Enantiospecific synthesis of pyridinones as versatile intermediates toward asymmetric piperidines

Article abstract of DOI:10.1021/ol201698m

The enantiospecific syntheses of pyridinones from amino acids via a gold-catalyzed strategy are reported. Excellent stereocontrol was observed during the cyclization. This approach provides a straightforward tool for further synthetic applications toward

Full text of DOI:10.1021/ol201698m

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4371–4373
Enantiospecific Synthesis of Pyridinones
as Versatile Intermediates toward
Asymmetric Piperidines
ꢀ
Nicolas Gouault,* Myriam Le Roch, Adele Cheignon, Philippe Uriac, and
ꢀ
Michele David
ꢀ
ꢁ
Equipe Produits Naturels, Synthese et Chimie Medicinale, UMR 6226 Sciences
ꢁ
ꢁ
Chimiques de Rennes, Universite de Rennes 1, 2 Avenue du Pr Leon Bernard 35043
Rennes Cedex, France
nicolas.gouault@univ-rennes1.fr
Received June 24, 2011
ABSTRACT
The enantiospecific syntheses of pyridinones from amino acids via a gold-catalyzed strategy are reported. Excellent stereocontrol was observed
during the cyclization. This approach provides a straightforward tool for further synthetic applications toward piperidines.
The piperidine ring is an important structural pattern
present in natural and/or synthetic products that display
a broad range of biological activities.1 Therefore, much
effort has been devoted to the development of new
approaches for its preparation.2 The use of pyridinones
(2,3-dihydropyridin-4(1H)-ones) as versatile intermediates
for piperidine synthesis synthesis has attracted significant
attention.3 Many synthetic methods are reported in the
literature to obtain asymmetric pyridinones including the
hetero-DielsÀAlder reaction, the nucleophilic addition to
pyridinium salts utilizing chiral auxiliaries or chiral
catalysts.3,4 The search for more efficient, convenient,
functional groups that are compatible and highly stereo-
selective alternative syntheticroutes isof interest. Thus two
approaches were recently developed from amino acids using
amino ynone5 or diazoketone6 intermediates (Scheme 1).
The amino ynone strategy developed by Georg5a
(Scheme 1a) involves the in situ deprotection of the amine
function to permit cyclization by Michael addition. How-
ever in some instances partial racemization of the reaction
products was observed during these reactions as pointed
out by the authors.6
(1) For reviews, see: Struntz, G. M.; Findlay, J. A. In The Alkaloids;
Brossi, A., Ed.; Academic: New York, 1985; Vol. 26, p 89. (b) Schneider, M.
In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon: Oxford, 1996; Vol. 10, p 155.
(2) Synthesis of piperidines. Reviews: (a) Michael, J. P. Nat. Prod.
Rep. 2008, 25, 139. (b) Chemler, S. R. Curr. Bioact. Compd. 2009, 5, 2.
(c) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (d) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (e) Weintraub, P. M.; Sabol,
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953.
(f) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
(3) For reviews, see: (a) Comins, D. L.; Joseph, S. P. Adv. Nitrogen
Heterocycl. 1996, 2, 251. (b) Joseph, S.; Comins, D. L. Curr. Opin. Drug
Discovery Dev. 2002, 5, 870. (c) Comins, D. L.; O’Connor, S.; Al-awar,
R. S. In Comprehensive Heterocyclic ChemistryIII;Alan, R.K., Christopher,
A. R., Eric, F. V. S., Richard, J. K. T., Eds.; Elsevier: Oxford, 2008; p 41.
(4) (a) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96,
7807. (b) Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4261. (c)
Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am.
Chem. Soc. 1994, 116, 10520. (d) Kobayashi, S.; Kusakabe, K.-I.;
Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220. (e) Yao, S.;
Saaby, S.; Hazell, R. G.; Jorgensen, K. A. Chem.;Eur. J. 2000, 6, 2435.
(f) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2003, 125, 4018. (g) Mancheno, O. G.; Carretero, J. C. J. Am. Chem. Soc.
2004, 126, 456. (h) Yamashita, Y.; Mizuki, Y.; Kobayashi, S. Tetrahe-
dron Lett. 2005, 46, 1803. (i) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006,
128, 12370. (j) Keller Friedman, R.; Rovis, T. J. Am. Chem. Soc. 2009,
Previously we have reported a gold-catalyzed approach
for the synthesis of pyrrolidinones from amino ynones. In
some instances, however, moderate stereocontrol during
(5) (a) Turunen, B. J.; Georg, G. I. J. Am. Chem. Soc. 2006, 128, 8702.
(b) Niphakis, M. J.; Turunen, B. J.; Georg, G. I. J. Org. Chem. 2010, 75,
6793. (c) Acharya, H. P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 5223.
(6) (a) Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512. (b)
Seki, H.; Georg, G. I. Org. Lett. 2011, 13, 2147.
€
131, 10775. (k) Stoye, A. S.; Quandt, G.; Brunnhofer, B.; Kapatsina, E.;
Baron, J.; Fischer, A.; Weymann, M.; Kunz, H. Angew. Chem., Int. Ed.
2009, 48, 2228.
r
10.1021/ol201698m
2011 American Chemical Society
Published on Web 07/26/2011

To optimize the cyclization reaction conditions, various
gold sources, the presence or absence of cocatalyst, and
different solvents were evaluated. The results are reported
in Table 1. We performed a catalyst screening to optimize
the cyclization conditions (Table 1). Thus, reactions were
conveniently performed under an inert atmosphere with
the substrate 1 and a variety of gold catalysts. We found
that the use of PPh3AuCl in the presence of a silver salt in
dichloroethane (DCE) at room temperature afforded in
0.5 h the desired product 2a in good yield (entry 5) whereas
ring closure was not efficient in the presence of AuCl or
AuCl3 (entries 1À2).
Scheme 1. Previously Reported Approaches for the Synthesis of
Pyridinones from Amino Acids and Our Work
Table 1. Optimization Studies
these reactions was observed.7 In this paper we reported
the cyclization of N-protected β-amino ynones into pyr-
idinones under mild conditions. The use of a gold catalyst,8
acting as a soft Lewis acid, allows cyclization to proceed
through a triple bond electrophilic activation pathway and
subsequent nucleophilic attack of N-protected amines.
Thus, our approach is revealed to be complementary to the
Georg approach since N-protected compounds are obtained
which may be useful for further transformations. Moreover,
we illustrate the synthetic utility of such compounds for the
synthesis of asymmetric polysubstituted piperidines.
Initially, a series of β-amino ynones derivatives 1aÀg
were easily prepared from commercially available amino acids
via ArndtÀEistert homologation,9 Weinreb amide forma-
tion, and subsequent addition of various lithium acetylides
(Scheme 2). Thus, amino ynones 1aÀg could be produced
in two steps with moderate to excellent overall yields
(50À97%) from the corresponding enantiopure L-amino
acids. Data were reported in the Supporting Information.
entry
catalysts (mol %)
conditions
yield (%)a
1
2
3
4
5
6
7
8
AuCl (5)
AuCl3 (5)
THF, rt, 24 h
THF, rt, 24 h
<20
<20
84
PPh3AuCl (10)/AgSbF6 (30) THF, rt, 5 h
PPh3AuCl (10)/AgSbF6 (30) THF, 60 °C, 1 h
PPh3AuCl (10)/AgSbF6 (30) DCE, rt, 0.5 h
82
85
PPh3AuCl (5)/AgSbF6 (5)
PPh3AuCl (5)
DCE, rt, 1 h
DCE, rt, 1 h
DCE, rt, 1 h
85
nrb
nrb
AgSbF6 (5)
a Isolated yield. b No reaction.
A complementary study on solvents prompted us to
choose DCE that proved more efficient than THF (entries
3À4). A lower catalyst loading (5 mol %) did not affect the
yield but delayed the accomplishment of this reaction
(entry 6). As expected, no reaction was observed when we
used a [Ag] or [Au] catalyst independently (entries 7 and 8).
These results emphasize the importance of the anion
exchange to obtain catalytic activity. Finally, similar re-
sults were obtained when we varied the silver source
(AgOTf), but the less hygroscopic AgSbF6 was preferred.
With these results in hand, the scope of this gold-catalyzed
cyclization was further examined. We turned our attention to
the synthesis of enantiopure pyridinones since our strategy was
developed from chiral amino acids. As shown in Table 2, the
intermediates 1aÀg were efficiently converted under mild
conditions to the corresponding pyridinones 2aÀg in good to
excellent yield. The enantiomeric purity of 2bÀgwas confirmed
by chiral HPLC to be >99% ee, with the assessment that no
epimerization occurs during this process. Therefore, we inves-
tigated the synthetic utility of such chiral pyridinones for the
obtention of asymmetric piperidines focusing on the stereocon-
trol of the reactions during these transformations. For this
purpose, substrates 2b and 2c possessing variously hindered
substituents, methyl and isobutyl respectively, served as models.
We first examined reduction reactions. Hydrogenation
of substrates 2bÀc over 10% Pd/C in MeOH was carried
Scheme 2. Synthesis of β-Amino Ynones 1aÀg
ꢁ
(7) Gouault, N.; Le Roch, M.; Cornee, C.; David, M.; Uriac, P.
J. Org. Chem. 2009, 74, 5614.
(8) For recent reviews on gold catalysis, see: (a) Rudolph, M.;
Hashmi, S. K. Chem. Commun. 2011, 47, 6536. (b) Krause, N.; Belting,
V.; Deutsch, C.; Erdsack, J.; Fan, H.-T.; Gockel, B.; Hoffmann-Roder,
A.; Morita, N.; Volz, F. Pure Appl. Chem. 2008, 80, 1063. (c) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (d) Shen, C. Tetrahedron
2008, 64, 7847. (e) Das, A.; Sohel, S.; Md., A.; Liu, R.-S. Org. Biomol.
Chem. 2010, 8, 960. Cossy, J. Pure Appl. Chem. 2010, 82, 1365. (f)
Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896.
€
(9) Arndt, F.; Eistert, B. Ber. 1935, 68B, 200.
4372
Org. Lett., Vol. 13, No. 16, 2011

Table 2. Substrate Scope of the Reaction
Table 3. Synthesis of Piperidine Derivativesa
yield
(%)a
ee
(%)b
substrate
R1
R2
PG
product
1a
1bc
1c
1d
1e
1f
H
Ph
Boc
Boc
Boc
Boc
Boc
Cbz
Boc
2a
2b
2c
2d
2e
2f
85
70
73
87
93
86
85
À
Me
iBu
iBu
nPr
nPr
Ph
>98
>98
>98
>98
>98
>98
BnOÀCH2
Bn
Ph
nPr
Ph
1g
secBu
2g
a Isolated yield. b Determined by chiral HPLC. c R-Enantiomer was
also synthesized from D-alanine for HPLC conditions optimization.
product
3a
Me
3b
4a
Me
4b
5
R1
R2
iBu
nPr
83
iBu
nPr
94
iBu
nPr
61
nPr
65
nPr
83
yield (%)b
dr (cis/trans)c
out, and 3aÀb were obtained as single diastereoisomers
(Table 3). The cis-stereochemistry was easily demonstrated
by NOE experiment and is in accordance with results
previously reported by Ma et al.10 Reduction of 2bÀc
under Luche conditions gave the corresponding allylic
alcohols 4aÀb with a 15/85 and 12/88 diastereoisomeric
ratio respectively.11 The trans configuration of the major
isomer was confirmed by NOESY experiment. Finally,
2,6-disubstituted piperidine 5 was obtained from 3b by its
conversion into the corresponding enol triflate under
standard conditions, hydrogenation, and then removal of
the Boc protecting group by using HCl (3 N) in MeOH.
The piperidine5 was obtainedwithanoverallyieldof61%.
The existence of 5 as a single enantiomer was confirmed by
13C NMR spectroscopy analysis of diastereomeric salts
utilizing (S)- and (R,S)-tert-butylphenylphosphinothioic
acid as a chiral solvating agent.12 Data were reported in the
Supporting Information.
>98/2
>98/2
15/85
12/88
>98/2
product
6a
6b
7a
Me
7b
8a
8b
R1
R2
Me
iBu
nPr
85
iBu
nPr
73
Me
nPr
65
iBu
nPr
70
nPr
nPr
yield (%)b
82
60
dr (cis/trans)c <2/98 <2/98 <2/98 <2/98 <2/98 <2/98
a Conditions: (a) H2 4.5 bar, Pd/C 10%, MeOH, rt, 16 h; (b) NaBH4,
CeCl3. 7H2O, À40 °C, MeOH, 2 h; (c) (i) KHMDS, PhNTf2, THF, À78 °C
to rt, 2 h, 18 h, (ii) H2 4 bar, Pd/C 40%, Li2CO3, EtOAc, 3 h; (iii) HCl (3 N)/
MeOH, rt, 24 h then K2CO3; (d) LiHMDS, Methyl chloroformate, À78 °C
to rt, 18 h, THF; (e) LiHMDS, MeI, À78 °C to rt, 18 h, THF; (f) Pb(OAc)4,
Toluene, reflux, 4 h. b Isolated yield. c 1H NMR of the crude material.
Finally, 3bÀc were subjected to oxidation, C-3 acetoxyla-
tion, with Pb(OAc)4 in refluxing toluene.14 This reaction was
regio- and stereoselective15 providing the trans-2,3-disubsti-
tuted products 8aÀb in good yields. These results are note-
worthy since piperidine compounds are obtained with very
good control of the stereochemistry during these reduction
reactions and allow an application toward natural products.
In summary, we have developed a novel enantiospecific
synthetic method to obtain pyridinones from the chiral
pool of amino acids. Moreover, the use of gold catalysis in
this process allows an excellent stereocontrol during the
cyclization. This approach provides a straightforward tool
for further synthetic applications toward piperidines.
Further investigation regarding the synthetic utility of this
methodology toward natural products is ongoing.
Next, we envisioned a series of transformations aiming
at functionalization of the C-3 position. In this case,
formation of enolate intermediates was achieved by using
LHMDS as base followed by condensation of two electro-
philes (methyl chloroformate or iodomethane).13 Corre-
sponding compounds 6aÀb and 7aÀb were obtained in
good yields and excellent diastereoselection (in all cases, a
1
single diastereoisomer could be detected in H NMR).
(10) Ma, D.; Zhu, W. Tetrahedron Lett. 2003, 44, 8609.
(11) (a) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(b) Liu, D.; Acharya, H. P.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S.;
Chiruta, C.; Jachak, S. M.; Clive, D. L. J. J. Org. Chem. 2009, 74, 7414.
(12) Wang, F.; Polavarapu, P. L. J. Org. Chem. 2001, 66, 9015.
(13) (a) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett.
1995, 36, 9141. (b) Kranke, B.; Kunz, H. Org. Biomol. Chem. 2007, 5,
349. (c) Etayo, P.; Badorrey, R.; Diaz-de-Villegas, M. D.; Galvez, J. A.
Eur. J. Org. Chem. 2008, 6008.
Acknowledgment. The authors thank Prof. J.-P. Hurvois
(University of Rennes 1) for helpful discussions and provid-
ing phosphinothioic acid.
(14) Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle, C. L.
Tetrahedron Lett. 1998, 39, 5693.
(15) The use of Pb(OAc)4 (99% purity) afforded a single diastereoi-
somer. When the same reaction was conducted using Pb(OAc)4, (96%,
stabilized with acetic acid), two diastereoisomers were detected by 1H
NMR in a ratio of 85/15.
Supporting Information Available. Preparative meth-
ods and spectral and analytical data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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