Acid-induced and reductive transformations of enantiopure 3,6-dihydro-2H-1,2-oxazines - Synthesis of dideoxyamino carbohydrate derivatives

Article abstract of DOI:10.1002/ejoc.200700792

Acid-catalyzed transformations of carbohydrate-derived 3,6-dihydro-2H-1,2- oxazines such as 1, 5 and 13 provided a set of enantiopure furano-1,2-oxazines or pyrano-1,2-oxazines. The reaction conditions determined the degree of solvolysis of the compounds.

Full text of DOI:10.1002/ejoc.200700792

FULL PAPER
DOI: 10.1002/ejoc.200700792
Acid-Induced and Reductive Transformations of Enantiopure 3,6-Dihydro-2H-
1,2-oxazines – Synthesis of Dideoxyamino Carbohydrate Derivatives
Bettina Bressel,[a] Boris Egart,[a] Ahmed Al-Harrasi,[a] Robert Pulz,[a] and
Hans-Ulrich Reißig,*[a]Irene Brüdgam[a][‡]
Dedicated to Professor Hans Paulsen on the occasion of his 85th birthday
Keywords: 1,2-Oxazines / Furans / Pyrans / Carbohydrates / Reductions / Samarium diiodide
Acid-catalyzed transformations of carbohydrate-derived 3,6-
dihydro-2H-1,2-oxazines such as 1, 5 and 13 provided a set
of enantiopure furano-1,2-oxazines or pyrano-1,2-oxazines.
The reaction conditions determined the degree of solvolysis
of the compounds. An X-ray analysis of product 6 revealed
an interesting network of hydrogen bonds. Reductive cleav-
age of the N–O bond of the 1,2-oxazines either by hydrogen/
palladium or by samarium diiodide furnished enantiopure
aminofuran and -pyran derivatives, e.g. 9 and 11 or com-
pound 16, which can be regarded as protected 4-amino-1,4-
dideoxyhex-3-ulose or 4-amino-1,4-dideoxyoct-3-ulose de-
rivatives. We thus have established a short and stereocon-
trolled route to amino carbohydrate derivatives with 1,2-ox-
azines as crucial relay compounds.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
vestigated by our group. In this report we want to disclose
the details of the acid-induced reactions of 3,6-dihydro-2H-
1,2-oxazines C. The subsequent reductive steps provided
new enantiopure dideoxyamino carbohydrate derivatives[8]
in a simple fashion.
Introduction
In recent publications we reported that lithiated alk-
oxyallenes A smoothly add to chiral carbohydrate-derived
nitrones B to provide 3,6-dihydro-2H-1,2-oxazine deriva-
tives C by a [3+3] cyclization in a stereocontrolled manner
(Scheme 1).[1]
Results and Discussion
The 3,6-dihydro-2H-1,2-oxazines syn-1, its enantiomer
ent-syn-1, and their diastereomer anti-1 are smoothly avail-
able from lithiated methoxyallene and - or -glyceralde-
hyde-derived N-benzyl nitrone in a stereodivergent manner
and fairly large scale.[1] They therefore served as first-choice
substrates for the exploration of subsequent reactions of
this class of enantiopure heterocycles. Treatment of these
three isomers with p-toluenesulfonyl chloride in methanol
furnished the three bicyclic furano-1,2-oxazine derivatives
2, ent-2, and 3 in good yields (Scheme 2). When the re-
arrangement of syn-1 was performed in benzyl alcohol, ben-
zyloxy-substituted derivative 4 was obtained as main prod-
uct, beside a small amount of the expected furano-1,2-oxaz-
ine 2. These rearrangements are catalyzed by hydrochloric
acid which is slowly generated by the reaction of the sulfo-
nyl chloride with the solvent.[9] The detailed mechanism is
presented below (Scheme 4). The configuration of bicycles
2, 3, and 4 with cis fusion of the two rings was proved by
NOESY experiments and finally supported by the X-ray
analysis of the related compound 6 (see below; Figures 1
and 2).
Scheme 1. Synthesis of 3,6-dihydro-2H-1,2-oxazines C.
The resulting heterocycles C are extremely versatile inter-
mediates and serve as precursors for a variety of target
compounds. Reductive,[2] acid-induced,[3] and Lewis-acid-
promoted[4] transformations as well as cyclopropanations
followed by palladium-catalyzed processes[5] have recently
been reported by our group. These reaction sequences lead
to enantiopure pyrrolidines, azetidines, and amino-substi-
tuted polyol derivatives or other interesting polyfunction-
alized compounds. The synthetic potential of 2H-1,2-oxaz-
ines C thus nicely complements the chemistry of related 4H-
1,2-oxazines[6] and 6H-1,2-oxazines[7] which were earlier in-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
[‡] Responsible for X-ray analyses.
Eur. J. Org. Chem. 2008, 467–474
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Bressel, B. Egart, A. Al-Harrasi, R. Pulz, H.-U. Reißig, I. Brüdgam
FULL PAPER
ered pyridine/hydrogen fluoride the diastereomeric anti-5
furnished 74% of the expected semiketal 8.
The relative configuration of semiketal 6 was unequivo-
cally proven by an X-ray analysis clearly showing the cis
fusion of the two rings and the cis arrangement of the two
hydroxy groups (Figure 1).[11] The hydroxy group at the
bridgehead occupies the thermodynamically more stable ax-
ial position (anomeric effect). This X-ray analysis also
strongly supports the assignments for the closely related
compounds 2 and 7.
Scheme 2. Acid-induced rearrangements of 1,2-oxazines.
Figure 1. X-ray crystal structure of compound 6.
We also studied acid-promoted reactions of the two dia-
stereomeric 2-(trimethylsilyl)ethoxy-substituted 3,6-dihy-
dro-2H-1,2-oxazines syn-5 and anti-5.[1b] Treatment of the
syn isomer with pyridine/hydrogen fluoride (30% pyridine,
70% HF),[10] which is a milder acidic reagent than hydro-
chloric acid in methanol, afforded 61% of bicyclic semiketal
6 (Scheme 3). Addition of more pyridine (85% pyridine,
15% HF) reduced the acidity of this reagent even more and
hence allowed isolation of 2-(trimethylsilyl)ethoxy-substi-
tuted ketal 7 in moderate yield. By employing the unbuff-
The crystal structure of 6 reveals an intriguing network
of intra- and intermolecular hydrogen bonds with a repeti-
tion unit of two bicyclic furano-1,2-oxazine molecules (Fig-
ure 2, the subsequent discussion starting at the left side of
the Figure). The proton H3 is connected in a transannular
fashion with O4, and H4 interacts with the furan oxygen
atom O2A of the next molecule. The axial H3a forms an
intramolecular hydrogen bond to the axial O4A like in the
first molecule; however, H4a of this molecule interacts not
with the furan oxygen atom of the next molecule but with
O3. The distances between the different oxygen atoms in-
volved in this network of hydrogen bonds are collected in
Table 1.
The straightforward mechanism of these acid-induced re-
arrangements of 3,6-dihydro-2H-1,2-oxazines is depicted in
Scheme 4. Acid-catalyzed cleavage of the dioxolane unit[10c]
and protonation of the enol ether moiety provide a stabi-
lized carbenium ion D which can undergo an intramolecu-
lar cyclization leading to bicyclic ketal E with the OR1
group still being present. Further acid-induced dissociation
to F can finally lead to products G bearing, depending on
the solvent, either an alkoxy or a hydroxy group at the
bridgehead. The equilibria of all steps allow thermo-
dynamic control which leads to compounds E or G with
axially exposed oxygen substituents at the anomeric bridge-
head centre.
In general, the synthetic value of stereoselectively formed
1,2-oxazine derivatives is caused by the option that their
N–O bond can be cleaved under fairly mild reaction condi-
tions – usually by reductive methods.[12] When furano-1,2-
oxazine 2 was reduced by employing standard conditions
Scheme 3. Acid-induced rearrangements of 2-(trimethylsilyl)-
ethoxy-substituted 1,2-oxazines.
468
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Dideoxyamino Carbohydrate Derivatives
Scheme 5. Hydrogenation of furano-1,2-oxazine derivatives.
Whereas the removal of the N-benzyl group can hardly
be avoided with hydrogen/palladium, samarium diiodide as
reducing agent allows chemoselective cleavage of the N–O
bond without touching the N-protecting group.[13] Furano-
1,2-oxazines 3 and 6 were converted by SmI2 into monocy-
clic 3-aminofuran derivatives 11 and 12 still containing the
N-benzyl group (Scheme 6). Since compounds such as 2,
ent-2, 3, and 7 will allow protection of their secondary hy-
droxy group, the corresponding ring-opened products are
also available in selectively protected forms. It will therefore
be easily possible to incorporate these amino carbohydrate
derivatives into di- and oligosaccharides.
Figure 2. Hydrogen-bond networks within compound 6.
Table 1. Hydrogen bonds of compound 6 with H···Acc distance Ͻ
r(Acc) + 2.000 Å and Don–H···Acc angle Ͼ 110°.
Don–H···Acc
Don–H H···Acc Do···Acc Do–H···Acc
O(3)–H(3)···O(4)
0.87
0.79
0.81
0.87
2.02
2.09
1.96
1.97
2.75
2.77
2.76
2.81
141
144
171
163
O(3A)–H(3A)···O(4A)
O(4A)–H(4A)···O(3)[a]
O(4)–H(4)···O(2A)
[a] Symmetry transformations used to generate equivalent atoms:
x, y, z – 1.
Scheme 6. Ring cleavage of furano-1,2-oxazines promoted by sa-
marium diiodide.
-Arabinose-based 3,6-dihydro-2H-1,2-oxazine anti-
13[1b] was transformed by acid catalysis in methanol into
the pyrano-1,2-oxazine derivative 14 in 74% yield. As a sec-
ond product and result of an incomplete ketal cleavage, we
isolated a compound in ca. 7% yield, for which we propose
structure 15. The longer side chain of anti-13 allows the
acid-catalyzed formation of the thermodynamically more
Scheme 4. Mechanism of acid-induced rearrangement.
(hydrogen/palladium in methanol) it was quantitatively favoured pyran ring instead of the furan ring observed for
transformed into trisubstituted 3-aminotetrahydrofuran de- the dioxolanyl-substituted 1,2-oxazines shown in Scheme 2.
rivative 9 (Scheme 5). This transformation requires removal In analogy to the furan derivatives the assumed cis fusion
of the N-benzyl group (very likely the first step) and N–O of the two rings of 14 was confirmed by NOESY experi-
bond cleavage of the 1,2-oxazine ring. Similarly, enantiomer ments. When pyrano-1,2-oxazine 14 was exposed to hydro-
ent-2 and diastereomer 3 provided ent-9 and 10 in quantita- gen in the presence of palladium on charcoal the expected
tive yield.
deprotected amino carbohydrate 16 was quantitatively ob-
Eur. J. Org. Chem. 2008, 467–474
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469

B. Bressel, B. Egart, A. Al-Harrasi, R. Pulz, H.-U. Reißig, I. Brüdgam
FULL PAPER
tained. Selectively protected derivatives of this compound intermediate. An additional hydroxy group can be installed
should be easily available if protections at the stage of 14 in a highly stereoselective manner by hydroboration,[18] and
are performed (Scheme 7).
an intramolecular aldol-type reaction resulted in C–C bond
formation[4a] and generation of novel bicyclic 1,2-oxazine
derivatives. In all these functionalized 1,2-oxazines the
N–O bond can be reductively cleaved which stereoselec-
tively affords more complex amino-substituted polyols and
related compounds.
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks, and the components were added by syringe.
Dichloromethane was distilled from calcium hydride and stored
over molecular sieves (4 Å). Tetrahydrofuran was freshly distilled
from sodium/benzophenone under argon. Products were purified
by flash chromatography on silica gel (230–400 mesh, Merck) or
neutral alumina (Fluka). Unless otherwise stated, yields refer to
1
analytically pure samples. H NMR [CHCl3 (δ = 7.26 ppm), TMS
(δ = 0.00 ppm), MeOD (δ = 3.31 ppm), or DMSO (δ = 2.50 ppm)
as internal standards] and 13C NMR spectra [CDCl3 (δ =
77.0 ppm), CD3OD (δ = 49.0 ppm), or [D6]DMSO (δ = 39.5 ppm)
as internal standards] were recorded with Bruker AC 250,
DRX 500, or AC 500 or Joel Eclipse 500 instruments in CDCl3,
CD3OD, or [D6]DMSO solutions. Integrals are in accordance with
Scheme 7. Rearrangement of anti-13 and hydrogenation of interme-
diate 14 leading to pyran derivative 16.
Conclusions
We demonstrated in this report that acidic treatment of assignments; coupling constants are given in Hz. IR spectra were
measured with an FTIR spectrometer Nicolet 5 SXC, Perkin–El-
mer 205, or with a Nexus FT-IR instrument equipped with a Nico-
let Smart DuraSamplIR ATR. MS and HRMS analyses were per-
formed with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT 95 (EI,
70 eV), MAT CH7A (EI, 80 eV, 3 kV), CH5DF (FAB, 80 eV, 3 kV)
and Varian Ionspec QFT-7 (ESI-FT ICRMS) instruments. The ele-
mental analyses were recorded with “Elemental-Analyzers” (Per-
kin–Elmer or Carlo Erba). Melting points were measured with a
Reichert apparatus or according to Boëtius with a Rapido appara-
tus and are uncorrected. Optical rotations ([α]D) were determined
easily available enantiopure carbohydrate-derived 3,6-dihy-
dro-2H-1,2-oxazines smoothly provided furano- or pyrano-
1,2-oxazines, which were further reduced to give enantio-
pure 3-aminofuran and 3-aminopyran derivatives such as 9,
ent-9, 10, or 16. The monocyclic compounds prepared are
protected 4-amino-2,4-dideoxyhex-3-ulose[14] (with erythro
or threo configurations) or manno-configured 4-amino-2,4-
dideoxyoct-3-ulose derivatives[15] as illustrated in Scheme 8.
We have hence developed a very short and entirely ste-
reocontrolled route to these carbohydrate derivatives by with Perkin–Elmer 141 or Perkin–Elmer 241 polarimeters at the
temperatures given. Single-crystal X-ray data were collected with a
Bruker SMART CCD diffractometer (Mo-Kα radiation, λ =
0.71073 Å, graphite monochromator), structure solution and re-
finement by SHELXS-97[19] and SHELXL-97[20] in the WINGX
system.[21] CCDC-657955 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Starting materials syn-1,
anti-1, syn-5, anti-5, and anti-13 were prepared according to our
published procedures.[1b] All other chemicals are commercially
using 1,2-oxazines of type C as crucial compounds.
In our synthetic concept we employ lithiated alkoxyall-
enes[16,17] for the efficient and stereocontrolled elongation
of carbohydrate-derived nitrones by three functionalized
carbon atoms. This leads to enantiopure 3,6-dihydro-2H-
1,2-oxazines C as relay intermediates, which can be used for
a manifold of subsequent reactions. Whereas in the present
report the enol ether moiety of C just undergoes an acid-
induced hydrolysis, it can also be used for the introduction
of a variety of additional substituents at the 1,2-oxazine available and were used without further purification.
Scheme 8. Fischer projections of hypothetical products derived from 9, 12, ent-9, 10, 11, and 16.
470
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Eur. J. Org. Chem. 2008, 467–474

Dideoxyamino Carbohydrate Derivatives
(3R,4ЈR)-2-Benzyl-3-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-meth- C-7a), 72.7 (d, C-7), 73.0 (t, C-6), 105.4 (s, C-4a), 127.3, 128.3,
oxy-3,6-dihydro-2H-1,2-oxazine (ent-syn-1): In analogy to the prep-
aration of syn-1,[1b] its enantiomer ent-syn-1 was prepared from
(Z)-N-(1-deoxy-2,3-O-isopropylidene-l-glycero-1-ylidene)benzyl-
amine N-oxide[22,23] and lithiated methoxyallene. Yield: 71%. All
spectroscopic data are identical with those of syn-1. [α]2D2 = –37.6
(c = 1.0, CHCl3).[24] C17H23NO4 (305.4): calcd. C 66.86, H 7.59, N
4.59; found C 66.81, H 7.69, N 4.67.
128.5, 137.2 (3 d, s, Ph) ppm. IR (KBr): ν = 3460 (O–H), 3085–
˜
3030 (=C–H), 2960, 2890 (C–H) cm–1. C14H19NO4 (265.3): calcd.
C 63.38, H 7.22, N 5.28; found C 63.72, H 7.28, N 5.24.
(4aS,7S,7aS)-1-Benzyl-4a-benzyloxyhexahydro-1H-furano[3,2-c]-
[1,2]oxazin-7-ol (4): pTsCl (0.134 g, 0.701 mmol) and syn-1 (0.430 g,
1.41 mmol) were treated as described in GP 1 by using benzyl
alcohol (15 mL) instead of methanol (extraction with 3ϫ15 mL of
dichloromethane). The residue was purified by column chromatog-
raphy (neutral alumina; hexane/ethyl acetate, 4:1) to give 4 as
colourless oil (0.235 g, 49%) and 2 as colourless crystals (0.041 g,
11%). [α]2D0 = +73.6 (c = 0.42, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 2.03 (ddd, J = 6.2, 12.0, 12.8 Hz, 1 H, 4-H), 2.23 (br.
d, J ≈ 12.8 Hz, 1 H, 4-H), 3.23 (s, 1 H, 7a-H), 3.33 (d, J = 12.0 Hz,
1 H, OH), 3.83 (d, J = 15.2 Hz, 1 H, NCH2), 3.85 (dt, J = 2.6,
12.0 Hz, 1 H, 3-H), 3.91 (ddd, J = 1.0, 6.2, 12.0 Hz, 1 H, 3-H),
3.99 (dd, J = 1.4, 9.9 Hz, 1 H, 6-H), 4.09 (br. dd, J ≈ 5.5, 12.0 Hz,
1 H, 7-H), 4.21 (d, J = 15.2 Hz, 1 H, NCH2), 4.49 (dd, J = 5.5,
9.9 Hz, 1 H, 6-H), 4.55 (d, J = 11.0 Hz, 1 H, OCH2Ph), 4.75 (d, J =
11.0 Hz, 1 H, OCH2Ph), 7.26–7.39 (m, 10 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): δ = 31.4 (t, C-4), 59.7 (t, NCH2), 63.1 (t,
OCH2Ph), 65.8 (t, C-3), 74.6 (d, C-7), 76.4 (d, C-7a), 76.5 (t, C-6),
106.2 (s, C-4a), 127.1, 127.9, 128.0, 128.2, 128.3, 128.6, 137.4, 137.7
General Procedure 1 (GP 1): To a stirred solution of p-toluene-
sulfonyl chloride (pTsCl, 0.5 equiv.) in dry methanol (ca. 10 mL per
mmol pTsCl) under dry argon, a solution of the 1,2-oxazine (1
equiv.) in dry methanol (ca. 10 mL per mmol pTsCl) was added.
The mixture was stirred at room temperature for 24 h and then
quenched with satd. aq. NaHCO3 solution (ca. 20 mL per mmol
pTsCl). The aqueous layer was extracted with dichloromethane, the
combined organic phases were dried (MgSO4), and the solvent was
removed under vacuum.
(4aS,7S,7aS)-1-Benzyl-4a-methoxyhexahydro-1H-furano[3,2-c][1,2]-
oxazin-7-ol (2): pTsCl (0.156 g, 0.819 mmol) and syn-1 (0.500 g,
1.64 mmol) in dry methanol (10 mL each) were treated as described
in GP 1 (extraction with 3ϫ20 mL dichloromethane). The residue
was purified by column chromatography (silica gel, hexane/ethyl
acetate = 3:2) to give 2 as colourless crystals (0.400 g, 92%), m.p.
27–29 °C. [α]2D0 = +100.6 (c = 1.7, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 1.86 (ddd, J = 6.3, 11.9, 12.7 Hz, 1 H, 4-H), 2.12 (br.
d, J ≈ 12.7 Hz, 1 H, 4-H), 3.13 (s, 1 H, 7a-H), 3.33 (s, 3 H, OMe),
3.44 (d, J = 11.7 Hz, 1 H, OH), 3.80 (dt, J = 2.7, 11.9 Hz, 1 H, 3-
(6 d, 2 s, Ph) ppm. IR (film): ν = 3520 (O–H), 3030 (=C–H) 2960,
˜
2890 (C–H) cm–1. C20H23NO4 (341.4): calcd. C 70.36, H 6.79, N
4.10; found C 70.59, H 6.86, N 4.50.
General Procedure 2 (GP 2): To a solution of 5 in dichloromethane
H), 3.80 (d, J = 15.2 Hz, 1 H, NCH2), 3.88 (br. dd, J = 6.3, 11.9 Hz, (10 mL per 1 mmol of 5) was added HF/Py (ratio and amount see
1 H, 3-H), 3.91 (dd, J = 1.5, 9.8 Hz, 1 H, 6-H), 4.05 (br. dd, J = individual experiments) at 0 °C, and the resulting solution was
5.5, 11.7 Hz, 1 H, 7-H), 4.18 (d, J = 15.2 Hz, 1 H, NCH2), 4.42
(dd, J = 5.5, 9.8 Hz, 1 H, 6-H), 7.25–7.41 (m, 5 H, Ph) ppm. 13C reaction mixture was then diluted with ethyl acetate (50 mL per
NMR (125 MHz, CDCl3): δ = 30.4 (t, C-4), 47.8 (q, OMe), 59.7 1 mmol of 5) and washed twice with aq. NaHCO3 solution (5%)
(t, NCH2), 65.8 (t, C-3), 74.6 (d, C-7), 76.2 (t, C-6), 76.3 (d, C-7a), and brine. The organic layer was dried (MgSO4) and concentrated
stirred at 0 °C for 5 min, then at room temperature for 12 h. The
105.8 (s, C-4a), 127.1, 127.8, 128.3, 138.2 (3 d, s, Ph) ppm. IR
under vacuum.
(CCl ): ν = 3480 (O–H), 3110–3030 (=C–H) 2940–2890 (C–H)
˜
4
(4aS,7S,7aS)-1-Benzylhexahydro-4aH-furano[3,2-c]-1,2-oxazine-
4a,7-diol (6): syn-5 (0.100 g, 0.255 mmol) was treated with HF/Py
(0.12 mL of 70% HF in pyridine) in dichloromethane (3 mL) as
cm–1. C14H19NO4 (265.3): calcd. C 63.38, H 7.22, N 5.28; found C
63.33, H 7.18, N 5.18.
(4aR,7R,7aR)-1-Benzyl-4a-methoxyhexahydro-1H-furano[3,2-c]- described in GP 2. The resulting pale brown solid (0.046 g) was
[1,2]oxazin-7-ol (ent-2): pTsCl (0.096 g, 0.50 mmol) and ent-syn-1 purified by flash chromatography (silica gel; hexane/ethyl acetate,
(0.305 g, 1.00 mmol) in dry methanol (5 mL each) were treated as
described in GP 1. After quenching with satd. aq. NaHCO3 solu-
tion, water was added until the white precipitate was dissolved,
and the aqueous phase was extracted with dichloromethane (6ϫ
15 mL). Flash chromatography (silica gel; hexane/ethyl acetate, 4:1)
of the residue gave ent-2 (0.230 g, 87%) as colourless oil. All spec-
troscopic data are identical with those of 2. [α]2D0 = –106.8 (c = 1.0,
CHCl3). C14H19NO4 (265.3): calcd. C 63.38, H 7.22, N 5.28; found
C 63.36, H 7.34, N 5.34.
1:3) to give 6 (0.043 g, 66%) as pale yellow crystals. HPLC afforded
6 (0.039 g, 61%) as colourless crystals, m.p. 94–98 °C. [α]2D2
=
+106.5 (c = 0.28, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 2.00–
2.08 (m, 2 H, 4-H), 3.19 (br. s, 1 H, 7a-H), 3.30, 3.62 (2 br. s, 1 H
each, OH), 3.79–3.86 (m, 2 H, 3-H), 3.83 (d, J = 15.1 Hz, 1 H,
NCH2), 4.09 (dd, J = 0.8, 9.8 Hz, 1 H, 6-H), 4.15 (d, J = 15.1 Hz,
1 H, NCH2), 4.18 (br. d, J ≈ 4.8 Hz, 1 H, 7-H), 4.40 (dd, J = 4.8,
9.8 Hz, 1 H, 6-H), 7.24–7.29, 7.31–7.34 (2 m, 1 H, 4 H, Ph) ppm.
13C NMR (63 MHz, CDCl3): δ = 34.5 (t, C-4), 60.0 (t, NCH2),
66.0 (t, C-3), 74.9, 75.7, 75.9, (t, 2 d, C-6,7,7a), 103.2 (s, C-4a),
(4aR,7S,7aR)-1-Benzyl-4a-methoxyhexahydro-1H-furano[3,2-c]-
[1,2]oxazin-7-ol (3): pTsCl (0.062 g, 0.325 mmol) and anti-1
(0.200 g, 0.655 mmol) in dry methanol (4 mL each) were treated as
described in GP 1 (extraction with 3ϫ10 mL of dichloromethane).
The residue was purified by column chromatography (silica gel;
hexane/ethyl acetate, 3:2) to give 3 as colourless crystals (0.136 g,
78%), m.p. 66–68 °C. [α]2D4 = –75.9 (c = 0.54, CHCl3). 1H NMR
127.1, 128.2, 128.3, 137.4 (3 d, s, Ph) ppm. IR (KBr): ν = 3450–
˜
3300 (O–H), 3085–3025 (=C–H), 2985–2845 (C–H), 1675 (C=C)
cm–1. MS (EI, 80 eV, 50 °C): m/z (%) = 251 (29) [M]+, 91 (100)
[CH2Ph]+. HRMS (EI, 80 eV): calcd. for C13H17NO4 [M]+
251.1158; found 251.1183. C13H17NO4 (251.3): calcd. C 62.14, H
6.82, N 5.57; found C 62.22, H 6.81, N 5.18.
(500 MHz, CDCl3): δ = 2.07–2.13 (m, 2 H, 4-H), 3.10 (d, J = (4aS,7S,7aS)-1-Benzyl-4a-[2-(trimethylsilyl)ethoxy]hexahydro-1H-fu-
6.8 Hz, 1 H, OH), 3.13 (d, J = 5.5 Hz, 1 H, 7a-H), 3.26 (s, 3 H, rano[3,2-c]1,2-oxazin-7-ol (7): syn-5 (0.100 g, 0.255 mmol) was
OMe), 3.82–3.87 (m, 2 H, 3-H), 3.84 (d, J = 14.3 Hz, 1 H, NCH2), treated with HF/Py (0.12 mL of 15% HF in pyridine) in dichloro-
3.93 (dd, J = 2.5, 9.5 Hz, 1 H, 6-H), 3.99 (dd, J = 4.6, 9.5 Hz, 1 methane (3 mL) as described in GP 2. The resulting pale brown
H, 6-H), 4.28 (d, J = 14.3 Hz, 1 H, NCH2), 4.53 (mc, 1 H, 7-H), solid (0.057 g) was purified by column chromatography (silica gel;
7.19–7.38 (m, 5 H, Ph) ppm. 13C NMR (125 MHz, CDCl3): δ = hexane/EtOAc, 4:1) to give 7 (0.053 g, 58%) as colourless crystals,
30.0 (t, C-4), 48.4 (q, OMe), 61.3 (t, NCH2), 64.7 (t, C-3), 71.3 (d, m.p. 70–72 °C. [α]2D2 = +65.6 (c = 0.29, CHCl3). 1H NMR
Eur. J. Org. Chem. 2008, 467–474
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
471

B. Bressel, B. Egart, A. Al-Harrasi, R. Pulz, H.-U. Reißig, I. Brüdgam
FULL PAPER
(250 MHz, CDCl3): δ = 0.03 (s, 9 H, SiMe3), 0.87 (ddd, J = 5.3,
10.5, 13.8 Hz, 1 H, CH2Si), 0.93 (ddd, J = 6.6, 11.1, 13.8 Hz, 1 H,
CH2Si), 1.91 (ddd, J = 6.3, 12.5, 13.0 Hz, 1 H, 4-H), 2.13 (br. d, J
≈ 13.0 Hz, 1 H, 4-H) 3.13 (s, 1 H, OH), 3.54 (ddd, J = 6.6, 9.1,
10.5 Hz, 1 H, OCH2), 3.62 (d, J = 11.8 Hz, 1 H, 7a-H), 3.76–3.82
(m, 2 H, 3-H, OCH2), 3.79 (d, J = 15.1 Hz, 1 H, NCH2), 3.86 (br.
dd, J = 6.3, 11.8 Hz, 1 H, 3-H), 3.94 (dd, J = 1.3, 9.8 Hz, 1 H, 6-
H), 4.05 (br. dd, J = 5.4, 11.8 Hz, 1 H, 7-H), 4.17 (d, J = 15.1 Hz,
1 H, NCH2), 4.42 (dd, J = 5.4, 9.8 Hz, 1 H, 6-H), 7.24–7.28, 7.30–
7.35 (2 m, 1 H, 4 H, Ph) ppm. 13C NMR (63 MHz, CDCl3): δ =
–1.4 (q, SiMe3), 18.8 (t, CH2Si), 31.2 (t, C-4), 57.7 (t, OCH2), 59.8
(t, NCH2), 65.8 (t, C-3), 74.7, 76.3, 76.5 (t, 2 d, C-6,7,7a), 105.6 (s,
of ent-2 (0.093 g, 0.35 mmol) in dry methanol (3 mL) was added,
and the mixture was stirred under hydrogen (balloon) at normal
pressure at room temperature for 22 h. Filtration through a pad of
Celite® and removal of the solvent under vacuum provided ent-9
[0.062 g, quant., purity Ͼ 95% (1H NMR)] as colourless crystals,
m.p. 74–77 °C. All spectroscopic data are identical with those of 9.
[α]2D2 = –68.5 (c = 1.0, CHCl3).
Methyl 4-Amino-2,4-dideoxy-β-D-erythro-hex-3-ulofuranoside (10):
Hydrogen was bubbled through a stirred suspension of Pd/C
(10% Pd, 0.162 g) in dry methanol (11 mL) for 1 h. Then a solution
of 3 (0.137 g, 0.52 mmol) in dry methanol (4 mL) was added and
the mixture was stirred under hydrogen (balloon) at normal pres-
sure at room temperature for 50 h. Filtration through a pad of
Celite® and removal of the solvent under vacuum provided 10
[0.092 g, quant., purity Ͼ 95% (1H NMR)] as colourless crystals,
m.p. 57–59 °C. [α]2D3 = –90.6 (c = 0.5, CHCl3). 1H NMR (500 MHz,
CD3OD): δ = 1.98 (ddd, J = 6.1, 8.7, 15.0 Hz, 1 H, 2-H), 2.09 (td,
J = 5.0, 15.0 Hz, 1 H, 2-H), 3.16 (s, 3 H, OMe), 3.22 (br. s, 1 H,
4-H), 3.60–3.69 (m, 3 H, 1-,6-H), 3.94 (dd, J = 6.7, 8.8 Hz, 1 H, 6-
H), 4.54 (br. s, 1 H, 5-H) ppm. 13C NMR (125 MHz, CD3OD): δ
= 33.5 (t, C-2), 48.3 (q, OMe), 58.4 (t, C-1), 60.2* (d, C-4), 72.2*
(d, C-5), 72.3 (t, C-6), 111.7* (s, C-3) ppm; * signals appear as
C-4a), 127.1, 128.20, 128.24, 137.5 (3 d, s, Ph) ppm. IR (KBr): ν =
˜
3500 (O–H), 3060–3030 (=C–H), 2970–2855 (C–H) cm–1. MS (EI,
80 eV, 50 °C): m/z (%) = 351 (16) [M]+, 250 (4) [M – C2H4-
SiMe3]+, 234 (19) [M – SiMe3CH2CH2O]+, 91 (100) [CH2Ph]+, 73
(73) [SiMe3]+. HRMS (EI, 80 eV): calcd. for C18H29NO4Si [M]+
351.1857; found 351.1899.
(4aR,7S,7aR)-1-Benzylhexahydro-4aH-furano[3,2-c][1,2]oxazine-
4a,7-diol (8): anti-5 (0.200 g, 0.511 mmol) was treated with HF/Py
(0.36 mL of 70% HF in pyridine) in dichloromethane (5 mL) as
described in GP 2. The resulting pale yellow oil (0.150 g) was puri-
fied by flash chromatography (silica gel; hexane/EtOAc, 1:3) to give
broad peaks. IR (ATR): ν = 3380, 3300, 3225 (N–H, O–H), 2960–
˜
8 (0.095 g, 74%) as colourless crystals, m.p. 82–84 °C. [α]2D2 = –9.1
2830 (C–H) cm–1. MS (pos. ESI): m/z (%): 178 (70) [M + H]+, 146
1
(c = 0.52, CHCl3). H NMR (500 MHz, CDCl3): δ = 2.05 (td, J = (100) [M – MeO]+. HRMS (pos. ESI): calcd. for C7H16NO4 [M +
6.3, 13.6 Hz, 1 H, 4-H), 2.15 (ddd, J = 6.3, 6.9, 13.6 Hz, 1 H, 4-
H), 3.13 (d, J = 5.1 Hz, 1 H, 7a-H), 3.25 (br. s, 1 H, 7-OH), 3.48
(br. s, 1 H, 4a-OH), 3.83 (ddd, J = 6.3, 6.9, 10.7 Hz, 1 H, 3-H),
3.89 (d, J = 14.3 Hz, 1 H, NCH2), 3.91 (td, J = 6.3, 10.7 Hz, 1 H,
3-H), 3.93 (dd, J = 2.8, 9.5 Hz, 1 H, 6-H), 4.10 (dd, J = 4.4, 9.5 Hz,
1 H, 6-H), 4.30 (d, J = 14.3 Hz, 1 H, NCH2), 4.54 (mc, 1 H, 7-H),
7.25–7.29, 7.31–7.38 (2 m, 1 H, 4 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): δ = 35.1 (t, C-4), 60.9 (t, NCH2), 64.6 (t, C-3),
72.0 (d, C-7a), 72.4 (t, d, C-6,7), 102.5 (s, C-4a), 127.3, 128.3, 128.5,
H]+ 178.1074; found 178.1066.
4-(Benzylamino)-2,4-dideoxy-β-D-erythro-hex-3-ulofuranose (11): A
blue solution of SmI2 (0.1 m in THF, prepared under argon from
1,2-diiodoethane (1 equiv.) and samarium (1.2 equiv.), stored in the
dark) was added under argon to a solution of 3 (0.027 g, 0.10
mmol) in dry THF (1 mL) over ca. 1.5 h until the blue colour per-
sisted for 20 min (ca. 2 mL). Then the reaction was quenched with
satd. aq. NaHCO3 solution (0.3 mL) and filtered through Celite®.
The solvent was removed under vacuum, and the residue was puri-
fied by column chromatography (neutral alumina; dichlorometh-
ane/methanol, 98:2, then 97:3) to give 11 (0.019 g, 71 %) as a
colourless oil. [α]2D3 = –76.5 (c = 0.5, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 2.01 (ddd, J = 4.9, 6.3, 15.4 Hz, 1 H, 2-H), 2.11 (ddd,
J = 4.7, 5.7, 15.4 Hz, 1 H, 2-H), 3.18 (s, 3 H, OMe), 3.25 (d, J =
5.4 Hz, 1 H, 4-H), 3.73–3.78 (m, 2 H, 1-H), 3.82 (d, J = 15.4 Hz,
1 H, NCH2), 3.85 (d, J = 15.4 Hz, 1 H, NCH2), 3.87 (br. d, J ≈
10.1 Hz, 1 H, 6-H), 3.91 (dd, J = 3.3, 10.1 Hz, 1 H, 6-H), 4.28
(ddd, J = 0.9, 3.3, 5.4 Hz, 1 H, 5-H) ppm; OH and NH signals
could not be detected. 13C NMR (125 MHz, CDCl3): δ = 33.5 (t,
C-2), 48.4 (q, OMe), 52.9 (t, NCH2), 58.0 (t, C-1), 67.8 (d, C-4),
70.6 (d, C-5), 72.6 (t, C-6), 109.9 (s, C-3), 127.6, 128.4, 128.7, 138.3
137.0 (3 d, s, Ph) ppm. IR (KBr): ν = 3480–3360 (O–H), 3090–
˜
3030 (=C–H), 2950–2875 (C–H) cm–1. MS (EI, 80 eV, 90 °C): m/z
= 251 (16) [M]+, 91 (100) [CH2Ph]+. HRMS (EI, 80 eV): calcd. for
C13H17NO4 [M]+ 251.1158; found 251.1149. C13H17NO4 (251.3):
calcd. C 62.14, H 6.82, N 5.57; found C 62.02, H 6.62, N 5.42.
Methyl 4-Amino-2,4-dideoxy-α-D-threo-hex-3-ulofuranoside (9): Hy-
drogen was bubbled through a stirred suspension of Pd/C (10% Pd,
0.175 g) in dry methanol (8 mL) for 1 h. Then a solution of 2
(0.116 g, 0.437 mmol) in dry methanol (3 mL) was added, and the
mixture was stirred under hydrogen (balloon) at normal pressure
at room temperature for 8 h. Filtration through a pad of Celite®
and removal of the solvent under vacuum provided 9 (0.077 g,
quant.) as a colourless oil. [α]2D2 = +52.3 (c = 0.41, CHCl3).
(3 d, s, Ph) ppm. IR (ATR): ν = 3385 (N–H, O–H), 3090–3030
˜
1H NMR (500 MHz, CD3OD): δ = 1.91 (ddd, J = 6.2, 8.7, 15.4 Hz, (=C–H), 2950–2835 (C–H) cm–1. HRMS (pos. ESI): calcd. for
1 H, 2-H), 2.12 (td, J = 4.4, 15.4 Hz, 1 H, 2-H), 3.19 (s, 3 H, OMe),
3.22 (br. d, J ≈ 1.7 Hz, 1 H, 4-H), 3.58 (dd, J = 4.6, 9.5 Hz, 1 H,
6-H), 3.60–3.68 (m, 2 H, 1-H), 4.13 (ddd, J = 1.7, 4.6, 6.8 Hz, 1 H,
5-H), 4.30 (ddd, J = 0.5, 6.8, 9.5 Hz, 1 H, 6-H) ppm. 13C NMR
(125 MHz, CD3OD): δ = 32.3 (t, C-2), 48.0 (q, OMe), 58.0 (t, C-
1), 66.1 (d, C-4), 73.6 (t, C-6), 78.7 (d, C-5), 111.0 (s, C-3) ppm.
C14H22NO4 [M + H]+ 268.1543; found 268.1557. C14H21NO4
(267.3): calcd. C 62.90, H 7.92, N 5.24; found C 63.51, H 7.86, N
4.98.
4-(Benzylamino)-2,4-dideoxy-α-D-threo-hex-3-ulofuranose (12): Al-
ternative procedure for the N–O cleavage with SmI2: 1,2-Diiodo-
ethane (0.437 g, 1.55 mmol) and samarium (0.253 g, 1.68 mmol)
were transferred into a round-bottomed flask under argon. Dry
THF (5 mL) was added, and the solution was stirred until a deep
blue colour appeared (about 2 h). 1,2-Oxazine 6 (0.090 g, 0.358
mmol), dissolved in dry THF, was added, the reaction mixture was
stirred at room temperature for 7 h and then quenched with satd.
IR (film): ν = 3350 (N–H, O–H), 2950–2835 (C–H) cm–1. MS (pos.
˜
FAB, 3 kV): m/z (%) = 178 (37) [M + H]+, 160 (32) [M – OH –
NH2]+, 146 (100) [M – OMe]+, 128 (47) [M – OH – OMe]+, 77
(50). HRMS (80 eV): calcd. for C7H14NO3 [M – OH]+ 160.0974;
found 160.0967.
Methyl 4-Amino-2,4-dideoxy-α-L-threo-hex-3-ulofuranoside (ent-9): aq. NaHCO3 solution (2 mL). The mixture was filtered through
Hydrogen was bubbled through a stirred suspension of Pd/C
(10% Pd, 0.122 g) in dry methanol (7 mL) for 1 h. Then a solution
Celite®, the solvent was removed under vacuum, and the residue
was filtered through silica gel (EtOAc) to give 12 (0.073 g, 81%) as
472
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 467–474

Dideoxyamino Carbohydrate Derivatives
a colourless oil. [α]2D2 = +68.9 (c = 0.19, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 2.00–2.08 (m, 2 H, 2-H), 3.18 (br. s, 1 H,
6-H), 3.42 (br. s, 1 H, NH), 3.79–3.86 (m, 4 H, 1-H, 6-H, OH),
3.82 (d, J = 15.1 Hz, 1 H, NCH2), 4.09 (dd, J = 1.0, 9.8 Hz, 1 H,
6-H), 4.15 (d, J = 15.1 Hz, 1 H, NCH2), 4.18 (br. d, J ≈ 4.8 Hz, 1
H, 4-H), 4.40 (ddd, J = 0.4, 4.8, 9.8 Hz, 1 H, 5-H), 7.25–7.29, 7.31–
7.35 (2 m, 1 H, 4 H, Ph) ppm; 2 OH signals could not be detected.
(10% Pd, 0.192 g) in dry methanol (10 mL) for 1 h. Then a solution
of 14 (0.194 g, 0.60 mmol) in dry methanol (2 mL) was added and
the mixture was stirred under hydrogen (balloon) at normal pres-
sure at room temperature for 26 h. Filtration through a pad of
Celite® and removal of the solvent under vacuum provided 16
[0.142 g, quant., purity Ͼ 95% (1H NMR)] as a colourless foam,
m.p. 54–57 °C. [α]2D2 = +48.4 (c = 1.0, MeOH). 1H NMR (500 MHz,
13C NMR (125 MHz, CDCl3): δ = 34.4 (t, C-2), 59.9 (t, NCH2), CD3OD): δ = 1.96 (ddd, J = 7.0, 7.9, 15.2 Hz, 1 H, 2-H), 2.05 (td,
65.9 (t, C-1), 74.9 (d, C-4), 75.7 (t, C-6), 75.8 (d, C-5), 103.2 (s, C-
3), 127.1, 128.2, 128.3, 137.4 (3 d, s, Ph) ppm. IR (film): ν = 3430–
J = 5.4, 15.2 Hz, 1 H, 2-H), 3.06 (d, J = 4.0 Hz, 1 H, 4-H), 3.20
(s, 3 H, OMe), 3.35 (ddd, J = 2.2, 5.0, 9.6 Hz, 1 H, 7-H), 3.52 (t,
˜
3300 (O–H), 3090–3030 (=C–H), 2940–2875 (C–H) cm–1. MS (EI, J = 9.6 Hz, 1 H, 6-H), 3.58–3.64 (m, 2 H, 1-H), 3.73 (dd, J = 5.0,
80 eV, 100 °C): m/z (%) = 253 (1) [M]+, 106 (76) [C7H8N]+, 91 (100) 11.8 Hz, 1 H, 7-CH2), 3.80 (dd, J = 2.2, 11.8 Hz, 1 H, 7-CH2), 3.89
[CH2Ph]+. HRMS (EI, 80 eV): calcd. for C13H19NO4 [M]+
253.1321; found 253.1336.
(dd, J = 4.0, 9.6 Hz, 1 H, 5-H) ppm. 13C NMR (125 MHz,
CD3OD): δ = 34.5 (t, C-2), 48.0 (q, OMe), 56.7 (d, C-4), 57.7 (t,
C-1), 62.7 (t, 7-CH2), 67.6 (d, C-6), 72.0 (d, C-5), 75.3 (d, C-7),
Synthesis of 14 and 15: pTsCl (0.048 g, 0.25 mmol) and anti-13
(0.203 g, 0.50 mmol) in dry methanol (3 mL each) were treated as
described in GP 1. After quenching with satd. aq. NaHCO3 solu-
tion, water was added until the white precipitate was dissolved,
and the aqueous phase was extracted with dichloromethane (6ϫ
10 mL). Flash chromatography of the residue (silica gel; hexane/
ethyl acetate, 1:3, then 1:4) gave 14 (0.119 g, 73%) as colourless
crystals, m.p. 128–132 °C, and unstable side product 15 (0.014 g,
7%) as colourless crystals.
103.3 (s, C-3) ppm. IR (KBr): ν = 3435 (OH, NH), 2930–2830 (OH,
˜
NH, CH), 1645–1590 (NH) cm–1. MS (pos. ESI): m/z (%): 238 (100)
[M + H]+, 206 (85) [M – MeO]+. HRMS (pos. ESI): calcd. for
C9H20NO6 [M + H]+ 238.1285; found 238.1284. C9H19NO6·1/2H2O
(246.3): calcd. C 43.90, H 8.19, N 5.69; found C 44.01, H 7.98, N
5.47.
Acknowledgments
(4aS,6R,7S,8R,8aS)-1-Benzyl-6-(hydroxymethyl)-4a-methoxyhexa-
hydro-1H,3H-pyrano[3,2-c][1,2]oxazine-7,8-diol (14): [α]2D2 = +74.7
Support of this work by the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie and the Schering AG is most
gratefully acknowledged. We thank Dr. R. Zimmer for help during
preparation of the manuscript.
1
(c = 1.0, CHCl3). H NMR (500 MHz, [D6]DMSO): δ = 1.52 (dt,
J = 5.8, 12.5 Hz, 1 H, 4-H), 1.92 (ddd, J = 1.0, 2.1, 12.5 Hz, 1 H,
4-H), 2.92 (d, J = 3.1 Hz, 1 H, 8a-H), 3.19 (s, 3 H, OMe), 3.32
(ddd, J = 1.9, 6.6, 9.4 Hz, 1 H, 6-H), 3.44 (d, J = 15.5 Hz, 1 H,
NCH2), 3.52 (ddd, J = 5.1, 9.4, 10.2 Hz, 1 H, 7-H), 3.53 (ddd, J =
5.9, 6.6, 11.5 Hz, 1 H, 6-CH2), 3.66 (ddd, J = 1.0, 5.8, 11.3 Hz, 1
H, 3-H), 3.74 (ddd, J = 1.9, 5.9, 11.5 Hz, 1 H, 6-CH2), 3.78 (ddd,
J = 2.1, 11.3, 12.5 Hz, 1 H, 3-H), 4.18 (ddd, J = 3.1, 4.6, 10.2 Hz,
1 H, 8-H), 4.47 (t, J = 5.9 Hz, 1 H, 6-CH2OH), 4.92 (d, J = 5.1 Hz,
1 H, 7-OH), 5.11 (d, J = 15.5 Hz, 1 H, NCH2), 5.43 (d, J = 4.6 Hz,
1 H, 8-OH), 7.15–7.19, 7.25–7.31 (2 m, 1 H, 4 H, Ph) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = 33.9 (t, C-4), 46.9 (q, OMe),
59.5 (t, NCH2), 61.6 (t, 6-CH2OH), 65.6 (t, C-3), 65.8 (d, C-7), 69.4
(d, C-8), 70.1 (d, C-8a), 76.6 (d, C-6), 97.1 (s, C-4a), 126.0, 127.5,
[1] a) W. Schade, H.-U. Reißig, Synlett 1999, 632–634; b) M.
Helms, W. Schade, R. Pulz, T. Watanabe, A. Al-Harrasi, L.
Fisˇera, I. Hlobilová, G. Zahn, H.-U. Reißig, Eur. J. Org. Chem.
2005, 1003–1019; c) R. Pulz, S. Cicchi, A. Brandi, H.-U.
Reißig, Eur. J. Org. Chem. 2003, 1153–1156.
[2] R. Pulz, T. Watanabe, W. Schade, H.-U. Reißig, Synlett 2000,
983–986.
[3] R. Pulz, A. Al-Harrasi, H.-U. Reißig, Synlett 2002, 817–819.
[4] a) A. Al-Harrasi, H.-U. Reißig, Angew. Chem. 2005, 117, 6383–
6387; Angew. Chem. Int. Ed. 2005, 44, 6227–6231; b) F. Pfren-
gle, A. Al-Harrasi, H.-U. Reißig, Synlett 2006, 3498–3500.
[5] A. Al-Harrasi, H.-U. Reißig, Synlett 2005, 2376–2378.
[6] H.-U. Reißig, C. Hippeli, T. Arnold, Chem. Ber. 1990, 123,
2403–2411.
127.8, 140.1 (3 d, s, Ph) ppm. IR (KBr): ν = 3420 (OH), 3085–3030
˜
(=C–H), 2960–2725 (C–H), 1605, 1495 (C=C) cm–1. C16H23NO6
(325.4): calcd. C 59.06, H 7.13, N 4.31; found C 59.06, H 6.96, N
4.25.
[7] R. Zimmer, H.-U. Reißig, Angew. Chem. 1988, 100, 1576–1577;
(4aS,6R,7S,8R,8aS)-1-Benzyl-4a-methoxy-6-[(1-methoxy-1-methyl-
ethoxy)methyl]hexahydro-1H,3H-pyrano[3,2-c][1,2]oxazine-7,8-diol
(15): 1H NMR (500 MHz, CDCl3): δ = 1.41, 1.42 (2 s, 6 H, CMe2),
1.70 (dt, J = 5.8, 12.6 Hz, 1 H, 4-H), 1.93 (ddd, J = 1.2, 2.4,
12.6 Hz, 1 H, 4-H), 2.73, 3.19 (2 br. s, 1 H each, OH), 3.20 (d, J =
3.1 Hz, 1 H, 8a-H), 3.268 (s, 3 H, CMe2OMe), 3.270 (s, 3 H, 4a-
OMe), 3.63 (ddd, J = 4.9, 6.4, 9.1 Hz, 1 H, 6-H), 3.65 (d, J =
15.3 Hz, 1 H, NCH2), 3.70 (dd, J = 6.4, 9.5 Hz, 1 H, 6-CH2), 3.76
(ddd, J = 1.2, 5.8, 11.5 Hz, 1 H, 3-H), 3.81 (dd, J = 4.9, 9.5 Hz, 1
H, 6-CH2), 3.91 (ddd, J = 2.4, 11.5, 12.6 Hz, 1 H, 3-H), 4.01 (dd,
J = 9.1, 10.2 Hz, 1 H, 7-H), 4.51 (dd, J = 3.1, 10.2 Hz, 1 H, 8-H),
5.08 (d, J = 15.3 Hz, 1 H, NCH2), 7.20–7.23, 7.28–7.31, 7.37–7.39
(3 m, 1 H, 2 H, 2 H, Ph) ppm. 13C NMR (125 MHz, CDCl3): δ =
24.31, 24.32 (2 q, CMe2), 34.1 (t, C-4), 47.6 (q, 4a-OMe), 48.8 (q,
CMe2OMe), 60.1 (t, NCH2), 62.9 (t, 6-CH2), 66.3 (t, C-3), 68.9 (d,
C-8a), 69.7 (d, C-7), 70.6 (d, C-8), 72.4 (d, C-6), 97.9 (s, C-4a),
100.6 (s, CMe2), 126.3, 127.7, 128.0, 139.8 (3 d, s, Ph) ppm. Due to
its instability the product could not be analysed by other methods.
Angew. Chem. Int. Ed. Engl. 1988, 27, 1518–1519.
[8] For a review about deoxy sugar synthesis, see: A. Kirschning,
M. Jesberger, K.-U. Schöning, Synthesis 2001, 507–540.
[9] Employing directly hydrochloric acid in methanol furnished
compounds 2 and 3 in inferior yields. Probably, low concentra-
tions of HCl are advantageous for a clean transformation.
[10] a) G. A. Olah, J. T. Welch, Y. D. Vankar, M. Nojima, I.
Kerekes, J. A. Olah, J. Org. Chem. 1979, 44, 3872–3881; b)
G. A. Olah, J. G. Shih, G. K. S. Prakash, Fluorine Containing
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Y. Watanabe, Y. Kiyosawa, A. Tatsukawa, M. Hayashi, Tetra-
hedron Lett. 2001, 42, 4641–4643.
[11] In solution also only one epimer can be detected by NMR
spectroscopy.
[12] For a non-reductive method, see: A. Al-Harrasi, H.-U. Reißig,
Synlett 2005, 1152–1154.
[13] For the cleavage of N–O bonds with SmI2, see: a) G. E. Keck,
S. F. McHardy, T. T. Wager, Tetrahedron Lett. 1995, 36, 7419–
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Methyl 4-Amino-2,4-dideoxy-α-
D-manno-oct-3-ulopyranoside (16):
Hydrogen was bubbled through a stirred suspension of Pd/C
Eur. J. Org. Chem. 2008, 467–474
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B. Bressel, B. Egart, A. Al-Harrasi, R. Pulz, H.-U. Reißig, I. Brüdgam
FULL PAPER
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vuelta, S. Cicchi, A. Brandi, Tetrahedron Lett. 2004, 45, 8375–
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[16]
[17]
For a deoxy sugar synthesis using lithiated alkoxyallenes, see:
M. Brasholz, H.-U. Reißig, Angew. Chem. 2007, 119, 1659–
1662; Angew. Chem. Int. Ed. 2007, 46, 1634–1637.
Reviews for the use of alkoxyallenes as building blocks in or-
ganic synthesis: a) R. Zimmer, H.-U. Reißig, Donor-Substituted
Allenes in Modern Allene Chemistry (Eds.: N. Krause, A. S. K.
Hashmi), Wiley-VCH, Weinheim, 2004, vol. 1, p. 425–492; b)
R. Zimmer, Synthesis 1993, 165–178; c) R. Zimmer, F. A.
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[14] To the best of our knowledge, 4-amino-2,4-dideoxyhex-3-
uloses have not been reported before. For a 2-deoxyhex-3-ulose,
see: a) T. Bando, Y. Matsushima, Bull. Chem. Soc. Jpn. 1973,
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tives, see: c) J. Yoshimura, M. Funabashi, Carbohydr. Res. 1969,
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Tsukiura, T. Naito, H. Kawaguchi, J. Antibiot. 1976, 29, 1152–
1162.
[15] To the best of our knowledge, 4-amino-2,4-dideoxyoct-3-uloses
have not been reported before. A 4-amino-2,4-dideoxyoct-3-
ulosonic acid derivative is proposed as an intermediate in a
thiazole synthesis: a) S. Knapp, B. Amorelli, G. A. Doss, Tetra-
hedron Lett. 2004, 45, 8507–8510; for a 1,2-dideoxyoct-3-ulose
derivative, see: b) M. L. Wolfrom, D. I. Weisblat, E. F. Evans,
J. B. Miller, J. Am. Chem. Soc. 1957, 79, 6454–6457; for synthe-
sis and isolation of the first naturally occurring oct-3-ulose, see:
c) R. Schaffer, A. Cohen, J. Org. Chem. 1963, 28, 1929–1930;
d) K. Sakata, H. Hagiwara, A. Yagi, K. Ina, Agric. Biol. Chem.
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[18]
R. Pulz, A. Al-Harrasi, H.-U. Reißig, Org. Lett. 2002, 4, 2353–
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C. Hubschwerlen, J.-L. Specklin, J. Higelin, Org. Synth. 1995,
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methane without prior distillation.
[23]
[24]
Y. Kita, O. Tamura, F. Itoh, H. Kishino, T. Miki, M. Kohno,
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[1b]
We want to correct the optical rotation of syn-1
+35.0 (c = 1.0, CHCl3).
to [α]2D2
=
Received: August 27, 2007
Published Online: November 23, 2007
474
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 467–474