Total synthesis of new C-6 homologues of 1-deoxynojirimycin and 1-deoxy- L-idonojirimycin

Article abstract of DOI:10.1039/a908449e

Novel piperidine lactones 1 and 2, which represent direct precursors to the new C-6 homologues of 1-deoxynojirimycin (3) and 1-deoxy-L-donojirimycin 4, were prepared by key Pd(II)-catalysed aminocarbonylation of protected aminoalkene 10.

Full text of DOI:10.1039/a908449e

Total synthesis of new C-6 homologues of 1-deoxynojirimycin and
1-deoxy- -idonojirimycin†
L
Peter Szolcsányi,a Tibor Gracza,*a Marian Koman,b Naïa Prónayovác and Tibor Liptajc
a Department of Organic Chemistry, Faculty of Chemical Technology, Slovak University of Technology, Radlinského
9, 812 37 Bratislava, Slovakia. E-mail: gracza@chelin.chtf.stuba.sk
b Department of Inorganic Chemistry, Faculty of Chemical Technology, Slovak University of Technology,
Radlinského 9, 812 37 Bratislava, Slovakia
c
Central NMR Laboratories, Faculty of Chemical Technology, Slovak University of Technology, Radlinského 9,
812 37 Bratislava, Slovakia
Received (in Liverpool, UK) 21st October 1999, Accepted 25th January 2000,
Published on the Web, 2nd March 2000
Novel piperidine lactones 1 and 2, which represent direct
precursors to the new C-6 homologues of 1-deoxynojir-
imycin (3) and 1-deoxy- -idonojirimycin 4, were prepared by
L
key PdII-catalysed aminocarbonylation of protected ami-
noalkene 10.
The inhibitors of glycosidases, enzymes involved in many
crucial biochemical pathways,1 could be very valuable in the
treatment of serious human diseases such as diabetes,2 cancer3
and viral infections including AIDS.4 The prominent members
of this class of compounds are polyhydroxylated piperidines
(often referred to as ‘azasugars’). There has been an enormous
effort put toward their efficient syntheses as well as toward the
preparation of their various derivatives over the last decade.
However, only a few of the already published synthetic
strategies deal with the preparation of C-6 homologues of
azasugars.5–8 Here we report on the synthesis of new homo-
Scheme 1
aminoalkenes. However, properties of such protecting groups
(introduction, deprotection, chemical inertness and stability)
were not suitable for our proposed plan for the total synthesis.
Therefore, we decided to explore the applicability of the benzyl
protecting group in the aminocarbonylation producing the
piperidine lactones. We report here the above-mentioned
strategy in the total synthesis of new C-6 homologues of
logues of 1-deoxynojirimycin (3) and 1-deoxy-
imycin (4), (Fig. 1).
L
-idonojir-
1-deoxynojirimycin (3) and 1-deoxy- -idonojirimycin (4).
L
Thus, the key substrate 10 was prepared by analogy with the
Our synthetic plan relies on the successful PdCl2-catalysed
aminocarbonylation of the benzyl protected aminoalkene 10
yielding the desired lactones 1 and 2. Generally, amino-
carbonylation of 3-hydroxypent-4-enylamines giving pyrroli-
dine lactones proceeds easily,9,10 which is in contrast to
4-hydroxy-hex-5-enylamines producing the corresponding pi-
peridine lactones (Scheme 1).
To the best of our knowledge, there are only a few papers in
the literature which deal with such a transformation on similar
but simpler substrates.10,11 However, reported yields are fairly
low and no further synthetic elaboration of the prepared
piperidine lactones has been reported. The common feature of
almost all published amino-/amido-carbonylations (either pro-
ducing pyrrolidine or piperidine lactones) is the use of electron-
withdrawing protecting groups (tosyl, CO2Me, CO2Bn, CON-
HMe, CONHPh, CONHBn) on the NH function of the
known procedure according to the literature:12 benzylidenation
of the starting methyl-a- -glucoside 5 afforded the diol 6,
D
which was subsequently benzylated to a fully-protected com-
pound 7. Acidic hydrolysis of 7 and nucleophilic displacement
of the primary hydroxy function of 8 yielded bromide 9, the
latter being finally converted to the desired (2S,3S,4R)-N-
benzyl-2,3-di-O-benzyl-2,3,4-trihydroxyhex-5-enylamine 10.
First attempts to cyclise 10 under standard carbonylation
conditions11a (1 atm CO, 0.1 equiv. PdCl2, 3 equiv. CuCl2,
3 equiv. AcONa, AcOH, conditions A) at room temperature
failed and always the starting material was isolated. Gratify-
ingly, simply raising of temperature to 50 °C led to the complete
consumption of aminoalkene 10 while the colour of the reaction
mixture changed from dark green to ochre. However, amino-
carbonylation of 10 yielded a complex mixture of compounds
from which desired lactones 1 and 2 were isolated in the ratio
1+4.8 as main products. The major by-product of the reaction
turned out to be N-benzyl-2,3-di-O-benzyl-6-chloro-1,6-di-
deoxy- -idonojirimycin 11‡ (Scheme 2).
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We then searched for reaction conditions that would produce
more of lactone 1 than 2 and suppress the formation of the side
product 11. We were pleased to find that a catalytic system
consisting of 0.1 equiv. PdCl2, 1 equiv. p-benzoquinone,
2 equiv. LiCl, 2 equiv. AcONa in THF under 1 atm CO at room
temperature (conditions B) afforded a mixture of lactones 1 and
2 in the ratio 3.7+1 with no formation of 11. Our suspicion that
CuCl2 (used in excess as reoxidant) might be responsible for the
formation of undesired 11 was thus proved. The definitive
confirmation came from the experiment in which aminoalkene
10 was subjected to conditions A but with exclusion of CO
atmosphere. The only product we were able to isolate was the
chloroderivate 11§ (Scheme 3).
Fig. 1 Homologues of 1-deoxynojirimycin and 1-deoxy-L-idonojirimycin.
The separation and purification of 1 and 2 by FLC and
subsequent reduction of both lactone rings gave the piperidine
† Part of PhD Thesis of P. S. E-mail: szol@chelin.chtf.stuba.sk
DOI: 10.1039/a908449e
Chem. Commun., 2000, 471–472
This journal is © The Royal Society of Chemistry 2000
471

In addition, we have observed an interesting type of PdCl2/
CuCl2 catalysed chloroaminocyclisation of substituted 4-hy-
droxyhex-5-enylamine producing the corresponding piperidine
derivative 11 which could be useful in the synthesis of various
piperidine and azepine alkaloids.13 Investigation of the scope
and limitations of the presented methodology is under progress
and will be reported in due course.
We are grateful to Professor V. Jäger (Stuttgart) for very
helpful ideas, discussions and unlimited support. This research
was supported by VW Stiftung (Hannover) and The Slovak
Grant Agency. We thank TauChem Ltd. (Bratislava) for
providing us with carbon monoxide and to Dr Zálupsky for
language corrections.
Notes and references
‡ The ratio of diastereoisomeric lactones 1 and 2 was determined by
quantitative 13C NMR spectroscopy with suppressed NOE effect. Selected
data for 1: [a]2D4 264.9 (c 1.23, CH2Cl2); m/z 443 (M 2 1)+. For 2: [a]3D0
26.05 (c 0.74, CH2Cl2); m/z 444 (M)+. For 11: [a]D25 +35.1 (c 0.7, CH2Cl2);
m/z 451 (M 2 1)+. The relative configurations of 1, 2 and 11 were
established on the basis of NOESY and DIFNOE NMR experiments.
§ An analogous transformation using PdCl2(PhCN)2 and CuCl2 in PrCN has
been reported. However, neither the configuration of the product(s) nor the
diastereoisomeric excess were given: M. Wada, H. Aiura and K. Akiba,
Heterocycles, 1987, 26, 929.
Scheme 2 Reagents and conditions: i, PhCH(OEt)2, cat. CSA, CHCl3, 81%;
ii, BnBr, NaH, DMF, 75%; iii, H2SO4, MeOH, 97%; iv, Ph3P, CBr4,
pyridine, 79%; v, Zn dust, BnNH2, NaBH3CN, PrOH–H2O (19:1), 64%; vi,
conditions A, 50 °C, 4–7 h, FLC, 46% of 1 + 2 (dr = 1+4.8), 9% of 11 or
conditions B, room temp., 17 h, FLC, 66% of 1 + 2 (dr = 3.7+1).
¶ All new compounds exhibit satisfactory elemental analyses and spectro-
scopic data. The absolute configuration of 3.HCl was determined by single
X-ray analysis (ref. 14).
∑ The benzylamino group was used in a similar type of process for the
cyclisation of more reactive allenes that produced esters rather than
lactones: T. Gallagher, I. W. Davies, S. W. Jones, D. Lathbury, M. F.
Mahon, K. C. Molloy, R. W. Shaw and P. Vernon, J. Chem. Soc., Perkin
Trans 1, 1992, 433.
Scheme 3 Reagents and conditions: i, conditions A without CO, room
temp., 48 h, FLC, 70%.
diols 12 [mp = 97–98 °C; [a]3D1 219.4 (c 0.29, CH2Cl2); m/z
417 (M 2 CH2OH)+] and 13 [[a]D31 21.32 (c 0.34, CH2Cl2); m/z
447 (M 2 1)+]. Final catalytic debenzylation of both tetraols
afforded the desired (2R,3R,4R,5S)-2-(2-hydroxyethyl)-
3,4,5-trihydroxypiperidine 3 [mp 177–179 °C; [a]2D6 +30 (c
0.55, MeOH); m/z 177 (M 2 HCl)+] and (2S,3R,4R,5S)-
1 B. Winchester and G. W. J. Fleet, J. Glycobiol., 1992, 2, 199; M. L.
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Sci. U.S.A., 1988, 85, 9229.
5 I. Lundt and R. Madsen, Synthesis, 1995, 787; C. Herdeis and T.
Schiffer, Tetrahedron, 1996, 52, 14 745.
2-(2-hydroxyethyl)-3,4,5-trihydroxypiperidine
4
(mp
202–203 °C; [a]3D2 +20.2 (c 0.42, MeOH); m/z 177 (M 2 HCl)+]
as hydrochlorides (Scheme 4).¶
6 G. Rassu, L. Pinna, N. Culeddu, G. Casiraghi, G. Gasparri Fava, M.
Belicchi Ferrari and G. Pelosi, Tetrahedron, 1992, 48, 727; J. P.
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and P. Vogel, Carbohydr. Res., 1996, 281, 277.
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hedron Lett., 1994, 35, 9047; F. Compernolle, G. Joly, K. Peeters, S.
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Scheme 4 Reagents and conditions: i, LiBH4, THF, room temp., 64–65% ii,
H2, 10% Pd/C, MeOH, HCl, room temp., DOWEX (H+), 82–90%.
10 V. Jäger, T. Gracza, E. Dubois, T. Hasenöhrl, W. Hümmer, U. Kautz, B.
Kirschbaum, A. Lieberknecht, L. Remen, D. Shaw, U. Stahl and O.
Stephan, Pd(II)-Catalyzed Carbonylation of Unsaturated Polyols and
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Vieweg, Germany, 1997, p. 331.
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13 T. Morie and S. Kato, Heterocycles, 1998, 48, 427.
In conclusion, we have performed the first successful PdII-
catalysed aminocarbonylation of highly substituted 4-hydroxy-
hex-5-enylamine that contains a Bn-protected amine group.∑ In
contrast to the literature precedents,10,11 we observed the
formation of both diastereoisomeric cis- and trans-fused
piperidine lactones. Their ratio depended on the reaction
conditions and these compounds represent direct precursors for
the synthesis of new derivatives of polyhydroxylated piper-
idines. The applicability of this methodology has been demon-
strated in the total synthesis of new C-6 homologues of
14 M. Koman, P. Szolcsányi and T. Gracza, submitted for publication.
1-deoxynojirimycin (3) and 1-deoxy-
L
-idonojirimycin (4).
Communication a908449e
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Chem. Commun., 2000, 471–472