Stereoselective synthesis of (?)-3-PPP through palladium-catalysed unactivated C(sp3)–H arylation at the C-3 position of L-pipecolinic acid

Article abstract of DOI:10.1016/j.tetlet.2016.12.051

An efficient route for the preparation of (?)-3-PPP(preclamol) using the highly stereoselective palladium-catalysed C(sp³)-H arylation and radical decarboxylation reaction as the key steps is described. The chiral center at the C-3 position of

Full text of DOI:10.1016/j.tetlet.2016.12.051

Accepted Manuscript
Stereoselective Synthesis of (-)-3-PPP through Palladium-Catalysed Unactiva-
ted C(sp3)−H Arylation at the C-3 Position of L-Pipecolinic Acid
Shi-Jin Zhang, Wen-Wu Sun, Qun-Ying Yu, Pei Cao, Xiao-Ping Dong, Bin Wu
PII:
S0040-4039(16)31699-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.051
TETL 48463
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
15 November 2016
18 December 2016
20 December 2016
Please cite this article as: Zhang, S-J., Sun, W-W., Yu, Q-Y., Cao, P., Dong, X-P., Wu, B., Stereoselective Synthesis
of (-)-3-PPP through Palladium-Catalysed Unactivated C(sp3)−H Arylation at the C-3 Position of L-Pipecolinic
Acid, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.051
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Graphical Abstract
Stereoselective Synthesis of (-)-3-PPP
through Palladium-Catalysed Unactivated
C(sp3)−H Arylation at the C-3 Position of L-
Pipecolinic Acid
Leave this area blank for abstract info.
Shi-Jin Zhang,a Wen-Wu Sun,b Qun-Ying Yu,c Pei Cao, c Xiao-Ping Dong,a Bin Wu,b,c

1
Tetrahedron Letters
Stereoselective Synthesis of (-)-3-PPP through Palladium-Catalysed Unactivated
C(sp3)−H Arylation at the C-3 Position of L-Pipecolinic Acid
Shi-Jin Zhanga , Wen-Wu Sunb , Qun-Ying Yuc , Pei Cao,c Xiao-Ping Donga and Bin Wub, c, 
aPharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
bSchool of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China
cState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201,
China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient route for the preparation of (-)-3-PPP(preclamol) using the highly stereoselective
palladium-catalysed C(sp3)-H arylation and radical decarboxylation reaction as the key steps is
described. The chiral center at the C-3 position of L-pipecolinic acid derivative formed in the
key reaction was completely induced by the adjacent stereocenter of the substrate, which was
confirmed by the data of chiral HPLC analysis. Substitution effect of nitrogen on the efficiency
of Pd-catalysed C(sp3)-H arylation reaction
Available online
Keywords:
Keyword_1 preclamol
Keyword_2 stereoselective
Keyword_3 palladium
Keyword_4 C(sp3)-H activation
Keyword_5 arylation
2009 Elsevier Ltd. All rights reserved.
1. Introduction
[3+3] cycloaddition reaction of α-sulfonyl acetamide,18 Pd-
catalysed C(sp2)–H arylation of pyridine19 and C(sp3)–H arylation
at the C-3 position of N-Boc piperidines.20 Due to its significant
biological activities, a great many methods for the stereoselective
synthesis of (-)-3-PPP based on chiral-pool-derived routes,
auxiliary-controlled methods, and catalytic, asymmetric reactions
have been reported.21 However, these kinds of previous
procedures suffered from some limitations such as tedious chiral
resolution process, expensive air- or moisture-sensitive reagents
and expensive chiral ligands or auxiliary. Therefore, the
development of an efficient and stereoselective route for the
preparation of (-)-3-PPP is highly desirable.
3-Arylpiperidines have been attracting the chemist’s
interesting since the early 1980s because of their great
biologically active value. The most potent therapeutically active
compounds for central dopamine autoreceptor stimulating
activity is (-)-3-(3-hydroxyphenyl)-N-(n-propyl)-piperidine [(-)-
3-PPP, Preclamol],1-8 which is also reported to be the first
selective D2-like dopamine autoreceptor agonist.7,8 In addition,
preclamol was tested for antipsychotic potential with therapeutic
effect in the treatment of schizophrenia and Parkinson’s
diseases.9-11 Furthermore, preclamol has been extensively studied
as
a
pharmacological tool to investigate dopaminergic
mechanisms.12-15
Powerful synthetic methods based on the regioselective
functionalization of unactivated C(sp3)-H bonds with the assistant
of various directing groups are becoming readily available.22
Inspired by the Daugulis23 seminal report on the palladium-
catalysed arylation of unactivated C(sp3)-H bonds using 8-
aminoqunoline (AQ) as bidentate directing group, this
methodology was also employed in the direct C(sp3)-H arylation
of cyclopropanes,24 cyclobutanes,25 acyclic amino acids,26 and
proline derivatives.27 Recently, Bull28 and our group29 described
the C(sp3)-H arylation reaction at the C-3 position of L-
pipecolinic acid derivatives by palladium catalysis. Encouraged
by these promising results, we envisioned to develop an efficient
and stereoselective route for the preparation of (-)-3-PPP using
OH
N
Figure 1. The structure of (-)-3-PPP
Over the past few decades, methodologies have been
developed for the synthesis of the racemic proclamol, including
transition-metal catalysed cross-coupling reaction with the
Grignard reagents and aryl halides,16 Heck reaction,17 formal
———
 Corresponding author. e-mail: wubin@mail.kib.ac.cn

OMe
2
Tetrahedron
palladium-catalysed C(sp3)-H arylation reaction as a key step.
Pd(OAc)2 (10 mol%)
AgOAc (1.8 equiv)
H
(1) Boc2O, NaOH, dioxane
N
H
N
N
The chiral center at the C-3 position of L-pipecolinic acid
derivative formed in the key reaction was completely induced by
the adjacent stereocenter of the substrate, which was confirmed
by the data of chiral HPLC analysis.
3-Iodoanisole (3.0 equiv)
toluene, 100 oC, 12 h
(2) 8-amino-quinoline, EDCI
DMAP, CH2Cl2
N
COOH
N
Boc
O
N
H
Boc
O
N
72% for 2 steps
(-)-2, 91.8% ee
L(-)-pipecolinic acid
(+)-3
, 91.7% ee
1.07 g, 3.0 mmol, (-)-2
1.08 g, 77% yield of (+)-3
579.2 mg, 84% yield of (+)-3
533.1 mg, 1.5 mmol, (-)-2
OMe
2. Results and discussion
OMe
OMe
i-BuOCOCl (1.2 equiv)
Boc2O, DMAP
LiOH, H2O2
OMe
OH
N-Methylmorpholine (1.2 equiv)
Boc
N
OMe
CH3CN, 70 oC, 16h
83%
0 oC to rt
91%
PhSeNa (2 equiv)
THF,-10 oC to rt, 12h
78%
N
SePh
OMe
OH
N
N
H
N
CO2H
Boc
O
H
N
Boc
O
N
H
Boc
O
R
OH
H
O
N
N
N
NHQ
N
R
H
N
R
(+)-6
(+)-5
O
(+)-4
O
(-)-3-PPP
L-pipecolinic
acid
R = n-Propyl / Cbz / Boc
palladium-catalysed C(sp3)-H arylation
the key step
OMe
AIBN (0.5 equiv)
K2CO3 (3 equiv)
n-PrI (0.95 equiv)
CF3CO2H, CH2Cl2
n-Bu3SnH (2.0 equiv)
OMe
rt, 2h
Figure 2. Retrosynthetic analysis for the preparation of (-)-3-PPP
toluene, N2, 80 oC,2h
MeCN, 80 oC, 7h
N
79% for 2 steps
75%
N
H
N
Prn
Boc
In view of retrosynthetic analysis for the preparation of (-)-3-
PPP (Figure 2), we have set up the right conditions for
palladium-catalysed C(sp3)-H arylation in our previous work.29
However, the reaction proceeded with substrates bearing Boc or
Cbz group on the piperidinyl nitrogen. Obviously, the choice of
substitution groups on the nitrogen is still an issue. If the key
reaction occurred with substrate bearing n-propyl group on the
piperidinyl nitrogen, that would be a more efficient sequence to
make (-)-3-PPP.
(-)-7
(+)-8
92.6% ee
(+)-9
OH
48% HBr, N2
reflux, 120 oC, 2h
88%
N
Prn
(-)-3-PPP
93.7% ee
Scheme 2. An efficient route for the preparation of (-)-3-PPP.
Next, we moved back to use N-Boc protected amide
compound (-)-2 as the substrate. As outlined in Scheme 2, the
amide compound (-)-2 was synthesized from the readily
commercially available L-(-)-pipecolinic acid according to a
literature procedure.29 Enantioselective value of the purified
compound (-)-2 was identified to be 91.8% based on the data of
chiral HPLC analysis (see Experimental Section). That means
enantiopurity of the starting material L-(-)-pipecolinic acid we
bought is probably not 100%. Compound (-)-2 was smoothly
arylated through palladium catalysis with 3-iodoanisole to afford
compound (+)-3 in 84% yield and 91.7% ee. This result indicated
that the chiral center at the C-3 position of compound (+)-3
formed in the key reaction was completely induced by the
adjacent stereocenter of the substrate (-)-2. Furthermore, this
arylation reaction proceeded successfully on a larger scale,
affording 1.08 g of compound (+)-3 in 77% yield. Removal of
the 8-aminoquinoline directing group in (+)-3 delivered
compound (+)-5 through a mild, two-step sequence via (+)-4.
Compound (+)-6 was made with NaSePh under the help of
isobutyl chloroformate and N-methylmorpholine, and then
underwent radical decarboxylation reaction to afford compound
(-)-7 in excellent yield. On the other hand, after the free radical
reaction, addition of CF3COOH could remove the N-Boc
protecting group to give the piperidine (+)-8 in 79% yield and
92.6% ee. After SN2-type reaction of (+)-8 with 1-iodopropane,
compound (+)-9 was obtained in 75% yield. Finally, N-alkylated
piperidine (+)-9 was converted to the target drug (-)-3-
PPP(preclamol) in 88% yield and 93.7% ee after demethylation.
X-ray structure of Pd-complex-2
Scheme 1. Exploration of substitution effect of the piperidinyl
nitrogen on the efficiency of Pd-catalysed C(sp3)-H arylation
reaction
To test our hypothesis, we initiated our studies by preparing
substrate (-)-1 through 3 steps in 50% yield. We tried the Pd-
catalysed C(sp3)-H arylation reaction with substrate (-)-1 in our
standard conditions. However, the reaction did not work (a,
Scheme 1). In order to find out the reason, the reaction with a
stoichiometric amount of palladium acetate was conducted (b,
Scheme 1). Some characterized signals of Pd-complex-1 were
3. Conclusion
In conclusion, we have developed an efficient route for the
preparation of (-)-3-PPP(preclamol) employing the highly
stereoselective palladium-catalysed C(sp3)-H arylation and
radical decarboxylation reaction as the key steps. Substitution
effect of the piperidinyl nitrogen on the efficiency of Pd-
catalysed C(sp3)-H arylation reaction was explored with
substantial experiments including the X-ray single-crystal
diffraction analysis of palladium-complex-2.
found in the H and 13C NMR spectrum of the crude sample.
1
After isolation through a short column of diatomite, Pd-complex-
2 was obtained and its structure was confirmed by X-ray single-
crystal diffraction analysis.30 These results well demonstrate that
electron-donating groups on the piperidinyl nitrogen promote the
nitrogen atom to coordinate strongly with palladium to form the
stable palladium-complex-2, which inhibits the C(sp3)-H
arylation reaction.
Acknowledgments

3
Verendel, J. J.; Zhou, T. G.; Li, J. Q.; Paptchikhine, A.;
Lebedev, O.; Andersson, P. G. J. Am. Chem. Soc. 2010, 132,
We gratefully thank “Hundred Talents Project” of Chinese
Academy of Science, “High–end Science and Technology
Talents Program” of Yunnan Province (2011HA008), the
National Natural Science Foundation of China (Nos. 21472198)
and Grant (2014FA039) from Yunnan Province of China for
financial support of this work. We thank Dr. Xiaonian Li for the
X-ray crystallographic analysis.
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1
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4
Tetrahedron
Highlights
An efficient route for the preparation of (-)-3-PPP
is described.
The chiral center formed in the key reaction was
completely induced by the adjacent stereocenter of
the substrate.
Substitution effect of nitrogen on the efficiency of
the key reaction