Stereoselective cycloaddition on carbohydrates for the synthesis of new bicyclic oxazolidines bearing a quaternary bridgehead

Article abstract of DOI:10.1055/s-2005-869836

A new carbohydrate nitrone intramolecular cycloaddition reaction is described for the enantioselective synthesis of bicyclic oxazolidines. By choice of the precursor, the products possess a chiral quaternary bridgehead aryl substitution. Also described is the diverse synthesis of 6-keto and 6-alkenyl carbohydrates by a general approach. The overall protocol provides versatility through the possibility of introducing diverse reagents at several entry points. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869836

LETTER
1425
Stereoselective Cycloaddition on Carbohydrates for the Synthesis of New
Bicyclic Oxazolidines Bearing a Quaternary Bridgehead
Stereoselective
Cy
e
cloaddition
o
on
C
arbohyd
r
rates ge Bashiardes,* Céline Cano, Bernard Mauzé
Département de Chimie, Equipe Methodologie et Synthèse de Biomolécules, SFA – CNRS UMR 6514, Université de Poitiers, 40 Avenue
du Recteur Pineau, 86022 Poitiers, France
Fax +33(5)49454588; E-mail: george.bashiardes@univ-poitiers.fr
Received 22 December 2004
accommodated by the choice of the starting materials em-
Abstract: A new carbohydrate nitrone intramolecular cycloaddi-
ployed. It is thus possible to introduce diversity in a com-
binatorial manner in any of at least three entry points into
the reaction sequence. Moreover, the specific chirality of
tion reaction is described for the enantioselective synthesis of bicy-
clic oxazolidines. By choice of the precursor, the products possess
a chiral quaternary bridgehead aryl substitution. Also described is
the diverse synthesis of 6-keto and 6-alkenyl carbohydrates by a the starting carbohydrate should induce enantioselectivity
general approach. The overall protocol provides versatility through
to the cycloaddition reaction. Naturally, the original chiral
the possibility of introducing diverse reagents at several entry
centers of the carbohydrate are conserved.
points.
Key words: carbohydrates, cycloaddition, nitrone, oxazolidine,
quaternary
1,2-Oxazolidine compounds have often been used in the
synthesis of natural products such as shikimic acid,1
deoxynojiromycin2 or other products with potential bio-
logical activity.3 One of the major types of target com-
pounds prepared employing this reaction are b-amino
hydroxyl carbocycles, derived from the reductive or alky-
lating cleavage1,4 of the N–O bond. The cycloaddition of
nitrones is a powerful method for the construction of ox-
azolidines and has been employed on numerous occasions
spanning over several decades (Scheme 1).5
Scheme 2 Protocol for choice of substitution
Scheme 1 Nitrone cycloaddition
In order to achieve this goal of a general method, we rea-
soned that a key intermediate, accessible in a few straight-
forward steps by known procedures from readily available
precursors would be essential. As such, we developed our
We required a general method for the synthesis of bicyclic
heterocyclic compounds 1 containing either a bridgehead
substituent or a proton. In addition, the products, whether
approach starting from the carbohydrate chiral pool. In-
substituted or not, should be formed in a stereoselective
deed the chemistry of functional group modifications on
manner. In the present article we describe the use of a car-
sugars is one of the richest,6 including selective protec-
bohydrate intramolecular variant of the nitrone cycloaddi-
tions/deprotections, deoxygenations, oxidations, to men-
tion. By this protocol, the nitrone dipole and a non-
tion but a few. If required, numerous new derivatives with
activated alkene dipolarophile are introduced into carbo-
functional modifications would be accessible by any of
hydrates 2 in a few steps (Scheme 2).
these methods.
The nitrone is generated from the masked anomeric alde-
According to the retrosynthetic sequence described above
hyde function. The method was developed in such a
(Scheme 2), it is possible firstly to oxidize the primary al-
manner that the required substitution pattern can be
cohol function of a chosen carbohydrate to a 6-carbalde-
hyde sugar 3a and then create the monosubstituted alkene
SYNLETT 2005, No. 9, pp 1425–1428
Advanced online publication: 10.05.2005
DOI: 10.1055/s-2005-869836; Art ID: D39204ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
5
2 (H), which leads, in turn, to simple bicyclic compounds
1 (H) unsubstituted at the bridgehead. Alternatively, it is
possible to introduce any type of aryl or alkyl substituent

1426
G. Bashiardes et al.
LETTER
by sequential carbanion addition/oxidation. The resulting cursor (10) was treated in refluxing aqueous ethanol with
ketone 3b can then be transformed to alkene 2 (R) then to N-alkylhydroxylamines of varying substitution14 (benzyl,
the required bicyclic oxazolidine 1 (R) bearing a chiral methyl and isopropyl). For ease of purification, the crude
quaternary bridgehead substituent. It is worth noting that mixture was submitted to acetylation, and after purifi-
large diversity can be introduced at this stage of the cation, afforded diasteromerically and enantiomerically
synthesis by varying the carbanion species.
pure tetraacetyl bicyclic compounds 12a, 12b and 12c in
64%, 63% and 61% overall yields, respectively, from
10.15
Thus, suitably protected galactose was employed as a
model compound to apply the concept (Scheme 3). Swern
oxidation7 of 1,2:3,4-di-O-isopropylidengalactose (4)
furnished the aldehyde 5 which underwent addition with
phenylmagnesium bromide to the secondary alcohol 6.
The following oxidation step of 1,2:3,4-di-O-isopropyl-
iden-6-phenyl-a-D-galactopyranose 6 into ketone 7 was
attempted using manganese dioxide in dichloromethane,
at room temperature during 24 hours,8 but was unsuccess-
ful. Instead, chromium(VI) trioxide/pyridine9 in dichlo-
romethane was employed, and the desired ketone 7 was
obtained in a satisfactory yield of 78%. Next, the alkene
function was introduced by a Wittig reaction7,10 using
methyltriphenylphosphonium bromide and potassium
tert-butoxide. Since this reaction proceeded in only 35%
yield, we decided to perform a Peterson olefination,11
which successfully afforded the required alkene 9 in an
excellent overall yield of 94%. Finally, treatment of 6,7-
dideoxy-1,2:3,4-di-O-isopropylidene-6-phenyl-a-D-ga-
lactohept-6-enopyranose (9) in refluxing aqueous acetic
acid12 provided deprotected carbohydrate 10 in 68% yield.
Scheme 4 Intramolecular cycloaddition
The stereochemistry of the cycloadducts (3aS,4R,5S,6R,
7S,7aS)-1-alkyl-3a-phenyloctahydrobenzo[c]isoxazole-4,
5,6,7-tetraol tetraacetates (12a–c) was assigned by NMR
1
spectroscopic techniques. The observed H NMR cou-
pling constants (J7,7a) of 2.0 Hz, 0 Hz and 4.2 Hz, for prod-
ucts 12a, 12b and 12c, respectively, are consistent with an
equatorial/axial configuration. Since the chirality at C-4,
C-5, C-6 and C-7 was unchanged, we concluded that rel-
ative configuration between H-7 and H-7a was cis. As the
cyclic junction C-3a/C-7a is necessarily cis, the stereo-
chemistry of the new quaternary center was therefore
deduced. Indeed, in every case, intramolecular cycloaddi-
tion between the nitrone and the double bond proceeded
with high stereoselectivity to provide the (3aS)-diastereo-
isomer (Scheme 4). We suggest that the dipole approach-
es the alkene function from the face opposite to that of the
adjacent 5-hydroxyl group. In consequence, we speculate
that the opposite diastereoisomer at the quaternary center
would be obtained if a b-C-5 carbohydrate was employed.
As a further development of this method, we reasoned
that, since the dipolar reaction intermediates had a marked
dipole moment, activation by microwave irradiation
should be particularly useful to effect this cycloaddition
reaction. In general, microwaves can be advantageously
employed for carrying out the synthesis of numerous
types of compounds.16 We thus explored the present in-
tramolecular carbohydrate nitrone-alkene cycloaddition
reaction under microwave activation. The experimental
conditions employed were straightforward: the reagents
were mixed in a minimal amount of solvent to ensure thor-
ough contact in a test tube with a condenser and submitted
Scheme 3 Synthesis of 6,6-disubstituted carbohydrate alkene
The next step, which is also the key of our strategy, is the to microwave irradiation.17 After the condensation step
intramolecular nitrone-alkene cycloaddition reaction was concluded, the crude mixture was submitted to clas-
(Scheme 4). Being insoluble in the usual cycloaddition sical acetylation conditions, in order to facilitate the puri-
solvents such as toluene or xylene,13 the saccharide pre- fication and structural analysis of the cycloadducts 12a–c
Synlett 2005, No. 9, 1425–1428 © Thieme Stuttgart · New York

LETTER
Stereoselective Cycloaddition on Carbohydrates
1427
(Table 1). In all cases, the yields were in the 90% range,
approximately 30% higher than under classical thermal
conditions. Indeed, we also observed a clear advantage in
terms of reaction time (80 min vs. 48 h!).
Acknowledgment
We wish to thank the MENRT for a grant to CC, the CNRS, and G.
Anselme for some initial work.
References
Table 1 Cycloaddition under Thermal and Microwave (MW)
Conditions
(1) Jiang, S.; McCullogh, K. J.; Mkki, B.; Singh, G.; Wightman,
R. H. J. Chem. Soc., Perkin Trans. 1 1997, 1805.
(2) Rudge, A. J.; Collins, I.; Holmes, A. B.; Baker, R. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2320.
Entry Conditions15
Product
Yield
(%)
1
2
3
4
5
6
Thermal: refluxing EtOH,
48 h
64
63
61
87
90
91
(3) Panfil, I.; Chmielewski, M. Tetrahedron 1985, 41, 4713; and
references cited therein.
(4) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G. J. Chem.
Soc., Chem. Commun. 1989, 1280.
(5) For a comprehensive review, see: Gallos, J. K.; Koumbis, A.
E. Curr. Org. Chem. 2003, 7, 397.
(6) Example of monograph: Monosaccharides: Their Chemistry
and their Roles in Natural Products; Collins, P.; Ferrier, R.,
Eds.; John Wiley and Sons Ltd: Chichester, 1998.
(7) Lee, H. H.; Hodgson, P. G.; Bernacki, R. J.; Korytnyk, W.;
Sharma, M. Carbohydr. Res. 1998, 176, 59.
(8) (a) Hudlicky, J. M. In Oxidations in Organic Chemistry;
American Chemical Society Monograph: Washington D. C.,
1990, 33. (b) For an alternative method using the Dess–
Martin periodinane method: Liu, B.; Zhou, W. S.
12a
12b
12c
12a
12b
12c
Thermal: refluxing EtOH,
48 h
Thermal: refluxing EtOH,
48 h
Tetrahedron Lett. 2003, 44, 4933.
(9) Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 1970, 35, 4000.
(10) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(b) Fitjer, L.; Quabeck, U. Synth. Commun. 1985, 15, 855.
(c) Leeuwenburgh, M. A.; Overkleeft, H. S.; Van Der Marel,
G. A.; Van Boom, J. H. Synlett 1997, 1263.
MW: 100 W, 70 °C, 80 min
MW: 100 W, 70 °C, 80 min
MW: 100 W, 70 °C, 80 min
(11) Peterson, D. J. J. Org. Chem. 1968, 8, 780.
(12) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 2nd ed.; Greene, T. W.; Wuts, P. G. M.,
Eds.; Wiley Interscience: New York, 1991, 123–127.
(13) Examples: (a) Harwood, L. M.; Kitchen, L. C. Tetrahedron
Lett. 1993, 34, 6603. (b) Bashiardes, G.; Safir, I.; Barbot, F.;
Laduranty, J. Tetrahedron Lett. 2003, 44, 8417.
(14) It should be noted that this is a suitable entry point for
introducing diversity, since hydroxylamines of multiple
variation are very readily accessible.
(15) Typical Procedure for the Synthesis of (3aS,4R,5S,6R,7S,
7aS)-1-methyl-3a-phenyloctahydrobenzo[c]isoxazole-
4,5,6,7-tetraol Tetraacetate 12c.
Thermal conditions: in a two-necked, round-bottomed flask
equipped with a magnetic stirring bar, a reflux condenser
and a thermometer, NaHCO3 (218 mg, 2.6·10–3 mol, 2.6
equiv) was added to a solution of carbohydrate 10 (252 mg,
1.0·10–3 mol) and N-isopropylhydroxylamine hydrochloride
(290 mg, 2.6·10–3 mol, 2.6 equiv) in 80% aq EtOH (15 mL).
The mixture was stirred under reflux during 48 h. After
cooling and removal of the solvent under reduced pressure,
Ac2O (0.6 mL), pyridine (1 mL), DMAP (cat.), and CH2Cl2
were added. The mixture was stirred at r.t. during 6 h. The
mixture was then washed with 3 × 6 mL of H2O. The solvent
was removed under reduced pressure and the resulting oil
was purified by flash chromatography on silica gel (EtOAc–
CH2Cl2, 20:80, Rf = 0.36) to provide 12c in 61% yield as a
yellowish oil.
In conclusion, we have studied a new carbohydrate ni-
trone intramolecular cycloaddition, which represents a
new approach for the synthesis of chiral bicyclic oxazol-
idines. The reaction proceeded in a stereoselective
manner, providing new oxazolidines as single diastereo-
isomers. Moreover, the compounds possess a chiral qua-
ternary bridgehead aryl substitution. Also described is the
synthesis of 6-keto- and 6-alkenyl carbohydrates by a gen-
eral synthetic approach. This method is compatible with
numerous varieties of precursors (sugars, carbanions,
oximes), which can be introduced in the reaction sequence
at different entry points. This method is thus amenable to
the synthesis of new, diversely substituted compounds.
1H NMR (CDCl3): d = 2.16 (s, 12 H, CH3-CO-), 2.54 (s, 3 H,
H-8), 2.74 (dd, J7,7¢ = 13.9 Hz, J7-1 = 7.1 Hz, 1 H, H-7), 3.10
(d, J7¢,7 = 13.9 Hz, 1 H, H-7¢), 3.58–3.60 (m, 1 H, H-1), 5.00–
5.60 (m, 4 H, H-2, H-3, H-4, H-5), 7.23–7.39 (m, 5 H, H-10,
H-11, H-12, H-13, H-14) ppm.
13C NMR (CDCl3): d = 20.3, 20.8, 21.0, 21.1 (CH3-CO-),
33.8 (C-7), 47.0 (C-8), 63.1 (C-1), 71.3 (C-2), 71.4, 71.5,
Synlett 2005, No. 9, 1425–1428 © Thieme Stuttgart · New York

1428
G. Bashiardes et al.
LETTER
71.6 (C-3, C-4 et C-5), 86.5 (C-6), 126.5 (C-12), 127.6,
127.7 (C-11, C-13, C-10, C-14), 143.4 (C-9), 168.4, 169.2,
170.1, 170.5 (C=O) ppm.
IR: 3023 s (arom. =CH), 2966 m, 2930 w (CHn), 1742 s
(C=O), 1538 w, 1493 w, 1448 s (arom. C=C), 1372 s (C-N),
1217 s (C-O), 754 s, 703 s (arom. C-H) cm–1.
20), 135.8 (C-9), 142.1 (C-15), 168.4, 169.3, 169.7, 170.5
(C=O) ppm.
IR: 3020 m (arom. =CH), 2989 s, 2934 m (CHn), 1741 s
(C=O), 1497 m, 1450 m (arom. C=C), 1370 s (C-N), 1218 s
(C-O), 755 s, 701 s (arom. C-H) cm–1.
Compound 12b:
Compound 12a Major Conformer:
1H NMR (CDCl3): d = 2.16 (s, 12 H, CH3-CO-), 2.54 (s, 3 H,
H-8), 2.74 (dd, J3,3bis = 13.9 Hz, J3-7a = 7.1 Hz, 1 H, H-3),
3.10 (d, J3bis,3 = 13.9 Hz, 1 H, H-3bis), 3.58–3.60 (m, 1 H, H-
7a), 5.00–5.60 (m, 4 H, H-4, H-5, H-6, H-7), 7.23–7.39 (m,
5 H, H-10, H-11, H-12, H-13, H-14) ppm.
1H NMR (CDCl3): d = 1.99, 2.02, 2.04, 2.13 (4 s, 12 H, CH3),
2.27 (dd, J8,8bis = 13.0 Hz, J8,7a = 10.0 Hz, 1 H, H-8), 3.01 (d,
J8bis,8 = 13.0 Hz, 1 H, H-8bis), 3.60 (dd, J7a,8 = 10.0 Hz,
J7a,7 = 2.0 Hz, 1 H, H-7a), 4.18 (d, J3,3bis = 13.4 Hz, 1 H, H-
3), 4.21 (d, J3bis,3 = 13.4 Hz, 1 H, H-3bis), 5.11 (dd, J7,6 = 8.8
Hz, J7,7a = 2.0 Hz, 1 H, H-7), 5.31 (d, J4,5 = 8.6 Hz, 1 H, H-
4), 5.40 (dd, J5,4 = 8.6 Hz, J5,6 = 1.4 Hz, 1 H, H-5), 5.43 (dd,
13C NMR (CDCl3): d = 20.3, 20.8, 21.0, 21.1 (CH3-CO-),
33.8 (C-3), 47.0 (C-8), 63.1 (C-7a), 71.3 (C-7), 71.4, 71.5,
71.6 (C-4, C-5, C-6), 86.5 (C-3a), 126.5 (C-12), 127.6, 127.7
(C-11, C-13, C-10, C-14), 143.4 (C-9), 168.4, 169.2, 170.1,
170.5 (C=O) ppm.
J6,7 = 8.8 Hz, J6,5 = 1.4 Hz, 1 H, H-6), 7.13–7.31 (m, 10 H,
H-arom.) ppm.
13C NMR (CDCl3): d = 20.1, 20.5, 20.9, 21.0 (CH3), 34.6 (C-
3), 62.9 (C-8), 63.9 (C-7a), 70.2 (C-7), 73.5, 73.6 (C-5, C-6),
74.1 (C-4), 87.0 (C-3a), 126.1, 128.0, 128.2, 128.6, 129.8
(C-10, C-11, C-12, C-13, C-14, C-16, C-17, C-18, C-19, C-
20), 134.3 (C-9), 140.0 (C-15), 168.4, 169.3, 169.7, 170.5
(C=O) ppm.
IR: 3020 m (arom. =CH), 2989 s, 2934 m (CHn), 1741 s
(C=O), 1497 m, 1450 m (arom. C=C), 1370 s (C-N), 1218 s
(C-O), 755 s, 701 s (arom. C-H) cm–1.
IR: 3023 s (arom. =CH), 2966 m, 2930 w (CHn), 1742 F
(C=O), 1538 w, 1493 w, 1448 s (arom. C=C), 1372 s (C-N),
1217 s (C-O), 754 s, 703 s (arom. C-H) cm–1.
(16) (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199; and
references therein. (b) Bashiardes, G.; Safir, I.; Said
Mohamed, A.; Barbot, F.; Laduranty, J. Org. Lett. 2003, 5,
4915. (c) De La Hoz, A.; Diaz-Ortiz, A.; Langa, F. In
Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Germany, 2003.
Compound 12a Minor Conformer:
(17) Typical procedure for the synthesis of (3aS,4R,5S,6R,7S,
7aS)-1-methyl-3a-phenyloctahydrobenzo[c]isoxazole-
4,5,6,7-tetraol tetraacetate 12c.
1H NMR (CDCl3): d = 1.99, 2.02, 2.04, 2.13 (4 s, 12 H, CH3),
2.81 (dd, J8,8bis = 13.8 Hz, J8,7a = 6.7 Hz, 1 H, H-8), 3.19 (d,
J8bis,8 = 13.8 Hz, 1 H, H-8bis), 3.57 (d, J3,3bis = 12.9 Hz, 1 H,
H-3), 3.86 (dd, J7a,8 = 6.7 Hz, J7a,7 = 3.9 Hz, 1 H, H-7a),
3.86–3.96 (m, 2 H, H-6, H-4), 3.91 (d, J3bis,3 = 12.9 Hz, 1 H,
H-3bis), 5.04 (dd, J5,4 = 4.1 Hz, J5,6 = 1.3 Hz, 1 H, H-5), 5.17
(dd, J7,7a = 3.9 Hz, J7,6 = 3.8 Hz, 1 H, H-7), 7.13–7.31 (m, 10
H, H-arom.) ppm.
Microwave conditions: in a pyrex test tube (2 × 15),
NaHCO3 (218 mg, 2.6·10–3 mol, 2.6 equiv), N-isopropyl-
hydroxylamine hydrochloride (290 mg, 2.6·10–3 mol, 2.6
equiv), carbohydrate 10 (252 mg, 1.0·10–3 mol) and 80% aq
EtOH (1 mL) were submitted to microwave irradiations
(CEM Discover apparatus. Settings: 70 °C, 100 W) during
80 min. After cooling and the solvent evaporated under
reduced pressure, the crude product was acetylated and
purified as in Ref. 15.
13C NMR (CDCl3): d = 20.1, 20.5, 20.9, 21.0 (CH3), 34.3 (C-
3), 62.1 (C-8), 66.2 (C-7a), 71.9 (C-7), 72.4, 72.6 (C-4, C-6),
75.5 (C-5), 88.2 (C-3a), 126.7, 127.7, 127.8, 128.4, 128.9
(C-10, C-11, C-12, C-13, C-14, C-16, C-17, C-18, C-19, C-
Synlett 2005, No. 9, 1425–1428 © Thieme Stuttgart · New York