Synthesis of 6-deoxy-homoDMDP and its C(5)-epimer: Absolute stereochemistry of natural products from Hyacinthus orientalis

Article abstract of DOI:10.1016/S0957-4166(02)00081-2

A concise enantioselective synthesis of 2,5-imino-2,5,6-trideoxy-D-manno-heptitol (6-deoxy-homoDMDP) and 2,5-imino-2,5,6-trideoxy-L-gulo-heptitol has been achieved. These compounds were used as stereochemical references to establish the absolute configuration of the corresponding naturally occurring stereoisomers, recently isolated from Hyacinthus orientalis.

Full text of DOI:10.1016/S0957-4166(02)00081-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 111–113
Synthesis of 6-deoxy-homoDMDP and its C(5)-epimer: absolute
stereochemistry of natural products from Hyacinthus orientalis
Jean-Bernard Behr and Georges Guillerm*
Laboratoire de Chimie Bioorganique UMR 6519, UFR Sciences BP 1039, 51687 Reims Cedex 2, France
Received 21 December 2001; accepted 15 February 2002
Abstract—A concise enantioselective synthesis of 2,5-imino-2,5,6-trideoxy-
D-manno-heptitol (6-deoxy-homoDMDP) and 2,5-
imino-2,5,6-trideoxy- -gulo-heptitol has been achieved. These compounds were used as stereochemical references to establish the
L
absolute configuration of the corresponding naturally occurring stereoisomers, recently isolated from Hyacinthus orientalis.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(plants and micro-organisms) by enantiospecific synthe-
sis and was found to be the opposite to the previously
proposed one.6 Recently, two new structurally related
natural products, (+)-2,5-imino-2,5,6-trideoxy-manno-
heptitol (6-deoxy-homoDMDP 2 or its enantiomer) and
(+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol 3 (or its enan-
tiomer) have been isolated from Hyacinthus orientalis
and were found to display interesting specific glycosi-
dase inhibitory properties.7 The relative configurations
of these compounds were established by NMR studies
but to date, no syntheses of these iminosugars have
been performed to confirm their absolute configurations
(Fig. 1).
Iminosugars have gained increasing importance in the
emerging field of glycosidase and glycosyltransferase
inhibition. The ability of these alkaloids to interfere
with the degradation or the formation of oligosaccha-
rides is generally attributed to their potency in mimick-
ing the putative cation-like transition state involved in
both enzymatic reactions.1 A number of natural and
synthetic compounds in the pyrrolidine subgroup dis-
play interesting bioactivity.2 Among these DMDP 1
originally isolated from Derris elliptica3 was shown to
be a potent inhibitor of a large range of a- and b-
glucosidases4 whilst DMDP exhibits interesting anti-
viral, anti-feedant and nematicidal activity.5 The
defined absolute configuration of natural DMDP
(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)-3,4-dihydroxy-
pyrrolidine has been assigned a few years after the
isolation of this metabolite from different sources
In our aim dealing with research of new chitin syn-
thetase inhibitors (N-acetylglucosaminyl transferase,
EC 2.4.1.16), we planned to use 6-deoxy-homoDMDP
2 and its C(5)-epimer 3 as building blocks in molecular
structures of new models of transition-state and bisub-
H
H
H
OH
N
N
N
HO
HO
HO
HO
HO
HO
OH
HO
HO
OH
OH
DMDP,
6-deoxyhomoDMDP,
1
2
3
Figure 1. Structure of compounds 1–3.
* Corresponding author. Tel.: +33-326913308; fax: +33-326913166; e-mail: georges.guillerm@univ-reims.fr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00081-2

112
J.-B. Behr, G. Guillerm / Tetrahedron: Asymmetry 13 (2002) 111–113
strate analogue inhibitors of this enzyme.8 We wish to
report herein the synthesis of both iminosugars 2 and 3,
which could permit a definitive assignment of the abso-
lute configurations of the natural occurring 6-deoxy-
homoDMDP 2 and its diastereoisomer 3 recently
isolated by Asano et al.7
anomeric carbon followed by treatment with a Grig-
nard reagent and subsequent cyclisation is an easy
process which has widely been used for the preparation
of functionalised pyrrolidines.10 Compounds 2 and 3
were prepared by this process starting from
depicted in Scheme 1.
L-xylose, as
Anomerisation of L-xylose with methanol/HCl gave a
2. Synthesis
mixture of both methyl glycosides which were benzyl-
ated using classical procedures.11 After deprotection of
the acetal (1 M HCl in dioxane), the resulting protected
Many synthetic approaches have been described for the
preparation of iminosugars, including chemical and
enzymatic methods.9 Among these, the procedure ini-
tially described by Nicotra involving amination of the
L
-xylofuranose was treated with an excess of benzyl-
amine to give the corresponding glycosylamine 4 in
quantitative yield. Addition of allylmagnesium chloride
Scheme 1. Reagents and conditions: (i) MeOH/HCl, 100%; (ii) BnBr, Ba(OH)2, DMF, 40%; (iii) aq. HCl, reflux. Dioxane, 50%;
,
(iv) BnNH2, CH2Cl2, 4 A MS, 98%; (v) allylmagnesium choride, THF, 0°C; 91%; (vi) MsCl, Py (6a, 79%; 6b, 97%); (vii) H2SO4,
O3; then NaBH4, MeOH, 74%; (viii) 10% Pd–C, HCOONH4, MeOH, 60°C, 40%.

J.-B. Behr, G. Guillerm / Tetrahedron: Asymmetry 13 (2002) 111–113
113
to imine 4 at 0°C afforded a mixture (40:60) of the two
possible diastereoisomers 5a and 5b in good yield (91%).
gave a substantial NOE on C(1) protons, showing the
cis relationship between both substituents (Scheme 1).
Isomers 5a and 5b can be easily separated at this stage
by chromatography on silica gel eluting with diethyl
ether/petroleum ether (v/v, 1/1). The configuration of
the newly created C(5) stereogenic centre in 5a [h]2D0=
+9.9 (c=1.56, CHCl3) and 5b [h]2D0=−3.7 (c=0.86,
CHCl3) was unambiguously assigned after their conver-
sion to the respective pyrrolidines 6a and 6b (Scheme 1).
This was easily achieved in one step by treating amino
alcohols 5a and 5b with methanesulfonyl chloride. The
corresponding mesylates formed, which were not iso-
lated, underwent intramolecular cyclisation with the
secondary amine with concomitant inversion at C(2) to
give pyrrolidines 6a and 6b. Oxidation of the double
bond by ozonolysis was performed on the sulphate salts
of 6a and 6b to avoid oxidation of the amine function,
and led to the corresponding aldehydes, which were
somewhat unstable and could not be further purified.
Subsequently, reduction with sodium borohydride gave
alcohols 7a and 7b in 74% yield from 6a and 6b,
respectively. Final deprotection was best achieved by
transfer-catalysed hydrogenation (ammonium formate,
10% Pd–C in refluxing MeOH), to give after purification
by preparative HPLC, compound 2 [h]2D0=+46.0 (c 1.15;
H2O), and its C(5)-epimer 3 [h]2D0=+37.9 (c 1.8; H2O).†
The compounds thus obtained were analytically pure as
checked by LCMS (ESI).
The enantiopure 2,5-imino-2,5,6-trideoxy-
D-manno-hep-
titol (6-deoxy-homoDMDP) 2 and 2,5-imino-2,5,6-
trideoxy- -gulo-heptitol 3 synthesised in this study share
L
identical spectral data (1H and 13C NMR) with the
corresponding natural occurring compounds. Their dex-
trorotatory optical properties unambiguously establish
the absolute configuration of (+)-27 [h]D=+98.5 (c 1.13;
H2O) and (+)-37 [h]D=+41.4 (c 0.56; H2O).
In summary, a concise enantioselective synthesis of
optically pure polyhydroxypyrrolidines 2 and 3 has been
achieved starting from
L-xylose as chiral precursor,
thereby establishing for the first time the absolute
configuration of two new iminosugars isolated from
Hyacinthus orientalis.7 A significant difference in the
specific rotation value between the synthetic and natu-
rally occurring 6-deoxy-homoDMDP 2 has to be noted.
Acknowledgements
The authors would like to thank Dr. Geoff Bird and Dr.
Jean-Claude Arnould for their contribution to some
aspects of this project.
References
3. Structural analysis
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the target molecules. Configurations at C(3) or C(4)
were unchanged during the synthetic process, whereas
the stereochemistry at C(2), which resulted from a
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that in the starting material. Examination of nuclear
Overhauser effects carried out on 6a and 6b allowed the
assignment of the configuration at the newly formed
asymmetric carbon C(5). Thus for 6a, the enhancement
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1
† Compound 2: [h]D=+46.0 (c=1.15; H2O). H NMR (D2O–TSP, 500
MHz): l 3.85 (t, 1H, J=7.2, 3-H), 3.76 (dd, 1H, J=7.2, 7.6, 4-H),
3.72 (dd, 1H, J=4.2, 12.0, 1a-H), 3.66 (dd, 1H, J=6.1, 12.0, 1b-H),
3.68–3.62 (m, 2H, H-7a,b), 3.17 (ddd, 1H, J=4.2, 6.1, 7.2, 2-H),
3.13 (ddd, 1H, J=5.6, 7.6, 8.3, 5-H), 1.93 (dddd, 1H, J=5.6, 6.7,
8.3, 13.7, 6a-H), 1.75 (ddt, 1H, J=2×6.2, 8.3, 13.7, 6b-H). 13C NMR
(D2O–TSP, 125 MHz): l 84.0 (4-C); 80.2 (3-C); 64.7 (1-C); 64.1
(2-C); 61.8 (7-C); 60.0 (5-C); 38.0 (6-C). MS (ESI) m/z 178 (MH)+
(100). Compound 3: [h]D=+37.9 (c=1.8; H2O). 1H NMR (D2O–
TSP, 500 MHz): l 4.05 (dd, 1H, J=1.8, 3.2, 4-H), 3.92 (dd, 1H,
J=1.8, 2.8, 3-H), 3.78 (dd, 1H, J=5.1, 11.9, 1a-H), 3.72 (dd, 1H,
J=7.6, 11.9, 1b-H), 3.71 (t, 2H, J=6.3, 7a,b-H), 3.50 (dt, 1H,
J=3.2, 2×7.2, 5-H), 3.25 (ddd, 1H, J=2.8, 5.1, 7.6, 2-H), 1.90 (ddt,
1H, J=2×6.3, 7.2, 14.9, 6a-H), 1.72 (ddt, 1H, J=2×6.3, 7.2, 14.9,
6b-H). 13C NMR (D2O–TSP, 125 MHz): l 81.6 (3-C); 80.4 (4-C);
68.7 (2-C); 64.2 (1-C); 61.8 (5-C); 60.7 (7-C); 32.6 (6-C).
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