Acid-mediated transformations of enantiopure 3,6-dihydro-2H-1,2-oxazines into functionalised aminotetrahydrofuran derivatives

Article abstract of DOI:10.1055/s-0029-1218532

Two new routes to substituted aminotetrahydrofuran derivatives have been investigated. Treatment of 3,6-dihydro-2H-1,2oxazines with hydrochloric acid in the presence of zinc provided 4benzylamino-5-hydroxy furanose derivatives which contain a quaternary anomeric centre with a vinyl unit. Upon mesylation and subsequent heating in aqueous media 5-hydroxy-3,4,5,6-tetrahydro1,2-oxazines were converted into novel tricyclic 1,2-oxazines with complete regio- and stereoselectivity. Cleavage of the N-O bond and subsequent debenzylation furnished enantiopure polyhydroxylated aminotetrahydrofuran derivatives which are promising ligands for selectin inhibition studies. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218532

LETTER
47
Acid-Mediated Transformations of Enantiopure 3,6-Dihydro-2H-1,2-oxazines
into Functionalised Aminotetrahydrofuran Derivatives
Two New
Routes
to
Enan
e
tiopure
A
m
k
inotetrahydr
o
ofurans slav Dekaris, Bettina Bressel, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 24 September 2009
Table 1 Acid-Mediated Transformation of 3,5-Dihydro-2H-1,2-ox-
azines 1 into Aminofuran Derivatives 2a
Abstract: Two new routes to substituted aminotetrahydrofuran de-
rivatives have been investigated. Treatment of 3,6-dihydro-2H-1,2-
oxazines with hydrochloric acid in the presence of zinc provided 4-
benzylamino-5-hydroxy furanose derivatives which contain a qua-
ternary anomeric centre with a vinyl unit. Upon mesylation and sub-
sequent heating in aqueous media 5-hydroxy-3,4,5,6-tetrahydro-
1,2-oxazines were converted into novel bicyclic 1,2-oxazines with
complete regio- and stereoselectivity. Cleavage of the N–O bond
and subsequent debenzylation furnished enantiopure polyhydroxy-
lated aminotetrahydrofuran derivatives which are promising ligands
for selectin inhibition studies.
OMe
O
MeO
O
O
a or b
NBn
BnHN
OH
O
1
2
1,2-Oxazine
Conditions Product
Yield (%)
55
MeO
Key words: 1,2-oxazine, furan, amine, reduction, zinc, amino sugar
OMe
O
O
O
O
O
a
NBn
BnHN
OH
Over the past years we could demonstrate the surprisingly
diverse synthetic versatility of lithiated alkoxyallenes.
The stereoselective addition of these C3-intermediates to
various electrophiles1 allowed valuable transformations
and it enabled the construction of numerous heterocyclic
frameworks.2 Among the target compounds, furan deriva-
tives played an important role in our research. Two major
pathways led to the desired compounds, either by metal-
catalysed cyclisation of allenyl alcohols to dihydrofurans3
or by acid-induced transformations of 3,6-dihydro-2H-
1,2-oxazines 1 to furans and furanosides.4 In this letter we
are presenting two new methods for the stereoselective
preparation of substituted aminofuran derivatives includ-
ing useful subsequent modifications of the initially
formed cyclisation products, which nicely supplement
earlier results. Precursors for both newly introduced acid-
catalysed transformations are 3,6-dihydro-2H-1,2-ox-
azines 1 which are easily accessible by addition of lithiat-
ed alkoxyallenes to nitrones in stereocontrolled fashion.5
O
2
syn-1
MeO
OMe
O
b
43
NBn
BnHN
OH
O
ent-2
ent-syn-1
a Reagents and conditions: (a) 3 N HCl (5 equiv), Zn (20 equiv),
MeOH, r.t., 1 d; (b) 3 N HCl (5 equiv), Zn (20 equiv), MeOH, r.t., 6 h.
With respect to the possible reaction mechanism we sug-
gest an initial reductive N–O bond and an acid-promoted
ketal cleavage to form acyclic allylic alcohol A
(Scheme 1). Under the acidic conditions a fairly stabilised
allylic cation B is readily generated, which is then trapped
intramolecularly by the primary hydroxy group forming
the kinetically and thermodynamically preferred five-
membered ring in a stereoselective fashion. Loss of a pro-
ton completes the reaction leading to 2. The relative con-
figuration at the anomeric centre could not be proved
rigorously so far. We tried an iodocyclization with ent-2,
but unfortunately neither a cyclisation involving the ami-
no group nor the hydroxy group took place. The NOESY
spectrum of ent-2 shows correlation peaks between both
benzylic protons and one of the terminal vinylic protons,
which indicates that the given assignment is more likely
and in agreement with that of previously reported amino-
furan derivatives.4
The first conversion is directly performed with 1 using hy-
drochloric acid and zinc (Table 1).6,7 Treatment of syn-1
for one day under these conditions afforded vinyl-substi-
tuted aminofuranoside 2 with 55% yield, whereas ent-2
was isolated in 43% yield after six hours reaction time
starting from ent-syn-1. We applied these conditions also
to anti-1 (the C-3 epimer of syn-1), but the respective ami-
nofuran derivative was not observed. The only product
isolated in little amounts was a methyl furanoside with an
intact 1,2-oxazine ring whose formation was already de-
scribed by our group.4
Since the vinyl group of ent-2 is an attractive feature for
subsequent transformations we performed a few prelimi-
nary experiments. First choices were olefin metathesis
and dihydroxylation. In order to prevent side reactions
ent-2 was first diacetylated with acetic anhydride in the
SYNLETT 2010, No. 1, pp 0047–0050
x
x.
x
x.
2
0
1
0
Advanced online publication: 02.12.2009
DOI: 10.1055/s-0029-1218532; Art ID: G33109ST
© Georg Thieme Verlag Stuttgart · New York

48
V. Dekaris et al.
LETTER
pounds in an acetonitrile–water mixture at 90–100 °C for
one day. This protocol resulted in regio- and stereoselec-
tive formation of the novel bicyclic 1,2-oxazine deriva-
tives 6a–c in good yields (Scheme 3).10 In the case of the
TMSE-protected precursor cleavage of this group could
not be avoided and in addition to 36% of 6c 31% of 6d
were isolated.
OMe
O
O
MeO
OH
OH
HCl, Zn
NBn
N-O and
ketal cleavage
NHBn
O
HO
syn-1
A
– H2O
MeO
H
MeO
OR
OH
O
OR
O
O
OH
O
O
HO
OH
a, b
– H
BnHN
OH
NBn
NBn
NHBn
O
2
B
6a R = Me 73%
6b R = Bn 67%
6c R = TMSE 36%
6d R = H 31%
5
Scheme 1 Proposed mechanism for transformation of syn-1 to ge-
nerate aminofuran derivative 2
SiMe3
TMSE =
Scheme 3 Acid-mediated transformation of 5-hydroxy-3,4,5,6-tetra-
hydro-1,2-oxazines 5a–c into bicyclic compounds 6. Reagents and
conditions: (a) MsCl, pyridine, r.t., 1 d; (b) MeCN–H2O (1:1 or 3:1),
90–100 °C, 1 d.
presence of triethylamine and DMAP to yield compound
3 in 60% (Scheme 2). With respect to olefin metathesis
we tried homodimerisation as well as cross metathesis but
did not succeed in any case. Fortunately, dihydroxylation
was possible although a rather long reaction time was re-
quired. In the presence of potassium osmate, NMO, and
methanesulfonamide compound 3 was stereoselectively
converted into the respective dihydroxylated product 4
within 19 days at room temperature in 50% yield
(Scheme 2).8 The configuration at the newly formed ste-
reogenic centre is unknown and currently under investiga-
tion. The low reactivity of the vinyl group might be due to
the steric hindrance exhibited by the highly substituted fu-
ran ring. Amino ketose derivatives such as 4 are thus
available (in both enantiomeric forms) after three simple
steps.
A plausible mechanism for the furan ring formation is pre-
sented in Scheme 4. Mesylate C suffers ketal cleavage
when exposed to acetonitrile–water at higher temperature
furnishing diol D. A subsequent intramolecular nucleo-
philic displacement of the mesylate generates bicyclic
1,2-oxazine derivative 6. At least traces of acid are re-
quired for the initial ketal cleavage. If the crude mesyla-
tion products were used remaining pyridinium salts may
act as proton source. In case of purified mesylate C as
starting material, protons are probably generated by par-
tial hydrolysis of the mesylate in the aqueous environ-
ment.
MeO
MeO
O
O
a
OR
OR
O
O
O
O
HO
MsO
60%
MsCl
BnHN
OH
BnNAc
50%
OAc
NBn
NBn
ent-2
3
O
O
5
C
b
CH2OH
OH
H2O, (H
)
O
HO
OMe
O
NH2
HO
HO
OR
O
OH
OR OH
O
CH2OH
BnNAc
OAc
MsO
OH
4
4-amino-4-deoxy-L-threo-hex-3-ulose
NBn
NBn
O
Scheme 2 Acetylation of ent-2 and subsequent dihydroxylation of
3 leading to aminofuran derivative 4. Reagents and conditions: (a)
Ac2O, Et3N, DMAP, CH2Cl2, r.t., 1 d; (b) K2OsO4·H2O, NMO, meth-
anesulfonamide, t-BuOH–H2O (1:1), r.t., 19 d.
6
D
Scheme 4 Mechanism for transformation of 1,2-oxazine derivatives
5 into bicyclic compounds 6
The second acid-mediated transformation starts from 5-
hydroxy-1,2-oxazine derivatives which can routinely be
synthesised by hydroboration of 3,6-dihydro-2H-1,2-ox-
azines 1 and subsequent oxidative workup.9 Three differ-
ently protected 1,2-oxazines 5a–c were first mesylated
within one day at room temperature, and the resulting
products were heated either as crude or as purified com-
The observed stereoselectivity is a result of an SN2-type
process for the ring closure. To prove this assumption, we
conducted the reaction sequence also with the C-5 epimer
of 5b. In this case no cyclisation product was observed,
but a triol resulting from simple hydrolysis of the mesy-
late and ketal moieties. Thus involvement of an SN1-type
reaction via a carbenium ion is fairly unlikely. Regiose-
Synlett 2010, No. 1, 47–50 © Thieme Stuttgart · New York

LETTER
Two New Routes to Enantiopure Aminotetrahydrofurans
49
lective formation of a furan ring instead of the respective
pyran system is apparently strongly favoured. The consti-
tution of compounds 6 was proven by its 1H NMR spectra
in CD3CN, which showed a triplet for the hydroxy group
proton.
References and Notes
(1) For reviews, see: (a) Zimmer, R. Synthesis 1993, 165.
(b) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry;
Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
2004, 425.
(2) For reviews, see: (a) Reissig, H.-U.; Hormuth, S.; Schade,
W.; Okala Amombo, M.; Watanabe, T.; Pulz, R.; Hausherr,
A.; Zimmer, R. J. Heterocycl. Chem. 2000, 37, 597.
(b) Reissig, H.-U.; Schade, W.; Okala Amombo, M. G.;
Pulz, R.; Hausherr, A. Pure Appl. Chem. 2002, 74, 175.
(c) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem.
Res. 2009, 42, 45.
(3) (a) Flögel, O.; Reissig, H.-U. Eur. J. Org. Chem. 2004,
2797. (b) Chowdhury, M. A.; Reissig, H.-U. Synlett 2006,
2383. (c) Brasholz, M.; Reissig, H.-U. Synlett 2007, 1294.
(d) Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007,
46, 1634; Angew. Chem. 2007, 119, 1659. (e) Brasholz, M.;
Reissig, H.-U. Eur. J. Org. Chem. 2009, 3595.
(4) (a) Pfrengle, F.; Al-Harrasi, A.; Reissig, H.-U. Synlett 2006,
3498. (b) Bressel, B.; Egart, B.; Al-Harrasi, A.; Pulz, R.;
Reissig, H.-U.; Brüdgam, I. Eur. J. Org. Chem. 2008, 467.
(c) Pfrengle, F.; Al-Harrasi, A.; Brüdgam, I.; Reissig, H.-U.
Eur. J. Org. Chem. 2009, 282.
(5) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632.
(b) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-
Harrasi, A.; Fišera, L.; Hlobilová, I.; Zahn, G.; Reissig,
H.-U. Eur. J. Org. Chem. 2005, 1003.
An attractive feature in 1,2-oxazine derivatives is general-
ly the relatively weak N–O bond which can be cleaved un-
der mild conditions furnishing amino alcohols. We tried
this transformation also with the new bicyclic compounds
6a–b. Since the standard protocol employing samarium
diiodide for reductive ring opening9 did not lead to full
conversion, we again switched to the combination of hy-
drochloric acid and zinc in methanol which proved to be
more reliable for this compound class (Scheme 5). Final-
ly, removal of the benzyl groups was achieved by catalytic
hydrogenolysis giving polyhydroxylated amino tetrahy-
drofurans 7a and 7b in moderate overall yields. The NMR
data of these products clearly indicate that they contain a
furan core rather than a pyran ring, which further proves
the regioselective formation of a five-membered hetero-
cycle during the cyclisation described in Schemes 3 and 4.
Compounds 7a and 7b are promising components for the
preparation of gold-nanoparticle-based multivalent selec-
tin inhibitors.11,12
(6) Kumaran, S.; Shaw, D. M.; Ley, S. V. Chem. Commun.
2006, 3211.
(7) Typical Procedure for Furan Synthesis, Conversion of
ent-syn-1 into ent-2
OR1
OH
O
O
a, b
HO
OH
1,2-Oxazine ent-syn-1 (200 mg, 0.655 mmol) was dissolved
in MeOH (13 mL). Then Zn dust (214 mg, 3.27 mmol) and
3 N HCl (4.36 mL, 13.1 mmol) were added. The mixture was
stirred for 6 h at r.t. Upon completion of the reaction the
mixture was neutralised with solid NaHCO3, H2O was added
and extracted three times with EtOAc. The combined
organic layers were dried with MgSO4 and filtrated, and
solvents were removed in vacuo. Purification via silica gel
column chromatography (hexane–EtOAc) afforded ent-2
(70 mg, 43%) as a colourless oil.
NBn
R2O
NH2
O
6a R1 = Me
6b R1 = Bn
7a R2 = Me 56%
7b R2 = H 47%
(over 2 steps)
Scheme 5 N–O bond cleavage and deprotection of 6a,b leading to
amino furan derivatives 7. Reagents and conditions: (a) 3 N HCl, Zn,
MeOH, r.t., 1.5 h; (b) H2, Pd/C, MeOH, r.t., 1 d.
Analytical Data of Methyl-4-benzylamino-1,2,4-
trideoxy-a-L-threo-hex-1-en-3-ulofuranoside (ent-2)
[a]D20 +64.3 (c 0.80, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 2.84 (sbr, 2 H, NH, OH), 2.93 (d, J = 6.7 Hz, 1 H, 4-H),
3.20 (s, 3 H, OMe), 3.68 (dd, J = 5.3, 9.3 Hz, 1 H, 6-H), 3.74,
3.97 (2 d, J = 12.9 Hz, 2 H, NCH2), 4.01 (dd, J = 7.1, 9.3 Hz,
1 H, 6-H), 4.17 (ddd, J = 5.3, 6.7, 7.1 Hz, 1 H, 5-H), 5.32
(dd, J = 1.6, 10.8 Hz, 1 H, 1-H), 5.55 (dd, J = 1.6, 17.4 Hz,
1 H, 1-H), 5.87 (dd, J = 10.8, 17.4 Hz, 1 H, 2-H), 7.23–7.26,
7.30–7.34 (2 m, 5 H, Ph) ppm. 13C NMR (126 MHz, CDCl3):
d = 49.3 (q, OMe), 52.2 (t, NCH2), 70.8 (t, C-6), 73.9 (d,
C-4), 76.5 (d, C-5), 105.0 (s, C-3), 118.2 (t, C-1), 127.1,
128.2, 128.4, 139.9 (3 d, s, Ph) 136.2 (d, C-2) ppm. IR (film):
3410, 3330 (OH, NH), 3090–3030 (=CH), 2990–2830 (CH),
1605, 1585, 1495 (C=C) cm–1. HRMS (ESI-TOF-MS): m/z
calcd for C14H19NO3 [M + H]+: 250.1438; found: 250.1443.
Anal. Calcd for C14H19NO3 (249.3): C, 67.45; H, 7.68; N,
5.62. Found: C, 67.01; H, 7.66; N, 5.53.
In conclusion, we found two new methods for acid-pro-
moted transformations of 1,2-oxazine derivatives into
new highly functionalised aminotetrahydrofuran deriva-
tives. The first reaction provided vinyl-substituted com-
pounds which can be used for further functionalisations
whereas the second protocol involved 5-mesyloxy-substi-
tuted 3,4,5,6-tetrahydro-1,2-oxazines which were regio-
and stereoselectively transformed into novel bicyclic 1,2-
oxazine derivatives. Reductive cleavage of the N–O bond
and debenzylation furnished hydroxylated amino furans.
All resulting products should be of interest as new unusual
amino sugar derivatives.
Acknowledgment
(8) Product 4 contained small amounts (ca. 5%) of one
byproduct, possibly the second epimer with respect to the
newly formed stereogenic centre.
(9) (a) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002,
4, 2353. (b) Dekaris, V.; Reissig, H.-U. Synlett 2010, 42.
The authors thank the Deutsche Forschungsgemeinschaft (RE 514/
11 and SFB 765), the Fonds der Chemischen Industrie, and the
Bayer Schering Pharma AG for financial support. We gratefully
acknowledge the experimental assistance of Sebastian Fischer and
the help of Dr. R. Zimmer during preparation of this manuscript.
Synlett 2010, No. 1, 47–50 © Thieme Stuttgart · New York

50
V. Dekaris et al.
LETTER
(10) Typical Procedure for the Synthesis of Bicyclic 1,2-
Oxazines, Conversion of 5a into 6a
1¢-H), AB system (dA = 4.03, dB = 4.10, J = 13.9 Hz, 2 H,
NCH2), 4.10–4.14 (m, 1 H, 7-H), 4.26 (dd, J = 0.8, 4.1 Hz, 1
H, 5-H), 7.24–7.28, 7.31–7.36 (2 m, 5 H, Ph) ppm. 13C NMR
(126 MHz, CD3CN): d = 55.8 (q, OMe), 58.5 (t, NCH2), 61.7
(t, C-1¢), 65.6 (d, C-1), 69.6 (t, C-4), 76.3 (d, C-5), 81.0 (d,
C-8), 81.6 (d, C-7), 128.1, 129.2, 129.6, 139.3 (3d, s, Ph)
ppm. IR (film): 3420 (OH), 3085–3030 (=CH), 2930–2830
(CH) cm–1. MS (EI, 80 eV, 150 °C): m/z (%) = 265 (21)
[M+], 91 (100) [C7H7]+, 71 (29), 43 (28). Anal. Calcd for
C14H19NO4 (265.3): C, 63.38; H, 7.22; N, 5.28. Found: C,
62.90; H, 7.51; N, 5.27.
To a solution of 5a (734 mg, 2.27 mmol) in pyridine (10 mL)
under argon at r.t. MsCl (0.296 mL, 3.82 mmol) was added.
The mixture was stirred 1 d at r.t., quenched with 5% CuSO4
solution (4 mL), and extracted three times with Et2O. The
combined organic layers were washed twice with H2O and
dried with MgSO4. After filtration and removal of the
solvents the crude product was dissolved in MeCN (2.5 mL),
H2O (2.5 mL) was added, the mixture was placed in a sealed
tube and heated 1 d at 100 °C. After completion of the
reaction the mixture was extracted with Et2O (3 × 5 mL), the
combined organic layers were dried with MgSO4, filtrated,
and the solvents removed in vacuo. Purification via silica gel
column chromatography (hexane–EtOAc) afforded bicyclic
compound 6a (440 mg, 73% over both steps) as a colourless
oil.
(11) For the examination of another carbohydrate mimetic as
component of gold-nanoparticle-based multivalent selectin
inhibitors, see: Dernedde, J.; Enders, S.; Reissig, H.-U.;
Roskamp, M.; Schlecht, S.; Yekta, S. Chem. Commun. 2009,
932.
(12) Gold nanoparticles with sulfated aminotetrahydrofuran
derivative 7a were tested in a similar way as described in
ref. 11. Excellent activity and selectivity were observed with
IC50 values of 390 pm for L-selectin and 50 pm for
P-selectin. Dekaris, V.; Dernedde, J.; Enders, S.; Reissig,
H.-U.; Roskamp, M.; Schlecht, unpublished results.
Analytical Data of (1S,5S,7S,8R)-(2-Benzyl-8-methoxy-
3,6-dioxa-2-azabicyclo[3.2.1]oct-7-yl)methanol (6a)
[a]D20 +23.4 (c 0.71, CHCl3). 1H NMR (500 MHz, CD3CN):
d = 2.84 (t, J = 5.8 Hz, 1 H, OH), 3.33 (s, 3 H, OMe), 3.51
(mc, 1 H, 1-H), 3.55 (ddd, J = 0.8, 4.1, 11.4 Hz, 1 H, 4-HA),
3.56 (d, J = 11.4 Hz, 1 H, 4-HB), 3.98–4.02 (m, 3 H, 8-H,
Synlett 2010, No. 1, 47–50 © Thieme Stuttgart · New York

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