Regio- and enantioselective synthesis of novel functionalized pyranopyrrolidines by 1,3-dipolar cycloaddition of carbohydrates

Article abstract of DOI:10.1055/s-2005-862385

A new methodology is described for the rapid enantiomeric synthesis of a novel series of pyranopyrrolidines from readily available and inexpensive carbohydrate compounds. The major feature of the method is a highly selective [3+2] cycloaddition reaction of different azomethine ylides with a chiral carbohydrate-derived enone. The reaction proved to be extremely regio- and stereoselective, giving rise to single enantiomeric compounds in all cases. Moreover, the method is totally atom-efficient and amenable to diversity, since structural diversity of the new compounds is dictated by the choice of the starting materials employed.

Full text of DOI:10.1055/s-2005-862385

LETTER
587
Regio- and Enantioselective Synthesis of Novel Functionalized Pyrano-
pyrrolidines by 1,3-Dipolar Cycloaddition of Carbohydrates
Synthesisof
N
ove
e
l
Functiona
o
lized
P
yranop
r
yrrolidi
g
nes e 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
E-mail: george.bashiardes@univ-poitiers.fr
Received 16 December 2004
Abstract: A new methodology is described for the rapid enantio-
meric synthesis of a novel series of pyranopyrrolidines from readily
available and inexpensive carbohydrate compounds. The major fea-
ture of the method is a highly selective [3+2] cycloaddition reaction
of different azomethine ylides with a chiral carbohydrate-derived
enone. The reaction proved to be extremely regio- and stereoselec-
tive, giving rise to single enantiomeric compounds in all cases.
Moreover, the method is totally atom-efficient and amenable to di-
versity, since structural diversity of the new compounds is dictated
by the choice of the starting materials employed.
Scheme 1
Key words: cycloaddition, carbohydrates, azomethine ylides, pyr-
anopyrrolidines, asymmetric synthesis
commonly available carbohydrates and a short and flexi-
ble sequence of reactions, leading to the final key step.
Pyrrolidinic bicyclic systems are constituents of many
Thus, the synthesis of the chiral enone 55 was undertaken
biologically active compounds, such as, for example, an-
as indicated in Scheme 2, in which the required compound
tagonists of neuroexcitatory amino acids,1 which inter-
was prepared in few steps using commonplace reactions,
vene in disorders like epilepsies or Huntington’s chorea.
the judicious choice of which led to a relatively high over-
They are also useful as intermediates for total synthesis of
all yield. This key intermediate then underwent cyclo-
more complex therapeutic molecules.2 As such, it is of in-
addition reaction in a stereo- and regiocontrolled manner
terest to develop the synthesis of such target molecules,
to afford the required compounds. In each case, a single
using methods allowing control of stereochemistry and
isomer was obtained, indicating the excellent induction
permitting diversity.
conferred during the cyclization.
One of the most versatile methods for the synthesis of pyr-
As an example starting material, we used the commercial-
rolidines is the [3+2] cycloaddition reaction involving
ly available and inexpensive 1-bromo-tetra-O-acetyl glu-
azomethine ylides derived from a-aminoesters, an alde-
cose (1), which was firstly submitted to reductive
hyde and a suitable dipolarophile.3 The generation of
elimination6 using zinc/aqueous acetic acid to afford gly-
azomethine ylides from imines by formal 1,2-prototropy,
cal 2 in 78% yield. Treatment with catalytic boron triflu-
metal salt–tertiary amine combinations provides a simple,
oride diethyl etherate in ethanol7,8 and toluene led to
regio-and stereospecific process for the synthesis of
effective 1,4-substitution of one acetoxy group, with mi-
polysubstitued pyrrolidines.4 We describe herein a novel
gration of the double bond to provide the 1-ethoxy-2,3-
and potentially widely adaptable methodology for the
alkene 3 as a mixture of two anomeric isomers (a:b 10:90)
in 94% yield. The acetyl protecting groups of the two hy-
synthesis of pyranopyrrolidines from carbohydrate deriv-
atives using azomethine ylides (Scheme 1). The method is
droxyl functions were removed using 0.1 N sodium meth-
atom-economical, with no loss of chiral inducing
oxide in methanol9 to provide the diol 4 in 91% yield as a
fragments. Indeed, the carbohydrate moiety maintains its
specific stereochemistry and induces regio- and stereo-
selectivity to the cycloaddition reaction, providing the
new pyranopyrrolidines in a controlled manner.
single a-anomer. The basic conditions are most probably
responsible for this total isomerization to the single a-ano-
mer. Alternatively, the deprotection was attempted using
triethylamine in methanol–water,10 but the yield was
By this approach, we considered that an easily accessible
common key intermediate would provide diversely sub-
stituted fused pyrrolidines when treated with a variety of
1,3-dipolar azomethine ylides. As such, our strategy uses
much lower at only 72%. The next step, involving the ox-
idation of the reactive allylic 4-hydroxyl function was
achieved by either of two methods, namely using manga-
nese dioxide (MnO2) in dichloromethane (24 h at r.t., 65%
yield), or the Dess–Martin periodinane method11 (CH2Cl2,
4 h, r.t.). The latter proved more efficient, providing the
expected chiral enone 5 in a higher, yet non-optimized
yield of 76%.
SYNLETT 2005, No. 4, pp 0587–0590
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862385; Art ID: D37504ST
© Georg Thieme Verlag Stuttgart · New York

588
G. Bashiardes et al.
LETTER
Scheme 4
separable mixtures of numerous products. The results are
summarized in Table 1.
Scheme 2
Compounds 9a–c (Table 1) were obtained as single enan-
tiomeric compounds in spite of the potentially numerous
regio- or stereoisomers that could have been formed. We
suggest that the newly formed pyrrolidine unit was creat-
ed by the exclusive addition of the dipole from the face
opposing that of the anomeric aglycone ethoxide group. In
the case of the unsubstituted (glycinate) derivative, the
conformation of the approaching ylide is such that the car-
boxyl group is opposed to the carbohydrate moiety
(Figure 1). Thus in compound 9a the resulting syn ring
junction is of endo-configuration, and the carboxyl group
is anti with respect to the a-ethoxy group.
With this versatile intermediate in hand, the following
step was the key to our strategy, in which a [3+2] cycload-
dition reaction would provide the novel pyranopyrro-
lidines in a single step. For this, a series of N-benzylimine
derivatives of five different a-amino esters or a-aminoni-
triles were prepared. Thus, as examples, three a-ami-
noesters (glycinate, leucinate and phenylglycinate), and
two a-aminonitriles in their hydrochloride form, were
treated with benzaldehyde in presence of triethylamine
and magnesium sulfate (Scheme 3). The expected benz-
ylimines 8a–e were obtained efficiently in this manner
and were employed as such in the cycloaddition step.
In a similar manner, the phenyl substituent would occupy
the less hindered face when the ylide approaches the dipo-
larophile. By analogous reasoning, substituted aminoester
derivatives (leucine and phenylalanine), the bulkier alkyl
groups should be oriented furthest from the carbohydrate
moiety (Figure 2), thus giving rise to compounds 9b and
9c.
Table 1 Pyranopyrrolidines by Cycloaddition
Entry
1
R
H
Y
Product
Yield (%)
59
COOMe
Scheme 3
2
3
i-Bu COOMe
65
66
Compounds 8a–e were then used to generate the corre-
sponding metallo-azomethine ylide in situ in presence of
the enone 5 (Scheme 4). This was achieved by treating a
solution of enone 5 and benzylimine 7 in acetonitrile with
silver acetate (AgOAc) and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) at room temperature.
Ph
COOMe
Indeed, under these conditions, cycloaddition did occur
successfully and the expected pyranopyrrolidines 9a–c
were obtained12 in relatively good yields when the N-
benzylimines of a-aminoesters 7a–c were employed.
However, the a-aminonitrile benzylimines 7d,e led to in-
4
5
H
CN
CN
Mixtures
Mixtures
–
–
Ph
Synlett 2005, No. 4, 587–590 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Functionalized Pyranopyrrolidines
589
Figure 1 Controlled cycloaddition by the glycinate-derived ylide
The stereochemistry of all the chiral centers was deter-
mined by NMR spectroscopic analysis. The 300 MHz 1H
NMR spectrum of 9a indicated a singlet at d = 5.12 ppm
for H-4, with no coupling constant. This is indeed the ob-
servation that would be expected of a trans relationship
between adjacent protons H-4 and H-3a since the dihedral
angle between them is normally between 90° and 100°. A
cis relationship would have given rise to a coupling con-
stant J4,3a value of at least 3 Hz (dihedral angle of 60° or
less). We thus concluded that the configuration of the
junction in compound 9a was 3aR. Next, studies by two
dimensional 1H-1H NMR clearly showed correlations be-
tween H-3a and H-3 (J3a,3 = 9.4 Hz) and between H-7a
and H-1 (J7a,1 = 7.2 Hz).
Figure 2 Controlled cycloaddition to the chiral enone
propyl-7-oxo-1-phenyl-octahydro-pyrano[3,4-c]pyrrole-
3-carboxylate (9b) as the only isolated product. Reaction
between enone 7 and benzylimine 8c was also regio- and
stereospecific, and provided exclusively pyranopyrrol-
idine 9c.
Finally, to determine the configuration at C-1, a to the
pyrrolidine nitrogen, that is, the relative orientations of the
phenyl and ester groups, we performed a NOE analysis.
We observed a spatial proximity for H-4, H-3 and H-1.
Since the absolute configuration of the ‘anomeric’ carbon
C-4 was known, we concluded that the synthesized
compound 9a was methyl-(1S,3R,3aR,7aS)-4-ethoxy-6-
hydroxymethyl-7-oxo-1-phenyl-octahydro-pyrano[3,4-
c]pyrrole-3-carboxylate.
In view of the results, we conclude that the reactions de-
scribed herein provide a versatile methodology for the
highly stereoselective synthesis of novel pyranopyrro-
lidines possessing variable substituents. The major fea-
tures of this method include the use of a chiral enone
derived from carbohydrates and the selective, chirally in-
duced addition of differently substituted azomethine
ylides in a [3+2] cycloaddition. The process is efficient,
employing readily accessible and inexpensive starting
materials. Indeed, the choice of functionality on the start-
ing materials determines the substitution pattern present
in the final molecules, thus allowing for diversity in this
class of compounds.
Similar observations were made for compound 9b. The
signal for H-4 appeared as a doublet with J4,3a = 1,9 Hz,
corresponding once again to a trans-configuration be-
tween H-4 and H-3a. In a similar manner, examination of
the NOE analysis results, indicated spatial proximity for
H-1 and the methylene protons of the 6-hydroxymethyl
group. Hence we concluded that C-1 was of (S) configu-
References
1
(1) Goldberg, O.; Luini, A.; Teichberg, V. I. J. Med. Chem.
1983, 26, 39; and references cited therein.
(2) (a) Orlek, B. S.; Wadsworth, H.; Wyman, P.; Hadley, M. S.
Tetrahedron Lett. 1991, 1241. (b) Kende, A. S.; Luzzio, M.
J.; Mendoza, J. S. J. Org. Chem. 1990, 918.
(3) (a) Bashiardes, G.; Safir, I.; Mohamed, A. S.; Barbot, F.;
Laduranty, J. Org. Lett. 2003, 5, 4915. (b) Grigg, R.;
McMeekin, P.; Sridharan, V. Tetrahedron 1995, 51, 13347.
(c) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475.
ration. Further studies, by the H NOESY technique,
showed correlations between the aromatic protons of the
1-phenyl substituent and protons of the isobutyl (leucine-
derived) side-chain. We therefore concluded that the
[3+2] cycloaddition reaction proceeded once again with
high regio- and stereoselectivity, to give methyl-
(1S,3S,3aR,7aS)-4-ethoxy-6-hydroxymethyl-2-methyl-
Synlett 2005, No. 4, 587–590 © Thieme Stuttgart · New York

590
G. Bashiardes et al.
LETTER
(4) Vogel, A. I. Practical Organic Chemistry, 3rd ed.;
Longmans: London, 1956, 452.
(5) De Freitas, J. R.; Srivastava, R. M.; Da Silva, W. J. P.;
Cottier, L.; Sinou, D. Carbohydr. Res. 2003, 338, 673; and
references cited therein.
(6) Kozikowski, A. P.; Lee, L. J. Org. Chem. 1990, 55, 863.
(7) Ferrier, R. J. In Carbohydrates; Pigman, W.; Horton, D.,
Eds.; Academic Press: New York, 1980, 843–880.
(8) Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M. Synlett
1995, 306.
of NH4Cl solution. The organic layer was then dried over
MgSO4, and the solvent was removed under reduced
pressure. The resulting oil was purified by flash
chromatography on silica gel (EtOAc–pentane 70:30,
Rf = 0.30) to provide 9a in 60% yield as a viscous colorless
oil. 1H NMR and 13C NMR spectroscopy revealed two
conformers.
Major conformer: 1H NMR (300 MHz, CDCl3): d = 1.21 (t,
J = 7.1 Hz, 3 H, ethyl-CH3), 2.86 (dd, J3a,7a = 9.4 Hz,
J3a,3 = 9.0 Hz, 1 H, H-3a), 3.07 (dd, J7a,3a = 9.4 Hz, J7a,1 = 5.7
(9) Thompson, A.; Wolfrom, M. L.; Pacsu, E. In Methods in
Carbohydrate Chemistry, Vol. 2; Whistler, R. L.; Wolfrom,
M. L., Eds.; Academic Press: New York, 1963, 215–220.
(10) Fraser-Reid, B.; Walker, D. L. Can. J. Chem. 1980, 58,
2694.
Hz, 1 H, H-7a), 3.51–3.98 (m, 5 H, H-5, CH2-O and ethyl-
CH2), 3.77 (s, 3 H, ester-CH3), 4.04 (d, J3,3a = 9.0 Hz, 1 H,
H-3), 4.69 (d, J1,7a = 5.7 Hz, 1 H, H-1), 5.12 (br s, 1 H, H-
4a), 7.25–7.46 (m, 5 H, H-arom.) ppm. 13C NMR (CDCl3):
d = 14.7 (ethyl-CH3), 48.3 (C-3a), 52.5 (ester-CH3), 55.7 (C-
7a), 62.1 (ethyl-CH2), 62.7 (C-3), 63.0 (C-1), 63.8 (CH2-O),
76.8 (C-6), 97.0 (C-4), 124.9–139.3 (C-Ar), 172.8 (ester
C=O), 207.4 (C-7) ppm. IR = 3362 (OH), 3059 (arom. C-H),
2972, 2929, 2905 (CHn), 1736 (C=O ester), 1715 (C=O
ketone), 1606 (arom. C=C), 1180, 1132, 1063 (C-O), 736
(arom. C-H), 702 (arom. C-H) cm–1.
(11) Clark, D. Tetrahedron 2000, 56, 6181.
(12) All compounds were purified by the appropriate techniques
and fully characterized by spectroscopic means.
Typical Experimental Procedure – Synthesis of Methyl-
(1S,3R,3aR,7aS)-4-ethoxy-6-hydroxymethyl-7-oxo-1-
phenyl-octahydro-pyrano[3,4-c]pyrrole-3-carboxylate
(9a).
Minor conformer: 1H NMR (300MHz, CDCl3): d = 1.17 (t,
J = 7.1 Hz, 3 H, ethyl-CH3), 3.12–3.15 (m, 1 H, H-3a, 3.25
(dd, J7a,3a = 7.7 Hz, J7a,1 = 7.2 Hz, 1 H, H-7a), 3.51–3.98 (m,
5 H, H-5, CH2-O and ethyl-CH2), 3.86 (s, 3 H, ester-CH3),
4.19 (d, J3,3a = 9.4 Hz, 1 H, H-3), 4.41 (d, J1,7a = 7.2 Hz, 1 H,
H-1), 5.12 (br s, 1 H, H-4a), 7.25–7.46 (m, 5 H, H-arom.)
ppm. 13C NMR (CDCl3): d = 14.2 (ethyl-CH3), 45.9 (C-3a),
52.3 (ester-CH3), 52.4 (C-7a), 60.9 (C-1), 62.0 (ethyl-CH2),
63.7 (CH2-O), 65.9 (C-3), 75.5 (C-6), 96.1 (C-4), 124.9–
139.3 (C-Ar), 172.2 (ester C=O), 207.4 (C-7).
To a solution of methyl-N-benzylideneglycinate (7a, 0.23 g,
1.3 mmol, 1.5 equiv) in 20 mL of dry MeCN in a two-
necked, round-bottomed flask equipped with a magnetic
stirring bar and a reflux condenser were added enone 5 (0.15
g, 0.9 mmol), AgOAc (0.18 g, 1.05 mmol, 1.2 equiv), and
0.16 mL of DBU (1.05 mmol, 1.2 equiv). The mixture was
stirred at r.t. during 4 h in absence of light (flask covered in
aluminium foil). After filtration on celite and evaporation of
the solvent under reduced pressure, the resulting brown oil
was dissolved in 15 mL of CH2Cl2 and washed with 20 mL
Synlett 2005, No. 4, 587–590 © Thieme Stuttgart · New York