Kinetic resolution of 2-substituted 2,3-dihydro-4-pyridones by palladium-catalyzed asymmetric allylic alkylation: Catalytic asymmetric total synthesis of indolizidine (-)-209I

Article abstract of DOI:10.1021/ol500498m

The kinetic resolution of 2-substituted-2,3-dihydro-4-pyridones was realized via a Pd-catalyzed allylic substitution reaction using a commercially available (S)-P-Phos as a ligand, affording optically active dihydropyridones and C-allylated dihydropyridones in high yields and good enantioselectivities with the S-factor up to 43. With this protocol, a catalytic asymmetric total synthesis of indolizidine (-)-209I was realized for the first time.

Full text of DOI:10.1021/ol500498m

Letter
pubs.acs.org/OrgLett
Kinetic Resolution of 2‑Substituted 2,3-Dihydro-4-pyridones by
Palladium-Catalyzed Asymmetric Allylic Alkylation: Catalytic
Asymmetric Total Synthesis of Indolizidine (−)-209I
Bai-Lin Lei,† Qing-Song Zhang,† Wei-Hua Yu,§ Qiu-Ping Ding,§ Chang-Hua Ding,*,†
and Xue-Long Hou*,†,‡
‡
†State Key Laboratory of Organometallic Chemistry, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
§College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China
S
* Supporting Information
ABSTRACT: The kinetic resolution of 2-substituted-2,3-
dihydro-4-pyridones was realized via a Pd-catalyzed allylic
substitution reaction using a commercially available (S)-P-
Phos as a ligand, affording optically active dihydropyridones
and C-allylated dihydropyridones in high yields and good
enantioselectivities with the S-factor up to 43. With this
protocol, a catalytic asymmetric total synthesis of indolizidine
(−)-209I was realized for the first time.
Initially, dihydropyridone 1a was adopted as prenucleophile
ihydropyridones are extraordinarily versatile intermedi-
Dates and attractive building blocks for the synthesis of in the reaction with allyl reagent 3a using [Pd(η3-C3H5)Cl]2
piperidine-containing molecules.1 Indeed, this heterocycle
and (S,Rphos,R)-SiocPhox L1 as the catalyst in the presence of
LiHMDS as the base (entry 1, Table1); the allylation product
4a was afforded in 28% yield and 17% ee while 1a was
recovered in 24% yield and 20% ee. The investigation on the
influence of the N-substituent of dihydropyridone 1 revealed
that the ee and yield were improved when the benzoyl group of
1a was replaced with the tert-butoxycarbonyl (Boc) group
(entry 2 vs 1). The kinetic resolution did not take place with N-
tosyl (Ts) or N-methyl dihydropyridone 1 as reactants (entries
3 and 4). The use of N-Cbz dihydropyridone 1e did not lead to
good results (entry 5). When dihydropyridone 2a with a
methoxycarbonyl group on nitrogen was used as a prenucleo-
phile, the ee of allylated product 5a increased to 40% (entry 6).
The ee of both recovered 2a and product 5a were further
improved by using a commercially available chiral ligand (R)-
SEGPHOS (L2) (entry 7). The evaluation of a leaving group in
allyl reagents 3 clarified that 3b with −OCO2Me as the leaving
group was among the best as the ee value of recovered 2a
increased to 70% while that of allylated product 5a was 67%
compared to that using (EtO)2PO−, AcO−, and BocO− as a
leaving group (entry 8 vs entries 7, 9, 10). In all cases, the
exists in numerous drugs and drug candidates as an
indispensable binding element.2 Meanwhile, the piperidine
moiety is prevalent in biologically active natural products such
as indolizidines and quinolizidines. The chemistry of
dihydropyridone is rich because it contains multiple nucleo-
philic sites and two electrophilic sites, which enables 2,3-
dihydro-4-pyridones to be involved in a plethora of selective
transformations such as N-functionalization, 1,2-addition of a
carbonyl group, conjugated addition, and [2 + 2] cylization.3
Many procedures have been developed to synthesize these
heterocyclic compounds; however, efficient protocols to access
the optical active ones are few,4 and new avenues for the
construction of this useful scaffold are requested.
The Pd-catalyzed asymmetric allylic alkylation (AAA)
reaction has been widely recognized as a powerful protocol in
organic synthesis.5 Recent progress allows it to install a chiral
center at “hard” carbon nucleophiles.6 The reaction has also
been applied successfully in the kinetic resolution. However,
the majority of the studies have focused on the resolution of
allyl substrates.7 The resolution of a nucleophile is still very
limited. Recently, we succeeded in the kinetic resolution of
dihydroindoles and dihydroquinolones via Pd-catalyzed asym-
metric allylic amination and allylic alkylation.8 We disclose the
kinetic resolution of 2-substituted 2,3-dihydro-4-pyridones via a
Pd-catalyzed AAA reaction. With this strategy, catalytic
asymmetric total synthesis of indolizidine (−)-209I was
achieved.
1
product trans-5a was obtained, which was determined by H
NMR.
To further improve the efficiency of the reaction, the impact
of other reaction parameters including bases, solvents, ligands,
Received: February 17, 2014
Published: March 24, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Influence of N-Substituent and Allyl Reagents on
the Kinetic Resolution of 2-Phenyl-2,3-dihydro-4-pyridone
Table 2. Optimization of Reaction Parameters for Kinetic
Resolution of 2,3-Dihydro-4-pyridone 2a
a
a
b
c
b
c
yield
ee
yield
ee
entry substrate
(% 1/2)
(%)
product
(% 4/5)
(%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
2a
2a
2a
2a
2a
24
20
30
4a
4b
4c
4d
4e
5a
5a
5a
5a
5a
28
17
22
45
46
e
d
complex
>98
23
nd
complex
trace
43
nd
e
d
nd
nd
21
31
61
70
31
63
35
40
56
67
28
53
2a
5a
55
37
yield
b
ee
yield
b
ee
c
c
48
22
entry
L
solvent
base
(%)
(%)
(%)
(%)
e
f
40
49
1
L2
L2
L2
L2
L2
L2
L2
L2
L3
L4
L5
L6
L7
L8
L8
L8
THF
THF
THF
THF
ether
toluene
DCE
DME
THF
THF
THF
THF
THF
THF
THF
THF
LiHMDS
NaHMDS
KHMDS
t-BuOLi
40
70
49
trace
40
39
32
33
20
32
38
10
35
45
50
45
41
43
67
d
d
d
39
46
2
nd
nd
2
nd
6
g
10
48
45
3
47
40
42
27
23
46
37
60
62
26
34
31
48
50
a
Conditions: molar ratio 1/3a/[Pd(η3-C3H5)Cl]2/L/base =
200:100:6:12:200; L1 used for entries 1−5, and L2 used for entries
4
4
2
5
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
3
3
b
c
d
6−9. Isolated yield. Determined by chiral HPLC. Not determined.
6
11
8
22
13
7
e
f
g
3b used as allyl reagent. 3c used as allyl reagent. 3d used as allyl
7
reagent.
8
4
9
2
2
and reaction temperature was investigated using 2a as the
substrate and 3b as the reagent (Table 2). The allylated
product 5a was obtained in 49% yield and 67% ee and the
recovered 2a in 40% yield and 70% ee using LiHMDS as the
base (entry 1). In contrast, only a trace of allylated product 5a
was afforded if NaHMDS was the base (entry 2). Employing
KHMDS or t-BuOLi as base led to the significant decrease in
the ee value of both 2a and 5a (entries 3 and 4). The screen of
solvents revealed that THF was the choice among the solvents,
including ether, 1,2-dichloroethane (DCE), dimethoxyethane
(DME), and toluene (entry 1 vs entries 5−8). A dramatic
variation in enantioselectivity was observed when different
chiral P,N- and P,P-ligands including FcPHOX L3, PHOX L4,
(R)-BINAP (L5), (R)-SYNPHOS (L6), (R)-Difuorophos
(L7), and (S)-P-PHOS (L8) were examined (entries 9−14).
It was found that P,N-ligands L3 and L4 gave unsatisfactory
enantioselectivity (entries 9, 10) while bisphosphine ligands
showed different behavior. (R)-SEGPHOS (L2) gave higher
values than (R)-BINAP (L5), (R)-SYNPHOS (L6), and (R)-
Difuorophos (L7) did in terms of enantioselectivity (entry 1 vs
entries 11−13). Gratifyingly, better results were provided by
using (S)-P-PHOS (L8) compared to (R)-SEGPHOS (L2)
(entry 1 vs 14).9 The enantioselectivity was further improved
when the reaction run at lower temperature, providing 5a with
82% ee (43% yield) and 2a in 67% ee (50% yield) at −60 °C
(entry 16 vs 15). When the amount of base was 60 mol % of
2,3-dihydro-4-pyridone, the yield of allylated product decreased
significantly.
10
11
12
13
14
10
22
19
49
79
52
67
26
18
17
44
69
75
82
e
15
f
16
a
Conditions: molar ratio of 2a/3b/[Pd(η3-C3H5)Cl]2/L/base =
200:100:6:12:200. Isolated yield. Determined by chiral HPLC.
Not determined. Reaction was carried out at −20 °C. Reaction was
b
c
d
e
f
carried out at −60 °C.
idones 2 with allyl carbonate 3b was investigated (Table 3). In
general, the reaction afforded allylated trans-5 and recovered 2
in high yields with excellent enantioselectivities. The S-factor is
between 11 and 43. The electron-donating and -withdrawing
substituents at the meta or para position of the 2-aryl group had
limited effect on the enantioselectivity of allylated product 5, as
its ee was consistently excellent (entries 1−6). Use of 2-vinyl
dihydropyridones 2h led to allylated product 5h with 87% ee
(entry 8). This additional alkene functional group should
facilitate its further elaboration. Notably, 2-alkyl-2,3-dihydro-4-
pyridones were suitable substrates to produce the correspond-
ing products in high enantioselectivity (entries 9−12). The
reaction’s good tolerance for versatile substituents was a solid
foundation for the application of the protocol in organic
synthesis. However, the enantioselectivity of recovered
dihydropyridones 2 was greatly affected by the 2-substituents.
Although the aryl group with different substituents did not
On the basis of the above optimal conditions, the substrate
scope of the kinetic resolution of 2-substituted dihydropyr-
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Organic Letters
Letter
36% yield with 88% ee. The protective group of (2R,3S)-5l was
replaced with the easily removable benzyloxycarbonyl (Cbz)
group via a two-step reaction sequence (Scheme 1).12 The
Table 3. Substrate Scope for the Kinetic Resolution of 2-
Substituted 2,3-Dihydro-4-pyridones
a
Scheme 1. Enantioselective Total Synthesis of Indolizidine
(−)-209I
2
5
b
c
b
c
d
entry
substrate
yield%
ee (%)
yield%
ee (%)
S
1
2a
2b
2c
2d
2e
2f
50
40
41
42
42
57
37
52
32
40
40
46
67
49
62
68
77
43
86
48
85
88
41
40
43
36
40
35
39
31
43
36
33
42
44
35
81
85
89
91
84
93
73
87
83
79
79
77
20
20
33
43
27
42
17
23
29
24
14
11
2
3
4
5
6
7
2g
2h
2i
8
9
10
11
12
2j
resulting compound 6 was subjected to a Cu-catalyzed 1,4-
addition to deliver compound 7 with 87% ee in 80% yield.13
Deprotection of Cbz and the benzyl group and reduction of the
double bond of 7 using a catalytic amount of Pd/C under 1 atm
of H2 afforded 8 in quantitative yield. Subsequent cyclization of
compound 8 in the presence of Ph3P/I2/imidazole gave
tricyclic compound 9 with 88% ee.11e The ketone functionality
of compound 9 was reduced cleanly using NaBH4 followed by
an esterification to provide thiocarbamate with thiocarbonyl
diimidazole and DMAP. Finally, the resulting thiocarbamate
underwent a stannane-mediated radical reduction14 to afford
2k
2l
a
Molar ratio of 2/3b/[Pd(η3-C3H5)Cl]2/L8/LiHMDS
=
b
c
200:100:6:12:200. Isolated yield. Determined by chiral HPLC.
d
Calculated by the method described by Kagan.7b
influence the enantioselectivity very much (entries 1 and 3−5),
the ee values of recovered 2 were a little bit lower for the
reaction of 2-phenyl dihydropyridones with m-MeO and p-
phenyl as the substituent (entries 2 and 6). The reaction also
afforded recovered 2 in moderate ee with vinyl, isopropyl, and
benzoxypropyl as the substituent (entries 8 and 11−12).
The absolute configuration of the recovered 2-phenyl-2,3-
dihydro-4-pyridone (2a) was determined to be R by removing
its methoxycarbonyl group under basic conditions and then
comparing the sign of the optical rotation of the resulted
product with that reported in literature.10 Accordingly, the
absolute configuration of allylated product 5a is 2S,3R.
Indolizidine (−)-209I is an alkaloid found in poisonous frog
skin.11a,b Several groups have accomplished the synthesis of
indolizidine (−)-209I.11 Enders et al. first realized the synthesis
of indolizidine (−)-209I relying on the chemistry of the chiral
pyrrolidine hydrazone.11d Ma’s synthesis features a formal [4 +
2] cycloaddition between an optically pure 3-chloropropyl-
amine and a substituted propiolic acid ester to construct the
piperidine core.11e Charette employed a Grob fragmentation of
chiral aza-bicyclo[2.2.2]octene as the key step for the synthesis
of (−)-209I.11f All these syntheses rely on the use of
enantiopure substances. An enantioselective synthesis of
indolizidine (−)-209I based on a catalytic asymmetric strategy
is unknown.
indolizidine (−)-209I with 90% ee ([α]20 = −89.5° (1.0,
D
CHCl3), lit [α]22 = −92.1° (1.0, CHCl3)11e). Its NMR data
D
were well matched with those reported.11d−f The overall yield is
24% starting from (2R,3S)-5l in an eight-step process.
In summary, we have realized the kinetic resolution of 2-
substituted-dihydro-4-pyridones via Pd-catalyzed AAA reaction,
providing both 2,3-disubstituted-dihydro-4-pyridones and
recovered substrates in high yields and enantioselectivities.
With this methodology, the catalytic asymmetric total synthesis
of alkaloids indolizidine (−)-209I was accomplished.
ASSOCIATED CONTENT
* Supporting Information
■
S
General procedure for Pd-catalyzed kinetic resolution of 2 and
enantioselective synthesis of indolizidine (−)-209I, NMR and
HPLC spectra of compounds 2, 5−9, and indolizidine
(−)-209I. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
To synthesize indolizidine (−)-209I, (2S,3S)-5l was prepared
by kinetic resolution of racemic compound 2l using (R)-P-
PHOS as the ligand. When the reaction of 2l with 35 mol % of
3b was performed in the presence of [Pd(η3-C3H5)Cl]2 and
(R)-P-PHOS at 4.0 mmol scale, (2R,3S)-5l was obtained in
*E-mail: dingch@sioc.ac.cn.
*E-mail: xlhou@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
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Organic Letters
Letter
X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133,
19354.
ACKNOWLEDGMENTS
■
This work was financially supported by the Major Basic
Research Development Program (2010CB833300), National
Natural Science Foundation of China (21121062, 21272251,
21032007), the Chinese Academy of Sciences, the Technology
Commission of Shanghai Municipality and the Croucher
Foundation of Hong Kong. This paper is dedicated to
Professor Li Xin Dai on the occasion of his 90th birthday.
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