A new access to polyhydroxylated pyrrolidines from epoxyaldehydes

Article abstract of DOI:10.1055/s-2001-14593

Our approach relies on the stereocontrolled vinylation of a chiral α,β-epoxyimine derived from the corresponding aldehyde. Regioselective opening of the oxirane with carbonate anion allowed the formation of an oxazolidinone intermediate from which the glu

Full text of DOI:10.1055/s-2001-14593

866
LETTER
A New Access to Polyhydroxylated Pyrrolidines from Epoxyaldehydes
Tahar Ayad, Yves Génisson,* Michel Baltas,* Liliane Gorrichon
Synthèse et Physicochimie de Molécules d'Intérêt Biologique, UMR 5068 CNRS- Université Paul Sabatier, 118 route de Narbonne,
31062 Toulouse cedex 04, France
Fax +33- (0) 561556011; E-mail: genisson@ramses.ups-tlse.fr; baltas@iris.ups-tlse.fr
Received 4 April 2001
the primary hydroxyl group, treatment of the silyl ether 2
Abstract: Our approach relies on the stereocontrolled vinylation of
with HF/ pyridine followed by work up with sodium bi-
carbonate surprisingly yielded only 15% of the expected
primary alcohol 3 along with 80% of another compound.
a chiral
-epoxyimine derived from the corresponding aldehyde.
Regioselective opening of the oxirane with carbonate anion allowed
the formation of an oxazolidinone intermediate from which the glu-
cosidase inhibitor 1,4-dideoxy-1,4-imino-D-glucitol (14) was syn- Attribution of structure 4 to this product was based on the
thesised. Direct cyclisation into a 2-vinyl-3,4-epoxypyrrolidine
observation that spectroscopic data clearly indicated in-
afforded a valuable intermediate for the preparation of synthetic
azasugar analogues.
corporation of CO2 concomitant with epoxide ring open-
ing. The presence of a 1,2-diol pattern was evidenced by
13C NMR of the corresponding acetonide (quaternary car-
Key words: asymmetric synthesis, azasugars, epoxides, imines,
1,4-dideoxy-1,4-imino-D-glucitol
bon atom at 101.1 ppm characteristic of a dioxolane).
Unfortunately, as a consequence of the presence of the vi-
nyl substituant, the 3J coupling constant of 7 Hz between
Polyhydroxylated pyrrolidines, piperidines, and their bi-
cyclic congeners, indolizidines and pyrrolizidines, repre-
sent an important class of transition state analogue
inhibitors of glycosidases and glycosyl transferases. Giv-
en the key role of carbohydrates in cellular recognition
and signalling phenomena, these compounds represent
useful biological tools for a better understanding of glyco-
conjugate function. Some of them have already found
clinical application against HIV infection, cancer and dia-
betes,1 but efforts are still required to create novel struc-
tures with improved potency and selectivity towards a
target enzyme.
the oxazolidinone protons could not be attributed to either
a cis or trans relationship.5 The regiocontrolled opening
of the epoxide ring to the amine resulting from the initial
carbonatation of the amine was demonstrated by treat-
ment of silyl ether 2 with potassium carbonate in THF.
The reaction quantitatively provided the valuable inter-
mediate 5, which, upon desilylation, gave a product iden-
tical to diol 4. The stereochemistry attributed to 4 was
unambiguously proven by its transformation into 1,4-
dideoxy-1,4-imino-D-glucitol hydrochloride (14),
a
known glucosidase inhibitor.6a,d
We and others have already demonstrated the versatility
of epoxyaldehydes as chiral precursors in the enantiose-
lective synthesis of various biologically relevant com-
pounds.2 We wish to report here how epoxyaldehydes can
also constitute an efficient pathway towards azasugars.3
O
O
O
H
a
b
O
NHBn
2 (60%)
NHBn
3 (85%)
TBDPSO
TBDPSO
HO
1
d
c
Our synthetic plan was the following: conversion of the
-epoxyaldehyde into the corresponding imine should
allow incorporation of the nitrogen atom and, in turn, the
creation of a third chiral centre via the stereocontrolled
addition of an organometallic species. Direct access to the
pyrrolidine series should then rely on intramolecular cy-
clisation onto the activated primary alcohol function. Re-
giocontrolled opening of the epoxide could finally afford
a variety of substitution patterns, such as the trans-1,2-
diol through hydrolytic cleavage. The epoxide moiety in
itself could also represent an interesting structural varia-
tion of the parent glycosidase inhibitor.
OR
OR
TBDPSO
f
HO
g
OH
O
O
HO
NBn
NBn
OR NHBn
O
O
4, R = H (80%
+15% of 3, from 2)
7, R = Bn (85%, from 6)
8, R = H (95%, from 4)
9, R = Bn (95%, from 7)
5, R = H (90%)
6, R = Bn (85%)
e
Scheme 1 Reagents and conditions: a) i) C6H5NH2, 4 Å MS, Et2O,
rt, ii) Et2O·BF3, -78 °C to -40 °C, then CH2CHMgBr, THF/Et2O, -
78 °C to rt b) TBAF supported on SiO2, THF, rt c) HF-pyridine, THF/
pyridine, rt; then aq. NaHCO3 d) K2CO3, THF/H2O/pyridine, rt e) Bn-
Br, NaH, n-Bu4NI, THF, rt f) TBAF supported on SiO2, THF, rt g)
Readily available epoxyaldehyde 1 (3 steps, 70% global
yield from commercially available cis-2-butene-1,4-diol) LiOH, dioxane/H2O, reflux.
was chosen as the chiral precursor. Imine, formed after
treatment with benzylamine in diethyl ether, reacted with-
To this end, oxazolidinone 4 was first saponified to afford
the amino triol 8 quantitatively and this was then smooth-
ly cyclised in its unprotected form by means of the Appel
out being isolated with vinyl magnesium bromide in the
presence of Et2O BF3 to afford exclusively the anti epoxy
amine 2 in 60% isolated yield.4 In an attempt to deprotect
Synlett 2001, No. 6, 866–868 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Access to Polyhydroxylated Pyrrolidines from Epoxyaldehydes
867
reaction.7 The vinyl pyrrolidine 10 thus obtained, unfortu- analogues. In addition, it will be interesting to evaluate bi-
nately, proved to be inert to osmium catalysed dihydroxy- ological activity of epoxypyrrolidine 16 (or its debenzy-
lation conditions. In order to avoid possible participation lated form13) towards glycosidases. It is noteworthy that
of an osmate intermediate we decided to partially protect an epoxide-containing analogue of mannostatin A acts as
the diol moiety in 10. Benzyl ether 6 was thus prepared a potent, active site directed, irreversible inactivator of
from intermediate 5, which presents three suitably dis-
criminated hydroxyl groups. After desilylation, hydroly-
sis of the cyclic carbamate produced amino diol 9 that
underwent facile cyclisation into vinyl pyrrolidine 11.
But, the reluctance of the latter to provide the desired di-
hydroxylation product (no reaction after one week at
70 °C in 4:1 dioxane/water) prompted us to submit its ful-
ly benzylated congener 12 to the same osmium catalysed
reaction. Gratifyingly, this afforded the expected dihy-
droxylated derivative 13 as a single stereoisomer in 65%
isolated yield.8 Final hydrogenolysis of the benzyl groups
was accomplished in acidic medium to afford polyhy-
droxylated pyrrolidine 14 as its hydrochloride. Compound
14 gave physical and structural data essentially identical
to those reported for 1,4-dideoxy-1,4-imino-D-glucitol
hydrochloride as judged by 1H and 13C NMR, mass, and
D.9 This represents the first synthesis of 14 that does not
-mannosidase.14
O
O
HO
4
5
O
3
2
4
a
7
b
OH
3
3
+
6
N
6
N
2
5
Bn
N
Bn
OH
OH
7
Bn
16 (34%)
15 (73%)
17 (51%)
Scheme 3 Reagents and conditions: a) Ph3P, CCl4, Et3N, DMF, rt b)
NMO, OsO4, dioxane/H2O, 60 °C.
Acknowledgement
We thank the CNRS and the "Ministère de l'Education Nationale de
la Recherche et des Technologies" for financial support (UMR
5068). T.A. acknowledges the "Ministère de l'Education Nationale
de la Recherche et des Technologies" for a grant. We are also gra-
rely on the use of a sugar lactone6b,e or another carbohy- teful to Stéphane Massou for help in NMR structural assignment.
drate-derived chiral precursor.6a,d,c
References and Notes
OR2
OR2
(1) For a recent review see: Asano, N.; Nash, R.J.; Molyneux,
R.J.; Fleet, G.W.J. Tetrahedron: Asymmetry 2000, 11, 1645-
1680.
OH
R1O
R1O
a
c
O
OH
OR NHBn
N
N
(2) For preparation of optically active -lactones see: Nacro, K.;
Baltas, M.; Escudier, J.-M.; Gorrichon, L. Tetrahedron 1997,
53, 659-672. Nacro, K.; Baltas, M.; Zedde, C.; Jaud, J.
Tetrahedron 1999, 55, 5129-5132. For synthesis of
heptulosonic acid derivatives see: Devianne, G.; Escudier, J.-
M.; Baltas, M.; Gorrichon, L. J. Org. Chem. 1995, 60, 7343-
7347. Ruland, Y.; Zedde, C.; Baltas, M.; Gorrichon, L.
Tetrahedron Lett. 1999, 40, 7323-7327. For an access to
peptidonucleosides see: Dehoux, C.; Fontaine, E.; Escudier,
J.-M.; Baltas, M.; Gorrichon, L. J. Org. Chem. 1998, 63,
2601-2608. Dehoux, C.; Gorrichon, L.; Baltas, M. Eur. J. Org.
Chem. 2001, 6, 1105-1113.
R3
Bn
OH
10, R1 = R2 = H
8, R = H
9, R = Bn
13, R1 = R2 = R3 = Bn
(65%, from 12)
14, R1 = R2 = R3 = H
(95%)
(65%, from 8)
d
11, R1 = Bn, R2 = H
(73%, from 9)
b
12, R1 = R2 = Bn
(85%)
Scheme 2 Reagents and conditions: a) Ph3P, CCl4, Et3N, DMF, rt b)
BnBr, NaH, n-Bu4NI, THF, rt c) NMO, OsO4, dioxane/H2O, 60 °C d)
4 bars H2, 10% Pd/C, MeOH/ 1.2 N HCl.
(3) Access to polyhydroxylated piperidines from
-
In order to confirm the utility of our approach, we then
studied the viability of the epoxy analogues of polyhy-
droxylated pyrrolidines 13 and 14. Clean desilylation of 2
with TBAF supported on SiO2 afforded the alcohol 3 that
could be smoothly cyclised to vinyl pyrrolidine 15. When
treated with a catalytic amount of OsO4 at 60 °C in diox-
ane/water, the latter gave in 83% yield, a reproducible
60:40 mixture of two isomeric dihydroxylated products.10
The major diastereomer surprisingly suffered a rearrange-
ment with opening of the oxirane ring (as evidenced by
the absence of the two characteristic CH signals at 58-
60 ppm in 13C NMR spectra). A favoured 5-exo mode
cyclisation11 involving the primary hydroxyl group could
explain formation of the proposed fused tetrahydrofuran
structure 17.12 The minor product corresponded to one of
the expected diastereomers 16, which thus represents the
epoxy analogue of dihydroxylated pyrrolidine 13. Com-
pound 16 constitutes a valuable intermediate for further
transformation, via epoxide opening, into novel azasugar
epoxyaldehydes has been developed in our laboratory. See
Fontaine, E. PhD thesis, Université Paul Sabatier, 16/11/ 95.
(4) Assignment of the anti stereochemistry in 2 was based on the
work of G. Procter who first described this type of addition:
Beresford, K.J.M.; Howe, G.P.; Procter, G. Tetrahedron Lett.
1992, 33, 3355-3358.
(5) Such 3J coupling constants have been shown to be equivalent
in the cis and trans diastereomers of closely related vinyl
substituted oxazolidinones: Sakaitani, M.; Ohfune, Y. J. Am.
Chem. Soc. 1990, 112, 1150-1158.
(6) a) Kuszman, J.; Kiss, L. Carbohydr. Res. 1986, 153, 45-54
b) Fleet, G.W.J.; Son, J.C. Tetrahedron 1988, 44, 2637-2648
c) Bernotas, R.C. Tetrahedron Lett. 1990, 31, 469-472
d) Buchanan, J.G.; Lumbard, K.W.; Sturgeon, R.J.;
Thompson, D.K. J. Chem. Soc., Perkin Trans. 1 1990, 699-
706 e) Long, D.D.; Stetz, R.J.E.; Nash, R.J.; Marquess, D.G.;
Lloyd, J.D.; Winters, A.L.; Asano, N.; Fleet, G.W.J. J. Chem.
Soc., Perkin Trans. 1 1999, 901-908.
(7) Appel, R.; Kleinstück, R. Chem. Ber. 1974, 107, 5-12.
Schwardt, O.; Veith, U.; Gaspard, C.; Jäger, V. Synthesis
1999, 1473-1490.
Synlett 2001, No. 6, 866–868 ISSN 0936-5214 © Thieme Stuttgart · New York

868
T. Ayad et al.
LETTER
(8) The S stereochemistry was attributed to the newly formed
stereocenter in 13 by analogy with the work of R.C. Bernotas:
see ref. 6c.
CD3OD): 138.20 (C arom.); 129.37 (CH arom.); 128.82 (CH
arom.); 127.84 (CH arom.); 89.78 (C-4); 75.70 (C-3); 75.45
(C-6); 75.23 (C-5); 74.31 (C-7); 59.68 (C-2); 59.58 (CH2Ph).
SM (CI, NH3) MH+ 236. D - 1.2° (c, 0.9 in CHCl3).
(9) D - 25.3° (c, 0.8 in H2O). This value is in agreement with
those reported in the literature ( D - 27° (c, 1 in H2O)6a;
-
(11) Baldwin, J.E. J. Chem. Soc., Chem. Comm. 1976, 734-737.
(12) This structure is in full agreement with all spectral data (1D 1H
and 13C NMR; COSY, HMQC and long range HMQC 2D
experiments). Relative stereochemistry at C-6 is based on 1D
dpgse NOE experiment: a strong NOE is observed between H-
4 and H-5, whereas a comparatively weak NOE is observed
between H-5 and H-6, as well as between H-4 and H-3. For an
example of related cyclisation concomitant with osmium
catalysed dihydroxylation of a vinyl pyrrolidine see: Lin, G.-
Q.; Shi, Z.-C. Tetrahedron 1997, 53, 1369-1382.
D
28.1° (c, 0.4 in H2O)6b; D - 25° (c, 0.3 in H2O)6d) considering
the 95% ee of our starting epoxy-alcohol.
(10) Compound 16: 1H RMN (400 MHz, CDCl3/CD3OD): 7.35
- 7.25 (5H, m, Ph,); 3.89 (2H, ABq, J = 12.9 Hz, CH2Ph) a -
b = 28 Hz; 3.88 (1H, d, J = 2.8 Hz, H-4); 3.70 (1H, d, J = 2.8
Hz, H-3); 3.58 - 3.53 (3H, m, H-6, 2H-7); 3.26 (1H, d, J = 6.8
Hz, H-5); 3.07 (2H, ABq, J = 13.6 Hz, H-2) a - b = 58.4 Hz.
13C RMN (100 MHz, CDCl3/CD3OD): 138.69 (C arom.);
129.56 (CH arom.); 129.06 (CH arom.); 128.04 (CH arom.);
70.52 (C-6); 68.64 (C-5); 65.25 (C-7); 64.46 (CH2Ph); 59.85
(13) In preliminary attempts (atmospheric pressure H2, 10% Pd/C,
EtOH or 4 bars H2, 10% Pd/C, AcOEt) hydrogenolytic
debenzylation of epoxypyrrolidine 16 yielded a complex
reaction mixture.
(C-4); 58.05 (C-3); 54.19 (C-2). SM (CI, NH3) MH+ 236.
D
+1.4° (c, 0.5 in CHCl3).
Compound 17: 1H RMN (400 MHz, CDCl3/CD3OD): 7.35
- 7.24 (5H, m, Ph); 4.49 (1H, dd, J = 6.6 and 3.0 Hz, H-4); 4.12
(1H, m, H-3); 3.99 (1H, m, H-6); 3.93 (1H, dd, J = 9.6 and 3.2
Hz, H-7); 3.78 (1H, dt, J = 10.0 and 0.8 Hz, H-7); 3.75 (2H,
ABq, J = 12.4 Hz, CH2Ph) a - b = 122.0 Hz; 3.28 (1H, d,
J = 6.4 Hz, H-5); 3.14 (1H, dd, J = 9.6 and 6.4 Hz, H-2);
2.30 (1H, t, J = 8.4 Hz, H-2). 13C RMN (100 MHz, CDCl3/
(14) King, S.B.; Ganem, B. J. Am. Chem. Soc. 1994, 116, 562-570.
Article Identifier:
1437-2096,E;2001,0,06,0866,0868,ftx,en;D06001ST.pdf
Synlett 2001, No. 6, 866–868 ISSN 0936-5214 © Thieme Stuttgart · New York