Catalytic asymmetric intramolecular homologation of ketones with α-diazoesters: Synthesis of cyclic α-Aryl/Alkyl β-ketoesters

Article abstract of DOI:10.1002/anie.201409572

A catalytic asymmetric intramolecular homologation of simple ketones with α-diazoesters was firstly accomplished with a chiral N,N′-dioxide-Sc(OTf)₃ complex. This method provides an efficient access to chiral cyclic α-aryl/alkyl β-ketoesters containing an all-carbon quaternary stereocenter. Under mild conditions, a variety of aryl- and alkyl-substituted ketone groups reacted with α-diazoester groups smoothly through an intramolecular addition/rearrangement process, producing the β-ketoesters in high yield and enantiomeric excess.

Full text of DOI:10.1002/anie.201409572

Angewandte
Chemie
DOI: 10.1002/anie.201409572
Asymmetric Catalysis
Catalytic Asymmetric Intramolecular Homologation of Ketones with
a-Diazoesters: Synthesis of Cyclic a-Aryl/Alkyl b-Ketoesters**
Wei Li, Fei Tan, Xiaoyu Hao, Gang Wang, Yu Tang, Xiaohua Liu, Lili Lin, and Xiaoming Feng*
Abstract: A catalytic asymmetric intramolecular homologa-
tion of simple ketones with a-diazoesters was firstly accom-
plished with a chiral N,N’-dioxide–Sc(OTf)3 complex. This
method provides an efficient access to chiral cyclic a-aryl/alkyl
b-ketoesters containing an all-carbon quaternary stereocenter.
Under mild conditions, a variety of aryl- and alkyl-substituted
ketone groups reacted with a-diazoester groups smoothly
through an intramolecular addition/rearrangement process,
producing the b-ketoesters in high yield and enantiomeric
excess.
alkyl b-ketoesters,[9a,b] alternative strategies for the catalytic
enantioselective construction of cyclic a-aryl b-ketoesters are
much less developed and mainly based on C-acylations of silyl
ketene acetals[10] and SNAr reactions of b-ketoesters with
activated aromatic compounds.[11] In connection to our work
on the homologation reactions of carbonyl compounds with
a-diazoesters,[6b,8] we envisioned that this framework can be
achieved by designing a Lewis acid-catalyzed asymmetric
intramolecular homologation of simple ketones and a-diazo-
esters through an addition/1,2-rearrangement process
(Scheme 1, path a). This methodology would be more inter-
Lewis acid-catalyzed homologation of carbonyl compounds
using a-diazoesters has become a popular and efficient
method to achieve one-carbon unit insertion at the a-position
of the carbonyl, thus synthesizing useful b-ketoesters (also
known as a semipinacol rearrangement of in situ-formed a-
diazo alcohols).[1–3] Particularly, chemists have applied this
methodology to natural product synthesis.[4,5] In contrast, the
asymmetric variation, which can directly introduce a chiral
tertiary or quaternary stereocenter into the carbonyl com-
pounds to get optically active molecules, has received much
less attention so far. Examples of catalytic asymmetric
Roskamp reaction (also known as Roskamp–Feng reaction)
with aromatic and aliphatic aldehydes have recently been
reported.[6] Enantioselective ring expansions of cyclohexa-
nones[7] and isatins[8a] with diazo compounds could give access
to seven-membered rings and 2-quinolone derivatives, respec-
tively. Activated a-ketoesters underwent asymmetric inter-
molecular homologation to afford succinate derivatives with
chiral quaternary centers.[8b] However, asymmetric homolo-
gation reactions involving unactivated acyclic ketones still
remain an unsolved challenge; besides, no intramolecular
asymmetric version has ever been achieved. The main reasons
are low reactivity, complicated regiochemistry, and difficult
stereocontrol for such ketones.[1]
Scheme 1. Regiochemistry of the intramolecular homologation.
esting because it leads to a catalytic construction of a chiral
all-carbon quaternary stereocenter, which is a difficult chal-
lenge in asymmetric catalysis.[12] Nevertheless, complex regio-
chemical questions arise in this addition/rearrangement
reaction, because there are at least two side-migration
patterns of 1,2-alkyl shift (Scheme 1, path b) and epoxidation
(Scheme 1, path c),[1,8] not to mention the difficulties on
reactivity and enantioselectivity. We thought that a good
design of the substrate structure as well as a suitable choice of
the catalytic system will overcome these problems. Herein we
reported the first asymmetric intramolecular homologation of
simple ketones and a-diazoesters by a chiral N,N’-dioxide–
Sc(OTf)3 complex.[13]
With this idea in mind, we synthesized 2-diazo-6-keto-
alkanoate 1a containing both an a-diazoester group and
a simple ketone group. Fortunately, in the presence of chiral
N,N’-dioxide L1–Sc(OTf)3 catalyst, the intramolecular reac-
tion occurred through an asymmetric nucleophilic addition/
1,2-aryl-shift route, giving cyclic a-phenyl-b-ketoester 2a with
a newly formed chiral all-carbon quaternary center in 83%
yield and 92% ee (Table 1, entry 1). Other metal salts were
also evaluated, but the results did not improve (entries 2–4).
Next, we studied the effect of the chiral N,N’-dioxide ligands.
Chiral cyclic b-ketoesters with an a-aryl/alkyl group are
useful building blocks with the potential for diverse manip-
ulations.[9] In contrast to numerous routes to chiral cyclic a-
[*] Dr. W. Li, F. Tan, X. Y. Hao, G. Wang, Y. Tang, Prof. Dr. X. H. Liu,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University
Chengdu 610064 (China)
E-mail: xmfeng@scu.edu.cn
[**] We acknowledge financial support from the National Natural
Science Foundation of China (grant numbers 210321061, 21290182,
and 21332003).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409572.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Scope of ester and aromatic ketone groups.[a]
Entry
R1
R2
t [h]
Yield [%][b]
ee [%][c]
1
Et
Ph (1a)
Ph (1b)
Ph (1c)
5
5
81 (2a)
86 (2b)
63 (2c)
84 (2d)
88 (2e)
82 (2 f)
86 (2g)
88 (2h)
96 (2i)
85 (2j)
85 (2k)
80 (2l)
65 (2m)
87 (2n)
95 (2o)
93 (2p)
93
95 (S)
92
96
96
95
92
94
92
91
93
93
92
95
84
80
2[d]
3
Me
tBu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
15
18
15
12
18
6
44
18
15
18
20
12
20
40
4
5
6
7
8
9
10
11
12
13
14
15
16
3-MeC6H4 (1d)
3-MeOC6H4 (1e)
3-CH2 =CHC6H4 (1 f)
4-MeC6H4 (1g)
4-tBuC6H4 (1h)
4-MeOC6H4 (1i)
4-FC6H4 (1j)
4-ClC6H4 (1k)
4-BrC6H4 (1l)
3,5-Me2C6H3 (1m)
2-naphthyl (1n)
2-furyl (1o)
Entry
Ligand
Metal
x
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
Sc(OTf)3
Sn(OTf)2
Y(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
10
10
10
10
10
10
10
10
10
0.5
3
83
33
trace
30
83
83
82
68
60
92
5
10
48
72
3
1.5
20
15
3
n.d.
62
67
90
33
58
0
2-thienyl (1p)
9
[a] Reactions were performed with 1 (0.2 mmol), L1–Sc(OTf)3
10[d]
5
81
93
(0.5 mol%, 1:1), in 1.0 mL of CH2Cl2 at 308C. [b] Yield of isolated
products. [c] Determined by HPLC on a chiral stationary phase. [d] The
absolute configuration of 2b was determined to be S by X-ray crystallo-
graphic analysis of the corresponding hydrazone (for details, see SI).
[a] Reactions were performed with l–metal (x mol%, 1:1), 1a (0.1 mmol)
in 0.5 mL of CH2Cl2 at 308C. [b] Yield of the isolated product.
[c] Determined by HPLC on a chiral stationary phase. [d] L1–Sc(OTf)3
(0.5 mol%, 1:1), 1a (0.2 mmol) in 1.0 mL of CH2Cl2. n.d.=not
detectable.
Table 3: Scope of aliphatic ketone groups.[a]
Upon changing the amino acid backbone, ligand L2 derived
from l-pipecolic acid afforded 2a in 83% yield and 67% ee
(entry 5), whereas l-proline-derived N,N’-dioxide L3 gave 2a
in 83% yield and 90% ee (entry 6). Steric hindrance on the
amide of the N,N’-dioxide ligand influences the reaction
results greatly. Introducing bulky groups in the 2,6-position of
the aniline benefited the enantioselectivity (entries 7 and 8
versus entry 1). However, racemic product was obtained
when the steric hindrance at the para-position of the aniline
was increased (entry 9). Remarkably, the catalyst loading
could be reduced to 0.5 mol%, giving the similar enantiose-
lectivity and yield (entry 10). In addition, the reaction did not
have to be conducted under an inert atmosphere, and was
unaffected by moisture and oxygen.
Entry
R2
x
t [h]
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
Me (1q)
nBu (1r)
n-hexyl (1s)
cyclopropyl (1t)
tBu (1u)
0.05
0.5
0.5
2
0.25
2
3
8
24
80 (2q)
94 (2r)
89 (2s)
92 (2t)
0
66 (R)
86
85
54
–
10
[a] Reactions were performed with 1 (0.2 mmol), L1–Sc(OTf)3 (x mol%,
1:1), in 1.0 mL of CH2Cl2 at 208C. [b] Yield of isolated products.
[c] Determined by HPLC on a chiral stationary phase. [d] The absolute
configuration was determined by comparing the optical rotation data to
known literature values.
With the optimized conditions in hand (Table 1, entry 10),
we examined the substrate generality of the reaction as shown
in Table 2. Varying the ester group affected the enantiose-
lectivity slightly. Meanwhile, the methyl ester gave better
yield than the ethyl and tert-butyl ester (Table 2, entries 1–3).
These results indicate that enhancing the steric hindrance on
the ester group hampers the yield. The influence of position
and electronic nature of substituents on the phenyl group was
investigated. Almost all substrates with a substituent on the
meta- or para-position of the phenyl group provided the b-
ketoesters in excellent enantioselectivities (91–96% ee) and
good yields (80–96%; entries 4–12). Particularly, a 96% yield
was obtained when 4-MeOC6H4-substituted benzoyl group
was employed, owing to the excellent regioselectivity of the
transformation. Disubstituted substrate 1m gave 92% ee,
albeit with a lower yield (entry 13). Notably, condensed-ring
and heteroaromatic ketone substrates were tolerated under
the current system, producing the corresponding products
with excellent yields and high ee values (entries 14–16).
We then explored the substrate scope of aliphatic ketones
as shown in Table 3. Remarkably, the catalyst loading could
even be reduced to 0.05 mol% with methyl-substituted
substrate 1q (Table 3, entry 1). The reaction was completed
within 15 min, affording the product 2q in 80% yield but only
66% ee for the (R)-isomer.[14] No obvious improvement of the
enantioselectivity of 2q was observed at a lower reaction
temperature (À208C). Extending the alkyl length of the acyl
group improved the results (entries 2 and 3). Secondary alkyl
group was also tested and 92% yield and a moderate ee were
obtained (entry 4). However, the tert-butyl group did not
2
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show reactivity in this intramolecular homologation reaction
(entry 5). This might be due to steric hindrance of the tert-
butyl group inhibiting the nucleophilic addition of the
diazoester. The electronic nature of the benzoyl substituent
also affected the rate of the reaction, which was shown for
ketone 1i bearing an electron-donating 4-OMe group
(Table 2, entry 9). The conversion of 1i requires more time
than other benzoyl substituted substrates. On the other hand,
the intermolecular reaction of acetophenone and methyl 2-
diazopropanoate gives no homologation product in the
presence of 10 mol% L1–Sc(OTf)3 (see the Supporting
Information, SI). These experiments indicate that the first
nucleophilic addition step is most likely the rate-limiting step
for this homologation reaction.[15]
intermediates and natural products [Eq. (3) in Scheme 2].[18]
(+)-1x (43% ee) was converted to (À)-3x with À43% ee in
the presence of Sc(OTf)3 [Eq. (4) in Scheme 2]. The chirality
of the rearranged group was maintained and no racemization
of the substrate occurred in the process. Therefore, the
intramolecular addition is diastereoselective and positions the
alkyl group and the diazo moiety in an anti-periplanar
relationship thus keeping the chirality unchanged following
1,2-migration.
In summary, we have realized the first intramolecular
homologation of simple ketones with a-diazoesters. With
a low loading of chiral N,N’-dioxide-scandium(III) catalyst,
the intramolecular reaction performed well with a series of
substrates, affording the corresponding cyclic b-ketoesters
regioselectively with up to 96% yield and up to 96% ee under
mild reaction conditions. Influence of various aromatic and
aliphatic ketone groups as well as the linking-carbon-chain
length were investigated. This methodology provides a novel
and efficient method for the construction of a-aryl/alkyl-
substituted 2-oxocyclopentanecarboxylates with a chiral all-
carbon quaternary center. Further studies on related reac-
tions are underway.
To demonstrate the utility of this process, the intra-
molecular homologation of 1b was performed on a gram
scale, furnishing the major product 2b in 88% yield and 95%
ee [Eq. (1) in Scheme 2]. Meanwhile, tetrasubstituted epoxide
Experimental Section
200 mL of L1–Sc(OTf)3 catalyst solution (0.005m in THF) was added
to a dry reaction tube. After removing THF in vacuum, CH2Cl2
(1.0 mL) were added, and the mixture was stirred at 308C for 0.5 h.
Then, substrate 1 (0.20 mmol) was added, and the reaction was stirred
at 308C for the indicated time. The crude mixture was purified by
flash chromatography on silica gel (petroleum ether/dichlorome-
thane/ethyl acetate = 20:2:1) to afford the desired product 2.
Received: September 28, 2014
Revised: October 29, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · homologation · scandium ·
.
a-diazoesters · b-ketoesters
Scheme 2. Scaled-up version of the asymmetric intramolecular homo-
logation and the influence of the length of the tethering carbon-chain.
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obtained in 10% yield, > 99:1 d.r., and 78% ee. Only 1%
yield of the four-membered cyclic by-product 4b, formed
through an 1,2-alkyl migration, was obtained. Thus the
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a-diazoester and benzoyl group was probed. 2-Diazo-7-keto
alkanoate 1v dominantly reacted in an 1,2-alkyl migration
pattern instead of 1,2-aryl shift [Eq. (2) in Scheme 2], giving
the five-membered ring product 3v in 87% yield. This process
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in the SI). Additionally, a moderate kinetic resolution was
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diastereoselective addition/1,2-alkyl shift reaction, providing
the desired product 3x containing the octahydroazulen-
4(1H)-one backbone, which is found in various synthetic
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3th ed., Elsevier, Oxford, 2011, p. 408; d) L. Gao, B. C. Kang, G.-
S. Hwang, D. H. Ryu, Angew. Chem. Int. Ed. 2012, 51, 8322 –
8325; Angew. Chem. 2012, 124, 8447 – 8450; for related regiose-
lective examples, see: e) T. Hashimoto, Y. Naganawa, K.
Maruoka, J. Am. Chem. Soc. 2008, 130, 2434 – 2435; f) L. Gao,
B. C. Kang, D. H. Ryu, J. Am. Chem. Soc. 2013, 135, 14556 –
14559.
[7] a) T. Hashimoto, Y. Naganawa, K. Maruoka, J. Am. Chem. Soc.
2011, 133, 8834 – 8837; b) V. L. Rendina, D. C. Moebius, J. S.
Kingsbury, Org. Lett. 2011, 13, 2004 – 2007.
[8] a) W. Li, X. H. Liu, X. Y. Hao, Y. F. Cai, L. L. Lin, X. M. Feng,
Angew. Chem. Int. Ed. 2012, 51, 8644 – 8647; Angew. Chem. 2012,
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Catalysis
W. Li, F. Tan, X. Y. Hao, G. Wang, Y. Tang,
X. H. Liu, L. L. Lin,
X. M. Feng*
&&&& — &&&&
Catalytic Asymmetric Intramolecular
Homologation of Ketones with a-
Diazoesters: Synthesis of Cyclic a-Aryl/
Alkyl b-Ketoesters
A chiral N,N’-dioxide–Sc(OTf)3 complex
catalyzes the asymmetric intramolecular
homologation of simple ketones with a-
diazoesters. This method gives access to
chiral cyclic a-aryl/alkyl b-ketoesters with
an all-carbon quaternary stereocenter.
The reaction proceeds under mild reac-
tion conditions through an intramolecu-
lar addition/rearrangement process,
thereby generating the b-ketoesters in
high yield and enantiomeric excess.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!