Pyrrolidines bearing a quaternary α-stereogenic center. Part 2: Access to proline chimeras, stereoselective approach and mechanistic aspects

Article abstract of DOI:10.1016/S0040-4039(00)00505-0

The present work describes the access to various proline chimeras bearing a quaternary α-stereogenic center, via the Duhamel ring contraction of heterocyclic enamines. Attempts to induce diastereoselectivity are reported. The 'chiral enamine' strategy aff

Full text of DOI:10.1016/S0040-4039(00)00505-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3843–3847
Pyrrolidines bearing a quaternary α-stereogenic center. Part 2:
Access to proline chimeras, stereoselective approach and
mechanistic aspects
Delphine Trancard, Jean-Baptiste Tout, Thierry Giard, Ilhame Chichaoui, Dominique Cahard
and Jean-Christophe Plaquevent ∗
Laboratoire des Fonctions Azotées et Oxygénées Complexes de l’IRCOF, UPRES-A 6014, Université de Rouen,
Faculté des Sciences, Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France
Received 11 February 2000; accepted 24 March 2000
Abstract
The present work describes the access to various proline chimeras bearing a quaternary α-stereogenic center,
via the Duhamel ring contraction of heterocyclic enamines. Attempts to induce diastereoselectivity are reported.
The ‘chiral enamine’ strategy afforded the required aminoaldehydes with diastereomeric ratios as high as 85:15.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino aldehydes; diastereoselection; enamines; pyridinium salts; pyrrolidines.
Conformational constraint is a usual way to modify the properties of bioactive peptides. In some cases
such modification improves their activity as well as their affinity for their biological target.1 Proline
analogs play a pivotal role in such studies, thus encouraging the development of new methodologies
allowing access to so-called ‘proline chimeras’,2 in which the heterocycle of the amino acid is substituted
in such a way that the chimera combines the conformational constraint of proline with the side chain of
another amino acid. Our ongoing research on pyrrolidines bearing a quaternary α-stereogenic center3
gave us the methodology allowing easy access to new proline chimeras, which could be functionalized
in the α-position.4 Such compounds could be used for structural modifications of peptides, or as starting
materials for the synthesis of bioactive molecules such as kaitocephalin,5 cephalotaxin,6 anti HIV
agents,7 and peptidomimetics.1,2
∗
Corresponding author. Fax: 2 35 522971; e-mail: jean-christophe.plaquevent@univ-rouen.fr (J.-C. Plaquevent)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00505-0
tetl 16784

3844
1. Access to new proline chimeras
Our strategy for constructing the proline chimeras relies on a similar reaction scheme as published
previously for quaternary analogs of alkaloids (Scheme 1).3,8
Scheme 1. Reagents and conditions: (i) PhCH2X (X=Br or Cl); (ii) AgCl, MeOH, reflux (if X=Br) then H2/Pd/C (10%), MeOH;
(iii) Br2 (3 equiv.)/Et2O, −60°C then H2O/Et3N
Benzylation of the starting nicotinates by benzyl halide gave the corresponding pyridinium salts in
excellent yield. The hydrogenation was performed at atmospheric pressure according to Wenkert et al.9
The counteranion exchange by means of AgCl was necessary in the case of bromide since this anion
could poison the catalyst. Finally, the Duhamel ring contraction was realized under previously reported
conditions,3,8 thus giving the required aminoaldehydes 1a–b (glycinal-PRO chimeras) efficiently which
were purified by flash chromatography. One can observe that in the menthyl series, the diastereomeric
ratio of 1b was rather low (55:45). Discussion about diastereoselectivity of the ring contraction process
appears in the following part. Functional modifications of compounds 1 gave access to other proline
chimeras (β-alanine-PRO and vinylglycine-PRO), either protected or free (Scheme 2).
Scheme 2. Reagents and conditions: (i) PhCH2NH2, 3 ÅMS; (ii) NaBH4, EtOH; (iii) Pd(OH)2/H2; (iv) Ph3P+Me I−, n-Buli,
THF, −60°C
Thus the present methodology permits the construction of some new proline chimeras which can
be functionalized in the α-position. The compounds were readily obtained from 1 using standard
procedures and were purified by flash chromatography. Interestingly, the carbonyl group of 1 was
stable enough under most reaction conditions, thus leading to the desired quaternary products, bearing
various functional groups, such as imine (2), secondary amine (3), primary amine (4), and vinyl (5a,5b)
substituents. In the latter case, one can observe that the yield was significantly improved when starting
from compound 1b bearing a bulky ester moiety.
The lower yield obtained in the case of 1a (R=Me) resulted mainly from decarbonylation of the starting
material, as previously described in the literature.8b The rather high yields which were obtained highlight
the synthetic interest of the Duhamel ring contraction in this context.

3845
2. Study of the diastereoselectivity of the ring-contraction process: first attempts (chiral side chain)
Having in hand the possibility of preparing various proline chimeras, we turned our studies to the
asymmetric access to these compounds. Since the generally reported mechanism of the contraction
process relies on intramolecular substitution giving an aziridinium ion intermediate,8 we expected that the
diastereoselective control of the bromination step would be the key step for the asymmetric construction
of the chiral aldehydes 1. Nevertheless, one can also consider the possibility of a competitive mechanism
involving an intermediate carbocation, as previously postulated in the literature.10 In this latter case, one
cannot exclude a loss of stereoselectivity even if the bromination step was stereoselective.
First, we prepared starting materials bearing either chiral amide or ester residues on the side chain, and
submitted them to the contraction process (see Schemes 3 and 4).
Scheme 3.
Scheme 4.
In this first series, results were disappointing, while giving the expected peptide in satisfactory yields
(30–40% overall yield). Nevertheless, no asymmetric induction was obtained, as checked by NMR
analysis (1H and 13C). Interestingly, alkaline decarbonylation of the peptidic aldehyde occurred with
high diastereoselectivity. Obviously, this reaction proceeded through a prochiral anionic intermediate
which was stereoselectively protonated under the influence of the chiral side chain.
As in the previous case, no significant diastereoselectivity was observed in the chiral terpenic esters
series, as checked by NMR (1H and 13C) and GC/MS analyses. We then turned to another series of chiral
precursors in which the chiral moiety was directly linked to the nitrogen atom of the heterocyclic system
(chiral enamine strategy, vide infra).
3. Diastereoselectivity in the ring-contraction process via chiral enamine strategy
Chiral enamines 6 were prepared by hydrogenation of the corresponding pyridinium salts, which
were obtained by Zincke reaction starting from nicotinamide, according to recent developments.11 We

3846
expected that a chiral moiety directly linked to the nitrogen of the heterocyclic system could be more
efficient for asymmetric bromination compared with the chiral side chains approach (vide supra). Another
interesting point was the possibility to isolate the intermediate iminium salts 7,10 and thus to have
the possibility to examine a two-steps versus ‘one-pot’ ring-contraction process. Accordingly, the ring
contraction of enamines 6a,b led to major new information (see Scheme 5):
– poor but significant diastereoselection in the case of Ar_Ph (8a), with inversion of stereoselectivity in
the two-steps procedure (contraction starting from isolated iminium salt) with respect to the‘one-pot’
procedure (bromination and alkaline treatment without isolation of the intermediate iminium salt),
clearly indicating the competition of two mechanisms. This inversion was not observed when starting
from 6b.
– improvement of diastereomeric excess when crowding the chiral enamine (Ar_1-naphtyl, 8b), up to
78:22 (two-steps procedure).
– improvement of diastereoselection when cooling at 0°C the aqueous treatment of the iminium bromide
7b, giving a diastereomeric ratio as high as 85:15 (8b).
Scheme 5.
Diastereomeric ratios were determined by means of NMR analyses (1H and 13C), respectively by
integration of CHO and C_O signals. The mixture of diastereoisomers showed two distinct spots on
TLC, allowing the separation by chromatography.
4. Conclusion
The present study describes handy access to proline chimeras by means of Duhamel ring contraction
and demonstrates the possibility to control with rather high de the newly created stereogenic center.
The ‘chiral enamine’ strategy appears much more successful than the ‘chiral side chain’ approach.
To the best of our knowledge, these results constitute the first asymmetric Duhamel ring contraction
by means of a removable chiral auxiliary. Some experimental results suggest the possibility of two
concurrent mechanisms, depending on the starting material and experimental conditions. Current studies
are focusing on the improvement of asymmetric synthesis of the key aminoaldehydes 1.

3847
Acknowledgements
This research was supported by the ‘Réseau RINCOF’. We also thank the MRT for a grant attributed
to T.G., Professor M. C. Lasne, Dr, C. Perrio-Huard and Dr. J. Rouden for their interest in our work, and
Dr. R. Azerad for the generous gift of 5-endo-hydroxycineol.
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