Palladium-catalyzed asymmetric decarboxylative lactamization of γ-methylidene-δ-valerolactones with isocyanates: Conversion of racemic lactones to enantioenriched lactams

Article abstract of DOI:10.1021/ja807662b

A palladium-catalyzed asymmetric decarboxylative reaction of racemic γ-methylidene-δ-valerolactones with aryl isocyanates has been developed to give enantioenriched 3,3-disubstituted 2-piperidones. High enantioselectivity has been achieved by tuning the e

Full text of DOI:10.1021/ja807662b

Published on Web 11/11/2008
Palladium-Catalyzed Asymmetric Decarboxylative Lactamization of
γ-Methylidene-δ-valerolactones with Isocyanates: Conversion of Racemic
Lactones to Enantioenriched Lactams
Ryo Shintani,* Soyoung Park, Fumitaka Shirozu, Masataka Murakami, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received September 30, 2008; E-mail: shintani@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Table 1. Palladium-Catalyzed Asymmetric Reaction of 1 with 2a:
Effect of Ligands and Ester Groups on 1
2-Piperidones having a stereocenter at the 3-position constitute
a useful class of compounds,1 and asymmetric construction of these
compounds is therefore an important objective. Although various
methods are available to this end, most of them rely on the use of
a stoichiometric amount of enantiopure chiral reagents.2 In contrast,
only a few catalytic enantioselective routes to these compounds
are known to date, many of which are for the synthesis of
3-monosubstituted 2-piperidones.3 In fact, successful examples of
the catalytic asymmetric construction of 3,3-disubstituted 2-pip-
eridones are very limited.4 In this Communication, we describe the
development of a palladium-catalyzed asymmetric decarboxylative
reaction of γ-methylidene-δ-valerolactones5 with isocyanates,6
effectively converting racemic lactones to 3,3-disubstituted 2-pip-
eridones with high enantioselectivity.
entry
1
product
ligand
yield (%)a
ee (%)b
1
2c
3
4
5
6
7
1a
1a
1a
1a
1b
1b
1b
3aa
3aa
3aa
3aa
3ba
3ba
3ba
(S)-MeO-mop
(S)-binap
<2
49
84
95
70
88
87
-
29
51
57
68
76
88
(S,R,R)-4a
(S,S,S)-4a
(S,R,R)-4a
(S,S,S)-4a
(S,S,S)-4b
Initially, we conducted a reaction of γ-methylidene-δ-valero-
lactone 1a (1.4 equiv) with 4-methoxyphenyl isocyanate (2a) in
the presence of 5 mol % of Pd(PPh3)4 as a catalyst in THF at 40
°C (eq 1). The reaction proceeded smoothly to give the expected
3,3-disubstituted 2-piperidone 3aa in 79% yield. Having established
the catalytic formation of 3aa, we turned our attention to asymmetric
catalysis. Unfortunately, the reaction was shut down with (S)-MeO-
mop,7 a chiral monophosphine ligand (Table 1, entry 1). By
changing the ligand to (S)-binap,8 a chiral bisphosphine ligand,
moderate yield of 3aa was achieved with low enantioselectivity
(49% yield, 29% ee; entry 2). In contrast, the use of chiral
phosphoramidite ligand (S,R,R)-4a9,10 or its diastereomer (S,S,S)-
4a9 gave the desired product in high yield (84-95% yield) with
somewhat higher enantioselectivity (51% ee and 57% ee, respec-
tively; entries 3 and 4). The change of methyl ester of lactone 1a
to tert-butyl ester (1b) improved the enantioselectivity to 68% ee
with ligand (S,R,R)-4a (entry 5) and to 76% ee with ligand (S,S,S)-
4a (entry 6). We subsequently identified that higher enantioselec-
tivity for 3ba can be achieved by employing Alexakis phosphor-
amidite (S,S,S)-4b11 as the ligand (88% ee; entry 7).
a Determined by 1H NMR against an internal standard (3,5-
dimethylphenol). b Determined by chiral HPLC on a Chiralpak AD-H
with hexane/2-propanol ) 90/10. c 5 mol % of ligand was used.
Table 2. Palladium-Catalyzed Asymmetric Reaction of 1 with 2:
Scope
entry
1 (R)
2 (Ar)
product yield (%)a ee (%)b
1
1b (Ph)
2a (4-MeOC6H4)
2b (4-PhC6H4)
2c (4-ClC6H4)
3ba
3bb
3bc
88
80
79
73
85
82
79
93
86
75
51
93
91
83
93
90
91
87
87
96
94
74
2
1b
1b
1b
3c
4
2d (3,5-(MeO)2C6H3) 3bd
5
6
7
1c (4-MeOC6H4) 2a
1d (4-MeC6H4) 2a
1e (3-MeC6H4)
1f (2-naphthyl) 2a
1g (3-thienyl)
1h (3-furyl)
3ca
3da
3ea
3fa
3ga
3ha
3ia
2a
In the presence of ligand (S,S,S)-4b, the amount of lactone 1b
can be reduced to 1.2 equiv and higher enantioselectivity can be
realized by conducting the reaction at 20 °C, giving 3ba in 88%
yield with 93% ee (Table 2, entry 1). Several other aryl isocyanates,
such as 2b-2d, can also be used for the synthesis of lactams 3
with 1b in high yield with similarly high stereoselectivity (83-93%
ee; entries 2-4). Interestingly, the use of alkyl isocyanates, on the
otherhand,selectivelyleadstotheformationofazaspiro[2.4]heptanones
5 (eq 2).5b,12 With respect to the substituent on lactones 1, various
aryl and heteroaryl groups can be tolerated to give the corresponding
8
9d
10e
2a
2a
2a
11c,d,f 1i (Bn)
a Isolated yield. b Determined by chiral HPLC with hexane/
2-propanol. c The reaction was conducted at 40 °C. d Run using 2.0
equiv of 1. e Run using 4.0 equiv of 1. f Ligand (S,S,S)-4a was used.
products 3 with high enantioselectivity (87-96% ee; entries 5-10).
In addition, alkyl-substituted lactone 1i also undergoes the decar-
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16174 J. AM. CHEM. SOC. 2008, 130, 16174–16175
10.1021/ja807662b CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
boxylative reaction, albeit with somewhat lower efficiency (51%
yield, 74% ee; entry 11). The absolute configuration of compound
3bc (entry 3) was determined to be (S) by X-ray crystallographic
analysis after recrystallization from Et2O.13
valerolactones with isocyanates to give enantioenriched 3,3-
disubstituted 2-piperidones. By tuning the ester group on 1 and
the substituents of phosphoramidite ligand, high enantioselectivity
has been achieved for various substrate combinations.
It is worth noting that, during the course of the reaction of 1b
with 2a, the ee of remaining 1b is less than 15% ee and the ee of
product 3ba stays constant (93% ee (S)). In addition, when
enantiopure (+)-1b or (-)-1b is employed, high yield of 3ba with
93% ee (S) was obtained in each case (eq 3). These results indicate
that no effective kinetic resolution of (()-1 occurs during catalysis
and the stereochemical outcome of 3 is solely controlled by the
chirality of Pd/(S,S,S)-4b catalyst.
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 Foundation.
Supporting Information Available: Experimental procedures and
compound characterization data and X-ray data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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(17) Formation of 5 occurs through the central carbon attack by nitrogen in
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Figure 1. Proposed reaction pathway for the palladium-catalyzed asym-
metric decarboxylative lactamization of (()-1 with 2.
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