl-2-methyloctahydropyrano[2,3-
b]-1,5-oxazepin-4-one (12β): β-Nitroglycoside 10β (0.69 g,
1.00 mmol) was dissolved in ethanol (10 mL) and transferred to a
hydrogen vessel. Platinized Raney nickel T4 catalyst was freshly
prepared as described[11] and the material obtained from 2 g of
Raney nickel/aluminum alloy was suspended in ethanol (10 mL).
From a homogeneous suspension of this catalyst, 10 mL was added
to the reaction vessel and the suspension was 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, 95:5) to furnish O-(2-amino-
3,4,6-tri-O-benzyl-2-deoxy-α-d-glucopyranosyl)-N-(tert-butoxycarb-
onyl)-l-threonine methyl ester (11β; 0.58 g, 87%) as a colorless oil,
which was immediately used in the next step {TLC (CH2Cl2/
MeOH, 90:10): Rf = 0.36}. To a solution of 11β (0.50 g, 0.75 mmol)
in water (3 mL) was added lithium hydroxide (28 mg, 1.16 mmol).
The reaction mixture was stirred at room temperature for 24 h, and
then concentrated under reduced pressure to give the crude amino
acid. To a solution of the crude material in dimethylformamide
(15 mL) was added triethylamine (0.32 mL, 2.31 mmol). After stir-
ring for 10 min, diphenylphosphoryl azide (DPPA; 0.50 mL,
2.31 mmol) was added and the resulting reaction mixture was fur-
ther stirred at room temperature for 1.5 h. The reaction mixture
was quenched with saturated aqueous NaCl and extracted with
Et2O. The extract was dried with MgSO4 and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (CH2Cl2/MeOH, 99:1) to furnish 12β in 78% overall yield as
a white foam. TLC (CH2Cl2/MeOH, 95:5): Rf = 0.65. [α]D = +30.91
(c = 0.44; CHCl3). 1H NMR (600 MHz, CDCl3): δ = 1.15 (d, 3JMe,2
= 5.8 Hz, 3 H, CH3), 1.45 [s, 9 H, C(CH3)3], 3.63–3.83 (m, 5 H,
10a-H, 10b-H, 7-H, 6-H, 5a-H), 4.12 (m, 1 H, 8-H), 4.32 (m, 1 H,
(3R,2S,5aR,6R,7S,8R,9aR)-3-[N-(tert-Butyloxycarbonyl)amino]-
6,7-bishydroxy-8-hydroxymethyl-2-methyloctahydropyrano[2,3-b]-
1,5-oxazepin-4-one (13β): Compound 12β (0.10 g, 0.16 mmol) was
dissolved in methanol/acetic acid (9:1, 10 mL) and Pd/C (0.05 g,
10% Pd) was suspended in the solution. This mixture was stirred
for 24 h under H2 at room temperature. After complete disappear-
ance of the starting material (TLC: CH2Cl2/MeOH, 90:10), the cat-
alyst was filtered off and all the solvents were removed under re-
duced pressure. The residue was purified by flash column
chromatography (CH2Cl2/MeOH, 95:5) to furnish 13β (53 mg,
92%) as a white foam. TLC (CH2Cl2/MeOH, 90:10): Rf = 0.20.
[α]D = +47.50 (c = 0.08; MeOH). 1H NMR (250 MHz, [D6]-
3
DMSO): δ = 1.06 (d, JMe,2 = 6.1 Hz, 3 H, CH3), 1.41 [s, 9 H,
C(CH3)3], 2.99–3.11 (m, 2 H, 10a-H, 10b-H), 3.33–3.69 (m, 4 H,
5a-H, 3-H, 7-H, 6-H), 3.94–4.14 (m, 2 H, 2-H, 8-H), 4.53 (m, 2 H,
10-OH), 5.04 (br. s, 1 H, 7-OH), 5.32–5.37 (m, 2 H, 6-OH, 9a-H),
3
3
6.22 (d, JNH,3 = 8.7 Hz, 1 H, NHBoc), 7.16 (d, JNH,5a = 4.2 Hz,
1 H, NH) ppm. MS (MALDI): m/z = 385 [M + Na]+, 401 [M +
K]+. C15H26N2O8 (362.38): calcd. C 49.72, H 7.23, N 7.73; found
C 49.40, H 7.08, N 7.55.
(3R,2S,5aR,6R,7S,8R,9aS)-3-[N-(tert-Butyloxycarbonyl)amino]-
6,7-bisacetoxy-8-acetoxymethyl-2-methyloctahydropyrano[2,3-b]-
1,5-oxazepin-4-one (14α): Compound 13α (40 mg, 0.11 mmol) was
treated with pyridine/acetic anhydride (3:2, 6 mL) and stirred at
room temperature for 12 h. All volatiles were evaporated and the
residue was purified by flash column chromatography (CH2Cl2/
MeOH, 99:1) to furnish 14α (44 mg, 82%) as a white foam. TLC
(CH2Cl2/MeOH, 95:5): Rf = 0.45. [α]D = +72.77 (c = 0.22; CHCl3).
3
3-H), 4.47–4.60 (m, 6 H, OCH2Ph), 4.73 (dd, 3J2,Me = 5.6 Hz, J2,3
3
= 5.6 Hz, 1 H, 2-H), 4.78 (d, J9a,5a = 7.0 Hz, 1 H, 9a-H), 5.30 (d,
3
1H NMR (600 MHz, CDCl3): δ = 1.25 (d, JMe,2 = 5.5 Hz, CH3),
3JNH,3 = 5.9 Hz, 1 H, NHBoc), 5.89 (br. s, 1 H, NH), 7.22–7.34
(m, 15 H, Ar-H) ppm. 13C NMR (150.8 MHz, CDCl3): δ = 19.40
(CH3), 28.47 [C(CH3)3], 56.02 (C-2), 61.98 (C-5a), 68.69 (C-10),
71.25 (C-3), 71.70 (C-8), 71.82 (OCH2Ph), 72.01 (OCH2Ph), 73.54
(OCH2Ph), 74.13 (C-7), 76.35 (C-6), 80.64 [C(CH3)3], 99.51 (C-9a),
127.80, 128.00, 128.36, 128.44, 128.57, 128.80, 128.94, 137.07,
137.24, 138.07 (C-Ar), 155.32 (C-4), 173.46 (Boc-CO) ppm. MS
(MALDI): m/z = 655 [M + Na]+. C36H44N2O8 (632.74): calcd. C
68.34, H 7.01, N 4.43; found C 68.18, H 7.24, N 4.13.
1.46 [s, 9 H, C(CH3)3], 2.05, 2.08, 2.11 (3 s, 9 H, 3 Ac), 3.54 (m, 1
H, 5a-H), 4.12 (m, 1 H, 10a-H), 4.27 (m, 3 H, 10b-H, 8-H, 2-H),
3
3
4.64 (m, 1 H, 3-H), 5.03 (dd, J7,8 = 8.9 Hz, J7,6 = 8.9 Hz, 1 H, 7-
3
3
H), 5.34 (dd, J6,5a = 9.5 Hz, J9,8 = 9.2 Hz, 1 H, 6-H), 5.43 (br. s,
3
1 H, 9a-H), 5.75 (d, JNH,3 = 7.2 Hz, 1 H, NHBoc), 7.05 (br. s, 1
H, NH) ppm. 13C NMR (150.8 MHz, CDCl3): δ = 17.10 (CH3),
20.60, 20.64, 20.69 (3 Ac), 28.24 [C(CH3)3], 56.22 (C-5a), 58.35 (C-
3), 61.77 (C-10), 67.72 (C-7), 69.48 (C-8), 72.42 (C-6), 73.40 (C-3),
80.19 [C(CH3)3], 95.35 (C-9a), 155.58 (C-4), 169.45, 170.63, 170.76
(3Ac), 171.29 (Boc-CO) ppm. MS (MALDI): m/z = 511 [M +
Na]+. C21H32N2O11 (488.49): calcd. C 51.63, H 6.60, N 5.73; found
C 51.34, H 6.70, N 5.68.
(3R,2S,5aR,6R,7S,8R,9aS)-3-[N-(tert-Butyloxycarbonyl)amino]-
6,7-bishydroxy-8-hydroxymethyl-2-methyloctahydropyrano[2,3-b]-
1,5-oxazepin-4-one (13α): Compound 12α (0.10 g, 0.16 mmol) was
dissolved in methanol/acetic acid (9:1, 10 mL) and Pd/C (0.05 g,
10% Pd) was suspended in the solution. This mixture was stirred
for 24 h under H2 at room temperature. After complete disappear-
ance of the starting material (TLC: CH2Cl2/MeOH, 90:10), the cat-
alyst was filtered off and all the solvents were removed under re-
(3R,4R,5aR,7R,8S,9R,9aR)-3-[N-(tert-Butyloxycarbonyl)amino]-
6,7-bisacetoxy-8-acetoxymethyl-2-methyloctahydropyrano[2,3-b]-
1,5-oxazepin-4-one (14β): Compound 13β (40 mg, 0.11 mmol) was
treated with pyridine/acetic anhydride (3:2, 6 mL) and stirred at
7412
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7407–7413

New Pyrano[2,3-b][1,5]oxazepines
[9] T. Yuji, M. Keiji, K. Yoshinari, M. Masahiko, Kazuyoshi, O.
Hiroki, K. Toshiaki, I. Kimihiro, S. Makoto, US Patent no. 6
436 922, 2002.
[10] S. Kapur, R. McClelland, US Patent no. 6 890 919, 2005.
[11] G. Galley, R. Goodnow, A. Goodnow, J. Peters, U. Peters, EU
Patent no. 1 631 296, 2006.
room temperature for 12 h. All volatiles were evaporated and the
residue was purified by flash column chromatography (CH2Cl2/
MeOH, 99:1) to furnish 14β (50 mg, 93%) as a white foam. TLC
(CH2Cl2/MeOH, 95:5): Rf = 0.50. [α]D = +36.07 (c = 0.28; CHCl3).
3
1H NMR (600 MHz, CDCl3): δ = 1.24 (d, JMe,2 = 6.2 Hz, CH3),
1.44 [s, 9 H, C(CH3)3], 2.10, 2.14, 2.17 (3 s, 9 H, 3 Ac), 3.90–4.33
(m, 6 H, 5a-H, 10a-H, 10b-H, 3-H, 2-H, 8-H), 4.90 (m, 2 H, 7-H,
9a-H), 5.15 (m, 1 H, 6-H), 5.68 (d, 3JNH,3 = 7.5 Hz, 1 H, NHBoc),
6.35 (br. s, 1 H, NH) ppm. 13C NMR (150.8 MHz, CDCl3): δ =
19.08 (CH3), 20.74, 20.81, 20.85 (3 Ac), 28.24 [C(CH3)3], 52.02 (C-
5a), 56.19 (C-3), 61.80 (C-10), 67.77 (C-7), 69.21 (C-8), 72.52 (C-
6), 73.33 (C-2), 80.20 [C(CH3)3], 98.24 (C-9a), 155.02 (C-4), 169.14,
169.5, 170.606 (3 Ac), 172.60 (Boc-CO) ppm. MS (MALDI): m/z
= 511 [M + Na]+, 527 [M + K]+. C21H32N2O11 (488.49): calcd. C
51.63, H 6.60, N 5.73; found C 51.50, H 6.11, N 5.82.
[12] For a review on glycosyl amino acids and carbohydrate-based
peptide mimetics, see: F. Schweizer, Angew. Chem. 2002, 114,
240–264; Angew. Chem. Int. Ed. 2002, 41, 230–253 and refer-
ences cited therein.
[13] J. Das, R. R. Schmidt, Eur. J. Org. Chem. 1998, 169–1613.
[14] G. A. Winterfeld, Y. Ito, T. Ogawa, R. R. Schmidt, Eur. J. Org.
Chem. 1999, 1167–1171.
[15] G. A. Winterfeld, R. R. Schmidt, Angew. Chem. 2001, 113,
2718–2721; Angew. Chem. Int. Ed. 2001, 40, 2654–2657.
[16] G. A. Winterfeld, A. I. Khodair, R. R. Schmidt, Eur. J. Org.
Chem. 2003, 1009–1021.
[17] A. I. Khodair, G. A. Winterfeld, R. R. Schmidt, Eur. J. Org.
Chem. 2003, 1847–1852.
[18] A. I. Khodair, K. Pachamuthu, R. R. Schmidt, Synthesis 2004,
Acknowledgments
53–58.
[19] B. G. Reddy, Y. D. Vankar, Tetrahedron Lett. 2003, 44, 4765–
4767.
[20] G. A. Winterfeld, J. Das, R. R. Schmidt, Eur. J. Org. Chem.
2000, 3047–3050.
[21] K. Pachamuthu, A. Gupta, J. Das, R. R. Schmidt, Y. D. Van-
kar, Eur. J. Org. Chem. 2002, 1479–1483.
[22] G. A. Winterfeld, Ph.D. Thesis, University of Konstanz, 2000.
[23] L. A. Salvador, M. Elofsson, J. Kihlberg, Tetrahedron 1995, 51,
5643–5656.
This work was supported by the Deutsche Forschungsgemein-
schaft, the European Community (Grant No. HRPN-CT-2000–
00001/GLYCOTRAIN), and the Fonds der Chemischen Industrie.
A. I. K. is grateful for an Alexander von Humboldt Fellowship. We
are grateful to Ms. Anke Friemel for her help with the structural
assignments of NMR spectra.
[24] K. J. Jensen, P. R. Hansen, D. Venugopal, G. Barany, J. Am.
Chem. Soc. 1996, 118, 3148–3155.
[25] E. Meinjohanns, M. Meldal, T. Jensen, O. Werdelin, L. Galli-
Stampino, S. Mouritsen, K. Bock, J. Chem. Soc. Perkin Trans.
1 1997, 871–884.
[26] S. Bay, O. Berthier-Vergues, V. Biberovic, D. Cantacuzène, Car-
bohydr. Res. 1997, 303, 25–31.
[27] S. Nishimura, Bull. Chem. Soc. Jpn. 1959, 32, 61–64.
[28] This compound is commercially available.
[29] R. U. Lemieux, T. L. Nagabushan, S. W. Gunner, Can. J. Chem.
1968, 46, 405–411.
[1]
[2]
K. Toshima, K. Tatsuta, Chem. Rev. 1993, 93, 1503–1531.
X. Zhu, R. R. Schmidt, Angew. Chem. 2009, 121, 1932–1967;
Angew. Chem. Int. Ed. 2009, 48, 1900–1934.
J. P. Kamerling, G.-J. Boons, Y. C. Lee, A. Suzuki, N. Tanigu-
chi, A. G. J. Voragen (Eds.), Comprehensive Glycoscience, Elsev-
ier, Oxford, 2007, vol. 1.
[3]
[4]
A. I. H. Ando, H. Ishida, M. Kiso, Curr. Org. Chem. 2008, 12,
675–689.
[5] Z. N. Bang, V. N. Komissarov, Y. A. Sayapin, V. V. Tkachev,
G. V. Shilov, S. M. Aldoshin, V. I. Minkin, Russ. J. Org. Chem. [30] C. W. Holzapfel, C. F. Marais, M. S. van Dyk, Synth. Commun.
2009, 45, 442–448.
[6] A. V. Samet, K. A. Kislyi, V. N. Marshalkin, V. V. Semenov,
Izv. Ross. Akad. Nauk 2006, 529.
1988, 18, 97–114.
[31] T. Takamoto, R. Sudoh, T. Nakagawa, Carbohydr. Res. 1973,
27, 135–140.
[7] K. Sakata, T. Tsuji, N. Sasaki, K. Takahashi, US Patent no. 6
562 808, 2003.
[8] K. Sakata, T. Tsuji, N. Sasaki, K. Takahashi, EU Patent no. 1
471 060, 2004.
[32] T. Sakakibara, Y. Tachimori, R. Sudoh, Tetrahedron Lett.
1982, 23, 5545–5548.
Received: August 4, 2011
Published Online: October 21, 2011
Eur. J. Org. Chem. 2011, 7407–7413
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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