Access to pyrrolidine imino sugars via tin(II)-mediated aldol reactions of bislactim ethers: Synthesis of 2,5-dideoxy-2,5-imino-d-glucitol

Article abstract of DOI:10.1039/b810878a

2,5-Dideoxy-2,5-imino-d-glucitol (DGDP) has been synthesized via the tin(ii)-mediated anti-selective aldol reaction of bislactim ether 5 and a 3-O-silylated 2,4-ethylidene-d-erythrose derivative 6. In accordance with density functional theory calculations (at the B3LYP/cc-pVDZ-PP level), pericyclic transition structures with a boat-like conformation and a stabilizing hydrogen bond can account for the unexpected stereoselectivity. The 2008 Royal Society of Chemistry.

Full text of DOI:10.1039/b810878a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Access to pyrrolidine imino sugars via tin(II)-mediated aldol reactions of
bislactim ethers: synthesis of 2,5-dideoxy-2,5-imino-D-glucitol†
Olga Blanco, Cristina Pato, Mar´ıa Ruiz* and Vicente Ojea*
Received 2nd July 2008, Accepted 31st July 2008
First published as an Advance Article on the web 5th September 2008
DOI: 10.1039/b810878a
2,5-Dideoxy-2,5-imino-D-glucitol (DGDP) has been synthesized via the tin(II)-mediated anti-selective
aldol reaction of bislactim ether 5 and a 3-O-silylated 2,4-ethylidene-D-erythrose derivative 6. In
accordance with density functional theory calculations (at the B3LYP/cc-pVDZ-PP level), pericyclic
transition structures with a boat-like conformation and a stabilizing hydrogen bond can account for the
unexpected stereoselectivity.
nucleophilic substitution of an activated hydroxyl group, followed
by reduction of the carboxylic acid group (see Scheme 1).
Introduction
Given the potent and specific inhibitory activity toward carbo-
hydrate processing enzymes, polyhydroxylated piperidines and
pyrrolidines have emerged in recent years as highly promising
candidates for the development of new drugs against diabetes,
cancer metastasis and viral infections.1 In particular, pyrrolidine
imino sugar 2,5-dideoxy-2,5-iminogalactitol (DGADP) and its
C-4 epimer, 2,5-dideoxy-2,5-imino-D-glucitol (DGDP), recently
isolated from Thai medicinal plants, are potent inhibitors of sev-
eral galactosidases and glucosidases.2 In addition, N-adamantanyl
alkyl amide derivatives of DGDP have been found to act as
pharmacological chaperones for Gaucher disease,3a while N-acetyl
Scheme 1
We envisaged preparing key intermediates 2 by stereocontrolled
aldol additions between four-carbon building blocks and a chiral
glycine equivalent. Alkylidene-tetroses like 4 were sought as appro-
analogues of DGDP 1 are hexosaminidase inhibitors, which may
offer new therapeutic options in the treatment of osteoarthritis.3b
priate precursors, delivering various configurations and being suit-
ably functionalized at positions 2 and 4. Although commonly used
in stereoselective synthesis,8 to the best of our knowledgement,
2,4-alkylidene-threoses or erythroses had not been previously
employed as aldol acceptors.9 In addition, aldol reactions of
metalated bislactim ethers 3 with matched a-alkoxyaldehydes have
been reported to proceed with high levels of syn,anti-selectivity,
which has been rationalized by invoking chair-like pericyclic
transition structures with a Felkin-Anh or a Cornforth-like10
conformation for the aldehyde moiety.7,11 Thus, double asymmetric
induction of the 3,1¢-syn-1¢,2¢-anti configuration was expected
in the reaction of D-valine and D-erythrose derivatives 5 and 6
(see Scheme 2), which could enable selective access to a convenient
precursor of pyrrolidine imino sugar DGADP.
Consequently with the huge pharmacological potential of poly-
hydroxylated pyrrolidines,4 significant efforts have been devoted
to their synthesis. To date, DGDP has mostly been synthesized
through stereoselective transformations of readily available carbo-
hydrate precursors.5 Alternative approaches have relied on annula-
tion of a-amino acid derivatives,6a chemoenzymatic processes,2a,6b
or asymmetric aminohydroxylations.6c We have recently described
a general strategy for the synthesis of piperidine imino sugars, by
using an aldol reaction between metalated bislactim ethers and
threose or erythrose acetonides in the key-step.7 In this paper,
we introduce an extension of this methodology to the synthesis
of pyrrolidine imino sugars. In adapting the synthetic plan we
recognized that amino esters 2 might be valuable intermediates
since the target pyrrolidines would originate by cyclization via
Results and discussion
To this end, n-BuLi was added to a solution of bislactim ether 5
in THF at -78 ◦C, and the corresponding lithium azaenolate was
allowed to react with Cl2Sn for 1 h to produce the transmetalated
azaenolate SnCl+5-. Upon addition of freshly distilled aldehyde
6,12 reaction took place within 4 h at -78 ◦C and, after quenching
and aqueous workup, a crude mixture containing adducts 7a : 8 in
a 12 : 1 ratio13 was isolated in 80% combined yield. The separation
of the components of this mixture could be achieved by flash
chromatography to provide 7a with high purity (d.e. higher than
98%) and 74% yield. Surprisingly, the configuration of the major
Departamento de Qu´ımica Fundamental, Facultade de Ciencias, Universi-
dade da Corun˜a, Campus da Zapateira s/n, 15071 A Corun˜a, Spain. E-mail:
ojea@udc.es; Fax: +34 981167065; Tel: +34 981167000
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization and NMR spectra of new compounds and
computational methods, Cartesian coordinates and absolute energies for
the models reported. See DOI: 10.1039/b810878a
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dotted line in Fig. 1). This interaction was not present in the
competing TSs and therefore could contribute to the unexpected
kinetic preference for the trans,anti,syn-pathway.17
Scheme 2
Fig. 1 Chem3D representations of the most favored TSs located in the gas
phase (at the B3LYP/cc-pVDZ-PP level) for the reaction between SnCl+5-
and 6. Relative energies in THF (at the B3LYP(SCRF)/cc-pVTZ-PP level
using the PCM method) are shown in parenthesis in kcal mol-1. Distances
are in a˚ngstro¨ms. The hydrogen atoms are omitted for clarity except at
chiral and reaction centers.
adduct 7a was determined as 3,1¢-anti-1¢,2¢-syn instead of the
expected 3,1¢-syn-1¢,2¢-anti one. Evidence supporting the relative
configurations of the addition products was obtained from NMR
analysis14 and chemical correlation with DGDP (see Scheme 3).
The conversion of adduct 7a to the targeted imino sugar was
straightforward. After deprotection of the silyl ether, mesylation
of diol 7b (by treatment with MsCl, Et3N and a catalytic amount
of dimethylaminopyridine in CH2Cl2 at 0 ◦C) was completely
regioselective for the equatorial hydroxyl group (see Scheme 2).18
Protection of mesylate 7c was found necessary to achieve ac-
ceptable yields in the hydrolysis of the pyrazino moiety, as was
previously reported for other bislactim ethers with free hydroxyl
groups.19 After benzylation, the selective cleavage of the bislactim
ether in the presence of the ethylidene acetal took place with
concomitant cyclization (see Scheme 3). In this manner, hydrolysis
of 9 in acidic media gave rise to glucuronate 10 in 82% yield
after removing the auxiliary D-valine by flash chromatography.
Reduction of the ester group of 10 with LiBEt3H proceeded
cleanly, as previously described for other pyrrolidine derivatives.5e
Final deprotection of pyrrolidine 11, by catalytic hydrogenation
and hydrolysis of the acetal in hot HCl, followed by purification
of the crude mixture by ion-exchange chromatography (Dowex,
H+ form) and reversed-phase chromatography, led to DGDP in
excellent yield.20
Scheme 3 Reagents and conditions: i. NaH, BnBr, Bu4NI, THF (70%). ii.
0.25 M HCl : MeOH 1 : 3 (82%). iii. LiEt3BH, THF, 0 ◦C (90%). iv. (a)
0.25 M HCl : THF 1 : 1, H2, Pd/C; (b) 1 M HCl, D (96%).
To gain more insight into the origins of the unexpected anti,syn-
selectivity in the reaction between SnCl+5- and 6, we have com-
puted the competing diastereomeric transition structures (TSs) for
the aldol process. Geometry optimizations were performed using
the B3LYP procedure with the cc-pVDZ basis set and a small-
core relativistic pseudopotential (PP) for Sn. Single-point energy
calculations were performed at the B3LYP/cc-pVTZ-PP level in
THF solution using the PCM method (see ESI† for full details).15
In agreement with the experimental outcome, the most favorable
TS was located in the trans,anti,syn-diastereomeric pathway. This
TS, designated as tas-BN in Fig. 1, was characterized by a
boat-like conformation for the pericyclic ring and a non-Anh
conformation16 for the erythrose moiety. In the trans,syn,anti-
diastereomeric pathway, the most stable TS was tsa-CM, which
showed chair-like and Cornforth-like conformations for the per-
icyclic ring and the erythrose moieties and was calculated to be
1.2 kcal mol-1 higher in energy than tas-BN. Other competitive TSs
in the cis-pathways were also calculated to be higher in energy. It
should be noted that in tas-BN the distance between the oxygen
atom at the a-position of the erythrose moiety and one of the
Conclusions
In summary, with the efficient preparation of DGDP we have
outlined the utility of tin(II)-mediated aldol reactions between
bislactim ethers and 2,4-ethylidene-tetroses for the synthesis of
pyrrolidine imino sugars. Additional studies to extend this aldol-
based strategy to the synthesis of other biologically active 2,5-
iminohexitols are currently under progress and will be reported in
due course.
Acknowledgements
We gratefully acknowledge Ministerio de Ciencia y Tecnolog´ıa
(BQU2003-00692) and Xunta de Galicia (PGIDIT05BTF-
10301PR) for financial support. The authors are indebted to
˚
methoxy hydrogens of the bislactim ether was reduced to 2.22 A,
which indicated a hydrogen bond interaction (represented as a
3968 | Org. Biomol. Chem., 2008, 6, 3967–3969
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Centro de Supercomputacio´n de Galicia for providing computer
facilities. O. B. thanks Xunta de Galicia for an “Isidro Parga
Pondal” position at Universidade da Corun˜a.
N. O
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the baseline resolved doublets corresponding to the methyl groups
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mixture.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3967–3969 | 3969
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