Iridium(III) catalyzed diastereo- and enantioselective C-H bond functionalization

Article abstract of DOI:10.1021/ja9065267

(Chemical Equation Presented) Iridium(III)-salen complexes were found to efficiently catalyze the enantioselective C-H carbene insertion. The insertion reaction at the α-position of tetrahydrofuran or at the methylene of 1,4-cyclohexadiene proceeded with

Full text of DOI:10.1021/ja9065267

Published on Web 09/16/2009
Iridium(III) Catalyzed Diastereo- and Enantioselective C-H Bond
Functionalization
Hidehiro Suematsu and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu UniVersity, Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
Received August 4, 2009; E-mail: katsuscc@chem.kyushu-univ.jp
Table 1. Asymmetric C-H Insertion into THF Using Various
R-Substituted R-Diazoacetatesa
Direct functionalization of C-H bond is one of the great
contemporary challenges in organic synthesis.1 In particular, the
enantioselective metal-carbene insertion into the C-H bond
provides a method for atom-efficient C-C bond formation, and
high enantioselectivity has been achieved in various intramolecular
C-H insertion reactions.2 The seminal studies on intermolecular
carbenoid C-H insertion using the combination of a rhodium
catalyst and ethyl diazoacetate have been reported by Noels3 and
Callot.4 Recently, Davies and co-workers reported a breakthrough
in asymmetric carbene insertion reactions. The C-H insertion into
entry
R1
R2
5:6b
% yield of 5c
% ee of 5d
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
tBu
13:1
>20:1
19:1
19:1
>20:1
9:1
>20:1
>20:1
>20:1
13:1
75
64
71
82
76
75
82
80
9
95e
97e
97e
94e
93
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-BrC6H4
m-MeOC6H4
m-ClC6H4
2-naphthyl
o-MeOC6H4
Me
alkanes and tetrahydrofuran (THF) using
a Rh2(S-DOSP)4
/RC(N2)CO2Me system (R ) aryl or alkenyl) proceeded with high
enantioselectivity and moderate diastereoselectivity (up to 98% ee,
44-60% de),2c,5 and the C-H bond insertion at the allylic2c,6 and
benzylic positions2c and at the R-position of N-Boc-protected
amines occurred with high enantio- and diastereoselectivity.2c On
the other hand, many natural products have a subunit(s) arising
from the propionate biosynthetic pathway, and carbenoid C-H
insertion using R-diazopropionate should be an efficient method
for the construction of the subunit. However, no insertion method
using a simple R-alkyl-R-diazoacetate has been reported, probably
due to competitive ꢀ-hydride elimination.2a,7
We have discovered that iridium(III)-salen complexes bearing
an aryl group at the apical position show potent and diverse
cyclopropanation catalysis. Iridium-salen complex 1 catalyzes the
highly cis- and enantioselective cyclopropanation of a variety of
olefins including less reactive terminal alkenes and heterocyclic
compounds such as benzofuran, using an R-diazoacetate,8a,b while
the reactions of conjugated olefins using a vinyldiazolactone show
high trans- and enantioselectivity.8c Hence, we expected that
complex 1 might regulate the stereochemistry of a carbenoid
intermediate derived from diazo ester so as not to cause the
undesired ꢀ-hydride elimination and catalyze the desired C-H
insertion. Herein, we communicate the first example of iridium-
catalyzed asymmetric carbenoid insertion into the C-H bond at
the R-position of THF and at the allylic carbon using not only
R-aryl-R-diazoacetate but also R-diazopropionate.9
97
95
98e
95
9
10f
j
70
90
a Reaction was carried out in THF (2 mL) on a 0.5 mmol scale with
b
1
a molar ratio of 2/diazo compound ) 0.025/1. Determined by H NMR
analysis. c Isolated yield. d Determined by HPLC analysis. e The absolute
configuration was determined to be 2S,RR by comparison of the optical
rotation with the literature value (ref 5b). f Run for 5 h at -60 °C.
Table 2. Asymmetric C-H Insertion into 1,4-Cyclohexadiene
Using Various R-Substituted R-Diazoacetatesa
entry
R1
R2
7:8
% yieldb
% eec
1
a
b
c
d
e
f
g
h
i
C6H5
Me
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
91
39
79
95
80
54
53
95
67
68g
84g
94d
90
95
96
99
97
99
99
97
2e f
p-MeOC6H4
p-ClC6H4
m-MeOC6H4
m-ClC6H4
o-MeOC6H4
o-ClC6H4
3,4-Cl2C6H3
3-thienyl
Me
Me
Me
Me
Me
Me
Me
Me
C2H4Cl
Et
,
3
4
5
6
7
8
9
83h i j
, ,
10
j
k
11j
Me
tBu
>99h
a Reaction was carried out in diene (1 mL) on a 0.5 mmol scale with
a
molar ratio of 1/diazo compound )
0.025/1. b Isolated yield.
c Determined by HPLC analysis. d The absolute configuration was
determined to be R by comparison of the optical rotation with the
literature value (ref 5b). e 10 equiv of diene were used. f The reaction
was carried out in acetone as the solvent with 2.5 mol % of 3 at rt for
g
1
24 h. Determined by H NMR analysis with 1-bromonaphthalene as an
internal standard. h Determined by GLC analysis. i The absolute
configuration was determined to be R (see Scheme 1 and SI). j Run with
1.0 mol % of 2 at -50 °C for 5 h.
We initially examined the reaction of THF and methyl R-phenyl-
R-diazoacetate in the presence of 1 at room temperature. However,
the carbene dimer product was obtained as the major product. This
result indicated that the formation of the carbenoid intermediate
occurred but the ensuing C-H insertion was hampered by a
9
14218 J. AM. CHEM. SOC. 2009, 131, 14218–14219
10.1021/ja9065267 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
hindrance around the carbenoid. Thus, we examined the catalysis
of a sterically less congested iridium-salen complex 2. Optimization
of the reaction conditions (see, Table S1, Supporting Information
(SI)) revealed that the insertion proceeded well at -50 °C with
high diastereo- and enantioselectivity in an acceptable yield (Table
1, entry 1).10
Under the optimized conditions, the reactions with a variety of
R-aryl-R-diazoacetates and R-diazopropionates were examined
(Table 1, entries 2-10). All the R-aryl-R-diazoacetates reacted to
produce the corresponding R-aryl(tetrahydrofuran-2-yl)acetates with
good to high diastereoselectivity and high enantioselectivity. The
electronic nature of the aromatic p- or m-substituents did not affect
largely on the stereoselectivity of the reaction (entries 2-9). Yet,
the presence of the o-methoxy group slowed the reaction, probably
due to steric hindrance (entry 9). What is noteworthy for this
reaction, however, is that high diastereo- and enantioselectivity as
well as an acceptable yield was obtained at -60 °C with tert-butyl
R-diazopropionate (entry 10).11 To the best of our knowledge, this
is the first example of asymmetric intermolecular C-H carbene
insertion using an R-alkyl-substituted R-diazoacetate.
(1R,2R,6S,7R)-2-hydroxy-7-methyl-9-oxabi-cyclo[4.3.0]non-4-en-
8-one 11 that has a common skeleton with neostenine,17 in three
steps from commercial cyclohexadiene.
In conclusion, this study revealed the excellent but undeveloped
asymmetric catalysis of intermolecular carbene C-H insertion by
iridium(III)-salen complexes. The C-H insertion reactions exam-
ined were highly enantio- and diastereoselective, and both R-aryl-
R-diazoacetate and R-diazopropionate are available for these
reactions.
Acknowledgment. Financial support from the Specially Pro-
moted Research (Grant No. 18002011) and the Global COE
Programs, “Science for Future Molecular Systems” from the MEXT
(Japan) is gratefully acknowledged. H.S. is grateful for a JSPS
Research Fellowship for Young Scientists. We thank Dr. Kenji
Matsumoto (this laboratory) for the X-ray analysis of 12.
Supporting Information Available: Full experimental data of all
compounds and the X-ray data of 12. These materials are available
free of charge via the Internet at http://pubs.acs.org.
C-H insertion at the C3-methylene of 1,4-cyclohexadiene2c,12
using methyl R-phenyl-R-diazoacetate was also examined in the
presence of 2 (2.5 mol %) at 0 °C, but the enantioselectivity was
moderate (61% ee, 51%). To our delight, however, the desired
reaction using complex 1 as the catalyst proceeded with high
enantioselectivity in a high yield (Table 2, entry 1), and the
undesired cyclopropanation was not observed (7:8 ) >20:1). The
reactions using other R-aryl-substituted R-diazoacetates also pro-
ceeded with high enantioselectivity greater than 94% and moderate
to good yields (entries 3-9), except that the reaction with methyl
R-(p-methoxyphenyl)-R-diazoacetate gave moderate ee (79%) and
modest yield (34%). The enantioselectivity of this reaction was
significantly improved by using a bulky complex 3 in acetone,
though the yield was still modest (entry 2). The reaction with ethyl
R-diazopropionate using complex 1 as the catalyst did not proceed.
To our surprise and delight, the reaction proceeded with good
enantioselectivity at -50 °C, when complex 2 was used as the
catalyst (entry 10). Moreover, the reaction with tert-butyl R-dia-
zopropionate proceeded with significantly improved enantioselec-
tivity and yield (entry 11).
References
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(9) Recently, iridium catalyzed non-asymmetric C-H amination or N-H, O-
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Scheme 1. Stereoselective Approach to a
7-Methyl-9-oxabicyclo[4.3.0]nonane Skeleton
(10) The rate of the carbenoid dimerization catalyzed by 1 is significantly
temperature-dependent, and it becomes slow at lower temperature (ref 8).
(11) This insertion product has a common structure with the C1-C6 segment of
Pamamycin 621A. (a) Fischer, P; Segovia, A. B. G.; Griner, M.; Metz, P
Angew. Chem., Int. Ed. 2005, 44, 6231. (b) Calter, M. A.; Bi, F. C. Org.
Lett. 2000, 2, 1529.
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Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437.
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Chem. Soc. 2008, 130, 6018.
To explore the utility of this reaction, we examined the
conversion of 7j to 11. 7-Methyl-9-oxabicyclo[4.3.0]nonane skel-
etone is the subunit found in several Stemona alkaloids (e.g., stenine
and neostenine); however, their previous construction methods need
a rather long step.13 A combination of asymmetric C-H insertion
with an R-diazopropionate and enantioselective epoxidation was
expected to provide a short step approach toward it. Thus, we
examined the epoxidation of the cyclohexadiene 7j using titani-
um(salalen) complex 9 (for structure, see SI) as the catalyst.14 The
epoxidation proceeded with high exoselectivity and enantiomer
differentiation15 to give the corresponding epoxide 10 exclusively.
Treatment of 10 with perchloric acid in water-THF16 provided
(14) Sawada, Y.; Matsumoto, K.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 46,
4559.
(15) The configuration and the enantiomeric excess of the unreacted 7j (4.5%
yield) were found to be S and 60% ee, respectively.
(16) Wawrzenczyk, C.; Grabarczyk, M.; Bialonska, A.; Ciunik, Z. Tetrahedron
2003, 59, 6595.
(17) The absolute configuration of 11 was obtained by conversion of 11 to
crystalline 12, whose structure was confirmed by X-ray crystallography
(see SI).
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