Asymmetric synthesis of 3,4-dihydrocoumarins by rhodium-catalyzed reaction of 3-(2-hydroxyphenyl)cyclobutanones

Article abstract of DOI:10.1021/ja075141g

3,4-Dihydrocoumarin derivatives were synthesized in a highly enantioselective manner from 3-(2-hydroxyphenyl)cyclobutanones through enantioselective carbon-carbon bond cleavage. A cascade reaction with electron-deficient alkenes introduced a carbon-carbon

Full text of DOI:10.1021/ja075141g

Published on Web 09/18/2007
Asymmetric Synthesis of 3,4-Dihydrocoumarins by Rhodium-Catalyzed
Reaction of 3-(2-Hydroxyphenyl)cyclobutanones
Takanori Matsuda, Masanori Shigeno, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
Received July 11, 2007; E-mail: murakami@sbchem.kyoto-u.ac.jp
Scheme 1. Rhodium-Catalyzed Reaction of Cyclobutanone 1a
Significant advances have been made over the past decade in
the field of activation of carbon-carbon single bonds by means of
transition metal catalysis.1 Now a variety of catalytic processes are
available for organic transformations including cross-coupling and
ring-expansion reactions.2 We recently developed the rhodium-
catalyzed reaction of boron-substituted cyclobutanones forming
1-indanones. Enantioselectivities up to 95% ee were observed during
the sequence of intramolecular addition/ring-opening reactions when
stereogenic quaternary carbon centers arose at the benzylic position.3
It was also found that rhodium catalysts promote the ring-opening
reaction of cyclobutanones with phenols to form ester linkages via
inter-4 and intramolecular pathways.5 In this paper, we describe an
asymmetric synthesis of 3,4-dihydrocoumarins by way of a highly
enantioselective carbon-carbon bond cleavage.6 Deuterium-labeling
experiments led to the development of a new cascade reaction
involving 1,4-rhodium shift and intermolecular conjugate addition.
When 3-(2-hydroxyphenyl)cyclobutanone (1a)7 was treated with
a catalytic amount of a rhodium(I) catalyst, prepared in situ from
[Rh(OH)(cod)]2 (7 mol %) and (R)-SEGPHOS (16 mol %), in
toluene at room temperature for 19 h, 4-methyl-3,4-dihydrocoumarin
(2a) was produced in 77% isolated yield (Scheme 1).8 Only one
enantiomer was observed by chiral HPLC analysis. The absolute
configuration was assigned to be S by comparison with the reported
optical rotation.9 BINAP and Tol-BINAP were also effective as
the chiral ligands, both giving 96% ee. We propose a possible
mechanism which consists of (i) generation of rhodium aryloxide
3, (ii) addition to the carbonyl group forming rhodium cyclobu-
tanolate 4,10 (iii) ring opening of the cyclobutane skeleton by
â-carbon elimination11 generating 5, which is the enantiodifferen-
tiating step, and (iv) protonolysis affording the dihydrocoumarin
2a, as we proposed recently.4
Scheme 2. Deuterium-Labeling Experiment with 1a
Chart 1. Asymmetric Synthesis of 4-Monosubstituted
3,4-Dihydrocoumarins 2b-da
When the reaction of 1a was carried out in THF-D2O (4:1),
deuterium was incorporated at the 3-position (88% D; 61:39 dr)
(Scheme 2). This result indicates that protonolysis occurs not
directly from the intermediate 5 but via enolate 6. From intermediate
5, in which rhodium is located γ to the carbonyl group, 6 is
generated via a series of â-hydride elimination and re-additions.12
The excellent enantioselectivity observed with 2a is explained by
assuming that rhodium faithfully remains on the same enantioface
during the repetitive elimination/re-addition processes.
The results of the Rh(I)-(R)-SEGPHOS-catalyzed reaction of
other 3-monosubstituted cyclobutanones 1 are shown in Chart 1.
Methoxy- and chloro-substituted cyclobutanones gave the corre-
sponding 3,4-dihydrocoumarins, 2b and 2c, in good yields and high
levels of enantiomeric excess. The reaction of naphthalene deriva-
tive produced tricyclic lactone 2d in 91% yield and 98% ee.
We also tried to synthesize seven-membered ring lactones by
the rhodium-catalyzed reaction of 3-monosubstituted cyclobu-
tanones with their tethers extended by one carbon. The reaction of
cyclobutanone 7 possessing a benzylic alcohol moiety required
heating at 135 °C, and seven-membered lactone 8 was produced
in 76% yield and 34% ee (eq 1). Cyclobutanone 9 reacted at
110 °C to give benzolactone 10 in 61% yield with 28% ee (eq 2).
The more compact and less flexible 2-oxabicyclo[3.1.1]heptane
a 3.5 mol % of [Rh(OH)(cod)]2 and 8 mol % of (R)-SEGPHOS in toluene
for 2b or in toluene-THF (4:1) for 2c and 2d at rt for 12-14 h.
skeleton of 4 is likely preferable for the enantiodifferentiating
carbon-carbon bond cleavage step to occur with high selectivity.
9
12086
J. AM. CHEM. SOC. 2007, 129, 12086-12087
10.1021/ja075141g CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Synthesis of 4,4-Disubstituted
3,4-Dihydrocoumarins 2e-ja
product 13fa was obtained in 93% yield with 95% ee (Table 2,
entry 1). Other electron-deficient alkenes such as methyl vinyl
ketone (12b) and methyl acrylate (12c) could be employed (entries
2 and 3).16 Cyclobutanones 1g and 1h also underwent the cascade
reaction to furnish the corresponding alkylated dihydrocoumarins
13 (entries 4 and 5).
In summary, 3,4-dihydrocoumarins have been synthesized in a
highly enantioselective manner through an asymmetric â-carbon
elimination step. A new asymmetric cascade reaction consisting
of carbonyl addition/ring opening/1,4-addition has been developed
by utilization of the intermediary arylrhodium species generated
from 3,3-disubstituted cyclobutanones.
cyclobutanone
R1
dihydrocoumarin
entry
1
R2
2
%yieldb
%eec
1
1e
1f
1g
1h
1i
(CH2)2Ph
(CH2)2Ph
Et
i-Pr
Ph
(CH2)3OH
H
OMe
H
H
H
Me
2e
2f
2g
2h
2i
81 (79d)
92
94 (80d)
95
2e
3f
80
94
4f
87
93
5g
6e,f
68
92
Acknowledgment. We thank Takasago International Corpora-
tion for its generous gift of (R)-SEGPHOS. This work was sup-
ported by Grants-in-Aid for Scientific Research (Nos. 17750087
and 19205013) from MEXT, Japan, and the Asahi Glass Founda-
tion.
1j
2j
77
77
a Unless otherwise noted, cyclobutanone 1 was reacted in the presence
of 3.5 mol % of [Rh(OH)(cod)]2 and 8.0 mol % of (R)-Tol-BINAP in toluene
at room temperature for 11-24 h. b Isolated yield by preparative TLC.
c Determined by chiral HPLC. d Result with (R)-SEGPHOS. e Toluene-
THF (4:1) was used. f 7.0 mol % of [Rh(OH)(cod)]2 and 16 mol % of (R)-
Tol-BINAP were used. g THF was used.
Supporting Information Available: Experimental details and
selected spectral data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 3. Deuterium-Labeling Experiment with 1f
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Table 2. Rhodium-Catalyzed Cascade Reaction of 1 with
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1
1f ((CH2)2Ph, OMe)
12a (CN)
12b (COMe)
12c (CO2Me)
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13fb
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13gb
13ha
93
65
76
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89
95
96
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2
1f
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1f
1g (Et, H)
1h (i-Pr, H)
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a Cyclobutanone 1 was added dropwise to a THF solution of alkene 12
(10 equiv) over 1 h in the presence of the rhodium catalyst at 50 °C.
b Isolated yield. c Determined by chiral HPLC. d The reaction was carried
out at 60 °C for 17 h.
Next, the reaction of 3,3-disubstituted cyclobutanone 1e was
examined (Table 1). In contrast to the cases of 3-monosubstituted
cyclobutanones 1a-d, Tol-BINAP proved to operate more selec-
tively than SEGPHOS in constructing the chiral quaternary carbon
center (entry 1). Enantiomeric excesses ranging from 92 to 95%
were generally observed in the reaction of various 3,3-disubstituted
cyclobutanones 1f-i, except for the case of 1j having a 3-hydrox-
ypropyl side chain (entries 2-6).
A deuterium-labeling experiment was carried out also with the
3,3-disubstituted cyclobutanone 1f, for which it was impossible to
follow the protonolysis pathway shown in Scheme 2 because of
the lack of â-hydrogen. In this case, deuterium was incorporated
at the 5-position, implying the generation of arylrhodium species
11 via a 1,4-rhodium shift13 prior to protonolysis (Scheme 3).
These results led us to examine the competency of intermediary
arylrhodium 11 in a subsequent 1,4-addition reaction.14 When the
reaction of 1f was carried out in the presence of acrylonitrile (12a),
the arylrhodium generated in an enantioenriched form via 1,4-
rhodium shift underwent 1,4-addition to 12a,15 and the cascade
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(16) Cyclohex-2-enone, benzaldehyde, and oct-4-yne failed to react with the
arylrhodium species.
JA075141G
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J. AM. CHEM. SOC. VOL. 129, NO. 40, 2007 12087