A concise synthesis of 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and HomoDMDP from l-xylose

Article abstract of DOI:10.1016/j.tetlet.2007.01.125

A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP.

Full text of DOI:10.1016/j.tetlet.2007.01.125

Tetrahedron Letters 48 (2007) 2369–2372
A concise synthesis of 2,5-dideoxy-2,5-imino-D-mannitol
(DMDP) and HomoDMDP from L-xylose
Jean-Bernard Behr* and Georges Guillerm
Laboratoire Re´actions Se´lectives et Applications UMR 6519, UFR Sciences—CNRS, BP 1039, 51687 Reims Cedex 2, France
Received 4 December 2006; revised 21 January 2007; accepted 24 January 2007
Available online 30 January 2007
Abstract—A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2
substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization
to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of
the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP.
Ó 2007 Elsevier Ltd. All rights reserved.
Naturally occurring polyhydroxypyrrolidines such as
DMDP (2,5-dideoxy-2,5-imino-D-mannitol) 1 and the
related analogues 2 and 3 (Fig. 1) display potent bio-
logical activities including anti-HIV effect,1 tumour
growth inhibition2 or antifeedant properties against pest
insects.3 These nitrogen-containing sugar analogues are
known to interfere with glycoprocessing enzymes (glyco-
sidases or glycosyltransferases) by mimicking the natu-
ral glycoside substrate.4 In this regard, DMDP is a
powerful a- and b-glucosidase inhibitor displaying Ki’s
in the micromolar range and homoDMDP 2 inhibits
specifically a-glucosidases.5 Compound 3 (6-deoxy-
homoDMDP) has less pronounced glycosidase inhibi-
tory potencies but was found to inhibit potently chitin
synthase (Ki = 38 lM), an obligate and specific fungal
glycosyl transferase.6
It was found recently that O-alkylated as well as N-
alkylated derivatives of DMDP featuring a hydrophobic
substituent at C-2 (such as 4a), display unprecedented
Ki’s in the nanomolar range towards b-glucosidases.7
The synthesis of these derivatives is usually performed
starting from 1 itself or from the corresponding amine
4b.5,8 A new library of O-alkylated DMDP analogues
might also be obtained from a partially protected ana-
logue such as 5 (Fig. 1). Hence, in view of the biological
potential of DMDP, HomoDMDP and their deriva-
tives, efficient approaches are still needed. We report
herein a new synthesis of the key compounds 1, 2 or 5
that involves the stereoselective addition of vinylmagne-
sium bromide to a suitably protected L-xylose deriva-
tive, followed by a bis-mesylation/double nucleophilic
displacement sequence.
OH
H
N
H
N
HO
HO
R
OH
HO
1 : R=OH
3 : R=CH2OH
OH
HO
OH
2
4a : R=NHdansyl
4b : R=NH2
Bn
N
BnO
OH
In a previous work we have applied with success a
practical route to iminosugars, starting from benzyl-
glycosylamines, via the nucleophilic addition of an
organometallic species and subsequent cyclization with
methanesulfonylchloride (Scheme 1, X = NBn).9,10
However, in this case, the addition is syn selective and
affords, starting from benzyl-L-xylofuranosylamine, a
D-gluco configurated iminosugar B as the main product.
Due to the high selectivities observed with vinylmagne-
sium bromide or other organometallics, this synthetic
BnO
OBn
5
Figure 1. Structures of iminosugars 1–5.
Keywords: Pyrrolidines; Glycosidase inhibitors; HomoDMDP;
Homoazasugars.
*
Corresponding author. Tel.: +33 326 913 238; fax: +33 326 913
166; e-mail: jb.behr@univ-reims.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.125

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J.-B. Behr, G. Guillerm / Tetrahedron Letters 48 (2007) 2369–2372
The transformation of the major stereoisomer 7a into
OH
XH
O
XH
RMgBr
the targeted iminosugars required three distinct steps:
(i) activation of the free hydroxyl substituents at C-3
and C-6 by a leaving group, (ii) amination with benzyl-
amine via a sequential nucleophilic displacement at both
positions, (iii) bis-hydroxylation of the double bond.
Activation of the 3-OH and the 6-OH was performed
by standard esterification of 7a with an excess of meth-
anesulfonyl chloride in the presence of triethylamine
at 0 °C. Under these conditions, the transformation
occurred efficiently and bis-mesylate 8 was obtained in
91% yield after purification by silica gel chromato-
graphy (CHCl3/Et2O/petroleum ether: 5/3/2, v/v).
Attempts to introduce a more efficient leaving group
failed. Reaction of 7a with chloromethanesulfonyl chlo-
ride13 afforded C-vinyl furanosid 9 as the main product
(43%) after spontaneous cyclization of the intermediate
6-OMs monoprotected ester. Such cycloetherification
process has been observed frequently as an unexpected
side reaction with triflates derived from 1,4-diols and
even exploited for the synthesis of a series of C-vinyl
furanosides.14
R
BnO
BnO
BnO
BnO
OBn
OBn
X=O
X=NBn
X = NBn
X = O
1) MsCl
1) MsCl
2) BnNH2
Bn
N
Bn
N
R
R
BnO
BnO
A (D-manno)
BnO
BnO
B (D-gluco)
OBn
OBn
Scheme 1. Strategies for the synthesis of five-membered iminosugars.
route is not applicable to compounds like 1 or 2 which
would result from the minor anti isomer.
The formation of the pyrrolidine ring from bis-mesylate
8 was envisioned by reaction with benzylamine. Such a
transformation has already been performed in the liter-
ature and proved effective with primary mesylates.15
Only few examples of such ring formation are described,
which involve two secondary activated hydroxyl
groups.16 In this latter case, long time reaction and high
temperature are required to allow the substitution to
take place. Surprisingly, on reaction with benzylamine
at 50 °C, bis-mesylate 8a was readily converted to a
more polar product which was isolated in 76% yields
after chromatography on silica gel (eluent: AcOEt).
The so-obtained monomesylate 10a, the structure of
which was ascertained by spectroscopic and analytical
data, arose from a more favourable SN20 process as out-
lined in Scheme 2. The same reaction was observed when
8 was reacted with sodium azide affording 10b. Interest-
ingly, this unexpected reaction could be exploited for the
synthesis of 7-membered-ring iminosugars. Neverthe-
less, to circumvent this side reaction, osmylation of the
double bond was performed before the nucleophilic dis-
placement. Thus, the reaction of bismesylate 8 with
OsO4 in the presence of NMO according to well-exper-
imented procedures17 gave a mixture of the two possible
diols 11a,b (89% yield, 20% de), which could be resolved
by chromatography (Et2O/petroleum ether: 1/1, v/v)
after transformation to the corresponding acetonides
12a,b. The configuration of the newly formed stereocen-
tre was established after transformation of 12a to the
known HomoDMDP 2, which features the (10S) config-
uration at the corresponding position.18 At this stage of
our project, no attempts were undertaken in order to
improve the stereoselectivity of the bis-hydroxylation
procedure.
It is well known that the addition of organometallics to
aldoses follows the same syn selectivity.11,12 However,
only few attempts to prepare iminosugars by this chain
elongation strategy have been described.2a Interestingly,
the major stereoisomer obtained in this case would
afford a D-manno iminosugar A (Scheme 1, X = O) after
introduction of nitrogen with concomitant inversion of
configuration at both the free hydroxyl groups.
To demonstrate the efficiency of this methodology, we
initially examined its application to the synthesis of
homoDMDP (Scheme 2). Accordingly, we performed
the addition of vinylmagnesium bromide to 2,3,5-tri-
O-benzyl-L-xylose 6. When the Grignard reagent was
slowly added to a solution of the aldose 69 in THF at
room temperature, a mixture of the two possible stereo-
isomers was obtained in a 28% de in favour of the syn
adduct 7a (HPLC determination) and 90% isolated yield
(7a + 7b). These results are analogous to those obtained
by Boschetti et al. in the enantiomeric series.12 Interest-
ingly, adducts 7a,b could be easily separated by standard
flash chromatography on silica gel (eluent, CHCl3/Et2O:
7/3, v/v). The 1H and 13C NMR data of 7a and 7b were
identical to those described for the enantiomers and the
optical rotations that we measured were in good agree-
20
ment with the reported values: we found ½aꢀD ꢁ6.1 for
20
the major isomer 7a (lit. ½aꢀD +6.7 for the enantiomer)12
20
20
and ½aꢀD +17.7 for the minor 7b (lit. ½aꢀD ꢁ14.3 for the
enantiomer). When the reaction was performed at 0 °C,
an increase in stereoselectivity was observed (de = 46%
as determined by HPLC, 83% overall yield). Interest-
ingly, when the reaction was performed at room temper-
ature in the presence of ZnBr2 the selectivity was
markedly improved in favour of the expected syn isomer
(70% de), as already observed in the D-series.12 Never-
theless, in this case, only 70% conversion was obtained
after 6 days of reaction (40% isolated yield), hampering
the use of these reaction conditions at a preparative
scale.
The nucleophilic displacement of acetonide 12a with
benzylamine required some optimization. When the
reaction was performed in a sealed tube at 135 °C with
a slight excess of benzylamine according to the recom-
mended procedure,16b partial conversion was observed

J.-B. Behr, G. Guillerm / Tetrahedron Letters 48 (2007) 2369–2372
2371
HO
HO
OH
1
OH
O
OH
OBn
a
6
+
BnO
BnO
BnO
3
2
5
4
BnO
BnO
OBn
BnO
OBn
6
7a (73%)
7b (27%)
b
MsO
O
MsO
OMs
OBn
Nu
Nu
BnO
BnO
BnO
-
[BnNH2 or N3 ]
93%
BnO
OBn
BnO
OBn
10a,b
BnO
9
8
c
MsO
OMs
OH
BnO
OH
OBn
BnO
11a,b
d
MsO
MsO
OMs
OBn
OMs
OBn
O
O
BnO
BnO
O
O
BnO
BnO
60)
12a
( 40
:
12b
e
e
69%
73%
Bn
N
Bn
N
O
O
O
O
BnO
BnO
BnO
OBn
BnO
OBn
13a
13b
g,h
f
2
5
i
1
Scheme 2. Reactions and conditions: (a) vinylMgBr, THF, 0 °C, 91%; (b) MsCl, NEt3, CH2Cl2, 91%; (c) OsO4, NMO, acetone/water, 80%; (d)
acetone, TsOH, 89%; (e) BnNH2, 120 °C; (f) 80% HCOOH then H2, Pd(OH)2/C, 70%; (g) 5% TFA in CH2Cl2, 100%; (h) NaIO4 in EtOH/water, then
NaBH4, 66%; (i) HCOONH4, 10% Pd/C, MeOH, reflux, 67%.
and pyrrolidine 13a was isolated in an unsatisfactory
30% yield. Same results were obtained when the reaction
was conducted under microwave irradiation. Neverthe-
less, the best results were obtained when 12a was reacted
under argon with a large excess of freshly distilled benz-
ylamine at 120 °C. Complete conversion occurred after
24 h and the protected iminosugar 13a was isolated in a
pure form after silica gel chromatography (Et2O/petro-
leum ether: 2/8, v/v) in 69% yield. Standard deprotec-
tion procedures (80% formic acid, then H2–Pd/C)
afforded HomoDMDP 2 in 70% yield (2 steps) after
ion-exchange chromatography (Dowex 50WX-8, elution
with 0.8 M NH4OH). Spectral data as well as optical
20
rotation of 2 ð½aꢀD +32.0) were in agreement with the
20
reported values ð½aꢀD +25.6).18
DMDP 1 was prepared starting from acetonide 12b.
Cyclization with benzylamine gave the protected imino-
sugar 13b (61% yield), which was converted to the par-
tially protected DMDP derivative 419 by the following

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J.-B. Behr, G. Guillerm / Tetrahedron Letters 48 (2007) 2369–2372
4. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
reaction sequence: deprotection of the acetonide with
5% TFA in CH2Cl2, treatment with sodium periodate
and subsequent reduction of the aldehyde with sodium
borohydride (66% overall yield). Debenzylation of 4
was performed by hydrogen transfer with ammonium
formate in the presence of 10% Pd/C in refluxing meth-
anol, affording the title compound 1 in 67% yield.
Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, Ger-
¨
many, 1999.
5. Wrodnigg, T. M. Monatsh. Chem. 2002, 133, 393–
426.
6. (a) Djebaili, M.; Behr, J.-B. J. Enzyme Inhib. Med. Chem.
2005, 20, 123–127; (b) Behr, J.-B. Curr. Med. Chem. 2003,
2, 173–189.
7. Hermetter, A.; Scholze, H.; Stutz, A. E.; Withers, S. G.;
¨
In conclusion, a new method has been developed for the
preparation of iminosugars, which involves the stereo-
selective addition of a Grignard to a 2,3,5-protected
aldofuranose, followed by a bis-mesylation/double
nucleophilic displacement sequence. Our synthesis of
HomoDMDP (7 steps) compares favourably in terms
of length with the one reported in literature (12 steps).
Further investigations on synthetic applications of this
methodology are currently underway in our laboratory.
Wrodnigg, T. Bioorg. Med. Chem. Lett. 2001, 11, 1339–
1343.
8. (a) Wrodnigg, T.; Stutz, A. E.; Tarling, C. A.; Withers, S.
¨
G. Carbohydr. Res. 2006, 341, 1717–1722; (b) Izquierdo,
I.; Plaza, M. T.; Tamayo, J. A. Tetrahedron 2005, 61,
6527–6533.
9. Gautier-Lefebvre, I.; Behr, J.-B.; Guillerm, G.; Muzard,
M. Eur. J. Med. Chem. 2005, 40, 1255–1261.
10. Behr, J.-B.; Mvondo-Evina, C.; Phung, N.; Guillerm, G. J.
Chem. Soc., Perkin Trans. 1 1997, 1597–1601.
11. (a) Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.;
Haudrechy, A. Chem. Rev. 2006, 106, 2355–2403; (b)
Palmelund, A.; Madsen, R. J. Org. Chem. 2005, 70, 8248–
8251; (c) Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett.
2000, 41, 7801–7803; (d) Pearson, W. H.; Hembre, E. J. J.
Org. Chem. 1996, 61, 5546–5556; The anti selectivity has
been observed in some cases, confined to 2,3-O-isopropyl-
idene protected sugars: (e) Venkata, R. G.; Venkateswara,
R. B. Tetrahedron Lett. 2006, 47, 4441–4443; (f) Marco-
Contelles, J.; De Opazo, E. Tetrahedron Lett. 1999, 40,
4445–4448; (g) Mekki, B.; Singh, G.; Wightman, R. H.
Tetrahedron Lett. 1991, 32, 5143–5146.
Acknowledgement
The authors would like to thank H. Baillia and D. Hara-
kat for technical support (NMR and MS) as well as
Abdel Helimi for his participation to some aspects of
this project.
Supplementary data
1H and 13C NMR spectra for compounds 1, 2, 5, 7, 8,
12, 13 are provided. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.01.125.
12. Boschetti, A.; Nicotra, F.; Panza, L.; Russo, G. J. Org.
Chem. 1988, 53, 4181–4185.
13. Hiranuma, S.; Shimizu, T.; Nakata, T.; Kajimoto, T.;
Wong, C.-H. Tetrahedron Lett. 1995, 36, 8247–8250.
14. Martin, O. R.; Yang, F.; Xie, F. Tetrahedron Lett. 1995,
36, 47–50.
15. (a) Taylor, C. M.; Barker, W. D.; Weir, C. A.; Park, J. H.
J. Org. Chem. 2002, 67, 4466–4474; (b) Lee, R. E.; Smith,
M. D.; Nash, R. J.; Griffiths, R. C.; McNeil, M.; Gewal,
R. K.; Yan, W.; Besra, G. S.; Brennan, P. J.; Fleet, G. W.
J. Tetrahedron Lett. 1997, 38, 6733–6736.
16. (a) Nasri, R.; Pinto, B. M. Carbohydr. Res. 2006, 341,
2305–2311; (b) Esopsito, A.; Falorni, M.; Taddei, M.
Tetrahedron Lett. 1998, 39, 6543–6546.
References and notes
1. De Malo, E. B.; Gomes, A. D. S.; Carvalho, I. Tetrahe-
dron 2006, 62, 10277–10302; Robina, I.; Moreno-Vargas,
A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab. 2004,
5, 329.
2. (a) Moreno-Vargas, A. J.; Carmona, A. T.; Mora, F.;
Vogel, P.; Robina, I. Chem. Commun. 2005, 4949–4951;
17. Behr, J.-B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem.
2002, 1256.
(b) Fiaux, H.; Popowycz, F.; Favre, S.; Schutz, C.; Vogel,
¨
18. Takebayashi, M.; Hiranuma, S.; Kanie, Y.; Kajimoto, T.;
Kanie, O.; Wong, C.-H. J. Org. Chem. 1999, 64, 5280–
5291.
P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J. Med.
Chem. 2005, 48, 4237–4246; (c) Nishimura, Y. Curr. Top.
Med. Chem. 2003, 3, 575–591.
19. Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem.
2002, 67, 7203–7214.
3. Blaney, W. M.; Simmonds, M. S. J.; Evans, S. V.; Fellows,
L. E. Entomol. Exp. Appl. 1984, 36, 209–216.