Chemistry of imino glycals: Preparation and application to the synthesis of (+)-fagomine

Article abstract of DOI:10.1055/s-2001-16039

The synthesis of imino glucal 2 from tri-O-benzyl-D-glucal in 8 steps is described. This novel imino sugar building block is further converted into (+)-fagomine by a two-step hydrogenation sequence.

Full text of DOI:10.1055/s-2001-16039

LETTER
1329
Chemistry of Imino Glycals: Preparation and Application to the Synthesis of
(+)-Fagomine
Jérôme Désiré,a Paul J. Dransfield,a Paul M. Gore,b Michael Shipmana*
a School of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
b GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, UK
Fax +44 1392 263434; E-mail m.shipman@exeter.ac.uk
Received 10 May 2001
BnO
Abstract: The synthesis of imino glucal 2 from tri-O-benzyl-D-glu-
OH OBn
O
TPAP, NMO
CH2Cl2, 4Å sieves
2 steps
(ref 7)
cal in 8 steps is described. This novel imino sugar building block is
further converted into (+)-fagomine by a two-step hydrogenation
sequence.
64%
83%
BnO
OBn OBn
3
OBn
OBn
Key words: carbohydrates, piperidines, stereoselective synthesis,
imino glycals, (+)-fagomine
HO
O
N
OBn
NH2OH.HCl,
Py, EtOH, 60°C
98%
OBn OBn
OBn OBn
4
5
Glycals, carbohydrates incorporating a double bond be-
tween C-1 and C-2, have emerged as powerful building
blocks in synthetic chemistry especially in the context of
oligosaccharide assembly.1 In light of this fact, it is per-
haps surprising that the synthesis and chemistry of imino
glycals, glycals in which the ring oxygen atom is replaced
by nitrogen, has not been explored in a systematic fash-
ion.2,3 Such compounds (e.g. 1, Figure) should participate
in a diverse range of reactions (e.g. addition and cycload-
dition reactions, metal catalysed cross-couplings), and
thus provide access to many potentially useful classes of
imino sugars which are of interest because of their ability
to influence a variety of biological processes by the inhi-
bition of the glycosidase enzymes.4 Furthermore, imino
glycals might serve as precursors to various glycosyl do-
nors which could be used to make oligosaccharides incor-
porating nitrogen atoms, another area of current interest.5
In this Letter, as a first step towards realising these objec-
tives, we describe a practical approach to imino glucal 2,
and demonstrate that it can be used to prepare the natural-
ly occurring imino sugar, (+)-fagomine.6
i. LiAlH4, Et2O
ii. FmocCl, K2CO3,
THF/H2O, 0°C
FmocNH
OBn
FmocNH
OBn
+
OBn OBn
OBn OBn
6b (13%)
6a (44%)
Fmoc
BnO
O3, CH2Cl2, -78°C
then PPh3
OH
N
(COCl)2, CH2Cl2, DMF
95%
2
87% (from 6a)
BnO
7
OBn
Scheme 1
tri-O-benzyl-D-glucal, which was readily converted into
alkene 3 according to the known two-step protocol
(Scheme 1).7,8 Oxidation of the free hydroxyl group of 3
with tetra-n-propylammonium perruthenate yielded ke-
tone 4 in good yield, which was further converted into the
corresponding oxime 5 upon treatment with hydroxy-
lamine hydrochloride. Reduction of oxime 5 with lithium
aluminium hydride provided the primary amine, which
was immediately transformed into 6 in which the amino
group was protected with the base labile Fmoc group. The
oxime reduction occurred with modest selectivity in
favour of the required (6R)-diastereomer (6a:6b; ca 2.5:1
HO
HO
X
N
BnO
BnO
Fmoc
N
OH
H
N
HO
1
as judged by H NMR spectroscopy). Whilst stereocon-
OH
OBn
OH
trolled reduction in favour of this diastereomer might be
expected on the basis of literature precedent,9 more defin-
itive proof in support of our stereochemical assignments
has been obtained (vide infra). Importantly, at this junc-
ture, it was possible to separate (6R)-6a from the unwant-
ed minor diastereomer (6S)-6b. This could be
accomplished by flash chromatography using silica gel,
although it was more conveniently achieved on a prepara-
tive scale by MPLC using a Merck Lobar Lichroprep
Si60 column. Ozonolysis of diastereomerically pure 6a
imino glycal 1
(X = protecting group)
2
(+)-fagomine
Figure
As an initial synthetic target, we elected to make imino
glucal 2 possessing benzyl protection for the hydroxyl
groups, and the readily removed Fmoc group on the pipe-
ridine nitrogen. The starting point for our synthesis was
Synlett 2001, No. 8, 1329–1331 ISSN 0936-5214 © Thieme Stuttgart · New York

1330
J. Désiré et al.
LETTER
followed by treatment with triphenylphosphine provided
7 in good yield. Finally, dehydration of 7 to imino glucal
2 was accomplished in near quantitative yield upon treat-
ment with oxalyl chloride. Overall, this sequence provides
imino glucal 2 in 8 steps from tri-O-benzyl-D-glucal in
19% overall yield.
References and Notes
(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) Three reports have outlined the synthesis of imino glycals. In
the majority of these, they were as formed as by products and
no chemical studies were disclosed, 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.
(3) Hetero-exo-glycals have very recently been described, see
Tatibouët, A.; Rollin, P.; Martin, O.R. J. Carbohydr. Chem.
2000, 19, 641.
(4) For a leading reference, see Asano, N.; Nash, R.J.; Molyneux,
R.J.; Fleet, G.W.J. Tetrahedron: Asymmetry 2000, 11, 1645.
(5) For a leading reference, see Duff, F.J.; Vivien, V.; Wightman,
R.H. Chem. Commun. 2000, 2127.
To confirm the stereochemistry at C-5 of imino glucal 2,
and to provide an initial demonstration of its utility in syn-
thesis, we have converted it into the naturally occurring
imino sugar, (+)-fagomine (Scheme 2).6,10 Hydrogenation
of imino glucal 2 using 10% palladium on carbon yielded
piperidine 8, however, it was contaminated with 9-meth-
ylfluorene, produced as a result of the reductive cleavage
of the Fmoc group. To overcome this problem, the hydro-
genation of 2 was executed in the presence of morpholine,
which resulted in the production of the more polar by-
product, 4-fluoren-9-ylmethyl-morpholine, which could
be removed by simple column chromatography. Evidence
in support of the stereochemistry of 8 (and hence 2) was
obtained from nOe experiments performed on 8 and its C-
5 diastereomer 9 (made from 6b in 34% overall yield us-
ing the same reaction sequence). Enhancements were ob-
served between the axial hydrogens H-1, H-3 and H-5 in
8, but not in 9.11 This confirms that the reduction of oxime
5 leads predominately to the desired (6R)-diastereomer 6a
(after Fmoc protection). Finally, hydrogenation of piperi-
dine 8 in the presence of hydrochloric acid effected re-
moval of the benzyl ethers to furnish (+)-fagomine as its
hydrochloride salt. Our synthetic material displayed spec-
troscopic characteristics in good agreement with those re-
ported previously.10,12 Further work to explore the utility
of imino glucal 2 and related compounds is ongoing and
will be disclosed in due course.
(6) Koyama, M.; Sakamura, S. Agr. Biol. Chem. 1974, 38, 1111.
(7) (a) Bettelli, E.; Cherubini, P.; D'Andrea, P.; Passacantilli, P.;
Piancatelli, G. Tetrahedron 1998, 54, 6011; (b) Tius, M. A.;
Busch-Petersen, J. Tetrahedron Lett. 1994, 35, 5181 and
references cited therein.
(8) All new compounds have been fully characterised using
standard spectroscopic and analytical techniques.
(9) (a) Liu, P.S. J. Org. Chem. 1987, 52, 4717; (b) Moutel, S.;
Shipman, M. J. Chem. Soc., Perkin Trans. 1 1999, 1403.
(10) For previous syntheses, see (a) Fleet, G.W.J.; Smith P.W.
Tetrahedron Lett. 1985, 26, 1469; (b) Vonderosten, C.H.;
Sinskey, A.J.; Barbas, C.F.; Pederson, R.L.; Wang, Y.-F.;
Wong, C.-H. J. Am. Chem. Soc. 1989, 111, 3924; (c) Pederson
R.L.; Wong C.-H. Heterocycles 1989, 28, 477; (d) Fleet, G.W.
J.; Witty, D. R. Tetrahedron: Asymmetry 1990, 1, 119;
(e) Effenberger F.; Null, V. Liebigs Ann. Chem. 1992, 1211.
(11) Selected nOe data for 8. Enhancement of H-3 (4.9%) and H-5
(3.7%) from H-1 ; of H-3 (8.2%) from H-5; of H-4 (4.8%)
from H-2 Thus, H-1 , H-3 and H-5 reside on the -face of
the piperidine ring. No nOe's between H-5 and H-3 could be
detected in diastereomer 9.
Fmoc
H
N
N
(12) Selected physical and spectroscopic data: 2 [ ]D20-100 (c 1.0,
CHCl3); max 1715, 1644 cm-1; H (400 MHz; d6-DMSO at
100 °C) 7.82 (2H, d, J 7.6, ArH), 7.60 (2H, t, J 7.7, ArH), 7.37
(2H, m, ArH), 7.31-7.18 (17H, m, ArH), 6.76 (1H, br d, J 8.5,
H-1), 5.07 (1H, ddd, J 8.5, 4.8,1.8, H-2), 4.58-4.46 (7H, m,
H2, Pd/C, morpholine,
EtOH
BnO
BnO
BnO
BnO
5
70%
3
OBn
OBn
8
2
H
H
N
HCl
N
3
OCH2Ph, H-5), 4.35-4.26 (3H, m, CH-Fmoc, CH2-Fmoc),
4.02 (1H, m, H-4), 3.79 (1H, m, H-3), 3.61 (1H, dd, J6,6’ 9.6,
5,6 8.0, H-6), 3.40 (1H, dd, J6’,6 9.6, J6’,5 6.9, H-6'); Found:
H2, Pd/C, HCl,
EtOH
HO
HO
BnO
5
J
85%
BnO
9 (from 6b) OBn
M+NH4+ (ESI), 655.3174. C42H43N2O5 requires 655.3172.
8: [ ]D18+30.5 (c 1.90, CHCl3); H (400 MHz; CDCl3) 7.36-
7.25 (15H, m, ArH), 4.94 (1H, d, J 11.0, OCHHPh), 4.68 (2H,
AB quartet, OCH2Ph), 4.54 (1H, d, J 11.0, OCHHPh), 4.48
(2H, AB quartet, OCH2Ph), 3.72 (1H, dd, J6’,5 2.5, J6’,6 8.9, H-
6'), 3.58 (1H, dd, J6,5 6.1, J6,6’ 8.9, H-6), 3.52 (1H, m, H-3),
3.34 (1H, pseudo t, 9.1, H-4), 3.06 (1H, m, H-1 ), 2.72 (1H,
ddd, J5,6’ 2.5, J5,6 6.1, J5,4 9.1, H-5), 2.57 (1H, dt, J 2.3,12.7, H-
1 ), 2.36 (1H, br s, NH), 2.14 (1H, m, H-2 ), 1.50 (1H, m, H-
2 ); Found: MH+ (ESI), 418.2381. C27H32NO3 requires
418.2382.
3
OH
(+)-fagomine
Scheme 2
Acknowledgement
We are grateful to the Leverhulme Trust and GlaxoSmithKline for
financial support of this project. We are indebted to the EPSRC Na-
tional Mass Spectrometry Service Centre for performing mass spec-
tral measurements and the EPSRC Chemical Database Service at
Daresbury.13
9 [ ]D19-5.0 (c 1.0, CHCl3); H (400 MHz; d6-DMSO) 7.33-
7.26 (15H, m, ArH), 4.55-4.39 (6H, m, 3 OCH2Ph), 3.74
(1H, m, H-3), 3.48 (1H, m, H-4), 3.41 (2H, m, H-6, H-6'), 3.14
(1H, td, J 6.6, 2.2, H-5), 2.74 (1H, m, H-1), 2.66 (1H, m, H-
1'), 1.73 (1H, m, H-2), 1.58 (1H, m, H-2'); Found: MH+ (ESI),
418.2383. C27H32NO3 requires 418.2382.
Synlett 2001, No. 8, 1329–1331 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Chemistry of Imino Glycals: Preparation and Application to the Synthesis of (+)-Fagomine
1331
(+)-fagomine.HCl: [ ]D20+12.9 (c 0.93, H2O) {lit [ ]D20+17.9
(13) Fletcher, D.A.; McMeeking, R.F.; Parkin, D. J. Chem. Inf.
Comp. Sci. 1996, 36, 746.
(c 0.78, H2O)10d}; H (400 MHz; D2O) 3.84-3.73 (2H, m, H-6,
H-6’), 3.60 (1H, m, H-3), 3.40 (1H, pseudo t, J 9.8, H-4), 3.32
(1H, m, H-1’), 3.04-2.94 (2H, m, H-5, H-1), 2.09 (1H, m, H-
2’), 1.60 (1H, m, H-2); C (100 MHz; D2O) 70.4 (C-3), 69.5
(C-4), 60.0 (C-5), 57.6 (C-6), 41.8 (C-1), 28.5 (C-2); Found:
MH+ (ESI), 148.0976. C6H14NO3 requires 148.0973. We
cannot account for the discrepancy in the magnitude of the
optical rotation. (+)-Fagomine.HCl produced by our method is
a single diastereomer (and hence single enantiomer).
Article Identifier:
1437-2096,E;2001,0,08,1329,1331,ftx,en;D08501ST.pdf
Synlett 2001, No. 8, 1329–1331 ISSN 0936-5214 © Thieme Stuttgart · New York