Efficient stereodivergent synthesis of 1,4-dideoxy-1,4-iminohexitols from an (S)-glyceraldimine

Article abstract of DOI:10.1016/j.tetlet.2003.11.053

A stereodivergent synthesis of 1,4-dideoxy-1,4-imino-D-mannitol I and D-allitol III from an (S)-glyceraldimine, which is easily prepared from D-mannitol, has been achieved with overall yields of 62% and 49%, respectively. The synthesis is based on the add

Full text of DOI:10.1016/j.tetlet.2003.11.053

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 719–722
Efficient stereodivergent synthesis of 1,4-dideoxy-1,4-iminohexitols
from an (S)-glyceraldimine
*
ꢀ
Ramon Badorrey, Carlos Cativiela, Marıa D. Dıaz-de-Villegas, Roberto Dıez
ꢀ
ꢀ
ꢀ
*
ꢀ
and Jose A. Galvez
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Facultad de Ciencias, Instituto de Ciencia de Materiales de Aragon,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 7 October 2003; revised 6 November 2003; accepted 13 November 2003
Abstract—A stereodivergent synthesis of 1,4-dideoxy-1,4-imino-D-mannitol I and D-allitol III from an (S)-glyceraldimine, which is
easily prepared from -mannitol, has been achieved with overall yields of 62 and 49%, respectively. The synthesis is based on the
D
addition of vinylmagnesium bromide to N-benzylimine 1, derived from readily available (R)-2,3-O-isopropylideneglyceraldehyde,
followed by N-allylation or N-acryloylation, ring-closing metathesis and asymmetric dihydroxylation.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Polyhydroxylated pyrrolidines and piperidines (known
as azasugars) have attracted a great deal of attention in
recent years due to their ability to mimic sugars and
competitively and selectively inhibit glycosidases.1 Gly-
cosidase enzymes catalyse cleavage/formation of the
glycosidic bonds in carbohydrates and related mole-
cules2 and the effect of these enzymes on the structure of
cell-surface carbohydrates translates into important
biological consequences for processes such as carbohy-
drate absorption from the wall of the small intestine,3
tumour metastasis4 and viral infections.5 Such inhibitors
are therefore regarded as promising chemotherapeutic
agents against diabetes, metastatic cancer, malaria and
AIDS.
inhibitor of b-glucosidase and b-galactosidase and 1,4-
dideoxy-1,4-imino- -iditol V is a potent inhibitor of
L
a-galactosidases (Fig. 1). It therefore seems that modi-
fication of the configuration on one or more stereogenic
centres induces significant changes in their specificity or
potency as glycosidase inhibitors. Moreover, most 1,4-
dideoxy-1,4-iminohexitols that show biological activity
have the hydroxy groups on the pyrrolidine ring in a cis-
relative configuration.
The therapeutic importance of these compounds has led
to a great deal of synthetic effort being directed towards
their preparation.7 The majority of the reported meth-
odologies are based on the transformation of sugar
derivatives and are often lengthy and involved. How-
ever, to the best of our knowledge, approaches that
address the stereodivergent synthesis of 2,3-cis-1,4-
dideoxy-1,4-iminohexitols have not been undertaken.
1,4-Dideoxy-1,4-iminohexitols, which belong to the
family of polyhydroxylated pyrrolidines, are among the
most powerful glycosidase inhibitors.6 For example, 1,4-
dideoxy-1,4-imino-
furanose inhibitor of a-mannosidase and 1,4-dideoxy-
1,4-imino- -talitol II and 1,4-dideoxy-1,4-imino- -alli-
tol IV also show inhibitory activity towards a-man-
nosidases. In contrast, 1,4-dideoxy-1,4-imino- -allitol
D-mannitol I is the archetypal aza-
We previously reported8 reactions involving nucleo-
philic attack of vinylmagnesium bromide on imines 1
and 2, derived from (R)-2,3-O-isopropylideneglyceral-
dehyde and (R)-2,3-di-O-benzylglyceraldehyde, respec-
tively. The reactions proceed in high yield and with
excellent diastereoselectivity to give anti- and syn-am-
inodiol derivatives 3 and 4, respectively (Scheme 1).
These aminodiol derivatives have been successfully used
as synthetic precursors in the stereodivergent synthesis
of biologically important compounds with several chiral
centres.8b
D
L
D
III, the enantiomer of compound IV, was found to be an
Keywords: Asymmetric synthesis; Imines; Asymmetric dihydroxyla-
tion; Ring-closing metathesis.
* Corresponding authors. Tel.: +34-976-762274; fax: +34-976-761210;
e-mail addresses: loladiaz@unizar.es; jagl@unizar.es
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.053

720
R. Badorrey et al. / Tetrahedron Letters 45 (2004) 719–722
3,4-cis
OH
3,4-trans
OH
OH
OH
OH
OH
HO
OH HO
OHHO
OH
Dconfiguration
HN
II
HN
III
HN
I
OH
OH
OH
OH
HO
HO
OH
OH
Lconfiguration
HN
IV
HN
V
Figure 1. Structures of biologically active 1,4-dideoxy-1,4-iminohexitols.
OH
OH
OR
OR
DH
RCM
RO
HO
*
O
O
RO
OH
O
O
*
CH2=CHMgBr
Ref. 8
*
*
H
X
HN
BnN
BnN
N
HN
Bn
Bn
X = CH2, CO
OR
OR
1
3
RO
RO
*
H
BnO
BnO
CH2=CHMgBr
Ref. 8b
BnO
BnO
N
HN
Bn
Bn
H
N
HN
Scheme 2. Retrosynthetic analysis for the synthesis of 2,3-cis-1,4-di-
deoxy-1,4-iminohexitols from chiral imines derived from (R)-glycer-
aldehyde.
Bn
Bn
2
4
Scheme 1. Addition of vinylmagnesium bromide to chiral imines
derived from (R)-glyceraldehyde.
rolidine 6 in 85% yield. The yield was increased (up to
98%) when the RCM reaction was carried out using the
more active second generation GrubbsÕ catalyst B.14b
These results are remarkable given that dienes contain-
ing free amino groups are not usually good substrates
for ruthenium-catalysed RCM reactions.15
Ring-closing metathesis (RCM) reactions9 have been
widely used in the construction of five- or six-membered
nitrogen-containing heterocycles from functionalised
dienes. Moreover, in conjunction with dihydroxylation
(DH) reactions,10 RCM reactions have been successfully
used for the construction of enantiopure polyhydroxyl-
ated alkaloids.11 As depicted retrosynthetically in
Scheme 2, 2,3-cis-1,4-dideoxy-1,4-iminohexitols can be
prepared from readily available D-glyceraldimines. The
synthesis is based on the following key steps: addition of
vinylmagnesium bromide to N-benzylimines derived
from D-glyceraldehyde, N-alkylation or acylation of the
resulting aminodiol derivatives, ring-closing methathesis
and stereoselective dihydroxylation of the intermediate
dehydropyrrolidine.12 We report in this communication
our results obtained to date on applying the synthetic
scheme outlined above. This route has allowed the effi-
cient preparation of configurationally different 1,4-di-
deoxy-1,4-iminohexitols I and III from the same chiral
starting material.
In the next step, an asymmetric cis-dihydroxylation
reaction was assessed. First, catalytic dihydroxylation of
6 with osmium tetroxide was attempted in the presence
of different co-oxidants such as N-methylmorpholine
N-oxide (NMO) and K3Fe(CN)6. Extensive experimen-
tation gave rise to complex mixtures of products under
all the reaction conditions tested. The major compound
was isolated and identified as the pyrrole resulting from
aromatisation of 6. This compound was obtained
exclusively, albeit in a low yield, when the dihydroxyl-
ation reaction was carried with equimolar amounts of
potassium permanganate, a classical alternative to
osmium tetroxide. Sharpless16 showed that DH reac-
tions in the presence of cinchona alkaloid-based ligands
are much faster than those in the absence of such
systems and, on this basis, cis-hydroxylation of 6 using
commercially available AD-mix was tested. The use of
AD-mix-b in our reaction gave the desired diol 7 in a
very highly diastereoselective manner (dr 10/1 from
NMR analysis of the crude reaction mixture) and a
single diastereomer was isolated in 85% yield by column
chromatography. The use of AD-mix-a, on the other
hand, gave rise to a diastereoselectivity of almost zero
(mismatched pair).
Enantiopure aminodiol 3 was prepared following our
previously described procedure8 by addition of vinyl-
magnesium bromide to (S)-glyceraldimine 1, which is
readily available on a multi-gram scale from the inex-
pensive
tol
D
-mannitol.13 1,4-Dideoxy-1,4-imino-
and 1,4-dideoxy-1,4-imino- -allitol III were
obtained from anti-aminodiol derivative 3 as shown in
D-manni-
I
D
Scheme 3.
Allylation of 3 with allyl bromide in the presence of
NaH and DMF proceeded cleanly to give 1,6-diene 5 in
excellent yield. Treatment of compound 5 with first
generation GrubbsÕ catalyst A14a afforded dehydropyr-
Finally, N-debenzylation and acetonide deprotection in
compound 7 was achieved in one step by catalytic
hydrogenolysis with Pd(OH)2/C in the presence of HCl
to give 1,4-dideoxy-1,4-imino-D-mannitol I as its HCl

R. Badorrey et al. / Tetrahedron Letters 45 (2004) 719–722
721
OH
OH
OH
O
O
O
O
O
O
HO
OH
OH
ii)
iii)
iv)
HN
BnN
BnN
BnN
6
7
I
5
i)
-
Cl
-
Mes N N Mes
PCy3
Ru
O
Cl
O
Ru
Cl
Cl
Ph
Ph
HN
PCy3
PCy3
Bn
3
A
B
v)
OH
O
OH
OH
O
O
O
O
O
HO
OH
OH
vii)
vi)
viii)
ix)
HN
III
-allitol III. Reagents and conditions: (i) allyl bromide, NaH,
BnN
BnN
BnN
O
O
O
8
9
10
Scheme 3. Synthesis of 1,4-dideoxy-1,4-imino-
D
-mannitol I and 1,4-dideoxy-1,4-imino-
D
DMF, 0 ꢁC fi rt, 12 h, 93%; (ii) (a) 8% GrubbsÕ catalyst A, CH2Cl2, rt, 12 h, 85%; (b) 5% GrubbsÕ catalyst B, CH2Cl2, reflux, 24 h, 97%; (iii) AD-mix-
b, MeSO2NH2, tert-butanol/H2O (1:1), 0 ꢁC fi rt, 24 h, 85%; (iv) H2, Pd(OH)2/C, MeOH/HCl (100:1), rt, 12 h, ꢁ100%; (v) acryloyl chloride, Et3N,
CH2Cl2, 0 ꢁC fi rt, 3 h, 93%; (vi) (a) 8% GrubbsÕ catalyst A, CH2Cl2, reflux, 36 h, 85%; (b) 5% GrubbsÕ catalyst B, CH2Cl2, reflux, 36 h, 98%; (vii) 10%
OsO4, NMO, acetone/H2O, rt, 48 h, 80%; (viii) LiAlH4, THF, reflux, 3 h, 85%; (ix) H2, Pd(OH)2/C, MeOH/HCl (100:1), 98%.
25
D
25
D
salt, ½aꢀ )15.7ꢁ (c 1, H2O) [lit.17 ½aꢀ )16.3ꢁ (c 1, H2O)]
In conclusion, a very efficient diastereodivergent syn-
thesis of 1,4-dideoxy-1,4-imino- -mannitol I and 1,4-
dideoxy-1,4-imino- -allitol III from aminodiol deriva-
The spectral data of I are identical to those reported in
the literature.17 This synthetic process, which involves
five steps from starting imine 1, gave azasugar I in 62%
overall yield.
D
D
tive 3 has been developed. The key step in the stereo-
divergent synthesis is the asymmetric dihydroxylation
reaction of 2,5-dihydro-1H-pyrrole 6 and 1,5-dihydro-
pyrrol-2-one 9, which were obtained by RCM of N-allyl
and N-acryloyl derivatives of 3, respectively. These
synthetic routes can be adapted for the synthesis of
other diastereoisomers of 2,3-cis-1,4-dideoxy-1,4-imi-
nohexitols; for example, II could be synthesised starting
from aminodiol 4, obtained by the addition of vinyl-
magnesium bromide to (S)-2,3-di-O-benzylglyceralde-
Alternatively, aminodiol 3 was converted into 1,4-dide-
oxy-1,4-imino-D-allitol III by dihydroxylation of the
intermediate unsaturated c-lactam 9. N-Acylation of
compound 3 with acryloyl chloride followed by RCM of
the resulting amide 8 gave intermediate 9 in excellent
yield. Treatment of this compound with a catalytic
amount of OsO4 in the presence of NMO led to a highly
diastereoselective dihydroxylation reaction that gave
diol 10 together with a similar amount of a by-product.
The by-product was isolated by column chromatogra-
phy and identified as a cyclobutane derived from 9. It
was reasoned that this by-product could be formed
through a photochemical reaction. The dihydroxylation
was subsequently carried out in the absence of light and
this change in the reaction conditions led to the exclusive
formation of cis-diol 10 as a single diastereoisomer in
80% yield without contamination by the undesired
by-product. In this case the dihydroxylation of 9 took
place with complete facial selectivity––syn to the 1,3-
dioxolane group. This stereochemical outcome is at first
sight surprising but similar results have been reported
for other five-membered rings.7e;10b;18 Finally, reduction
of the carbonyl group in compound 10 followed by one-
hyde
-configuration could also be obtained using the corre-
sponding imines derived from -glyceraldehyde, which
are readily available from
-mannonic c-lactone.20 This
N-benzylimine.
Similar
azasugars
with
L
L
L
methodology is very flexible in terms of stereochemical
manipulation, since the stereochemistry of up to three
new stereogenic centres can be efficiently controlled. The
extension of the work described here to the stereo-
divergent synthesis of 2,3-trans-1,4-dideoxy-1,4-imino-
hexitols and the synthesis of other related alkaloids with
five- or six-membered rings is now in progress and
detailed results will be published in due course.
Acknowledgements
step acetonide and benzyl deprotection provided 1,4-
25
-allitol III as its HCl salt, ½aꢀ
dideoxy-1,4-imino-
D
This work was carried out with the financial support of
D
25
D
+28.5ꢁ (c 0.5, H2O) [lit.19 ½aꢀ +29.4ꢁ (c 0.53, H2O)], in
the Ministerio de Ciencia y Tecnologıa and FEDER
ꢀ
ꢀ
(project PPQ2001-1834) and the Diputacion General de
49% overall yield from imine 1. The NMR data and
specific rotation are in good agreement with those
reported in the literature.19
ꢀ
Aragon. R.D. was supported by a Spanish MCYT
Predoctoral Fellowship

722
R. Badorrey et al. / Tetrahedron Letters 45 (2004) 719–722
1998, 54, 4413–4450; (c) Phillips, A. J.; Abell, A. D.
References and notes
€
Aldrichim. Acta 1999, 32, 75–89; (d) Furstner, A. Angew.
Chem., Int. Ed. Engl. 2000, 39, 3012–3043; (e) Trnka, T.
N.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (f)
Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–
3712, and references cited therein.
1. (a) Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, 1999;
(b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645–1680.
10. (a) Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.;
Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817–819;
(b) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67,
7774–7780; (c) Lindsay, K. B.; Tang, M.; Pyne, S. G.
2. (a) Sinnott, M. L. Chem. Rev. 1990, 90, 1171–1202; (b)
Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed.
Engl. 1999, 38, 750–770; (c) Zechel, D.; Withers, S. G. Acc.
Chem. Res. 2000, 33, 11–18.
3. (a) Rhinehart, B. L.; Robinson, K. M.; Payne, A. J.;
Wheatly, M. E.; Fisher, J. L.; Liu, P. S.; Cheng, W. Life
Sci. 1987, 41, 2325–2331; (b) Johnson, P. S.; Lebovitz, H.
E.; Coniff, R. F.; Simonson, D. C.; Raskin, P.; Munera, C.
L. J. Clin. Endocrinol. Metab. 1998, 83, 1515–1522.
4. Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R.
Cancer Res. 1988, 48, 1091–1094.
5. (a) Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L.
E.; Tyms, A. S.; Peturrson, S.; Namgoong, S. K.;
Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F.;
Witty, D. R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett.
1988, 237, 128–132; (b) Gruters, R. A.; Neefjes, J. J.;
Tersmette, M.; de Goede, R. E. Y.; Tulp, A.; Huisman, H.
G.; Miedema, F.; Ploegh, H. L. Nature 1987, 330, 74–77.
6. (a) Carmona, A. T.; Fuentes, J.; Robina, I. J. Org. Chem.
2003, 68, 3874–3883, and references cited therein; (b)
Lundt, I.; Madsen, R.; Al Daher, S.; Winchester, B.
Tetrahedron 1994, 50, 7513–7520, and references cited
therein.
ꢀ
ꢀ
ꢀ
Synlett 2002, 731–734; (d) Martın, R.; Alcon, M.; Pericas,
M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896–6901.
11. For recent reviews on asymmetric dihydroxylation, see: (a)
Kolb, H. C.; VanNieuwhenze, M.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547; (b) Kolb, H. C.; Sharpless, K.
B. In Transition Metals in Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2; pp
219–242.
12. During the preparation of this manuscript, Madhan and
Rao (see Ref. 7e) reported the preparation of 1,4-dideoxy-
1,4-imino-D-allitol III in 17% overall yield from N-
benzylimine 1 derived from (R)-2,3-O-isopropylideneglyc-
eraldehyde through a synthetic strategy based on previous
investigations developed in our laboratory (see Ref. 8a).
13. Imine 1 ws obtained according to synthetic procedure
ꢀ
described in Cativiela, C.; Dıaz-de-Villegas, M. D.;
Galvez, J. A. Tetrahedron: Asymmetry 1996, 7, 529–536.
ꢀ
14. (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041; (b)
Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247–2250.
7. See, for example: (a) Blanco, M.-J.; Sardina, F. J. J. Org.
Chem. 1996, 61, 4748–4755; (b) Kieß, F. M.; Poggendorf,
15. See, for example: Rutjes, P. J. T.; Schoemaker, H. E.
Tetrahedron Lett. 1997, 38, 677–680.
16. Sharpless, K. B.; Amberg, W.; Bennari, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.;
Morikawa, K.; Wang, Z. M.; Xu, D.; Zan, X. L.
J. Org. Chem. 1992, 57, 2768–2771.
€
P.; Picasso, S.; Jager, V. Chem. Commun. 1998, 119–120;
(c) Jonson, L. L., Jr.; Houston, T. A. Tetrahedron Lett.
2002, 43, 8905–8908; (d) Pulz, R.; Al-Harrasi, A.; Reissig,
H.-V. Org. Lett. 2002, 4, 2353–2355; (e) Madhan, A.; Rao,
B. V. Tetrahedron Lett. 2003, 44, 5641–5643, and refer-
ences cited therein.
17. Bashyal, B. P.; Fleet, G. W. J.; Gough, M. J.; Smith, P. W.
Tetrahedron 1987, 43, 3083–3093.
ꢀ
8. (a) Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M. D.;
Galvez, J. A. Synthesis 1997, 747–749; (b) Badorrey, R.;
ꢀ
18. Poli, G. Tetrahedron Lett. 1989, 30, 7385–7388.
19. Fleet, G. W. J.; Cahn Son, J. Tetrahedron 1988, 44, 2637–
2647.
ꢀ
ꢀ
ꢀ
Cativiela, C.; Dıaz-de-Villegas, M. D.; Dıez, R.; Galvez, J.
A. Eur. J. Org. Chem. 2003, 2268–2275.
9. For recent reviews on olefin metathesis, see: (a) Schuster,
M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036–2055; (b) Grubbs, R. H.; Chang, S. Tetrahedron
ꢀ
20. Badorrrey, R.; Cativiela, C.; Dıaz-de-Villegas, M. D.;
ꢀ
Galvez, J. A. Tetrahedron 2002, 58, 341–354.