Stereoselective synthesis of nipecotic acid derivatives via palladium-catalyzed decarboxylative cyclization of γ-methylidene-δ- valerolactones with imines

Article abstract of DOI:10.1021/ol802569q

(Chemical Equation Presented) A new synthetic method of multisubstituted nipecotic acid (piperidine-3-carboxylic acid) derivatives has been developed by way of palladium-catalyzed decarboxylative cyclization of γ-methylidene- δ-valerolactones with (mines.

Full text of DOI:10.1021/ol802569q

ORGANIC
LETTERS
2009
Vol. 11, No. 2
457-459
Stereoselective Synthesis of Nipecotic
Acid Derivatives via Palladium-Catalyzed
Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactones with
Imines
Ryo Shintani,* Masataka Murakami, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
shintani@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Received November 7, 2008
ABSTRACT
A new synthetic method of multisubstituted nipecotic acid (piperidine-3-carboxylic acid) derivatives has been developed by way of palladium-
catalyzed decarboxylative cyclization of γ-methylidene-δ-valerolactones with imines. By employing the diethoxyphosphinoyl group as the
N-protecting group for imines, the reaction proceeds smoothly with high diastereoselectivity. The products thus obtained can be further
derivatized with high efficiency under simple reaction conditions.
Nipecotic acid derivatives are widely spread as a common
structural motif in natural and synthetic biologically active
compounds such as GABA uptake inhibitors.1,2 It is therefore
of high value to devise an efficient synthetic method for these
compounds. Functional group manipulation of preformed
nipecotic or nicotinic acid derivatives is most commonly
utilized for their preparation,2,3 and construction of the
piperidine ring in a convergent manner is very rare in this
context. Herein we describe the development of a palladium-
catalyzed decarboxylative cyclization of γ-methylidene-δ-
valerolactones4 with N-diethoxyphosphinoyl imines to pro-
duce multisubstituted nipecotic acid derivatives in a
diastereoselective fashion.5,6
We began our investigation by conducting reactions of
γ-methylidene-δ-valerolactone 1a with benzaldimines (1.2
equiv) in the presence of 5 mol % of Pd/dppf catalyst in
(1) For a review, see: (a) Clausen, R. P.; Madsen, K.; Larsson, O. M.;
Frølund, B.; Krogsgaard-Larsen, P.; Schousboe, A. AdV. Pharmacol. 2006,
54, 265. See also: (b) Wang, H.; Hussain, A. A.; Wedlund, P. J Pharm.
(4) (a) Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 12356. (b) Shintani, R.; Park, S.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 14866. (c) Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi,
T. J. Am. Chem. Soc. 2008, 130, 16174.
Res. 2005, 22, 556
.
(2) (a) Zhou, C.; Guo, L.; Morriello, G.; Pasternak, A.; Pan, Y.; Rohrer,
S. P.; Birzin, E. T.; Huskey, S. W.; Jacks, T.; Schleim, K. D.; Cheng, K.;
Schaeffer, J. M.; Patchett, A. A.; Yang, L. Bioorg. Med. Chem. Lett. 2001,
11, 415. (b) Manfredini, S.; Pavan, B.; Vertuani, S.; Scaglianti, M.;
Compagnone, D.; Biondi, C.; Scatturin, A.; Tanganelli, S.; Ferraro, L.;
Prasad, P.; Dalpiaz, A. J. Med. Chem. 2002, 45, 559. (c) N’Goka, V.;
Stenbøl, T. B.; Krogsgaard-Larsen, P.; Schlewer, G. Eur. J. Med. Chem.
2004, 39, 889. (d) Zhang, J.; Zhang, P.; Liu, X.; Fang, K.; Lin, G. Bioorg.
(5) For recent examples of substituted piperidine synthesis by (formal)
[4 + 2] cycloadditions, see: (a) Toure´, B. B.; Hall, D. G. Angew. Chem.,
Int. Ed. 2004, 43, 2001. (b) Yu, S.; Zhu, W.; Ma, D. J. Org. Chem. 2005,
70, 7364. (c) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
(d) Wang, C.; Tunge, J. A. Org. Lett. 2006, 8, 3211. (e) Han, R.-G.; Wang,
Y.; Li, Y.-Y.; Xu, P.-F. AdV. Synth. Catal. 2008, 350, 1474. (f) Sarkar, N.;
Med. Chem. Lett. 2007, 17, 3769
(3) (a) Lei, A.; Chen, M.; He, M.; Zhang, X. Eur. J. Org. Chem. 2006,
4343. (b) Szo¨llo¨si, G.; Szo¨ri, K.; Barto´k, M. J. Catal. 2008, 256, 349
.
Banerjee, A.; Nelson, S. G. J. Am. Chem. Soc. 2008, 130, 9222
(6) For a review on piperidine synthesis, see: Weintraub, P. M.; Sabol,
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953
.
.
.
10.1021/ol802569q CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society

toluene at 20 °C to evaluate the effect of nitrogen substituents
on reactivity and stereoselectivity (Table 1). The use of
N-phenyl benzaldimine resulted in no formation of the
desired product presumably due to the low electrophilicity
of the imine (entry 1), and we decided to focus on the use
of electron-deficient substituents on nitrogen. It turned out
that both N-tosyl and N-diphenylphosphinoyl imines are
suitable substrates to produce the desired heterocycles in high
yield (90-93% yield; entries 2 and 3), but the diastereose-
lectivities were only moderate in both cases. We subsequently
found that the diastereoselectivity was significantly improved
by changing the nitrogen substituent to dialkoxyphosphinoyl
groups with maintenance of the high reactivity (91-95%
yield, dr ) 91/9; entries 4 and 5).
Table 2. Palladium-Catalyzed Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactones 1 with Imines 2: Scope
Table 1. Palladium-Catalyzed Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactone 1a with Benzaldimines: Effect of
N-Substituents, Ligands, and Solvents
convn yield
entry
PG
ligand
dppf
dppf
dppf
solvent
(%)a
(%)b
dra
1
2
3
4
5
6
7
Ph
Ts
toluene
toluene
toluene
toluene
toluene
THF
CH2Cl2
toluene
toluene
toluene
48
100
100
100
100
100
72
100
36
100
100
0
90
94
95
91
94
64
81
32
55
91
-
58/42
69/31
91/9
91/9
91/9
83/17
72/28
84/16
97/3
P(O)Ph2
P(O)(OEt)2 dppf
P(O)(OR)2
P(O)(OEt)2
P(O)(OEt)2
c
dppf
dppf
dppf
dppf
dppe
PPh3
8d P(O)(OEt)2
9
10e
11e
a
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
a Determined by 1H NMR of the crude material. b Isolated yield of the
major diastereomer unless otherwise noted. c Combined isolated yield of
the two diastereomers.
P(Oi-Pr)3 toluene
83/17
Determined by H NMR of the crude material. b Combined yield of
1
the two diastereomers (determined by 1H NMR against an internal standard).
c (OR)2 ) (OCH2CMe2CH2O). d Methyl ester of 1a was replaced by tert-
butyl ester. e 10 mol % of ligand was used.
diastereoselectivity (dr ) 87/13 to 95/5; Table 2, entries
1-5).8 R-Alkyl lactones such as 1f can also give the
corresponding product in high yield, albeit with somewhat
lower diastereoselectivity (dr ) 74/26; entry 6). With regard
to the imine component, various aryl groups can be tolerated
to give the products with high diastereoselectivity (entries
7-11), but the use of a heteroaryl or an alkenyl imine results
in lower stereoselectivity (entries 12 and 13). The relative
configuration of the major diastereomer of 3ea (entry 5) was
determined by X-ray crystallographic analysis as shown in
Figure 1.
With these imines in hand, we also found that similar
reactivity and stereoselectivity could be observed in THF
(entry 6), but the use of dichloromethane as a solvent gave
the product with somewhat lower efficiency (entry 7). The
change of ester group on 1a from Me to t-Bu resulted in
significantly lower diastereoselectivity (dr ) 72/28; entry 8).7
With regard to the effect of ligands on palladium, the use of
other bisphosphines, such as dppe, or monodentate phos-
phorus ligands, such as PPh3 and P(Oi-Pr)3, gave the product
in lower yield (entries 9 and 10) and/or lower diastereose-
lectivity (entries 9 and 11).
(8) General Procedure. A solution of PdCp(π-C3H5) (2.1 mg, 10 µmol)
and dppf (6.1 mg, 11 µmol) in toluene (0.50 mL) was stirred for 10 min at
room temperature. Lactone 1 (0.20 mmol) and imine 2 (0.24 mmol) were
added to it with additional toluene (0.50 mL), and the resulting solution
was stirred for 24 h at 20 °C. The reaction mixture was directly passed
through a pad of silica gel with EtOAc, and the solvent was removed under
vacuum. The residue was purified by silica gel preparative TLC to afford
compound 3.
Under the optimized conditions, various R-(hetero)aryl-
γ-methylidene-δ-valerolactones 1 undergo decarboxylative
cyclization with imine 2a in high yield with good to excellent
(7) Lactones without an ester group cannot be employed under the
present conditions.
458
Org. Lett., Vol. 11, No. 2, 2009

example, selective removal of the diethoxyphosphinoyl group
on nitrogen of compound 3aa is accomplished under acidic
conditions to give deprotected amine 4 in 82% yield. In
contrast, treatment of 3aa with KOH in EtOH leads to
carboxylic acid 5 with its N-protecting group intact in 95%
yield. Furthermore, a reaction of 3aa with LiAlH4 simulta-
neously reduces the ester and cleaves the N-protecting group
to give aminoaocohol 6 in 91% yield.
Scheme 2. Derivatization of Compound 3aa
Figure 1. X-ray structure of 3ea with thermal ellipsoids drawn at
the 50% probability level.
A proposed catalytic cycle of this process is illustrated in
Scheme 1. Thus, oxidative addition of the allyl ester moiety
of 1 to palladium(0), followed by decarboxylation,9,10 gives
1,4-zwitterionic species A. The anionic carbon of A then
attacks the electrophilic carbon of 2 to give intermediate B,
which undergoes a ring-closure through a nucleophilic attack
of the nitrogen atom to the π-allylpalladium moiety, leading
to the formation of 3 along with regeneration of palladium(0).
In summary, we have developed a new synthetic method
of highly functionalized nipecotic acid derivatives through
palladium-catalyzed decarboxylative cyclization of γ-meth-
ylidene-δ-valerolactones with imines. By employing the
diethoxyphosphinoyl group as the nitrogen protecting group
for imines, the reaction proceeds smoothly with high
diastereoselectivity. The products thus obtained can be further
derivatized under simple reaction conditions. Future studies
will be directed toward further expansion of the reaction
scope as well as the development of an asymmetric variant.11
Scheme 1. Proposed Catalytic Cycle for the
Palladium-Catalyzed Decarboxylative Cyclization of 1 with 2
(PG ) P(O)(OEt)2)
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research, the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(the Global COE Program “Integrated Materials Science”
on Kyoto University), and in part by the Sumitomo Founda-
tion.
The products obtained under the present catalysis can be
further manipulated with high efficiency (Scheme 2). For
Supporting Information Available: Experimental pro-
cedures and compound characterization data (PDF) and X-ray
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199. (b) Tsuda, T.; Chuji, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6381. For reviews, see: (c) Tunge, J. A.; Burger,
E. C. Eur. J. Org. Chem. 2005, 1715. (d) You, S.-L.; Dai, L.-X. Angew.
Chem., Int. Ed. 2006, 45, 5246
.
(10) For leading references, see:(a) Burger, E. C.; Tunge, J. A. Org.
Lett. 2004, 6, 4113. (b) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc.
2005, 127, 13510. (c) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127,
17180. (d) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2005, 44, 6924. (e) Patil, N. T.; Huo, Z.; Yamamoto, Y. J.
OL802569Q
(11) In our preliminary experiment, a reaction of 1a with 2a in the
presence of (R)-binap as the ligand gave 3aa with 38% ee, and chiral
phosphoramidites are less effective for this reaction.
Org. Chem. 2006, 71, 6991
.
Org. Lett., Vol. 11, No. 2, 2009
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