Acid promoted syntheses of new enantiopure amino sugar derivatives from 3,6-dihydro-2H-1,2-oxazines

Article abstract of DOI:10.1055/s-2002-25361

The acid promoted rearrangement of syn-1 with HCl led to bicyclic acetal 2 from which enantiopure furan derivative 4 was obtained by hydrogenolysis. The same sequence was applied to anti-1 leading to bicyclus 3 and diastereomeric tetrahydrofuran 5. Treatm

Full text of DOI:10.1055/s-2002-25361

LETTER
817
Acid Promoted Syntheses of New Enantiopure Amino Sugar Derivatives from
3,6-Dihydro-2H-1,2-oxazines
A
cid Promote
d
S
o
yntheses of
A
b
mino Sugar
e
D
erivative
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s
t Pulz, Ahmed Al-Harrasi, Hans-Ulrich Reissig*
Institut für Chemie - Organische Chemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 22 February 2002
Abstract: The acid promoted rearrangement of syn-1 with HCl led
to bicyclic acetal 2 from which enantiopure furan derivative 4 was
obtained by hydrogenolysis. The same sequence was applied to
anti-1 leading to bicyclus 3 and diastereomeric tetrahydrofuran 5.
Treatment of syn-6 with pyridinium hydrogen fluoride provided
either semiacetal 7 or bicyclic acetal 8, depending on the ratio of HF
and pyridine. Lewis acid mediated intramolecular aldol reaction of
syn-6 afforded bicyclic 1,2-oxazine 9. Protection and subsequent
stereoselective reduction of 9 led to 10, which was hydrogenated to
yield enantiopure amino substituted pyran derivative 11.
Key words: 1,2-oxazines, reductions, furans, carbohydrates, aldol
reactions
We recently reported1 that the addition of lithiated
methoxyallene to D-glyceraldehyde derived nitrone2 and
subsequent cyclisation of the primary allene adduct fur-
Scheme 1
nish new enantiopure 3,6-dihydro-2H-1,2-oxazines 1 in
One valuable property of 1,2-oxazines is the smooth
high diastereoselectivity.3 The stereochemistry of this for-
mal [3+3] cyclization is controlled by the reaction condi-
tions: use of THF as solvent leads to syn-1,
precomplexation of the nitrone with Et2AlCl in diethyl
ether furnishes anti-1. We have also demonstrated that
enantiopure 3-methoxypyrrolidine derivatives are easily
available in a stereodivergent manner by hydrogenolysis
of 1,2-oxazines 1 followed by cyclisation of the inter-
mediate 1,4-amino alcohols.4 Herein, we wish to present
the acid catalysed reactions of these highly functionalised
C6 building blocks syn-1 and anti-1 which afford novel
enantiopure amino sugar derivatives.
cleavage of the relatively weak N-O bond leading to inter-
esting cyclic and acyclic amino alcohols.4 Thus, the hy-
drogenation of 2 using palladium on charcoal as catalyst
produced highly functionalised tetrahydrofuran 4 in quan-
titative yield.5 Similar treatment of 3 with hydrogen pro-
vided the expected enantiopure tetrahydrofuran derivative
5.7 Furan derivatives 4 and 5 correspond to diastereomeric
acyclic 4-amino 3-keto-hexoses (Scheme 2).
Treatment of syn-1 with 0.5 equivalents of p-toluenesulfo-
nyl chloride in methanol led to bicyclic compound 2.5 Un-
der HCl catalysis, the dioxolane ring is cleaved and the
primary hydroxyl group attacks the enol ether moiety to
form acetal 2 as a single diastereomer. Reaction of anti-1
under the same conditions provided diastereomeric bicy-
clic 1,2-oxazine 3 in good yield (Scheme 1). In both cases
the cis fusion of the two rings was proved by NOESY ex-
periments. For this reaction the use of p-toluenesulfonyl
chloride is advisable since treatment of syn-1 with p-tolu-
enesulfonic acid in acetone provided a rather complex
mixture of two diastereomers of semiacetal 7 (see below)
and other products.6
Scheme 2
Bicyclic compounds can also be prepared starting from
(trimethylsilyl)ethoxy (TMSE) substituted 2H-1,2-ox-
azine syn-6. Stereoselective synthesis of syn-6 was
smoothly achieved in 76% yield by addition of lithiated
(trimethylsilyl)ethoxyallene8 to the D-glyceraldehyde de-
rived nitrone using our standard procedure.1,9 Treatment
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0817,0819,ftx,en;G05202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

818
R. Pulz et al.
LETTER
of syn-6 with pyridinium hydrogen fluoride (30% pyri-
dine, 70% HF) in dichloromethane led to semiacetal 7 as
a single isomer. Using the same reagent and adding an ex-
cess of pyridine (85% pyridine, 15% HF) to reduce the
acidity of the solution afforded bicyclic acetal 8 in similar
yield (Scheme 3). The mechanism of this reaction is not
exactly known, however, it is well known that HF·py
cleaves silyl ethers10 as well as the dioxolane group.11
Thus, acetal 8 is likely to be an intermediate during the
formation of 7.
Scheme 4
versatility of these allenes as valuable C3 building blocks
in stereoselective organic synthesis.14
Acknowledgement
Generous support of this work by the Deutsche Forschungsgemein-
schaft, Fonds der Chemischen Industrie and Schering AG is most
gratefully appreciated. We thank Sultan Qaboos University (Oman)
for financial support of master studies of A.-H.
Scheme 3
Interestingly, the reaction of syn-6 with boron trifluoride
etherate led to a novel bicyclic compound 9 where the 1,2-
oxazine ring is bridged by a newly formed pyran ring
(Scheme 4). This reaction can be understood as an aldol
type reaction between the dioxolane acetal and the enol
ether.12 Related intramolecular reactions between enol
ethers and acetals are described in literature.13 BF3 proba-
bly coordinates to the less hindered oxygen of the diox-
olane group and provides an intermediate carbenium ion
which attacks the enol ether double bond to form 9 as sin-
gle diastereomer. However, there must also be a crucial
influence of the TMSE group because the treatment of
syn-1 with BF3 OEt2 under identical conditions afforded
only acetal 2 in low yields. Subsequent protection of the
primary hydroxy group of 9 with TBSOTf followed by
stereoselective reduction of the carbonyl group with sodi-
um borohydride led to bicyclic alcohol 10, whose struc-
ture was proved by NOE experiments. Debenzylation and
N–O bond cleavage with hydrogen in the presence of pal-
ladium on charcoal produced pyran derivative 11. This se-
quence opens a new entry to unnatural and highly
functionalised amino sugar derivatives.
References
(1) Schade, W.; Reissig, H.-U. Synlett 1999, 632.
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2000, 983; and references cited herein.
(5) Typical procedure, syn-1 to 2: To a stirred solution of p-
TsCl (0.156 g, 0.819 mmol) in dry methanol (10 mL) at r.t.
a solution of syn-1 (0.500 g, 1.64 mmol) in dry methanol (10
mL) was added. The mixture was stirred for 24 h at r.t., then
sat. NaHCO3 solution (20 mL) was added. The aqueous layer
was extracted with dichloromethane (3 20 mL) and the
combined extracts were dried with MgSO4. Removal of the
solvent in vacuo yielded crude 2 which was purified by
column chromatography (silica gel, n-hexane–ethyl acetate,
3:2). Compound 2 was obtained as colourless crystals (0.400
g, 92%).
Analytical data of (4aS,7S,7aS)-1-benzyl-4 -methoxyhexa-
hydro-1H-furo[3,2-c][1,2]oxazin-7-ol(2): 1H NMR (CDCl3,
500 MHz): = 7.41–7.25 (m, 5 H, Ph), 4.42 (dd, J = 5.6,
9.8 Hz, 1 H, 6-HA), 4.18, 3.80 (2 d, J = 15.2 Hz, each 1 H,
CH2Ph), 4.05 (ddbr, J 5.4, 11.7 Hz, 1 H, 7-H), 3.91 (dd,
J = 1.5, 9.8 Hz, 1 H, 6-HB), 3.88 (ddbr, J 6.3, 11.9 Hz, 1 H,
3-HA), 3.80 (dt, J = 2.7, 11.9 Hz, 1 H, 3-HB), 3.44 (d, J = 11.7
Hz, 1 H, OH), 3.33 (s, 3 H, OMe), 3.13 (s, 1 H, 7a-H), 2.12
(dbr, J 12.7 Hz, 1 H, 4-HA), 1.86 (dt, J = 6.3, 12.7 Hz,
In summary, we have shown a new short route to highly
functionalised enantiopure amino sugar derivatives, like
furan derivatives 4 and 5 and pyran 11. They are all acces-
sible in a few straightforward steps from 1,2-oxazines 1
and 6. As these 1,2-oxazines are easy prepared from chiral
nitrones and alkoxyallenes, this again demonstrates the
Synlett 2002, No. 5, 817–819 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
1 H, 4-HB). 13C NMR (CDCl3, 125 MHz): = 138.2, 128.3,
Acid Promoted Syntheses of Amino Sugar Derivatives
819
HRMS: calcd. for C7H14NO3 (M+ – OH) 160.09737, found
160.09666.
(6) Schade, W. Dissertation; Technische Universität Dresden:
Germany, 1999.
(7) Compound 5 was isolated as a mixture containing 14% of a
so far unknown side product.
(8) Hoffmann, R. W.; Kemper, B.; Metternich, R.; Lehmeier, T.
Liebigs Ann. Chem. 1985, 2246.
127.8, 127.1 (s, 3 d, Ph), 105.8 (s, C-4a), 76.3 (d, C-7a), 76.2
(t, C-6), 74.6 (d, C-7), 65.8 (t, C-3), 59.7 (t, CH2Ph), 47.8
(q, OMe), 30.4 (t, C-4). Mp = 27–29 °C. [ ]D20 = +100.6
(c = 1.7, CHCl3). IR (CCl4): = 3480 cm–1 (OH), 2940–2890
(C-H). C14H19NO4 (265.3) Calcd. C 63.38, H 7.22, N 5.28;
found C 63.33, H 7.18, N 5.18.
2 to 4: A stirred suspension of Pd(10%)/C (0.175 g, 0.164
mmol) in dry methanol (8 mL) was saturated with hydrogen
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 atmosphere at normal pressure for 8 h at r.t.
Filtration through a pad of celite and removal of the solvent
in vacuo provided 4 (0.077 g, quant.) as colourless oil.
Analytical data of (2S,3S,4R)-3-amino-4-hydroxy-2-(2 -
hydroxy-1 -ethyl)-2-methoxytetrahydrofuran(4): 1H NMR
(CD3OD, 500 MHz): = 4.30 (ddd, J = 0.5, 6.8, 9.5 Hz, 1 H,
5-HA), 4.13 (ddd, J = 1.7, 4.6, 6.8 Hz, 1 H, 4-H), 3.68–3.60
(m, 2 H, 2 -H), 3.58 (dd, J = 4.6, 9.5 Hz, 1 H, 5-HB), 3.22 (dbr,
J = 1.7 Hz, 1 H, 3-H), 3.19 (s, 3 H, OMe), 2.12 (td, J = 4.4,
15.4 Hz, 1 H, 1 -HA), 1.91 (ddd, J = 6.2, 8.7, 15.4 Hz, 1 H,
1 -HB). 13C NMR (CD3OD, 125 MHz): = 111.0 (s, C-2),
78.7 (d, C-4), 73.6 (t, C-5), 66.1 (d, C-3), 58.0 (t, C-2 ), 48.0
(q, OMe), 32.3 (t, C-1 ).- [ ]D20 = +52.3 (c = 0.41, CHCl3).
IR (Film): = 3350 cm–1 (NH, OH), 2950–2835 (C-H). MS
(pos. FAB): m/z (%) = 178 (M+ + H, 37), 160 (M+ – OH, 32),
146 (M+ – OMe, 100), 128 (M+ – OH – OMe, 47), 77 (50).
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Germany, 2002.
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Amombo, M.; Watanabe, T.; Pulz, R.; Hausherr, A.;
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Synlett 2002, No. 5, 817–819 ISSN 0936-5214 © Thieme Stuttgart · New York