Palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary carbon stereocenter

Article abstract of DOI:10.1039/c2cc35259a

A palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary stereocenter at the 3-position has been achieved by the reaction of γ-methylidene-δ-valerolactones with alkyl isocyanates. High enantioselectivity has been realized by employing a newly synthesized chiral phosphoramidite ligand. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35259a

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COMMUNICATION
Palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a
quaternary carbon stereocenterw
Ryo Shintani,*a Tomoaki Ito,a Midori Nagamoto,a Haruka Otomoa and Tamio Hayashi*ab
Received 21st July 2012, Accepted 13th August 2012
DOI: 10.1039/c2cc35259a
A palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones
with a quaternary stereocenter at the 3-position has been
achieved by the reaction of c-methylidene-d-valerolactones with
alkyl isocyanates. High enantioselectivity has been realized by
employing a newly synthesized chiral phosphoramidite ligand.
effective ligand for the related asymmetric synthesis of
2-piperidinones.4a Under these conditions, 2-pyrrolidinone
3aa was obtained as the major product over 2-piperidinone
4aa as expected, but the yield and ee were only moderate (42%
ee; Table 1, entry 1). By changing the ligand to (S,S,S)-L2,8
significantly higher yield and ee of 3aa were realized (entry 2),9
and further improvement of enantioselectivity was achieved by
conducting the reaction in toluene instead of in THF (67% ee;
entry 3). We subsequently found that 2,5-diphenylpyrrolidine-
based phosphoramidite ligand (S,S,S)-L310 gave 3aa with
81% ee (entry 4). In the hope of further enhancement of
enantioselectivity, we newly synthesized ligand (S,S,S)-L4
having 3,5-dimethylphenyl groups on the pyrrolidine ring
and it turned out that 3aa could be obtained with as high as
92% ee (entry 5).11 In comparison, substituting tert-butyl ester
of lactone 1a with methyl ester (1b) somewhat decreased the
enantioselectivity (78% ee; entry 6).
Enantioenriched 3-substituted 2-pyrrolidinones constitute a
useful and biologically relevant class of compounds,1 many
of which are synthesized using stoichiometric amounts of
chiral reagents,1,2 and only a few catalytic enantioselective
methods have been known to date for the synthesis of these
compounds.3 In this context, herein we describe a palladium-
catalyzed enantioselective synthesis of 2-pyrrolidinones with a
quaternary stereocenter at the 3-position from g-methylidene-
d-valerolactones and alkyl isocyanates through the nucleophilic
ring-closure at the central carbon of a p-allylpalladium inter-
mediate,4,5 whose modes of stoichiometric and catalytic reactions
have been both explored in the past few decades since the first
report by Hegedus and coworkers.5a
Table 1 Palladium-catalyzed asymmetric decarboxylative cyclization
1 with benzyl isocyanate 2a:
of g-methylidene-d-valerolactones
optimization
With regard to catalytic asymmetric preparation of lactams,
we previously developed a palladium-catalyzed asymmetric
synthesis of 3,3-disubstituted 2-piperidinones by decarboxylative
cyclization of g-methylidene-d-valerolactones with aryl isocyanates
with high enantioselectivity.4a We also described that the use
of alkyl isocyanates instead of aryl isocyanates changed the
course of the reaction presumably due to the more electron-rich
nature of the nitrogen atom,4b leading to the formation of
3,3-disubstituted 2-pyrrolidinones with a spirocyclopropyl
moiety.4,6 On the basis of these findings, we decided to focus
on the development of enantioselective synthesis of 2-pyrrolidi-
nones and began our study by conducting a reaction of
g-methylidene-d-valerolactone 1a with benzyl isocyanate (2a)
in THF at 30 1C in the presence of a palladium catalyst
coordinated with chiral phosphoramidite (S,S,S)-L1,7 a highly
Entry
1
Ligand
Solvent Yielda (%) 3/4b
ee of 3c (%)
1
2
3
1a (S,S,S)-L1 THF
1a (S,S,S)-L2 THF
1a (S,S,S)-L2 Toluene 74
1a (S,S,S)-L3 Toluene 75
1a (S,S,S)-L4 Toluene 89
1b (S,S,S)-L4 Toluene 89
35
81
91/9
95/5
93/7
42
63
67
4d
5d
6d
90/10 81
90/10 92
92/8
78
a
b
Combined isolated yield of 3 and 4. Determined by 1H NMR.
d
Determined by chiral HPLC with hexane/2-propanol. The reaction
c
was conducted for 12 h.
a Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: shintani@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-3988;
Tel: +81-75-753-3986
b Institute of Materials Research and Engineering, A*STAR,
3 Research Link, Singapore 117602. E-mail: tamioh@imre.a-star.edu.sg;
Fax: +65-6872-0785; Tel: +65-6514-1547
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 892796. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc35259a
c
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9936 Chem. Commun., 2012, 48, 9936–9938

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Table 2 Palladium-catalyzed asymmetric decarboxylative cyclization
of g-methylidene-d-valerolactones 1 with alkyl isocyanates 2: scope
ee of
Yielda
3c
(%)
Entry 1 (Ar)
2 (R)
(%) 3/4b
1
2
3
1a (Ph)
1a
1a
1a
1a
1a
1c (4-MeOC6H4)
1d (4-MeC6H4)
1e (4-PhC6H4)
1f (4-FC6H4)
1g (3,4-(OCH2O)C6H3) 2a
1h (3-MeC6H4)
1i (2-MeOC6H4)
2b (4-MeOC6H4CH2) 86
2c (4-MeC6H4CH2) 92
2d (4-BrC6H4CH2) 76
2e (2-furylmethyl) 82
88/12 93
89/11 92
93/7 92
90/10 93
91/9 90
>99/1 92
89/11 93
89/11 93
92/8 93
90/10 93
91/9 92
90/10 92
97/3 83
Fig. 1 X-ray crystal structure of (S)-3af with thermal ellipsoids
drawn at the 50% probability level (Flack parameter = 0.040(15);
hydrogen atoms are omitted for clarity).
4d
5e
6d
7
2f (ClCH2CH2)
2g (EtO2CCH2CH2) 72
77
Table 3 Palladium-catalyzed asymmetric decarboxylative cyclization
of g-methylidene-d-valerolactones 1 with aryl isocyanates 2: examples
2a (PhCH2)
81
83
93
94
85
83
53
8
9
10
11
12
13f
2a
2a
2a
2a
2a
a
b
Combined isolated yield of 3 and 4. Determined by 1H NMR.
c
d
Determined by chiral HPLC with hexane/2-propanol. The reaction
e
was conducted with 1.6 equiv. of 1a. The reaction was conducted for
f
45 h. The reaction was conducted with 2.0 equiv. of 1i.
ee of
4c (%)
Entry 1 (Ar)
2 (Ar0)
Yielda (%) 3/4b
1
2
3
4
5
1a (Ph)
1a
1a
1e (4-PhC6H4) 2i
1h (3-MeC6H4) 2i
2h (4-MeOC6H4) 89
6/94
1/99
94
94
Under the conditions of using ligand (S,S,S)-L4, several
substituted benzyl isocyanates undergo the reaction with lactone
1a to give 2-pyrrolidinones 3 selectively over 2-piperidinones 4
with high enantioselectivity (92–93% ee; Table 2, entries 1–3).
Other functionalized alkyl isocyanates such as 2e–2g also provide
products 3 with high efficiency (90–93% ee; entries 4–6). With
respect to the a-substituent of g-methylidene-d-valerolactones 1,
various para- or meta-substituted aryl groups are well tolerated,
selectively giving 2-pyrrolidinones 2 in the reaction with benzyl
isocyanate with uniformly high ee (92–93% ee; entries 7–12). The
use of lactones 1 having ortho-substituted aryl groups results in
somewhat lower yield and ee, but the selectivity toward 2-pyrrolidi-
nones 2 stays high (entry 13). Unfortunately, however, lactones
with a-alkyl substituents are not suitable substrates under the
present conditions. The absolute configuration of product 3af
(entry 5) was determined to be S by X-ray crystallographic
analysis after recrystallization from Et2O (Fig. 1).12
2i (Ph)
2j (4-ClC6H4)
89
95
91
91
o1/99 94
1/99
1/99
94
93
a
b
Combined isolated yield of 3 and 4. Determined by 1H NMR.
Determined by chiral HPLC with hexane/2-propanol.
c
place for compound 3ag (92% ee) in the presence of NaH to
give N-deprotected product 6 with high efficiency (93% yield,
92% ee; eqn (2)).
ð1Þ
The newly developed phosphoramidite ligand (S,S,S)-L4
was found to be highly effective as well for the synthesis of 3,3-
disubstituted 2-piperidinones 4 by using aryl isocyanates as the
reaction partner. For example, reaction of lactone 1a with
4-methoxyphenyl isocyanate (2h) selectively provides 2-piperidi-
none 4ah in high yield with 94% ee (Table 3, entry 1). Several
other combinations of lactones 1 and aryl isocyanates 2 also led to
compounds 4 with high selectivity as summarized in entries 2–5. It
is worth noting that these results using ligand (S,S,S)-L4 compare
favorably with our previous results with ligand (S,S,S)-L1.4a
Enantioenriched 2-pyrrolidinones 3 obtained in the present
catalysis can be used for further derivatizations. For example,
compound 3aa (92% ee) is converted to pyrrolidine-based
aminoalcohol 5 in 87% yield with 91% ee by reducing it with
LiAlH4 (eqn (1)). In addition, retro-Michael addition takes
ð2Þ
In summary, we have developed a palladium-catalyzed asymmetric
synthesis of 2-pyrrolidinones with a quaternary stereocenter at
the 3-position from g-methylidene-d-valerolactones and alkyl
isocyanates. High enantioselectivity has been achieved by
employing a newly synthesized chiral phosphoramidite ligand
((S,S,S)-L4), and this ligand has also turned out to be highly
effective for the enantioselective synthesis of 3,3-disubstituted
2-piperidinones by employing aryl isocyanates as the reaction
partner.
Support has been provided in part by Taisho Pharmaceutical
Co., Ltd.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9936–9938 9937

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12 CCDC 892796. See also ESIw.
c
9938 Chem. Commun., 2012, 48, 9936–9938
This journal is The Royal Society of Chemistry 2012