Imino glycals in synthesis: Preparation of novel deoxymannojirimycin analogues

Article abstract of DOI:10.1055/s-2001-16049

The synthesis of imino glucal 2 from tetra-O-benzyl-D-glucopyranose in 7 steps is described. This imino sugar building block is converted into conformationally constrained deoxymannojirimycin analogue (+)-9 by means of a stereocontrolled cyclopropanation followed by a two step deprotection sequence. Regioselective fission of the cyclopropane ring prior to deprotection provides access to related analogue (+)-11.

Full text of DOI:10.1055/s-2001-16049

1332
LETTER
Imino Glycals in Synthesis: Preparation of Novel Deoxymannojirimycin
Analogues
Jérôme Désiré, Michael Shipman*
School of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK.
Fax+44 1392 263434; E-mail: m.shipman@exeter.ac.uk
Received 22 May 2001
base labile Fmoc group. The oxime reduction occurred
Abstract: The synthesis of imino glucal 2 from tetra-O-benzyl-D-
with modest selectivity in favour of the required (6R)-di-
glucopyranose in 7 steps is described. This imino sugar building
astereomer (6a:6b; ca 2.4:1 as judged by 1H NMR spec-
block is converted into conformationally constrained deoxyman-
nojirimycin analogue (+)-9 by means of a stereocontrolled cyclo-
troscopy).8 Separation of (6R)-6a from the unwanted
propanation followed by a two step deprotection sequence. minor diastereomer (6S)-6b was accomplished by MPLC
Regioselective fission of the cyclopropane ring prior to deprotec-
tion provides access to related analogue (+)-11.
using a Merck Lobar Lichroprep Si60 column. Ozonolysis
of 6a followed by treatment with triphenylphosphine pro-
Key words: carbohydrates, piperidines, stereoselective synthesis,
imino glycals, glycosidases
vided 7, which underwent elimination to glucal 2 in excel-
lent yield upon treatment with oxalyl chloride. Overall,
this sequence provides imino glucal 2 in 7 steps from tet-
ra-O-benzyl-D-glucopyranose in 23% overall yield.
Glycals, carbohydrates incorporating a double bond be-
tween C-1 and C-2, have proven to be useful building
blocks in organic chemistry especially in the context of
oligosaccharide synthesis.1 By analogy, we reasoned that
imino glycals, glycals in which the ring oxygen atom is re-
placed by nitrogen, might prove to be useful synthetic in-
termediates, as the alkene double bond would be expected
to undergo a variety of addition, cycloaddition and metal
catalysed cross-coupling reactions. In this way, we envis-
aged that a variety of novel imino sugars could be assem-
bled, enabling us to probe further the binding specificity
of the glycosidase family of enzymes.2 Very recently, we
described our first studies relating to the synthesis and
chemistry of imino glycals, wherein we reported the prep-
aration of imino glucal 1 from tri-O-benzyl-D-glucal, and
used it to prepare the naturally occurring imino sugar, (+)-
fagomine.3,4 In this Letter, we report the synthesis of relat-
ed imino glucal 2, bearing a benzyloxy group at C-2, and
describe stereocontrolled cyclopropanation reactions of
this system. Further synthetic manipulations provide nov-
el analogues of the naturally occuring imino sugar, deoxy-
mannojirimycin 3.5
BnO
HO
O
OH
N
OBn
3 steps
67%
(ref. 6)
BnO
OBn
OBn OBn OBn
OBn
4
5
i. LiAlH4, Et2O
ii. FmocCl, K2CO3,
THF/H2O, 0°C
FmocNH
OBn
FmocNH
OBn
+
OBn OBn OBn
OBn OBn OBn
6a (43%)
6b (18%)
Fmoc
N
BnO
BnO
O3, CH2Cl2, -78°C
then PPh3
OH
(COCl)2, CH2Cl2, DMF
94%
2
86% (from 6a)
OBn
OBn
7
Scheme 1
With imino glucal 2 in hand, we have begun to explore its
reactivity. In the first instance, we chose to examine meth-
ods for the cyclopropanation of this system. This transfor-
mation was readily accomplished using excess
diiodomethane and diethyl zinc (Scheme 2).9 The reaction
was highly stereoselective and only one diastereomer
OH
Fmoc
N
BnO
Fmoc
N
BnO
H
N
HO
BnO
BnO
OH
1
OBn
could be detected in the crude reaction mixture by H
OH
OBn
OBn
NMR spectroscopy. Further treatment of the resultant cy-
clopropane with morpholine provided secondary amine 8
in 64% yield over the two steps. The stereochemical out-
come of the reaction was established on the basis of nOe
measurements performed on 8.10,11 To account for the ob-
served stereoselectivity, we suggest that imino glucal 2
adopts a half-chair conformation in which the substituents
at C-4 and C-5 adopt pseudo equatorial orientations. Car-
benoid addition anti to the OBn substituent at C-3 ac-
counts for the formation of the observed diastereomer.
deoxymannojirimycin 3
2
1
Figure
Tetra-O-benzyl-D-glucopyranose 4 was converted into
oxime 5 in three steps essentially by the published method
(Scheme 1).6,7 Reduction of this oxime with lithium alu-
minium hydride furnished the primary amine, which was
immediately transformed into 6 by protection with the
Synlett 2001, No. 8, 1332–1334 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Imino Glycals in Synthesis: Preparation of Novel Deoxymannojirimycin Analogues
1333
Other methods of cyclopropanation were also briefly ex-
amined {CHCl3, NaOH, BnNEt3Cl; PhHgCCl3, DME,
85 °C; N2CHCO2Et, CH2Cl2, Cu powder or Rh2(OAc)4}
although these proved to be ineffective.
HCl
H
N
H
N
H2, Pd/C, HCl,
EtOH
BnO
BnO
HO
HO
100%
OBn
OH
OBn
OH
8
(+)-9
H2, EtOH,
Pd(OH)2 / C,
Fmoc
H
79%
N
N
5
1
i. Et2Zn, CH2I2, toluene
ii. morpholine
1
BnO
BnO
BnO
BnO
6
2
HCl
H
N
H
N
H2, Pd/C,
HCl, EtOH
OBn
4
3
BnO
BnO
OBn
HO
HO
64%
Me
Me
OH
OBn
OBn
8
2
100%
OBn
OBn
OH
Scheme 2
10
(+)-11
Scheme 3
From an examination of the vicinal coupling constants of
piperidine 8 (J4,5 = 5.8 Hz), we conclude that the cyclopro-
pane ring fusion forces the piperidine out of the traditional
chair conformation.12 Consequently, we felt that it would
be of interest to deprotect this material and compare its en-
zyme inhibitory activity against that of the naturally oc-
curring imino sugar, deoxymannojirimycin 3 which does
not possess this conformational constraint. Initially, we
attempted to effect debenzylation using trimethylsilyl io-
dide as we were concerned that catalytic hydrogenation
might result in fission of the cyclopropane ring. However,
whilst exhaustive debenzylation to (+)-9 could be accom-
plished using TMSI, we were unable to obtain it in a sat-
isfactorily pure state. Despite our initial reservations,
catalytic hydrogenation using palladium on carbon
proved to be very effective method for debenzylation pro-
vided the reaction was performed in the presence of hy-
drochloric acid. In this way, conformationally constrained
deoxymannojirimycin analogue (+)-9 could be isolated in
quantitative yield as its hydrochloride salt.11 Interestingly,
using palladium hydroxide on carbon in the absence of ac-
id, it was possible to regioselectively cleave the cyclopro-
pane ring between C-1 and C-2 without concomitant
debenzylation. The resultant piperidine 10 appears to
adopt a chair conformation as indicated by the large vici-
nal coupling constants for H-4 (J = 10.4 and 9.2 Hz). Fur-
ther hydrogenation of 10 using Pd/C as catalyst under
acidic conditions yielded deoxymannojirimycin analogue
(+)-11 in quantitative yield.11
References
(1) (a) Danishefsky, S.J.; Bilodeau, M.T. Angew. Chem. Int. Ed.
Engl. 1996, 35, 1380 (b) Seeberger, P.H.; Haase, W.-C. Chem.
Rev. 2000, 100, 4349.
(2) For a review, see Heightman, T.D.; Vasella, A.T. Angew.
Chem. Int. Ed. Engl. 1999, 38, 750.
(3) Désiré, J.; Dransfield, P.J.; Gore, P.M.; Shipman, M. Synlett
2001, 8, 1329.
(4) For other work relating to imino glycals, see (a) Natsume, M.;
Wada, M.; Ogawa, M. Chem. Pharm. Bull. 1978, 26, 3364;
(b) Khanna, I.K.; Koszyk, F.J.; Stealey, M.A.; Weier, R.M.;
Julien, J.; Mueller, R.A.; Rao, S.N.; Swenton, L.; Getman,
D.P.; DeCrescenzo, G.A.; Heintz, R.M. J. Carbohydr. Chem.
1995, 14, 843; (c) Fuchss, T.; Streicher, H.; Schmidt, R.R.
Liebigs Ann. Recl. 1997, 7, 1315; (d) Tatibouët, A.; Rollin, P.;
Martin, O.R. J. Carbohydr. Chem. 2000, 19, 641.
(5) Fellows, L.E.; Bell, E.A.; Lynn, D.G.; Pilkiewicz, F.; Miura,
I.; Nakanishi, K. J. Chem. Soc., Chem. Commun. 1979, 977.
(6) Liu, P.S. J. Org. Chem. 1987, 52, 4717. We found it more
convenient to use TPAP/NMO for the oxidation step rather
than DCC/DMSO as originally reported.
(7) All new compounds have been fully characterised using
standard spectroscopic and analytical techniques.
(8) We have been unable to reproduce the higher levels of
diastereocontrol (d.r. 6:1) reported for the reduction of oxime
5 in ref. 6.
(9) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 3353.
(10) Selected nOe data for 8. Enhancement of H-1 (9.7%), H-4
(7.0%) and H-6 (9.9%) from H-2/H-2'; of H-2/H-2' (1.4%) and
H-6 (2.4%) from H-4; Thus, the cyclopropane (H-2, H-2'), H-
4 and H-6 reside on the -face of the piperidine ring.
(11) Selected physical and spectroscopic data:
Imino sugars (+)-9 and (+)-11 display weaker inhibitory
activity against -mannosidase (from jackbean) at pH 5
than deoxymannojirimycin 3 itself {(+)-9 (Ki = 1.5 mM);
(+)-11 (Ki = 5.1 mM); 3 (Ki = 0.06 mM {lit values: Ki = 68
M at pH 5.5; Ki = 400 M at pH 4.513}).14 Further work
to explore the utility of imino glucals 1 and 2 is ongoing
and will be disclosed in due course.
8: [ ]D20 -6.8 (c 1.2, CHCl3); max 3334, 3027, 2852, 1450,
1265, 1096 cm-1; H (400 MHz; CDCl3) 7.33-7.24 (20H, m,
ArH), 4.85 (1H, d, J 11.6, OCHHPh), 4.74-4.69 (3H, m,
3
OCHHPh), 4.55-4.46 (4H, m, 4 OCHHPh), 4.06 (1H, d,
J
4,5 5.8, H-4), 3.60 (3H, m, H-5, 2 H-7), 2.89 (1H, m, H-6),
2.83 (1H, dd, J 5.9, 7.8, H-1), 1.82 (1H, br s, NH), 1.10-1.06
(2H, m, 2 H-2); Found: MH+ (ESI), 536.2794. C35H38NO4
requires 536.2801.
Acknowledgement
9.HCl: [ ]D20+22.1 (c 0.95, H2O); max 3339, 2950, 2832, 1024
cm-1; H (400 MHz; CD3OD) 4.03 (1H, d, J4,5 3.2, H-4), 4.00
(1H, dd, J7’,7 12.4, J7’,6 9.1, H-7'), 3.83 (1H, m, H-5), 3.75 (1H,
dd, J7,6 3.6, J7,7’12.4, H-7), 3.17 (1H, m, H-6), 2.79 (1H, dd,
J1,2’ 4.7, J1,2 9.1, H-1), 1.55 (1H, dd, J2’,1 4.7, J2’,2 7.7, H-2'),
1.28 (1H, dd, J2,2’ 7.7, J2,1 9.1, H-2); C (100 MHz; CD3OD)
We are grateful to the Leverhulme Trust for financial support of this
project, and to Dr Claus Jacob for assistance with the enzyme inhi-
bition studies. We are indebted to the EPSRC National Mass Spec-
trometry Service Centre for performing mass spectral
measurements and the EPSRC Chemical Database Service at Dar-
esbury.15
Synlett 2001, No. 8, 1332–1334 ISSN 0936-5214 © Thieme Stuttgart · New York

1334
J. Désiré, M. Shipman*
LETTER
(13) Legler, G.; Julrich, E. Carbohydrate Res. 1984, 128, 61.
(14) -D-Mannosidase from jackbean purchased from Sigma. Ki
determinations using p-nitrophenyl- -D-mannopyranoside at
pH 5.0 (acetate buffer) and at 20 °C. Dissociation constants
for inhibition were calculated from the slopes of the plots 1/v
against 1/[S] from the rates of substrate hydrolysis in the
absence and presence of varying inhibitor concentrations
(Lineweaver_Burk plots).
69.1 (C-5), 68.8 (C-4), 59.5 (C-6), 59.0 (C-7), 53.1 (C-3), 33.3
(C-1), 16.6 (C-2); Found: C, 36.60; H, 7.09; N, 5.71.
.
C7H14ClNO4 H2O requires C, 36.61; H, 7.02; N, 6.10%.
11.HCl: [ ]D20+3.1 (c 0.64, H2O); max 3339, 2950, 1050 cm-1;
H (400 MHz; CD3OD) 3.99 (1H, dd, J6’,5 3.4, J6’,6 11.8, H-6’),
3.76 (1H, dd, J6,5 7.3, J6,6’ 11.8, H-6), 3.71 (1H, dd, J 10.4, 9.2,
H-4), 3.30 (1H, m, H-3), 3.13 (1H, d, J 13.0, H-1), 3.06 (1H,
d, J 13.0, H-1’), 3.07-2.99 (1H, m, H-5), 1.31 (3H, s, CH3);
C
(100 MHz; CD3OD) 77.9 (C-3), 70.7 (C-2), 68.8 (C-4), 62.6
(C-5), 60.0 (C-6), 53.4 (C-1), 23.2 (CH3); Found: MH+ (ESI),
178.1081. C7H16NO4 requires 178.1079.
(15) Fletcher, D.A.; McMeeking, R.F.; Parkin, D. J. Chem. Inf.
Comp. Sci. 1996, 36, 746.
(12) It is unclear whether 8 (and 9) prefer to adopt half-chair or
boat conformations. Conformer distribution calculations
conducted using MacSpartan Pro® (MMFF force field)
indicate that both are energetically accessible.
Article Identifier:
1437-2096,E;2001,0,08,1332,1334,ftx,en;D12901ST.pdf
Synlett 2001, No. 8, 1332–1334 ISSN 0936-5214 © Thieme Stuttgart · New York