Catalytic Asymmetric Intermolecular Cyclopropanation of a Ketone Carbene Precursor by a Ruthenium(II)-Pheox Complex

Article abstract of DOI:10.1002/adsc.201801077

The diazo derivative of acetonyl acetate is a useful basic skeleton for the synthesis of cyclopropyl ketones. The intermolecular cyclopropanations of diazo acetoxy acetone with olefins are accomplished by using a novel p-nitro-Ru(II)-diphenyl-Pheox catalyst to give the corresponding optically active cyclopropane derivatives in good yields (up to 95%) with excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to 98% ee). (Figure presented.).

Full text of DOI:10.1002/adsc.201801077

Title: Catalytic Asymmetric Intermolecular Cyclopropanation of a
Ketone Carbene Precursor by a Ruthenium(II)-Pheox Complex
Authors: Chi Le, Agus Suharto, Linh Da Ho, Soda Chanthamath,
Kazutaka Shibatomi, and Seiji Iwasa
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801077
Link to VoR: http://dx.doi.org/10.1002/adsc.201801077

10.1002/adsc.201801077
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Asymmetric Intermolecular Cyclopropanation of a
Ketone Carbene Precursor by a Ruthenium(II)-Pheox Complex
Le Thi Loan Chia, Agus Suhartoa, Ho Linh Daa, Soda Chanthamatha, Kazutaka
Shibatomia, and Seiji Iwasaa,*
a
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho,
Toyohashi 441-8580, Japan
Fax: +81-(0)532-48-5833; e-mail: Iwasa@ens.tut.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The diazo derivative of acetonyl acetate is a
useful basic skeleton for the synthesis of cyclopropyl
ketones. The intermolecular cyclopropanations of diazo
acetoxy acetone with olefins are accomplished by using a
novel p-nitro-Ru(II)-diphenyl-Pheox catalyst to give the
corresponding optically active cyclopropane derivatives in
good
yields
(up
to
95%)
with
excellent
diastereoselectivities (up to 99:1) and enantioselectivities
(up to 98% ee).
Keywords: Asymmetric synthesis; Cyclopropanation;
Ruthenium catalyst; Diazo ketone
Optically active cyclopropane derivatives have
received considerable attention in the fields of
organic and pharmaceutical chemistry owing to the
biological activities of cyclopropanes.[1] The
transition
metal-catalyzed
asymmetric
cyclopropanations of diazoacetates with olefins
using chiral Cu,[2a-d] Rh,[2e-g], Ru,[2h-j] Co,[2k-l] and Ir[m]
catalysts have been reported with excellent
stereoselectivities. In most cases, steric hindrance
plays an important role in obtaining high
stereoselectivities (Scheme 1, reaction 1). For
example, for
a
carbene transfer reaction of
Scheme
diazoacetates.
1. Cyclopropanation reactions of
diazoacetate to olefins, sterically hindered ester
substituents such as i-Pr and t-Bu gave generally
higher stereoselectivities than that from the less
hindered Et substituent. This prompted us to modify
functionalized diazo compounds that promotes the
catalytic asymmetric cyclopropanation in high yields
with excellent enantioselectivity.
Recently, we reported on the modification of
diazoacetates to improve catalytic asymmetric
cyclopropanations not only for electron-rich olefins,
but also for allenes and electron-deficient olefins.
olefins and allenes resulted in cyclopropanes with
high yields and excellent enantioselectivities (up to
99%) (Scheme 1, reaction 2).[3] Continuing this line
of research, an asymmetric cyclopropanation of -
unsaturated carbonyl compounds with acetonyl
diazoacetate by using Ru(II)-pheox was reported
(Scheme 1, reaction 3).[4] Succinimidyl diazoacetate
and acetonyl diazoacetate gave much higher
stereoselectivities (diastereoselectivity >99:1 and
enantioselectivity up to 99%) in the cyclopropanation
Thus,
Ru(II)-pheox-catalyzed
asymmetric
cyclopropanation of succinimidyl diazoacetate with
1
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10.1002/adsc.201801077
Advanced Synthesis & Catalysis
reactions compared with sterically hindered esters.[4]
Consequently, we proposed that the carbonyl groups
of succinimidyl diazoacetate and acetonyl
diazoacetate played an important role in the
improvement of stereoselectivity.
As part of our ongoing interest in
cyclopropanation reactions with alternative diazo
esters, we first examined the reaction of styrene 1a
with diazo acetoxy acetone 2a using Rh2(OAc)4 and
the series of Ru(II)-Pheox derivatives 3a-g as
catalysts. The results are summarized in Table 1.
Rh(OAc)2 and other transition metals such as
FeSO4.7H2O, Cu(OAc), and Cu(OAc)2 are well-
known carbene transfer catalysts, yet had almost no
effect on the cyclopropanation reaction at room
temperature. In contrast, using Ru(II)-Pheox
derivatives 3a-g as catalysts gave moderate to high
reactivities and moderate to good stereoselectivities.
Having a phenyl group on the oxazoline ring of the
catalyst improved the enantioselectivity to 70% ee
(Table 1, entries 1–4). The influence of the electron
donating or withdrawing ability of the R2 and R3
groups on the Ru(II)-pheox complexes were then
examined. Changing the R2 or R3 group improved
the enantioselectivity to up to 74% ee (Table 1,
entries 5–7). A Ru(II)-pheox skeleton bearing an R4
substituent at the C5 position of the oxazoline ring
was also examined (R4=Ph, catalyst 3h). This was
the most efficient catalyst for both stereoselectivity
and yield (73% yield and 75% ee) (Table 1, entry 8).
The enantioselectivity and yield were further
improved when Ru(II)-Pheox 3h was modified with
bulky dialkyl substituents at the C5 position of the
oxazoline ring (catalysts 3i–l). Based on the
previous method for synthesizing Ru(II)-Pheox
derivatives,[9] catalysts 3i–l were prepared as shown
in Scheme 2. First we synthesized dialkyl-
phenylglycinol[10] from the corresponding Grignard
reagent, alkyl magnesium bromide, and (S)-2-amino-
2-phenylacetic acid, and then treated it with benzoyl
chloride and methanesulfonic acid[11] to give ligand 6.
Ru(II)-diphenyl-Pheox derivatives were synthesized
from ligand 6 in high yields for each step, for an
overall yield from the amino acid up to 60% in yield.
Since the reaction of acetonyl diazoacetate with
olefins gave the corresponding cyclopropyl esters in
high yields and high stereoselectivities, we thought to
introduce the diazo group onto the acetonyl group.
This could give the corresponding cyclopropyl
ketone moiety with high stereoselectivity, since the
carbonyl group is the same distance from another
carbonyl group of the acetyl group and therefore we
would expect the same effect on the
stereoselectivity.[5] Furthermore, cyclopropyl ketone
moieties are found in natural products having
important physiological properties,[6] but only -
diazoacetophenone has been developed as a ketone
source, having been obtained in 67% yield with 86%
ee.[7] Thus, we report herein the first catalytic
asymmetric synthesis of a ketone carbene precursor
based on an acetonyl acetate skeleton by using novel
Ru(II)-Pheox complexes as chiral catalysts (Scheme
1).
Diazo acetoxy acetone[8] was prepared by
modification of the diazo acetonyl acetate synthesis,
and examined in the carbene transfer reaction by
using a series of Ru(II)-Pheox complexes, which had
been found to be efficient catalysts for the inter- and
intramolecular cyclopropanation of various diazo
compounds.[9]
Table 1. Initial catalyst screening.a
Entry Catalyst Yield [%]b) dr c)
-ee [%]d)
1
2
3
4
5
6
7
8
70
54
60
68
50
53
60
73
92:8
68
3a
3b
3c
3d
3e
3f
85:15 50
90:10 65
75:25 46
95:5
90:10 55
90:10 43
74
3g
3h
95:5
75
a) Reaction conditions: A solution of diazo ketone 2a (0.2 mmol) in
CH2Cl2 (2.0 mL) was added to Ru(II)-Pheox 3 (3%) in CH2Cl2 (2.0 mL)
b)
c)
d)
Determined by 1H NMR analysis.
Scheme 2. Synthesis of Ru(II)-dialkyl-Pheox complexes.
under Ar.
Isolated yield.
Determined by chiral HPLC analysis.
2
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10.1002/adsc.201801077
Advanced Synthesis & Catalysis
The screening of Ru(II)-diphenyl-Pheox catalysts
Dichloromethane was the best solvent among those
examined, and the catalytic cyclopropanation
proceeded at –50 °C to give the highest yield (85%)
with excellent enantioselectivity (95% ee) (Table 3,
entry 9). Although diethyl ether (Et2O) was a more
efficient solvent for diastereoselectivity, its use
resulted in a very low yield (Table 3, entry 1).
3i–l for the carbene transfer reaction is summarized
in Table 2. We found that the bulky p-nitro-Ru(II)-
diphenyl-Pheox complex 3k had higher activity and
enantioselectivity compared with Ru(II)-phenyl-
Pheox 3h, giving the corresponding product in high
yield (78% yield) and good enantioselectivity (83%
ee) (Table 2, entry 3). Ru(II)-dimethyl-Pheox
catalyst 3j was also tested for use in the
Table 4. Asymmetric cyclopropanation of various olefins.
cyclopropanation
reaction,
however,
the
enantioselectivity and yield decreased in comparison
with 3k.
Table 2. Screening of various Ru(II)-pheox catalysts.
Entry 1: R1, R2
Yield drc)
[%]b)
-ee
[%]d)
1
2
1a: R1 = Ph, R2 = H
85
79
99:1
98:2
95
96
1b: R1 = p-CH3-C6H4
R2 = H
3
4
5
6
7
1c: R1 = p-OMe-C6H4
R2 = H
62
72
95
85
92
97:3
98:2
97:3
91:9
99:1
83
91
98
92
97
1d: R1 = p-tBu-C6H4
R2 = H
1e: R1 = p-Cl-C6H4
R2 = H
1f: R1 = m-CH3-C6H4
R2 = H
Entry Catalyst Yield [%]a) drb)
-ee [%]c)
95:15 79
92:8 75
90:10 83
90:10 62
1
2
3
4
75
72
78
70
3i
1g: R1 = o-Cl-C6H4
R2 = H
3j
3k
3l
8
9
1h: 2-vinylnaphthalene 90
90:10 97
98:2 -85
1i: R1 = Ph, R2 = CH3
55
a) Isolated yield. b) Determined by 1H NMR analysis.
c) Determined by chiral HPLC analysis.
a) Isolated yield. b) Determined by 1H NMR analysis; the enantioselectivity
is for the trans product only. c) Determined by chiral HPLC analysis.
Table 3. Optimization of the reaction conditions.
Encouraged by the above results, we investigated
the cyclopropanation of diazo acetoxy acetone 2a
with olefins 1a–j using p-nitro-Ru(II)-diphenyl-
Pheox 3k under the optimized conditions. The
results are summarized in Table 4. Styrene
derivatives having ortho, meta, or para substituents
were all tolerated under the reaction conditions (Table
4, entries 2–7). It is noteworthy that styrenes bearing
an electron-withdrawing group at the para position
were more effective than those with an electron-rich
substituent at that position, due to the strong
electrophilic nature (Table 4, entries 2–5). The
highest enantioselectivity (98% ee) and yield (95%)
were obtained for the styrene bearing a para-Cl
substituent (Table 4, entry 5). In contrast, the
cyclopropanation of -methyl substituted styrene
afforded the desired product with good
enantioselectivity (85% ee) but in only moderate
yield (55%) (Table 4, entry 9).
Entry Solvent
Temp Yield drb)
-ee
[%]c)
[°C]
[%]a)
1
2
3
4
5
6
7
8
Et2O
RT
23
60
60
75
78
80
80
82
85
85
99:1
95:5
99:1
90:10
90
77
80
60
CH2Cl2/ Et2O RT
Acetone
RT
RT
RT
0
-10
-30
-50
-70
EDCd)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
90 : 10 83
95:1
99:1
99:1
99:1
99:1
84
88
90
95
92
9
10
a) Isolated yield. b) Determined by 1H NMR analysis, the enantioselectivity
In summary, we found that highly stereoselective
catalytic asymmetric cyclopropanation reactions of
diazo derivatives of acetonyl acetate with olefins
using a novel p-nitro-Ru(II)-diphenyl-Pheox catalyst
gave the corresponding optically active cyclopropyl
ketone derivatives in good yields (up to 95%) with
excellent diastereoselectivities (up to 99:1) and
c)
d)
for trans product only. Determined by chiral HPLC analysis. 1,2-
Dichloroethane
Next, we optimized the reaction using p-nitro-
Ru(II)-diphenyl-Pheox 3k as the catalyst in various
solvents and temperatures as shown in Table 3.
3
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10.1002/adsc.201801077
Advanced Synthesis & Catalysis
enantioselectivities (up to 98% ee). Diazo acetonyl
acetate can be used for a ketone carbene precursor.
T. J. Kim, Tetrahedron Lett. 2007, 45, 8014–8017; For
Co(II), see: n) Y. Chen, X. P. Zhang, J. Org. Chem.
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Perman, X. P. Zhang, J. Am. Chem. Soc. 2010, 132,
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2008, 130, 10327–10337.
Experimental Section
Typical
Procedure
for
the
intramolecular
cyclopropanation reaction of various diazo ketone
derivatives using Ru(II)-Pheox as a catalyst.
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To a solution of Ru(II)-Pheox catalyst (0.003 mmol) and
olefin (5.0 mmol) in CH2Cl2 (2.00 mL) was slowly added a
solution of diazo ketone (1.0 mmol) in CH2Cl2 (2.00 mL)
over 4 hours at –50 °C. The progress of the reaction was
monitored by TLC. After the reaction was complete, the
solvent was evaporated and the residue was purified using
column chromatography on silica gel (10:1 Hex/EtOAc) to
give the desired product. The enantiomeric excess of the
product was determined by HPLC analysis.
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research (B, No. 26288087) from the Japan Society for the
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5
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10.1002/adsc.201801077
Advanced Synthesis & Catalysis
COMMUNICATION
Catalytic Asymmetric Intermolecular
Cyclopropanations of Ketone Carbene Precursors
by a Novel Ru(II)-Pheox Complex
Adv. Synth. Catal. Year, Volume, Page – Page
Le Thi Loan Chi, Agus Suharto, Soda
Chanthamath, Kazutaka Shibatomi, and Seiji
Iwasa*
6
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