The first asymmetric synthesis of 1,4-dideoxy-1,4-imino-D-talitol

Article abstract of DOI:10.1055/s-2005-871534

The first stereoselective synthesis of 1,4-dideoxy-1,4-imino-D-Talitol has been achieved in 24% overall yield from conveniently protected (S)-glyceraldimine (1), which is easily prepared from inexpensive D-mannitol. The synthesis is based on the addition

Full text of DOI:10.1055/s-2005-871534

1734
LETTER
The First Asymmetric Synthesis of 1,4-Dideoxy-1,4-imino-D-talitol
A
symmetric Synt
a
hesis of 1,4
m
-
Dideoxy-1, 4-imin
ó
o-
D
-talitol n Badorrey, Carlos Cativiela, María D. Díaz-de-Villegas,* Roberto Díez, José A. Gálvez*
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Instituto Universitario de Catálisis,
Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Fax +34(97)6761210; E-mail: loladiaz@unizar.es; E-mail: jagl@unizar.es
Received 24 February 2005
initial approach this compound was subjected to N-allyl-
ation with allyl bromide using sodium hydride as a base to
give diene 3. Compound 3 was subjected to ring-closing
metathesis6 in the presence of first generation Grubbs’
Abstract: The first stereoselective synthesis of 1,4-dideoxy-1,4-
imino-D-Talitol has been achieved in 24% overall yield from con-
veniently protected (S)-glyceraldimine (1), which is easily prepared
from inexpensive D-mannitol. The synthesis is based on the addition
of vinylmagnesium bromide to this N-benzylimine followed by N- catalyst to give dehydropyrrolidine 4 in moderate yield.
acylation, ring-closing metathesis and asymmetric dihydroxylation.
In this synthesis as many as three stereogenic centres are construct-
ed with total stereoselectivity.
Unfortunately, attempts to perform a cis-dihydroxylation
reaction on compound 4 using OsO4 and a co-oxidant
[such as NMO or K3Fe(CN)6] were unsuccessful. After
several days under all conditions tested, complex mixtures
Key words: stereoselective synthesis, alkaloids, addition reactions,
metathesis, dihydroxylations
of products, which contained unaltered starting material
and the corresponding pyrrole derived from 4, were ob-
tained. Asymmetric dihydroxylation using commercially
In recent years the synthesis of polyhydroxylated pyrro-
lidines has attracted particular attention.1 These com-
pounds are of special interest because many of them
behave as glycosidase and/or glycosyltransferase inhibi-
tors and have shown promising chemotherapeutic proper-
ties against diabetes, cancer and viral infections including
AIDS.2 In particular, 1,4-dideoxy-1,4-imino-D-talitol has
proven to be a specific inhibitor of human liver a-man-
nosidase in vitro and also blocks the lysosomal catabolism
of asparagine linked glycans of glycoproteins in vivo.3
available AD-mix-a or AD-mix-b under Sharpless
conditions7 also failed and the desired cis-diol could not
be obtained in this way (Scheme 1).
BnO
BnO
BnO
BnO
BnO
BnO
ref. 5
i
H
BnN
BnN
BnNH
1
2
3
OH
BnO
BnO
BnO
OH
BnO
ii
The synthesis of 1,4-dideoxy-1,4-imino-D-talitol has re-
ceived relatively little attention. The few reported
methodologies4 are based on transformations starting
from sugar derivatives and, in some cases, are not partic-
ularly efficient. To the best of our knowledge, approaches
have not been reported that address a stereoselective syn-
thesis of 1,4-dideoxy-1,4-imino-D-talitol in which some
stereogenic centres in the molecule are created with high
stereoselectivity from inexpensive starting materials.
BnN
BnN
4
Scheme 1 Reagents and conditions: i) allyl bromide (6 equiv), NaH
(2.2 equiv), dry DMF, 0 °C to r.t., 7 h, 86%; ii) benzylidenebis(tri-
cyclohexylphosphine)ruthenium dichloride (8%), dry CH2Cl2, r.t., 24
h, 60%.
We reasoned that the tertiary amine moiety in compound
4 could hamper the dihydroxylation reaction by coordi-
nating to the active oxidant species, i.e., catalytic osmium
tetraoxide. In an effort to overcome this synthetic draw-
back we decided to perform the N-acylation of compound
2 and apply the outlined synthetic scheme to the resulting
compound.
Encouraged by the usefulness of 1,4-dideoxy-1,4-imino-
D-talitol we have developed the first stereoselective
synthesis of this compound from N-benzylimine (1).
Compound 1 is derived from (R)-2,3-di-O-benzylglycer-
aldehyde, which is readily available on a multigram scale
from inexpensive D-mannitol. Key steps of the reported
synthesis are (a) addition of vinylmagnesium bromide to
the imine, (b) ring-closing metathesis and (c) dihydroxyl-
ation.
As we have previously reported,5 nucleophilic attack of
vinylmagnesium bromide to the C=N bond of N-benz-
ylimine (1) occurs with high yield and nearly total dia-
stereoselectivity to give syn-allylaminodiol (2). In an
As depicted in Scheme 2, N-acylation of compound 2
with acryloyl chloride cleanly afforded compound 5.
Treatment of this compound with first generation Grubbs’
catalyst afforded unsaturated d-lactam 68 in moderate
yield. Fortunately, the yield could be increased to 85%
when ring-closing metathesis was carried out with the
more active second generation Grubbs’ catalyst. Sub-
sequent diastereoselective dihydroxylation of 6 with cata-
lytic amounts of OsO4 in the presence of NMO took place
with acceptable yield and complete facial selectivity.
Dihydroxylation led to compound 7, with the expected
SYNLETT 2005, No. 11, pp 1734–1736
0
7
.0
7
.2
0
0
5
Advanced online publication: 14.06.2005
DOI: 10.1055/s-2005-871534; Art ID: D04805ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of 1,4-Dideoxy-1,4-imino-D-talitol
1735
stereochemistry, resulting from the addition of the bulky magnesium bromide to the N-benzylimine derived from
osmium reagent anti to the 1,2-dibenzyloxyethyl sub- (R)-glyceraldehyde, in the synthesis of polyhydroxylated
stituent. This change in our methodology necessitated pyrrolidines. N-Acylation, ring-closing metathesis and
the incorporation of an extra reduction step after the di- stereoselective dihydroxylation are key steps in the
hydroxylation reaction to transform the obtained d-lactam methodology described here, which allows efficient con-
into the desired pyrrolidine. Total reduction of the lactam trol of the stereochemistry in the creation of up to three
carbonyl group was satisfactorily accomplished with new stereogenic centres. Moreover, it is worth mentioning
LiAlH4 to yield 8.
that unsaturated lactam 6 can be considered as a structural
analogue of the versatile building block 3,4-didehydro-
pyroglutamate,10 in which the carboxylate moiety has
been replaced by the 1,2-dibenzyloxyethyl group. This
modification offers some important synthetic advantages
such as the absence of the carboxylate group, which re-
duces the acidity of the hydrogen atom at the stereogenic
centre in the five-membered ring, and the presence of an
additional stereogenic centre in the 1,2-dibenzyloxyethyl
side chain, which offers the possibility of transformation
and functionalisation. Elaboration of the side chain and/or
the lactam ring in compound 6 would allow the prepara-
tion of a variety of poly-substituted chiral heterocyclic
compounds such as pyrrolidines, pyrrolizidines, indoliz-
idines and fused lactams.
BnO
BnO
BnO
BnO
i
ii
BnN
BnNH
O
2
BnO
5
OH
BnO
OH
BnO
BnO
iii
iv
BnN
O
BnN
O
6
7
OH
OH
HO
BnO
OH
OH
HO
BnO
v
BnN
1,4-dideoxy-1,4-imino-D-talitol (9)
BnN
8
Acknowledgment
Scheme 2 Reagents and conditions: i) acryloyl chloride (1.2 equiv),
Et3N (1.5 equiv), dry CH2Cl2, 0 ºC to r.t., 15 h, 85%; ii) (a) benzyli-
denebis(tricyclohexylphosphine)ruthenium dichloride (8%), dry
CH2Cl2, r.t., 24 h, 50% or (b) benzylidene(1,3-dimesitylimidazolidin-
2-ylidene)(tricyclohexylphosphine)ruthenium dichloride (5%), dry
CH2Cl2, r.t., 15 h, 85%; iii) OsO4 (10%), NMO (2 equiv), acetone–
H2O 4:3, r.t., 24 h, 75%; iv) LiAlH4 (4 equiv), dry THF, r.t., 12 h,
70%; v) (a) H2, 10% Pd(OH)2/C, MeOH, D, 12 h; (b) Boc2O (2 equiv),
Et3N (2 equiv), dioxane, 60 ºC, 12 h; (c) H2, 10% Pd(OH)2/C, MeOH,
r.t., 24 h; (d) sat. AcOEt–HCl 10:1, r.t., 45 min, overall yield 80%.
This work was carried out with the financial support of the Ministe-
rio de Ciencia y Tecnología and FEDER (project CTQ2004-05358)
and the Diputación General de Aragón. R.D. was supported by a
Spanish MCYT Predoctoral Fellowship.
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Synlett 2005, No. 11, 1734–1736 © Thieme Stuttgart · New York

1736
R. Badorrey et al.
LETTER
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Synlett 2005, No. 11, 1734–1736 © Thieme Stuttgart · New York