Intramolecular mitsunobu reaction in the regio- and stereoselective synthesis of cis-4,5-disubstituted piperidin-2-ones

Article abstract of DOI:10.1016/S0040-4039(00)01461-1

Enantiopure cis-4,5-disubstituted piperidin-2-ones were synthesized through the cyclization of O-benzyl hydroxamates under Mitsunobu conditions, followed by samarium diiodide reduction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01461-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8285–8288
Intramolecular Mitsunobu reaction in the regio- and
stereoselective synthesis of cis-4,5-disubstituted
piperidin-2-ones
Nicole Langlois* and Olivier Calvez
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 17 July 2000; accepted 30 August 2000
Abstract
Enantiopure cis-4,5-disubstituted piperidin-2-ones were synthesized through the cyclization of O-benzyl
hydroxamates under Mitsunobu conditions, followed by samarium diiodide reduction. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: polysubstituted piperidinones; hydroxamates; Mitsunobu reaction; samarium diiodide.
Polysubstituted piperidines are common structural sub-units in numerous natural products
and drugs. As this class of compounds exhibit a wide range of biological activities,1 regio- and
stereoselective syntheses of enantiopure substituted piperidines are a target of particular
interest.2 Thus, many structural analogues of pyranose-type azasugars, particularly 2-substituted
3,4,5-trihydroxypiperidines with transition-state like half-chair conformation, have been synthe-
sized and studied as glycosidase inhibitors.3,4 Among the 2,4,5-trisubstituted members, (4S,5S)-
5-acetamido-4-hydroxypipecolic acids 1 are weak sialidase inhibitors,5 whereas pseudodistomins
A, B, F (2) and E, C (3) are known for their activity as calmodulin antagonists and/or their
cytotoxicity against L1210 leukemia cells.6,7 In these marine piperidines isolated from tunicates,
a cis relationship is observed between the substituents at C-4 and C-5.6,7 Focusing our interest
on this characteristic structural feature, we report here a new route to the diastereo- and
enantioselective construction of cis-4,5-disubstituted piperidin-2-ones, the amide carbonyl of
which allows further functionalization.
* Corresponding author. Fax: 0169077247; e-mail: nicole.langlois@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01461-1

8286
Starting from the rigid bicyclic a,b-unsaturated lactam 4 derived from inexpensive (S)-pyrog-
lutaminol, the synthetic route, summarized in the general Scheme 1, took advantage of the high
diastereoselectivity observed in the substitution at C-6. The 6S-hydroxy derivative 5 was
obtained by regiospecific opening of 6R,7R-epoxide with SmI2 at −78°C (83% for two steps),8
whereas the 6S-N-benzylamino compound 6 resulted from stereospecific conjugate addition of
N-benzylamine (88%).9 The nitrogen of the targeted piperidin-2-ones could be introduced by the
opening of N-tert-butoxycarbonylpyrrolidin-2-one rings with O-benzylhydroxylamine to form
hydroxamates. The low pK of O-benzyl hydroxamates, indeed, is known to induce a good
chemoselectivity towards an intramolecular Mitsunobu reaction of substrates also containing
carbamate functions. This selectivity has been widely used in b and v-lactam formation,10,11 and
has been extended in our laboratory to d-lactam preparation, as exemplified by the synthesis of
enantiopure (S)-5-aminopiperidin-2-one 7.12
Scheme 1. Reagents and conditions (all the reactions were performed at room temperature): (a) CF3CO2H, H2O–THF
1:1; (b) (i) ethylvinylether, CCl3CO2H, CH2Cl2; (ii) (Boc)2O, DMAP, CH3CN; (c) BnONH2, H2O, Na2CO3; (d) 0.1N
HCl; (e) PPh3, DEAD, THF; (f) SmI2, THF

8287
Accordingly, the alcohol 5 gave rise quantitatively to the diol 8 after hydrolysis of the
oxazolidine protection with aqueous trifluoroacetic acid in THF. The diol 8 was converted into
suitably protected N-Boc pyrrolidin-2-one 9 by classical methods (89% for two steps, Scheme 1).
At first, O-benzyl hydroxamate 10 was obtained from 9 (40%) by triisobutylaluminum mediated
transamidation13 with O-benzylhydroxylamine, but this reaction was unreliable and N-Boc
deprotection was observed in some cases. The cleavage in the presence of a catalytic amount of
potassium cyanide,14 or using lithium amide as the nucleophile, led to a mixture of products
resulting from deprotonation at C-3 with b-elimination. The major product resulted from
Michael addition of an unsaturated lactam to another molecule, providing a dimeric compound
characterized after deprotection of the hydroxyl groups (Scheme 2).15 The opening of the
g-lactam ring with the amine in the presence of H2O and Na2CO3 was preferred, following our
recently developed method.14 Under these conditions, however, the reaction with 9 is very slow
and was stopped before completion to avoid a possible b-elimination of the functional group at
C-4. Compound 10 was isolated in 60% yield, together with starting 9 (25%).
Scheme 2.
A selective Mitsunobu reaction with O-deprotected diol 11 (100% from 10) was performed in
THF at room temperature using 1.2 equiv. of reagents (PPh3, DEAD) and provided 12 (68%).
Previous cyclization through selective Mitsunobu reaction with unprotected amino-polyols
leading to five-membered rings has been described in pyridine as solvent.16 In the NMR spectra
of the cyclization product 12, the chemical shifts of C-6-H2 (13C: l=49.8 ppm), consistent with
a NCH2 methylene, prove that N-alkylation occurred versus O-alkylation. The NꢀO bond of 13
was cleanly cleaved by SmI2 in THF at room temperature,17,18 and the required piperidinone 13
was obtained in 84% yield (Scheme 1).
A similar scheme was applied to the synthesis of the protected cis-4,5-diamino piperidin-2-one
19 as an analogue. The 6-N-benzylamino derivative 6 led, after N-benzoylation (PhCOCl, 2.4
equiv., CH2Cl2, Et3N, rt, 95%) and acid hydrolysis (100%), to the g-lactam 14, which was
converted into N-Boc pyrrolidinone 15 (70% for two steps). The g-lactam ring of 15 was
smoothly opened with O-benzylhydroxylamine to afford the pentanamide 16 (72%) and unre-
1
acted 15 (11%). These compounds gave broad signals in H NMR, probably owing to the
presence of conformers. By intramolecular alkylation under Mitsunobu reaction conditions, the
primary alcohol 17 (100% from 16) gave rise efficiently to 4,5-disubstituted piperidin-2-one 18
(82%). This compound was treated with SmI2 to afford the 4,5-disubstituted piperidin-2-one 19

8288
in good yield (84%). In this way, cis cyclic vicinal diamines in diastereomerically and
enantiomerically pure form become accessible and could be useful as scaffolds to synthesize not
only more complex molecules but also new metal chelating agents.20
In conclusion, a synthesis of new enantiopure 4-substituted 5-(N-Boc)aminopiperidin-2-ones
of defined 4S and 5R configurations was developed taking advantage of stereospecific function-
alization of the versatile bicyclic a,b-unsaturated lactam 4.
Acknowledgements
We are grateful to Dr. Pierre Potier for a grant (O.C.).
References
1. (a) Schneider, M. J. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W. Ed.; Pergamon: Oxford,
1996; Vol. 10, pp. 155–299. (b) O’Hagan, D. Nat. Prod. Reports 1997, 14, 637–651.
2. Bailey, P. D.; Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998, 633–640.
3. (a) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C.-H. J. Org. Chem. 1991, 56,
6280–6289. (b) Kajimoto, T.; Liu, K. K. C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y.; Porco, J. A., Jr.; Wong,
C.-H. J. Am. Chem. Soc. 1991, 113, 6187–6196. (c) Frankowski, A.; Seliga, C.; Bur, D.; Streith, J. Helv. Chim.
Acta 1991, 74, 934–940. (d) Ganem, B. Acc. Chem. Res. 1996, 29, 340–347.
4. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680.
5. Gla¨nzer, B. I.; Gyo¨rgydea´k, Z.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1991, 74, 343–369 and references cited
therein.
6. (a) Kobayashi, J.; Ishibashi, M. Heterocycles 1996, 42, 943–970. (b) Ninomiya, I.; Kiguchi, T.; Naito, T.
Alkaloids 1998, 50, 317–342.
7. Freyer, A. J.; Patil, A. D.; Killmer, L.; Troupe, N.; Mentzer, M.; Carte, B.; Faucette, L.; Johnson, R. K. J. Nat.
Prod. 1997, 60, 986–990.
8. (a) Herdeis, C.; Aschenbrenner, A.; Kirfel, A.; Schwabenla¨nder, F. Tetrahedron: Asymmetry 1997, 8, 2421–2432.
(b) Panday, S. K.; Langlois, N. Synth. Commun. 1997, 27, 1373–1384 and references cited therein.
9. Langlois, N.; Calvez, O.; Radom, M.-O. Tetrahedron Lett. 1997, 38, 8037–8040.
10. Hughes, D. L. Org. React. 1992, 42, 335–656.
11. (a) Miller, M. J. Acc. Chem. Res. 1986, 19, 49–56. (b) Maurer, P. J.; Miller, M. J. J. Org. Chem. 1981, 46,
2835–2836.
12. Panday, S. K.; Langlois, N. Tetrahedron Lett. 1995, 36, 8205–8208.
13. Rotella, D. P. Synlett 1996, 479–480.
14. Langlois, N.; Moro, A. Eur. J. Org. Chem. 1999, 3483–3488.
15. Langlois, N. Second Euroconference on Marine Natural Products, Sept. 1999, Santiago de Compostela, Spain.
16. (a) Chen, Y.; Vogel, P. J. Org. Chem. 1994, 59, 2487–2496. (b) Veith, U.; Schwardt, O.; Ja¨ger, V. Synlett 1996,
1181–1183.
17. (a) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995, 36, 7419–7422. (b) Chiara, J. L.; Destabel,
C.; Gallego, P.; Marco-Contelles, J. J. Org. Chem. 1996, 61, 359–360. (c) Falborg, L.; Jorgensen, K. A. J. Chem.
Soc., Perkin Trans. 1 1996, 2823–2826. (d) Keck, G. E.; Wager, T. T.; McHardy, S. F. Tetrahedron 1999, 55,
11755–11772.
18. This reagent is easier to handle than TiCl3 generally used to reduce the corresponding hydroxamic acids.12,19
19. Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1980, 45, 410–415.
20. Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580–2627.
.
.