Synthesis of enantiopure protected 3-hydroxy-4-amino pyrroline N-oxides

Article abstract of DOI:10.1016/S0040-4039(99)02335-7

The synthesis of new five-membered enantiopure cyclic nitrones bearing protected cis vicinal amino and hydroxy functionalities is reported. The key step was a Mitsunobu reaction, which allowed placement of an azido group, with inversion of configuration, at the reacting centre. Cycloaddition of the novel nitrones to but-3-en-1-ol followed by simple elaboration of the adducts readily afforded protected amino dihydroxy indolizidines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02335-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1583–1587
Synthesis of enantiopure protected 3-hydroxy-4-amino pyrroline
N-oxides
Stefano Cicchi, Paola Ponzuoli, Andrea Goti and Alberto Brandi ∗
Dipartimento di Chimica Organica ‘U. Schiff’, Università di Firenze, Centro di Studio C.N.R. sulla Chimica e la Struttura dei
Composti Eterociclici e loro Applicazioni, Via G. Capponi 9, I-50121, Firenze, Italy
Received 4 October 1999; accepted 16 December 1999
Abstract
The synthesis of new five-membered enantiopure cyclic nitrones bearing protected cis vicinal amino and hydroxy
functionalities is reported. The key step was a Mitsunobu reaction, which allowed placement of an azido group,
with inversion of configuration, at the reacting centre. Cycloaddition of the novel nitrones to but-3-en-1-ol followed
by simple elaboration of the adducts readily afforded protected amino dihydroxy indolizidines. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: nitrones; pyrrolidines; Mitsunobu reactions; cycloadditions.
Many indolizidine alkaloids act as powerful and selective inhibitors of glycosidases.1 This biological
activity has promoted considerable interest in the synthesis of these compounds and their analogues.
Castanospermine, swainsonine, lentiginosine and their analogues are the most common targets of
synthetic efforts (Fig. 1).2
Fig. 1.
∗
Corresponding author. Fax: +0552476964; e-mail: brandi@chimorg.unifi.it (A. Brandi)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02335-7
tetl 16263

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Other natural products such as mannostatin3 or threazolin4 possess a similar activity towards glycosi-
dases. Their common and most relevant feature is the presence of a cis vicinal aminoalcohol or -alkoxy
functionality. This substitution pattern seems to play an important role in many biological processes
since it is present in other active compounds.5 Moreover, it is also necessary to form an oxazolidine that
appears essential for biological activity.6
The introduction of this substitution pattern in a class of compounds, such as indolizidines, which
already show inhibitory activity towards glycosidases becomes, then, an important synthetic goal for
further bioactivity studies.
A useful approach to the synthesis of the indolizidine skeleton is offered by the 1,3 dipolar cycloaddi-
ton of five-membered cyclic nitrones 1 to but-3-en-1-ol 2 followed by simple transformations (Fig. 2).7 In
this communication we report the synthesis of new enantiopure five-membered cyclic nitrones 3 and 4 via
a Mitsunobu reaction as the key step (Fig. 3). The new nitrones with a protected cis vicinal aminoalcohol
functionality have been used in the synthesis of protected amino substituted dihydroxy indolizidines.
Fig. 2.
Fig. 3.
Commercially available (3S,4S)-N-benzyl-3,4-dihydroxypyrrolidine 5, upon reaction with a subs-
toichiometric amount of TBDMSCl or BzCl, afforded derivatives 6 and 7, respectively, in quantitative
yields, considering recycling of side products (Scheme 1).
Scheme 1. (a) TBDMSCl (0.6 equiv.), imidazole, DMF (6, 60%) or benzoyl chloride (0.9 equiv.), NEt3 (7, 90%); (b) DEAD,
diphenylphosphorylazide, PPh3 (8, 95%; 9, 91%); (c) (i) H2, Pd/C; (ii) (t-BOC)2O, NEt3 (10, 63%; 11, 45%)
The introduction of nitrogen at C4 with inversion of configuration was achieved by a Mitsunobu
reaction with diphenylphosphorylazide, diethylazodicarboxylate and triphenylphosphine. Compounds 6
and 7 gave the azido derivatives 8 and 9 in excellent yield,8 as single diastereoisomers. The inversion
1
of configuration at C4 was ascertained by H NMR analysis (JH3–H4=6.3 Hz consistent with a cis
relationship).9

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However, reduction of the azido group in 9 to an amine under the standard conditions proved somewhat
troublesome.
Under Staudinger conditions (PPh3/H2O)10 9 gave a mixture of two compounds in an equimolar ratio.
Spectroscopic analysis allowed their characterization as amines 12 and 13, with differing configuration
at C4 (Scheme 2). Addition of an equimolar amount of a strong base such as DBU drove the reaction
exclusively towards amine 12 that was, however, recovered in low yield. On the other hand, addition
of p-toluenesulfonic acid had no effect on the ratio. A possible neighbouring group participation by
the ring nitrogen atom cannot be ruled out although the experiment with p-toluenesulfonic acid and
previous reports on similar substrates exclude this hypothesis in our case.11 The benzoate group, in
contrast to TBDMSO, might favour the deprotonation of the intermediate phosphorimine, causing the
partial epimerization of the C-4 centre.
Scheme 2.
However, catalytic hydrogenation with Pd/C, gave the desired cis amines in good yield, and these were
transformed into the corresponding crystalline t-BOC amides 10 and 11 (Scheme 1).12
X-Ray analysis of 11 confirmed the cis relationship of the substituents. Apparently the cis-benzoyloxy
group induced the epimerization of the vicinal stereocentre during reduction of the azide. In fact,
reduction of azido derivative 8 with the Staudinger method proceeded smoothly to the desired cis amine.
Finally, debenzylation of N-benzyl pyrrolidines 10 and 11 afforded the secondary amines 14 and 15,
which were oxidized to the desired nitrones with C-phenyl-N-benzenesulfonyloxaziridine. As already
reported for similar substrates, this reagent was the only one able to perform the oxidation without
extensive decomposition of the pyrrolidine skeleton.9,13 The oxidation reactions afforded, as expected,
mixtures of regioisomeric nitrones whose structures were unambiguously assigned on the basis of their
1H NMR spectra (Scheme 3).
Scheme 3. (a) H2, Pd(OH)2/C, MeOH (95%); (b) N-benzenesulfonyl-C-phenyloxaziridine, rt, 2 h (3a–b, 50%; 4a–b, 52%).
Although the effect is limited, the regioselectivity is higher for the benzoyloxy derivative confirming
previous results obtained in the oxidation of 3-substituted N-hydroxypyrrolidines with mercury oxide
and other oxidants.14
The cycloadditon of these nitrones to but-3-en-1-ol 2 afforded bicyclic isoxazolidines which were
transformed into indolizidines.9,14,15 The reaction with nitrone 3a, easily separated from the regioisomer

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by flash column chromatography, is reported in Scheme 4. The cycloaddition proceeded smoothly with
complete regioselectivity and high stereoselectivity (d.e. 83%) (Scheme 4). The major cycloadduct 16
derives from an anti–exo approach of the dipolarophile to the nitrone.13,15
Scheme 4. (a) Benzene, 60°C, 3 days (89%); (b) methansulfonyl chloride, NEt3, CH2Cl2, rt, 1 h; (c) Pd/C 5%, H2 (1 atm), 12 h
then Ambersep 700 (17, 65%)
Compound 16 was transformed into the target indolizidine by mesylation of the hydroxyl functionality
followed by cyclization to the isoxazolidinium salt which underwent N–O bond cleavage to the desired
indolizidine 17 by catalytic hydrogenation.16
In conclusion, the efficient synthesis of enantiopure, diversely functionalized, five-membered cyclic
nitrones, useful synthons of amino polyhydroxy indolizidines, has been accomplished. Further applica-
tions are under investigation.
Acknowledgements
The authors thank M.U.R.S.T.-Cofin98 (Nuove Metodologie e Strategie di Sintesi di Composti di
Interesse Biologico) for financial support. Dr. Cristina Faggi and Dr. Annalisa Guerri are acknowledged
for X-ray crystallographic analysis. Degussa A.G. is gratefully acknowledged for a generous gift of
enantiopure (3S,4S)-N-benzyl-3,4-dihydroxypyrrolidine 5.
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1
16. All new compounds were fully characterized: 3a: [α]D20=32.3 (c 0.82, CHCl3); H NMR (CDCl3): δ 6.82 (d, J=1.1 Hz,
1H), 5.16 (d, J=8.1 Hz, 1H), 4.83 (d, J=6.6 Hz, 1H), 4.56 (m, 1H), 4.07 (dd, J=13.9, 7.7 Hz, 1H), 3.91 (dd, J=13.9, 6.9
Hz, 1H), 1.42 (s, 9H), 0.89 (s, 9H), 0.1 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3): δ 155.1 (s), 134.0 (d), 80.1 (s), 71.12
(d), 65.8 (d), 48.4 (t), 28.2 (q, 3C), 25.5 (q, 3C), 18.1 (s), −4.8 (q), −5.2 (q); MS (70 eV): m/z 330 [M+]; anal. calcd for
C15H30N2O4Si: C, 54.51; H, 9.15; N, 8.48. Found: C, 54.27; H, 9.48; N, 8.18. 3b: [α]D20=−20.1 (c 0.82, CHCl3); m.p.
96–97°C; 1H NMR (CDCl3): δ 6.76 (s, 1H), 5.07 (s, 1H), 4.55 (m, 1H), 4.10 (ddd, J=14.3, 4.8, 1.8 Hz, 1H), 3.75 (d, J=14.3
Hz, 1H), 1.43 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3): δ 154.9 (s), 133.5 (d), 80.4 (s), 71.12
(d), 69.9 (d), 67.7 (d), 55.2 (t), 28.2 (q, 3C), 25.5 (q, 3C), 17.9 (s), −5.0 (q), −5.3 (q); MS (70 eV): m/z 274 [M+−56]; anal.
calcd for C15H30N2O4Si: C, 54.51; H, 9.15; N, 8.48. Found: C, 54.76; H, 9.05; N, 8.85. 17: [α]D20=−40.6 (c 0.8, CHCl3);
1H NMR (CDCl3): δ 5.15 (d, J=7.0 Hz, 1H), 4.08 (q, J=7.3 Hz, 1H), 3.82 (t, J=7.0 Hz, 1H), 3.66–3.43 (m, 2H), 2.96 (dt,
J=11.4, 2.6 Hz, 1H), 2.18 (dt, J=11.4, 2.2 Hz, 1H), 2.04–1.82 (m, 4H), 1.60–1.35 (m, 2H), 1.40 (s, 9H), 0.89 (s, 9H), 0.05 (s,
3H), 0.04 (s, 3H); 13C NMR (CDCl3): δ 155.6 (s), 79.1 (s), 74.6 (d), 69.3 (d), 67.7 (d,), 61.2 (d), 49.8 (t), 49.2 (t), 38.0 (t),
34.6 (t), 28.3 (q, 3C), 25.7 (q, 3C), 18.0 (s), −5.0 (q), −5.1 (q); MS (70 eV): m/z 387 [M+]; anal. calcd for C19H38N2O4Si:
C, 59.03; H, 9.91; N, 7.25. Found: C, 58.88; H, 10.19; N, 7.46.