Enantioselective synthesis of α-alkyl-β-ketoesters: Asymmetric Roskamp reaction catalyzed by an oxazaborolidinium ion

Article abstract of DOI:10.1002/anie.201204350

Breaking kamp: A catalytic route toward chiral α-alkyl-β- ketoesters using the title reaction of α-alkyl diazoester with aldehydes has been developed (see scheme). The reaction proceeds with high to excellent enantioselectivities and this methodology was applied to a concise two-step synthesis of the natural pheromone sitophilate. Copyright

Full text of DOI:10.1002/anie.201204350

Angewandte
Chemie
DOI: 10.1002/anie.201204350
Asymmetric Synthesis
Enantioselective Synthesis of a-Alkyl-b-ketoesters: Asymmetric
Roskamp Reaction Catalyzed by an Oxazaborolidinium Ion**
Lizhu Gao, Byung Chul Kang, Geum-Sook Hwang,* and Do Hyun Ryu*
The Roskamp reaction,[1] a Lewis acid catalyzed reaction of
alkyl diazoesters with aldehydes, is a powerful and useful
synthetic method to construct b-keto carbonyl compounds,
which have been utilized in the synthesis of natural products[2]
(Scheme 1). An asymmetric variant of this transformation
was previously effected using the chiral-auxiliary-based
Figure 1. Catalysts screened for the enantioselective synthesis of a-
alkyl-b-ketoesters. Tf=trifluoromethanesulfonyl.
lective carbon–carbon bond-forming reactions.[4] In addition,
much evidence exists to support the formation of a complex
between catalysts 1 and aldehydes.[4e] We have applied these
oxazaborolidinium catalysts to the asymmetric Roskamp
reaction of aliphatic aldehydes and a-alkyl-a-diazoesters.
Initially, the asymmetric Roskamp reaction between a-
benzyl diazoester and benzaldehyde was examined in the
presence of 20 mol% of the oxazaborolidinium ion 1a, which
was prepared by activation of its precursor with triflic acid
(Table 1, entry 1). When the reaction was carried out at
À788C in dichloromethane, the desired optically active a-
Scheme 1. Asymmetric Roskamp reaction.
approach with a camphorsultam-derived diazocarbonyl com-
pound.[3a] To the best of our knowledge, only a single
successful example of an enantioselective Lewis acid cata-
lyzed Roskamp reaction of a-alkyl-a-diazoesters with aro-
matic aldehydes using chiral N,N’-dioxide-scandium(III)
complexes was recently reported.[3b] However, this method-
ology could not be applied to aliphatic aldehydes. In this
context, we were interested in the possibility of developing
a catalytic, asymmetric Roskamp reaction with broad applic-
ability. Herein we report such an asymmetric transformation
using the oxazaborolidinium ion Lewis acid catalysts
1 (Figure 1), one of which was recently found to effectively
catalyze the enantioselective cyclopropanation of a-substi-
tuted acroleins with diazoacetates.[4a]
Table 1: Optimization of the Roskamp reaction of a-benzyl diazoester
with benzaldehyde.
Entry
Solvent
Cat.
t [h]
2/3[a]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
propionitrile
toluene
toluene
toluene
1a
1b
1c
1c
1c
1d
1e
1
1
1.5
1
1.5
1
90:10
89:11
82:18
67:33
91:9
82
80
77
60
87
90
92
87[d]
90
82
79
88
92
95
Catalysts 1 (Figure 1), which are generated from the
corresponding oxazaborolidine by protonation with triflic
acid or triflic imide, are powerful Lewis acids which have been
demonstrated to be effective catalysts for various enantiose-
93:7
94:6
2
[*] L. Gao, B. C. Kang, Prof. Dr. D. H. Ryu
Department of Chemistry, Sungkyunkwan University
300 Cheoncheon-Dong, Jangan-gu
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of isolated 2. [c] The ee value of 2 was determined by chiral
HPLC. [d] The absolute configuration R was assigned to the major
product. For details see the Supporting Information.
Suwon, Gyeoneggi, 440-746 (Korea)
E-mail: dhryu@skku.edu
Prof. Dr. G.-S. Hwang
Korea Basic Science Institute and Graduate School of Analytical
Science and Technology, Chungnam National University
Seoul, 136-713 (Korea)
alkyl-b-ketoester was formed in 82% yield and 87% ee with
concomitant formation of 3, the phenyl migration product
(migration of R3 instead of hydride; Scheme 1).[5] Product 2
was isolated by silica gel chromatography at À788C without
erosion of the ee value.[3b]
The same reaction performed with chiral catalyst 1b,
which was prepared by activation of its precursor with triflic
imide, afforded an improved ee value despite slight decreases
E-mail: gshwang@kbsi.re.kr
[**] This work was supported by grants NRF-2011-0031392 (Priority
Research Centers Program), NRF-2011-0029186 (Midcareer
Researcher Program) and the Korea Basic Science Institute
(T32409).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204350.
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in chemoselectivity and yield (Table 1, entry 2). Next, we
investigated the effect of solvent with catalyst 1c, and found
that toluene gave the best chemoselectivity, enantioselectiv-
ity, and yield (entries 3–5). Additional studies focused on
changes in the structure of the catalyst. Reaction in toluene
with the catalyst modified by substitution of the 1-naphthyl
group on boron with a less hindered phenyl group (1d)
provided the product with improved yield and ee value
(entry 6). Reintroduction of the more hindered 3,5-dimethyl-
phenyl groups into the catalyst led to the optimized reaction
conditions. The reaction with catalyst 1e in toluene at À788C
provided the optically active a-alkyl-b-ketoester in 92% yield
and 95% ee with a 94:6 chemoselectivity (entry 7).
With optimized reaction conditions for the asymmetric
Roskamp reaction in hand, we evaluated this methodology
with a range of substituted benzaldehydes. Regardless of the
electronic properties of the substituents on the aromatic
aldehyde, the reactions proceeded in a highly chemoselective
manner, and the corresponding products were obtained in
high yields and excellent enantioselectivities (Table 2,
aliphatic aldehydes. However, the best chiral catalyst, 1e, for
aromatic aldehydes was not the optimal catalyst for aliphatic
substrates. The catalyst 1b, bearing the more bulky naphthyl
group on boron, was found to be more suitable for generating
higher enantioselectivity (Table 3, entries 1 and 2).
Table 3: Asymmetric Roskamp reaction between a-benzyl diazoester and
aliphatic aldehydes catalyzed by 1b.
Entry
R
t [h]
2/3[a]
Yield [%][b]
ee [%][c]
1[d]
2[e]
3
4
5
Et
Et
Et
Hex
iPr
Cy
0.5
0.5
1.5
1.5
3
79:21
82:18
89:11
92:8
91:9
91:9
73
76
85
90
87
89
92
87
97
98[f]
98
97
96
97
6
7
3
3
CH3O2C(CH2)2
94:6
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of isolated 2. [c] The ee value of 2 was determined by HPLC
using a chiral stationary phase. [d] The reaction was performed at À788C
catalyzed by 1e. [e] The reaction was performed at À788C. [f] The
absolute configuration R was assigned to the major product. For details
see the Supporting Information. Cy=cyclohexyl.
Table 2: Asymmetric Roskamp reaction between a-benzyl diazoester
and aromatic aldehydes catalyzed by 1e.
As shown in Table 3, propionaldehyde, long-chain hep-
taldehyde, as well as more sterically hindered isopropyl and
cyclohexyl carboxaldehydes successfully reacted with a-
benzyl diazoester to provide the corresponding a-benzyl-b-
ketoesters in high yields and excellent enantioselectivities
(entries 3–6). This catalytic system was also applied to the
functionalized aldehyde methyl 4-oxobutanoate to afford the
a-benzyl-b-keto diester in 92% yield with excellent chemo-
and enantioselectivity (entry 7). To the best of our knowledge,
these are the first examples of chiral Lewis acid catalyzed
asymmetric Roskamp reactions with aliphatic aldehydes.
Encouraged by the good results exhibited in Table 3, we
applied this catalytic Roskamp methodology to reactions of
various a-alkyl diazoesters and propionaldehyde. As sum-
marized in Table 4, the reactions produced the corresponding
a-alkyl-b-ketoesters in high yields and chemoselectivities
with excellent enantioselectivities (entries 1–7 and 9–11).
While more sterically hindered R1 groups gave enhanced
selectivity for 2, high product enantioselectivities were
consistently observed (entries 1–4, and 12). Conversely, steri-
cally hindered R2 substituents, such as an isopropyl group,
caused significant reductions in the ratio of 2/3, as well as the
product enantioselectivity (entry 8). Use of ent-1b as the
catalyst (Figure 1) was found to effectively provide (S)-a-
methyl-b-ketoester (ent-2) in 92% yield and 97% ee
(entry 12).
Entry
Ar
T [8C]
t [h]
2/3[a] Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
Ph
À78
À78
À55
À78
À95
À78
À55
2
2
1
1
1
2
5
94:6
92
87
85
91
82
83
69
95
95
91
94
96
95
80
4-MeC6H4
4-OMeC6H4
4-BrC6H4
4-CF3C6H4
3-OMe
90:10
92:8
94:6
89:11
90:10
76:24
2-OMe
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of isolated 2. [c] The ee value of 2 was determined by HPLC
using a chiral stationary phase after silica gel chromatography at À788C.
entries 2–6). However, ortho-anisaldehyde gave the desired
a-benzyl-b-ketoester with lower enantioselectivity (entry 7).
We believe the bulky 2-methoxy group of ortho-anisaldehyde
significantly reduces the degree of complexation with the
catalyst in the pretransition-state assembly (Scheme 2), thus
leading to the observed lower enantioselectivity and yield.
To further investigate the substrate scope of the present
catalytic system, we performed the catalytic asymmetric
Roskamp reaction with a-benzyl diazoester and a range of
The observed product stereochemistry from the asym-
metric Roskamp reaction with the oxazaborolidinium ion
catalyst 1b could be rationalized based on the transition-state
model shown in Scheme 2. The mode of coordination of
propionaldehyde to 1b is the same as has previously been
shown to operate in enantioselective cyanosilylation,[4f] 1,3-
dipolar cycloaddition,[4b] and cyclopropanation reactions.[4a] In
Scheme 2. Transition-state model for asymmetric Roskamp reaction of
a-benzyl diazoester and propionaldehyde catalyzed by 1b.
2
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tivity and high yield without racemization[8] (Scheme 3).
Table 4: Asymmetric Roskamp reaction of various a-alkyl diazoesters
and propionaldehyde catalyzed by 1b.
Spectral data for the purified major diastereomer of 6 isolated
after silica gel chromatography were in accord with literature
data.[6] Comparison of the optical rotation data confirmed the
absolute (2S,3R) stereochemistry [measured: [a]D20 = À3.5
(CHCl3, c 1.0; Ref. [6]: [a]D25 = À3.1 (CHCl3, c = 1.7)].
In summary, we have developed a novel, catalytic
asymmetric Roskamp reaction of a-alkyl diazoesters with
both aromatic and aliphatic aldehydes, thereby producing a-
alkyl-b-ketoesters in high yields and excellent enantioselec-
tivities. The absolute configuration of the major reaction
product was the same as that predicted by the transition-state
model in Scheme 2. This methodology was successfully
applied to a concise two-step synthesis of sitophilate. Addi-
tional applications of this catalytic asymmetric transformation
and extension of the substrate scope are in progress.
Entry R1
R2
t [h]
2/3[a] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
Me
Et
Bn
Bn
Bn
Bn
Me
allyl
Et
1
1.5
3
2
0.5
3
3
12
1
2
1
1
76:24
89:11
93:7
93:7
92:8
89:11
89:11
71:29
96:4
96:4
88:12
93:7
70
85
91
92
89
86
85
69
94
83
85
92
96
98
97
95
94
93
85
45
95
86
95
97[f]
tBu
Bn
Bn
Bn
Bn
Bn
Et
8[d]
9
iPr
Me
propargyl
Et
10[e]
11
12
Et
Et
3-pentyl Me
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of isolated 2. [c] The ee value of 2 was determined by HPLC or
GC using a chiral stationary phase. [d] The reaction was performed at
À558C. [e] The ee value of the corresponding product decreased during
isolation by silica gel chromatography at À788C. [f] Catalyst ent-1b was
used. The ee value was determined by chiral HPLC after reduction with
Zn(BH4)2 and p-methoxy benzoylation. The absolute configuration of ent-
2 was assigned as the S enantiomer. For details see the Supporting
Information.
Received: June 5, 2012
Published online: && &&, &&&&
Keywords: asymmetric synthesis · boron · diazo compounds ·
.
homogeneous catalysis · synthetic methods
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the pretransition-state assembly 4 (Scheme 2), the aldehyde is
situated above the 3,5-dimethylphenyl group, which effec-
tively shields the Re face (back) from attack by the diazo-
ester. Because of a dipole–dipole interaction between the two
carbonyl groups, the diazoester approaches the aldehyde
group for nucleophilic addition with the ester group situated
away from the aldehyde group. In addition, as a result of steric
interactions, the large benzyl group is situated away from the
aldehyde alkyl group. Thus, nucleophilic addition of the
diazoester to the Si face (front) of the aldehyde, as shown in 4,
is facilitated and leads to the intermediate 5. Chemoselective
hydride transfer with loss of nitrogen provides the (R)-a-
benzyl b-ketoester as the major enantiomer. Because of the
greater screening ability of a 3,5-dimethylphenyl group, the
catalyst 1e provided a 3% higher ee value than catalyst 1d
(Table 1, entries 6 and 7).
Synthetic utility of the present reaction was further
demonstrated by the synthesis of sitophilate (6; (2S,3R)-1-
ethylpropyl 3-hydroxy-2-methylpentanoate; Scheme 3), the
aggregation pheromone of the granary weevil Sitophilus
granarius, a major cosmopolitan pest of stored cereal grains.[6]
Purified (S)-a-methyl-b-ketoester (ent-2; Table 4, entry 12),
which was generated using the current catalytic system was
[7]
reduced with Zn(BH4)2 to afford 6 in good diastereoselec-
[5] a) T. Hashimoto, Y. Naganawa, K. Maruoka, J. Am. Chem. Soc.
2008, 130, 2434; b) M. E. Dudley, Md. M. Morshed, C. L.
Brennan, M. S. Islam, M. S. Ahmad, M.-R. Atuu, B. Branstetter,
Scheme 3. Synthesis of the natural pheromone sitophilate.
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[8] Direct reduction without isolation of ent-2 provided 6 in 80%
yield and 97% ee (see the Supporting Information).
4
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Asymmetric Synthesis
L. Gao, B. C. Kang, G.-S. Hwang,*
D. H. Ryu*
&&&& — &&&&
Enantioselective Synthesis of a-Alkyl-b-
ketoesters: Asymmetric Roskamp
Reaction Catalyzed by an
Breaking kamp: A catalytic route toward
chiral a-alkyl-b-ketoesters using the title
reaction of a-alkyl diazoester with alde-
hydes has been developed (see scheme).
The reaction proceeds with high to excel-
lent enantioselectivities and this meth-
Oxazaborolidinium Ion
odology was applied to a concise two-
step synthesis of the natural pheromone
sitophilate.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!