A new procedure for the synthesis of C-glycosides of nojirimycin

Article abstract of DOI:10.1039/b003877f

Reaction with allylmagnesium bromide of N,2,3,4,6-pentabenzyl-D- glucopyranosylamine 2, obtained from tetrabenzylglucose and benzylamine, afforded stereoselectively the open chain amino alcohol 3, which was converted into the C-glycoside of nojirimycin 6 by full protection of the amino function by Fmoc, oxidation of the free hydroxy group, hydrolysis of the Fmoc group and final intramolecular reductive amination with NaBH(OAc)₃; compound 6 was also converted into methyl ketone 7, by manipulation of the allylic appendage.

Full text of DOI:10.1039/b003877f

A new procedure for the synthesis of C-glycosides of nojirimycin
Laura Cipolla, Barbara La Ferla, Francesco Peri and Francesco Nicotra*
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, I-20126
Milano, Italy. E-mail: francesco.nicotra@unimib.it
Received (in Cambridge) 15th May 2000, Accepted 30th May 2000
Published on the Web 26th June 2000
Reaction with allylmagnesium bromide of N,2,3,4,6-penta-
benzyl- -glucopyranosylamine 2, obtained from tetraben-
affording stereoselectively the threo isomer 3 (81% yield, 90%
de).13 The cyclisation of 3 to the ‘allyl-a-C-glycoside’ of 6, was
accomplished by oxidation followed by reductive amination,14
which turned out to be troublesome. Oxidation of the free –OH
group of 3 with PCC resulted in over-oxidation and partial
degradation of the product.15 Swern oxidation with DMSO–
Ac2O provided the desired ketone with concomitant acetylation
of the amine, and failed when Ac2O was replaced with P2O5 or
oxalyl chloride. These results clearly suggested that the amino
group must be fully protected in order to perform a successful
oxidation, and then deprotected to afford the cyclic azasugar by
reductive amination. Both the protection/deprotection and the
reductive amination reactions were difficult. Different protect-
ing groups and reducing agents were tested. In terms of yields
and stereoselection, the best results were obtained as follows: 3
was protected as 4 (FmocCl, Na2CO3, dioxane–H2O, 89%
yield), oxidised with PCC (CH2Cl2, 4 Å molecular sieves, 90%
yield) to ketone 5, then the amino group of 5 was deprotected
with piperidine in DMF. Reductive amination of the crude
product with Na(OAc)3BH (AcOH, dry Na2SO4, 1,2-dichloro-
ethane, 235 °C) afforded 6,† the protected allyl-a-C-glycoside
of nojirimycin, in 78% yield and 90% de.‡ As an example of
manipulation of the allylic appendage, 6 was treated with
catalytic Na2PdCl4 (0.3 equiv.) and CuCl2 (1 equiv.) in DMF–
THF–H2O (8/5/1) affording 7§ in 50% yield. Alternatively, the
allylic appendage can undergo a 5-exo iodocyclization–de-
benzylation, involving the benzyloxy group in the g position.16
Treatment of 6 with NIS in THF, afforded stereoselectively the
bicyclic compound 8¶ (2AR, determined by NOE experiments,
as the only detected isomer) in 42% yield. Deprotection of 6 by
D
zylglucose and benzylamine, afforded stereoselectively the
open chain amino alcohol 3, which was converted into the C-
glycoside of nojirimycin 6 by full protection of the amino
function by Fmoc, oxidation of the free hydroxy group,
hydrolysis of the Fmoc group and final intramolecular
reductive amination with NaBH(OAc)3; compound 6 was
also converted into methyl ketone 7, by manipulation of the
allylic appendage.
Deoxynojirimycin (1,5-dideoxy-1,5-imino- -glucitol, DNJ) is a
D
sugar-like plant alkaloid with inhibitory activity of a variety of
glucosidases.1 In particular, the capacity of deoxynojirimycin to
inhibit trimming glucosidase I and II, interfering in N-linked
oligosaccharide processing,2 makes this molecule particularly
attractive as a potential drug. It is well established that many
pathological processes such as viral infections3 and adhesion of
tumour metastasis to endothelial cells,4 involve complex N-
linked oligosaccharides. Furthermore, inhibitors of glucosi-
dases can find application in regulation of carbohydrate
metabolic disorders.5 In view of current interest in anti-HIV
activity, the synthesis of DNJ derivatives and their analogues,
which can reduce replication and infectivity of HIV, has
attracted particular attention. Homologues,6 deoxygenated,7 N-
alkylated,7,9 O-glycosylated7 and other DNJ derivatives have
been synthesised by chemical8 and enzymatic9 methods.
Investigation of their activity led to the interesting observation
that short lipophylic appendages, e.g. a butyl group, at the N
atom, strongly enhance the biological response.10
We wanted to find an efficient method for the introduction of
a lipophylic substituent at position 1 of protected DNJ instead of
at the N atom, particularly one affording stereoselectively the a-
derivative, since the trimming a-glucosidases are the most
interesting enzymes to be inhibited. We identified the allyl
group as the substituent of choice, since its transformation into
other functional groups, and its exploitation in the synthesis of
neoglycoconjugates and C-disaccharides is widely de-
scribed.11
Protected a-1-allyl-1-deoxynojirimycin has already been
synthesised12 from glucose through the key intermediate
1-fluoro-1-deoxynojirimycin, using a complex multistep se-
quence. We herein report an efficient approach allowing the
stereoselective synthesis of protected a-1-allyl-1-deoxynojir-
imycin in 6 steps and 36% overall yield, using tetra-
benzylglucose (1) as commercially available starting material
(Scheme 1). This requires first the introduction of the amino
function, secondly of the allylic appendage and finally the
cyclisation to the desired piperidine derivative. From a
stereochemical point of view, the allylation reaction and the
cyclization are crucial to the effectiveness of the synthesis, and
must be highly stereoselective. The amino group was in-
troduced by reaction of 1 with benzylamine in CH2Cl2, in the
presence of 4 Å molecular sieves and 1 equiv. of toluene-p-
sulfonic acid. The resulting glycosylamine 2 (80% yield) was
then treated with allylmagnesium bromide (10 equiv., Et2O), in
order to introduce stereoselectively the allylic appendage. The
Grignard reaction occurs at the imino function, in equilibrium
with the glycosylamine, via a Cram-chelated intermediate,
Scheme 1 Reagents and conditions: i, PhCH2NH2 10 equiv., PTSA 1 equiv.,
CH2Cl2, 4 Å m.s., 80% yield, 5 days; ii, CH2NCHCH2MgBr 10 equiv., dry
Et2O, 81% yield, 90% de; iii, FmocCl, dioxane–10% aq. Na2CO3, 89%
yield; iv, PCC 3 equiv., CH2Cl2, 4 Å m.s., 90% yield; v, piperidine, DMF;
vi, NaHB(OAc)3, AcOH, dry Na2SO4, 1,2-dichloroethane, 235 °C, 78%
yield, 90% de.
DOI: 10.1039/b003877f
Chem. Commun., 2000, 1289–1290
This journal is © The Royal Society of Chemistry 2000
1289

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1 Carbohydrate Analogues as Glycosidase Inhibitors—Nojirimycin and
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The procedure herein reported allows the synthesis of
protected allyl-a-C-glycoside of nojirimycin through a highly
stereoselective (80% de) and high yielding procedure (36%, 6
steps), from commercially available tetrabenzylglucose. The
manipulation of the allylic appendage, widely reported in C-
glycosides and to some extent also in iminosugars, allows the
synthesis of a variety of functional groups and derivatives. The
reported approach will be exploited in future projects devoted to
the synthesis of imino-C-disaccharides.
We thank the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica (MURST) for financial support and
Paolo Petroni for contributing to the experimental work.
Notes and references
† Selected data for 6: oil, [a]D + 21.4 (c 1, CHCl3); dH(500 MHz, C6D6):
2.39 (dt, 1H, J 14.0, 8.1, H-1Aa), 2.53 (dt, 1H, J 14.0, 5.8, H-1Ab), 3.11 (ddd,
1H, J 9.5, 4.9, 2.1, H-5), 3.16 (dt, 1H, J 8.6, 5.4, H-1), 3.63 (dd, 1H, J 10.3,
2.1, H-6a), 3.75–3.83 (m, 2H, H-2, H-6b), 3.84–3.90 (m, 3H, PhCHN, H-3,
H-4), 4.04 (d, 1H, J 14.0, PhCHN), 4.14, 4.20 (ABq, 2H, J 11.9, PhCH2O),
4.34 (s, 2H, PhCH2O), 4.65, 5.04 (ABq, 2H, J 11.4, PhCH2O), 4.84, 5.03
(ABq, 2H, J 11.2, PhCH2O), 4.98–5.13 (m, 2H, H-3A), 5.78–5.92 (m, 1H, H-
2A), 7.00–7.41 (m, 25H, Ph-H); dC(75.43 MHz, CDCl3, aromatic C omitted)
29.11 (t, C-1A), 52.95 (t, NCH2Ph), 57.19 and 57.53 (2d, C-1 and C-5), 68.57
(t, C-6), 72.17, 72.90, 75.09 and 75.38 (4t, OCH2Ph), 78.72, 79.31, 83.99
(3d, C-2, C-3, C-4), 115.30 (t, C-3A), 137.76 (d, C-2A). Anal. Calcd. for
7 For a comprehensive review see: C. W. Ekhart, M. H. Fechter, P.
Hadwiger, E. Mlaker, A. E. Stütz, A. Tauss and T. Wrodnigg in
Carbohydrate Analogues as Glycosidase Inhibitors—Nojirimycin and
Beyond, ed. A. Stütz, VCH, Weinheim, 1998, p. 254.
8 For a recent review of synthetic methods see: B. La Ferla and F. Nicotra
in Carbohydrate Analogues as Glycosidase Inhibitors—Nojirimycin
and Beyond, ed. A. Stütz, VCH, Weinheim, 1998, p. 68.
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C.-H. Wong, J. Am. Chem. Soc., 1991, 113, 6187.
C
44H47NO4: C 80.82, H 7.25, N 2.14%; Found C 80.77, H 7.28, N
10 See for example: A. Karpas, G. W. Fleet, R. A. Dwek, S. Petursson,
S. K. Namgoong, N. G. Ramsden, G. S. Jacob and T. W. Rademacher,
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2.11%.
‡ Determined by 13C NMR of the crude reduction product, in comparison
with the spectrum of the epimer at C-5 (ref. 8).
§ Selected data for 7: oil, [a]D + 9.6 (c 1, CHCl3); dH(300 MHz, C6D6): 1.76
(s, 3H, H-3A), 2.23 (dd, 1H, J 15.3, 5.0, H-1Aa), 2.57 (dd, 1H, J 15.3, 7.1, H-
1Ab), 2.83–2.94 (m, 1H, H-5), 3.61 (dd, 1H, J 10.2, 1.6, H-6a), 3.64–3.82 (m,
5H, H-2, H-3, H-4, H-6b, PhCHN), 3.84–3.90 (m, 2H, H-1, PhCHN), 4.10,
4.15 (ABq, J 11.8, PhCH2O), 4.24, 4.32 (ABq, J 11.8, PhCH2O), 4.61, 5.02
(ABq, J 11.4, PhCH2O), 4.84, 5.03 (ABq, J 11.2, PhCH2O), 7.01–7.48 (m,
25H, Ph-H); Anal. Calcd. for C44H47NO5: C 78.89, H 7.0, N 2.09%; Found
C 78.92, H 7.08, N 2.06%.
¶ Selected data for 8: yellow oil, [a]D + 11 (c 0.65, CHCl3); dH(300 MHz,
CDCl3): 1.66 (bq, 1H, J 11.0, H-1Aa), 2.24 (ddd, 1H, J 11.0, 5.7, 5.7, H-1Ab),
2.98–3.03 (m, 1H, H-5), 3.21 (dd, 1H, J 9.9, 6.8, H-3Aa), 3.30 (dd, 1H, J 9.9,
4.8, H-3Ab), 3.55 (dd, 1H, J 8.1, 5.1, H-4), 3.60–3.72 (m, 4 H, H-1, H-6a, H-
6b, PhCHN), 3.86 (t, 1H, J 8.3. H-3), 3.90–3.97 (m, 2H, H-2A, PhCHN), 4.15
(t, 1H, J 8.3. H-2), 4.41 (s, 2H, PhCH2O), 4.43, 4.61 (ABq, J 11.0,
PhCH2O), 4.78, 4.97 (ABq, J 11.4, PhCH2O); dC(75.43 MHz, CDCl3,
aromatic C omitted) 9.92 (t, C-3A), 36.20 (t, C-1A), 59.34, 60.83 (2d, C-1 and
C-5), 54.76 (t, NCH2Ph), 67.02 (t, C-6), 72.84, 73.26 and 74.06 (3t,
OCH2Ph), 77.56, 80.00, 80.75 and 84.16 (4d, C-2, C-3, C-4 and C-2A);
Calcd. for C37H40INO4: C 64.44, H 5.85, I 18.40, N 2.03%; Found C 64.60,
H 5.70, I 18.55, N 1.99%.
16 L. Cipolla, L. Lay and F. Nicotra, J. Org. Chem., 1997, 62, 6678.
1290
Chem. Commun., 2000, 1289–1290