A new nitrone from C2 symmetric piperidine for the synthesis of hydroxylated indolizidinone

Article abstract of DOI:10.1016/S0040-4039(02)02336-5

The oxidation of a C₂ symmetric piperidine, obtained through a ring enlargement process of the enantiopure protected (4R)-hydroxy-(2S)-hydroxymethyl pyrrolidine, is reported. Oxidation with C-phenyl-N-phenylsulfonyloxaziridine afforded the corr

Full text of DOI:10.1016/S0040-4039(02)02336-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9357–9359
A new nitrone from C2 symmetric piperidine for the synthesis of
hydroxylated indolizidinone
Alberto Brandi,a,* Stefano Cicchi,a Valentina Paschetta,a Domingo Gomez Pardob and
Janine Cossyb,*
aDipartimento di Chimica Organica ‘Ugo Schiff’, Universita` degli Studi di Firenze, Via della Lastruccia 13, Polo Scientifico,
50019 Sesto Fiorentino, Italy
bLaboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 22 July 2002; accepted 18 October 2002
Abstract—The oxidation of a C2 symmetric piperidine, obtained through a ring enlargement process of the enantiopure protected
(4R)-hydroxy-(2S)-hydroxymethyl pyrrolidine, is reported. Oxidation with C-phenyl-N-phenylsulfonyloxaziridine afforded the
corresponding nitrone that is too unstable for isolation and which reacted in situ with dimethyl maleate. The major adduct was
transformed to the corresponding protected dihydroxyindolizidinone. © 2002 Elsevier Science Ltd. All rights reserved.
Polyhydroxyindolizidines are valuable biologically
active molecules that can function as glycosidase
inhibitors.1 1,3-Dipolar cycloadditions are convenient
methods that afford various examples of optically
active polyhydroxyindolizidines2 starting from enan-
tiopure mono- and dialkoxy five-membered ring
nitrones derived from compounds of the ‘chiral pool’.3
Lentiginosine (4), the most powerful indolizidine
inhibitor of amyloglycosidase, was synthesized from
nitrone 2 (Scheme 1).4 The key step of the synthesis was
the oxidation of pyrrolidine 1a, or N-hydroxy deriva-
tive 1b, both derived from natural tartaric acid, to the
corresponding nitrone 2. Furthermore, indolizidine 5
was synthesized from 1c by applying a Mitsunobu
reaction to the monoprotected derivative of 1c, which
produced the desymmetrized meso form of the (3S,4R)
3,4-dihydroxypyrrolidine 3.5 The recent development,
by one of our groups, of a straightforward synthesis of
enantiopure substituted 3-hydroxypiperidines from
enantiopure 2-hydroxymethylpyrrolidines6 allowed us
to study the 1,3-dipolar cycloaddition of substituted
piperidine nitrones to activated olefins and to compare
the results with those obtained with substituted pyrro-
lidine nitrones. Furthermore, the use of enantiopure
six-membered alkoxynitrones will be an alternative syn-
thetic pathway to synthesize indolizidine derivatives
with a strict control of the relative and absolute stereo-
chemistry of the substituents on the six-membered ring
of the indolizidines.7 In this communication we would
like to report the oxidation of an enantiopure C2 3,5-
disilyloxypiperidine 9, the subsequent cycloaddition
reaction of the corresponding nitrone with dimethyl
maleate 12 and the transformation of the major
cycloadduct to the corresponding indolizidinone.
When compound 6, synthesized from the commercially
available (4R)-hydroxy-(2S)-hydroxymethylpyrrolidine,
was treated with trifluoroacetic anhydride and then
with triethylamine and then with NaOH, the substi-
Keywords: C2 symmetry; 1,3-dipolar cycloaddition; nitrone;
indolizidinone.
* Corresponding
authors.
E-mail:
alberto.brandi@unifi.it;
janine.cossy@espci.fr
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02336-5

9358
A. Brandi et al. / Tetrahedron Letters 43 (2002) 9357–9359
tuted piperidine 7 was isolated in 82% yield. The
obtained piperidine 7 was then transformed to the C2
symmetric piperidine 8 in 95% yield by protecting the
free hydroxyl group with TBDMSCl (Et3N, DMAP,
CH2Cl2) (Scheme 2). Reductive debenzylation of 8
afforded the secondary amine 9 but its transformation
to the corresponding nitrone 11, proved to be trouble-
some. The usual oxidative reagents such as SeO2,8
obtained from sugars.13,7 Due to its instability, nitrone
11 was used in situ directly for 1,3-dipolar cycloaddi-
tion reactions. Reactions with non-activated dipolar-
ophiles such as allyl alcohol or 3-buten-1-ol as well as
simple acrylates afforded only complex mixtures of
which the expected adducts were only a minor part and
could not be isolated. The use of a reactive dipolar-
ophile such as dimethyl maleate (12) afforded two
diastereoisomeric adducts 13 and 14 in an 8:1 ratio
(similar to that obtained with five-membered nitrones)3c
9
Na2WO4 and H2O2 afforded only complex mixture of
compounds. This is a first marked difference between
C2 symmetric piperidine 9 and C2 symmetric pyrro-
lidine 1a, as this latter compound was smoothly oxi-
dized to 2 in good yield.5 Nevertheless, this behavior is
not peculiar to substituted piperidines, since pyrrolidi-
nes derived from 3 could not be oxidized with these
reagents. Finally, a good conversion of 9 to 11 was
obtained by using C-phenyl-N-phenylsulfonylox-
aziridine (10)10 as piperidine 9 was transformed in
quantitative yield to nitrone 11.11 Nitrone 11 was
extremely unstable and unsuitable for isolation in
appreciable chemical purity and yield. It is worthy of
note that its instability is common to other members of
this group and in general six-membered ring nitrones
are known to form dimers.12 Furthermore, this nitrone
represents an example of a small group of enantiopure
alkoxy substituted six-membered ring nitrones, often
1
in acceptable yield (50%) (Scheme 3). H and 13C NMR
spectra showed broad signals presumably due to slow
nitrogen interconversion. Heating at 100°C (d6-DMSO)
caused sharpening of the signals.13c The structure
derived from an exo approach of the reagents was
assigned to both compounds 13 and 14, on the basis of
1
1
their H NMR spectra and by comparison with the H
NMR spectra of the adducts derived from cycloaddi-
tion of unsubstituted six-membered ring nitrone with
dimethyl maleate (12).14 The major isomer 13 showed
the same pattern for H3 and H2 (H3: 3.54 ppm, t,
J=9.9 Hz; H2: 4.80 ppm, d, J=9.9 Hz) as the major
isomer obtained from the non-substituted piperidine
nitrone (H3: 3.41 ppm, t, J=10.0 Hz; H2: 4.74 ppm, d,
J=10.0 Hz).14 The presence of the same pattern for the
minor isomer 14 (H3: 3.68 ppm, t, J=9.0 Hz; H2: 4.79
ppm, d, J=9.0 Hz) led us to assign the same relative
stereochemistry to H3a, H3, and H2. The cycloaddition
indicates that nitrone 11, is more selective with respect
to the corresponding five-membered ring nitrone 2,
which gave a mixture of three products with dimethyl
maleate in a ratio 13:1.4:1.3c As in the case of nitrone
11 the products derived from an endo approach were
not isolated, it seems that the axial orientation of the
5-alkoxy substituent hampers the endo approach of the
reacting maleate due to severe steric interaction (Fig.
1).
The major diastereoisomer 1315 was finally transformed
to the corresponding indolizidinone 1516 by reductive
1
cleavage of the NꢀO bond (Scheme 3). The H and 13C
NMR spectra of compound 15 and NOE experiments
confirmed the structural assignment. NOE experiments
showed a cis relationship between protons H8ꢀH1 and
Scheme 2.
Scheme 3.

A. Brandi et al. / Tetrahedron Letters 43 (2002) 9357–9359
9359
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example of polyhydroxyindolizidinones constructed
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1
11. 11: H NMR (CDCl3): l 7.08 (m, 1H), 4.63 (m, 1H), 4.34
(m, 1H), 3.86 (dd, 1H, J=14.5, 1.5 Hz), 3.60 (dd, 1H,
J=14.5, 4.0 Hz), 2.00 (m, 1H), 1.75 (ddd, 1H, J=12.8,
7.3, 2.6 Hz), 0.87 (s, 9H), 0.86 (s, 9H), 0.08 (s, 6H), 0.07
(s, 6H); 13C NMR (CDCl3): l 128.9 (d), 64.9 (d), 63.9 (d),
36.7 (t), 29.8 (t), 25.8 (q), 18.1 (s), −4.72 (q); MS (m/z):
359 [M+], 342, 286, 210, 197, 147, 128, 73.
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Acknowledgements
The authors thanks Ministero per l’Istruzione l’Univer-
sita` e la Ricerca (MIUR-Italy) for financial support
(Cofin 2000). CINMPIS (Consorzio Interuniversitario
Nazionale Metodologie e Processi Innovativi di Sintesi,
Bari, Italy) is gratefully acknowledged for the provision
of a post-doctoral fellowship to V.P.
1
15. 13: [h]2D0=+10 (c 0.38, CHCl3); mp=77–79°C; H NMR
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1
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