Asymmetric synthesis of novel polyhydroxylated derivatives of
indolizidine and quinolizidine by intramolecular 1,3-dipolar
cycloaddition of N-(3-alkenyl)nitrones†
Piotr Ge˜barowski and Wojciech Sas*
Warsaw University of Technology, Faculty of Chemistry, ul. Noakowskiego 3, 00 664 Warszawa, Poland.
E-mail: sas@ch.pw.edu.pl
Received (in Cambridge, UK) 31st January 2001, Accepted 10th April 2001
First published as an Advance Article on the web 1st May 2001
Reaction of 3-O-benzyl-1,2-O-isopropylidene-1,5-penta-
dialdo-a- -xylofuranose with N-(1,1-dimethylbut-3-enyl)-
D
hydroxylamine followed by intramolecular 1,3-dipolar
cycloaddition yields 7-oxa-1-azabicyclo[2.2.1]heptane deriv-
ative 4, which is easily converted into novel polyhydroxy-
lated quinolizidine 6 and indolizidine 8.
Polyhydroxylated derivatives of indolizidine and quinolizidine
(frequently named as azasugars) are powerful glycosidase
inhibitors and potential therapeutics.1 Consequently, these
compounds are targets of intensive synthetic studies.
Many syntheses of azasugars use derivatives of natural sugars
as starting materials.1 Based on our experience in intra-
molecular 1,3-dipolar cycloaddition of N-(3-alkenyl)nitrones2,3
we envisaged that this reaction, proceeding with high regio- and
diastereoselectivity,4 might be a useful tool for conversion of
sugar dialdehydes, with one carbonyl group masked, into
bicyclic azasugars E (Fig. 1).
Scheme 1 Reagents and conditions: i, toluene, argon, 85–90 °C, 43 h,
52%; ii, 5% HCl aq., rt, 2 d, 96%; iii, H2 (10 bar), Raney-Ni, MeOH,
75–80 °C, 21 h, 70% based on 4; iv, NaIO4, MeOH–H2O, 0 °C; v, H2 (10
bar), Raney-Ni, MeOH, rt, 24 h then 45 °C, 24 h, 55% based on 4.
We reasoned that the nitrone C, attained from the protected
cyclic or acyclic sugar dialdehydes A and N-homoallylhydrox-
ylamine B, (a sugar ring in Fig. 1 is symbolised by the dashed
bow) might undergo intramolecular 1,3-dipolar cycloaddition to
give the 7-oxa-1-azabicyclo[2.2.1]heptane derivative D with
high stereoselectivity induced by the sugar moiety.‡ Sub-
sequent unmasking of the carbonyl function, which could be
combined with a modification of the sugar residue (e.g.
shortening of the carbon skeleton by a diol cleavage), followed
by hydrogenolysis of the N–O bond accompanied by intra-
molecular reductive amination would complete the synthesis of
the target derivative E.
usefulness of the proposed method for the bicyclic azasugar
preparation (Scheme 1).
The N-homoallylhydroxylamine 2, necessary for the prepara-
tion of 4, was obtained from the aluminium amalgam reduction
of 4-methyl-4-nitropent-1-ene (readily accessible from palla-
dium(0)-catalysed C-allylation of 2-nitropropane6).3 The alde-
hyde 1 heated with 2 in toluene, under argon, gave N-
(3-alkenyl)nitrone 3 (Scheme 1), which in situ underwent
intramolecular 1,3-dipolar cycloaddition. Although the possi-
bility exists for formation of two adducts 4 and 4A, we separated
only one diastereoisomer 4 in 52% yield.§ Its structure was
1
We describe herein the transformation of the cyclic sugar
determined from H NMR spectra and molecular modelling
dialdehyde 1,2-O-isopropylidene-1,5-pentadialdo-a-
D
-xylofur-
(AM1). The coupling constant between H6 and H4A was very
helpful for configurational assignment; the value of this
anose 1,5 readily available from a-
D
-glucose, into the novel
3
polyhydroxylated quinolizidine 6 and indolizidine 8, possessing
a tertiary carbon at an a position to nitrogen, to illustrate the
constant, J6,4A = 9.9 Hz, is characteristic for protons in an
antiperiplanar arrangement. Molecular modelling revealed that
only for the adduct 4 did the lowest energy minimum
correspond to the conformation in which H6 and H4A are
antiperiplanar.
The conversion of 4 into quinolizidine 6 was straightforward.
Removal of isopropylidene protection by acidic hydrolysis gave
cleanly the derivative 5, which was hydrogenated in the
presence of Raney-nickel to afford directly the quinolizidine 6
1
in 70% yield based on 4. The structure of 6 from its H NMR
spectrum is consistent with the structure of 4. Thus the
heterobicyclic system adopts a structure close to trans-decaline
and all hydroxy groups occupy equatorial positions.
The preparation of the indolizidine 8 was also easy. In this
case the carbon skeleton of 5 was cut down by sodium periodate
1,2-diol cleavage to give the aldehyde 7, which also without
purification was hydrogenated in the presence of the nickel
catalyst to yield 8 in 55% yield, based on 4.
Fig. 1 General approach for asymmetric synthesis of bicyclic azasugars E
by intramolecular 1,3-dipolar cycloaddition of N-(3-alkenyl)nitrones.
In conclusion, it has been shown that the intramolecular
1,3-dipolar cycloaddition of N-(3-alkenyl)nitrones, obtained
from N-homoallylhydroxylamines and sugar dialdehydes, is
very useful for the synthesis of polyhydroxylated derivatives of
both quinolizidine and indolizidine. Further studies on improve-
† Electronic supplementary information (ESI) available: configurational
assignment of the adduct 4 and experimental details of preparation and
characterisation of
b101057n/
DOI: 10.1039/b101057n
Chem. Commun., 2001, 915–916
This journal is © The Royal Society of Chemistry 2001
915
Gebarowski
