Catalytic Asymmetric Homologation of Ketones with α-Alkyl α-Diazo Esters

Article abstract of DOI:10.1021/jacs.0c12683

The homologation of ketones with diazo compounds is a useful strategy to synthesize one-carbon chain-extended acyclic ketones or ring-expanded cyclic ketones. However, the asymmetric homologation of acyclic ketones with α-diazo esters remains a challenge due to the lower reactivity and complicated selectivity. Herein, we report the enantioselective catalytic homologation of acetophenone and related derivatives with α-alkyl α-diazo esters utilizing a chiral scandium(III) N,N′-dioxide as the Lewis acid catalyst. This reaction supplies a highly chemo-, regio-, and enantioselective pathway for the synthesis of optically active β-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones. Moreover, the ring expansion of cyclic ketones was accomplished under slightly modified conditions, affording a series of enantioenriched cyclic β-keto esters. Density functional theory calculations have been carried out to elucidate the reaction pathway and possible working models that can explain the observed regio- and enantioselectivity.

Full text of DOI:10.1021/jacs.0c12683

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Article
Catalytic Asymmetric Homologation of Ketones with α‑Alkyl α‑Diazo
Esters
Fei Tan,∥ Maoping Pu,∥ Jun He, Jinzhao Li, Jian Yang, Shunxi Dong, Xiaohua Liu,* Yun-Dong Wu,*
and Xiaoming Feng*
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ABSTRACT: The homologation of ketones with diazo com-
pounds is a useful strategy to synthesize one-carbon chain-
extended acyclic ketones or ring-expanded cyclic ketones.
However, the asymmetric homologation of acyclic ketones with
α-diazo esters remains a challenge due to the lower reactivity and
complicated selectivity. Herein, we report the enantioselective
catalytic homologation of acetophenone and related derivatives
with α-alkyl α-diazo esters utilizing a chiral scandium(III) N,N′-
dioxide as the Lewis acid catalyst. This reaction supplies a highly
chemo-, regio-, and enantioselective pathway for the synthesis of
optically active β-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones.
Moreover, the ring expansion of cyclic ketones was accomplished under slightly modified conditions, affording a series of
enantioenriched cyclic β-keto esters. Density functional theory calculations have been carried out to elucidate the reaction pathway
and possible working models that can explain the observed regio- and enantioselectivity.
α-ketone esters26 with α-diazo esters (Scheme 1d) which were
represented as electronically activated and readily bidentate-
coordinated ketones. Despite such progress, the challenge
1. INTRODUCTION
The homologation of aldehydes or ketones with diazo
compounds represents one of the most efficient and
remaining in this research field is the asymmetric intermo-
straightforward routes to one-carbon chain extension or ring
lecular homologation of acyclic aryl alkyl ketones (Scheme
expansion at the carbonyl moiety.1−10 Mechanistically, this
1e).6 The difficulties mainly stem from the following issues.
type of reaction is triggered by the nucleophilic addition of the
(1) The acyclic aryl alkyl ketones exhibit low reactivity to
diazoalkyl carbon to a carbonyl group, followed by a 1,2-shift
undergo the nucleophilic addition of α-diazo esters.5,6 (2) The
with the concerted extrusion of N2. This strategy has been
chemo- and regioselectivity associated with the homologation
frequently used in the synthesis of biologically active
reaction of acyclic arylalkyl ketones is complex, in view of the
compounds and complex natural products.11−15 With the
possible rotation of a carbon−carbon bond in the intermediate
or reversible addition of a α-diazo ester to a carbonyl group.
Once the intermediate Int. was formed, both R2 and the Ar
group have the possibity of migrating, resulting in the
formation of a mixture of products (path i or ii). Additionally,
the nucleophilic attack of an oxygen anion to the diazoalkyl
carbon would generate the epoxide byproduct (path iii).1,5,6,28
(3) The facial selection of both ketones and α-diazo esters
through differentiation of two sterically hindered groups is
difficult, which has a decisive influence on the regio- and
enantioselectivity.3−6
discovery of well-defined Lewis acid promoters and catalysts,5
asymmetric versions of homologation of aldehydes have been
extensively investigated over the past decade (Scheme
1a).16−21 In contrast, enantioselective homologation of ketone
substrates6 has mainly focused on either symmetrical cyclic
ketones22−24 or electronically activated ketones25−27 with an
electron-withdrawing carbonyl substituent. The Maruoka
group reported a desymmetrizing asymmetric ring expansion
of cyclohexanones with α-diazoacetates catalyzed by a chiral
aluminum Lewis acid, and various chiral quaternary β-keto
esters and medium-ring ketone products were provided
(Scheme 1b).23 Kingsbury and co-workers realized a highly
enantioselective desymmetrization of cycloalkanones with
substituted diazomethanes utilizing a chiral Sc(III)-trisox
catalyst; upon several studies of racemic versions, an array of
enantioenriched tertiary α-aryl cycloalkanones was readily
afforded (Scheme 1c).24 Later, the Feng group described the
enantioselective intermolecular homologation of isatins25 and
Received: December 6, 2020
Published: January 28, 2021
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the catalyst as well as the origin of the observed regio- and
enantioselectivity.
Scheme 1. Enantioselective Homologation of Aldehydes or
Ketones with Diazo Compounds
2. RESULTS AND DISCUSSION
2.1. Homologation of Aryl Alkyl Ketones with α-
Diazo Esters. To assess our hypothesis, we began by
evaluating the effects of Lewis acid catalysts on the
enantioselective homologation of acetophenone (1a) and
methyl α-benzyl-α-diazoacetate (2a) in dichloromethane. It
was found that both the metal salt and the ligand (Figure 1)
Figure 1. Chiral ligands used in the reaction.
had a significant influence on the reactivity. Almost no reaction
occurred in the presence of scandium triflate without a ligand
or other metal salt bonded N,N′-dioxide complexes (Table 1,
entry 1, and the Supporting Information). The investigation of
Table 1. Optimization of the Homologation of
a
Acetophenone 1a with α-Diazo Ester 2a
entry
L*
none
BOX
yield (%)
rr (3a:4a)
ee of 3a (%)
On the basis of the reaction mechanism and previous
work,17,25−27,29 we envisioned that a judicious selection of
diazo reagents and chiral catalysts may provide a possible
approach to address the above problem. The efficient
activation of aryl alkyl ketones with a strong Lewis acid
catalyst is necessary to improve their electrophilicity.5,6,27
Concurrently, the chiral catalyst should be capable of not only
differentiating the prochiral faces of both diazo esters and aryl
alkyl ketones but also limiting the rotation of the zwitterionic
intermediate, thus accelerating the final rearrangement through
a stereoscopic confinement effect.30−35
Herein, we wish to disclose our endeavor along this line. A
chiral scandium(III)-N,N′-dioxide Lewis acid catalyst36−42 has
been identified to be efficient in promoting the title reaction.
Various enantiomerically enriched β-keto esters with quater-
nary stereocenters were afforded in high yield with excellent
regioselectivity and enantioselectivity under mild conditions.
In addition, cyclic ketones are suitable substrates under slightly
modified conditions, yielding the desired ring-expanded cyclic
β-keto esters in moderate yield with high enantioselectivity.
Theoretical calculations were performed to illustrate the role of
1
2
3
NR
NR
trace
58
26
87
76
33
75
38
b
(S)-BINOL
L3-PiPr3
L4-PiPr3
L2-PiPr3
L2-PiPr2
L2-PrPr2
L2-RaPr2
L3-RaPr2
L2-RaPr2
L2-RaPr2
L2-RaPr3
4
5
95:5
90:10
95:5
91:9
91:9
92:8
89:11
92:8
92:8
95:5
84
94
86
81
80
94
88
94
94
96
c
6
7
8
9
10
b
11
70
77
92
d
12
e
13
a
Unless otherwise noted, all reactions were performed with Sc(OTf)3
(11 mol %), ligand (10 mol %), 1a (0.10 mmol), and 2a (1.0 equiv)
in CH2Cl2 (0.5 mL) at 30 °C for 45 h. Isolated yields of the mixture
of 3a and 4a are given. The regio ratio (rr) was determined by H
NMR analysis, and the ee value was determined by HPLC analysis on
a chiral stationary phase. Sc(OTf)3 (10 mol %). 117 h. Sc(OTf)3
(10 mol %) and La(OTf)3 (1 mol %). 2a (1.1 equiv) for 69 h.
1
b
c
d
e
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a
Table 2. Scope of α-Diazo Esters 2 with Acetophenone 1a
a
Unless otherwise noted, all reactions were performed with Sc(OTf)3 (11 mol %), L2-RaPr3 (10 mol %), 1a (0.10 mmol), and 2 (0.11 mmol) in
CH2Cl2 (0.5 mL) at 30 °C for the indicated time. Isolated yields of the mixture of 3 and 4 are given. The rr was determined by a 1H NMR analysis,
and the ee value was determined by HPLC analysis on a chiral stationary phase. 1a (5 mmol) and 2a (5.5 mmol) were used. The ee was detected
after deprotection of product 3q; see the Supporting Information for details.
b
c
other ligands used in previous studies indicated that the chiral
complex BOX−Sc(OTf)3 could not promote the reaction
(Table 1, entry 2). Utilizing the (S)-BINOL−Sc(OTf)3
combination in a 1:1 or 2:1 ratio led to the decomposition
of diazo ester 2a, and only a trace amount of the desired
product was detected (Table 1, entry 3). To our delight, the
reaction took place smoothly in the presence of the chiral
N,N′-dioxide catalyst L3-PiPr3−Sc(OTf)3, and the correspond-
ing major product 3a via methyl migration and the minor
product 4a via phenyl migration were isolated with a total 58%
yield with high regioselectivity (95:5 rr) and a promising
enantiomeric excess of 84% for 3a (Table 1, entry 4). These
results clearly showed that the chiral N,N′-dioxide was a robust
and unique ligand for such a transformation. Subsequently,
careful screening of chiral N,N′-dioxide ligands implied that
the length of the carbon tether displayed a pronounced effect
on the reactivity (Table 1, entries 4−6). The yield increased
gradually with the linker decreasing from a four- to a two-
carbon tether (L4-PiPr3 and L3-PiPr3 vs L2-PiPr3).43 The
ligand L2-PiPr3 gave the product in 87% yield, while the ligand
L4-PiPr3 resulted in a 26% yield after extending the reaction
time. Next, an examination of amino acid backbones of the
chiral N,N′-dioxide ligands with a two-carbon linker showed
that the L-ramipril-derived N,N′-dioxide L2-RaPr2 was
superior to others in terms of enantioselectivity, and a 94%
ee value was obtained (Table 1, entry 9 vs entries 7 and 8).
Comparably, the ligand L3-RaPr2 optimized in our previous
studies17,25,27 led to an obvious decrease in yield, regiose-
lectivity, and enantioselectivity (Table 1, entry 10 vs entry 9).
It was noteworthy that, although Sc(OTf)3 itself was unable to
promote the reaction, an excess amount of the metal salt (1
mol %) in the presence of the ligand was beneficial to the
reactivity, since a somewhat lower yield with retained
enantioselectivity was obtained with a 1:1 ratio of metal salt
to N,N′-dioxide (entry 11 vs entry 9; 75% vs 70%). Such a
positive effect of excess metal precursor on the yield was
observed as well when La(OTf)3 (1 mol %) was added to the
reaction system (entry 12 vs entry 11; 77% vs 70% yield).44,45
Finally, the 1,2-methyl-shift product 3a was obtained in high
yield along with good regioselectivity (95:5 rr) and excellent
enantioselectivity (96% ee) by employing the more sterically
hindered L2-RaPr3 as the ligand and a slight excess of diazo
ester (1.1 equiv) after 69 h (entry 13).
2.2. Substrate Scope. With the optimized conditions in
hand (Table 1, entry 13), a broad range of α-benzyl α-diazo
esters (2a−i) were investigated with acetophenone (1a)
(Table 2). All of them underwent the homologation in good
yield (69−92%) with high regioselectivity (Me-shift products;
92:8 to 95:5 rr) and excellent enantioselectivity (90−98% ee).
It was found that the position of the substituent at benzyl
moiety had a significant influence on the reactivity. An α-diazo
ester with a 2-fluorophenyl group showed much lower
reactivity, and moderate yield with good regioselectivity and
ee value (3b; 69% yield, 92:8 rr, 90% ee) was obtained after a
longer reaction time (147 h). The electronic nature of the
substituent displayed a limited effect on the outcomes (3c,d;
3h,i). The absolute configuration of the product 3g was
determined to be R by X-ray crystallographic analysis, and
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a
some other products exhibited a Cotton effect in the CD
spectra similar to that of 3g (for details, see the Supporting
Information). A 2-naphthalenyl-substituted α-diazo ester gave
a result comparable to that of a benzyl-substituted α-diazo
ester. Moreover, allyl-, alkynyl-, phenylethyl-, and ethyl-
substituted α-diazo esters were all well tolerated in the
reaction, giving the corresponding products 3k−3n in good
yield (72−91% yield) with high regioselectivity (>95:5 rr) and
enantioselectivity (90−93% ee). To our delight, highly
functionalized α-alkyl α-diazo esters were suitable for this
reaction, generating the desired products (3o−r) in moderate
to high yield (35−95% yield) with good regioselectivity and
slightly diminished enantioselectivity (83:17 to >95:5 rr, 76−
86% ee). To demonstrate the practicability of this trans-
formation, we carried out a gram-scale reaction under the
standard conditions. Acetophenone 1a (5 mmol, 0.60 g)
reacted well with α-diazo ester 2a (5.5 mmol, 1.05 g),
delivering the desired product 3a with the results maintained
(1.34 g, 95% yield, >95:5 rr, 95% ee) after a prolonged reaction
time (120 h).
Table 3. Scope of Acyclic Ketones 5
Next, various aryl-/alkyl-substituted ketones 5 were
examined (Table 3). For substituted acetophenone derivatives
(5a−f), both the electronic and steric properties of the
substitutions affected the outcomes of the reaction.46 The
yields of the electron-donating substituted acetophenones
could be improved via prolonging the reaction time, while
those of electron-deficient species could not be obviously
enhanced. The reaction of 2-fluoroacetophenone was slower
than those of 3- or 4-haloacetophenones. The desired 1,2-
methyl-shift product 6a was isolated in moderate yield (68%)
with lower regioselectivity (82:18 rr) but high enantioselec-
tivity (92% ee). It should be noted that the regioselective
isomers could be separated after reduction of the ketone
moiety to the corresponding alcohol with NaBH4 (for more
details, see page S10 in the Supporting Information). 4-
Acetylbenzonitrile exhibited lower reactivity (6e; 51%) and
enantioselectivity (89% ee), while p-tolylethanone performed
the reaction with almost maintenance of the results (6f; 89%
yield, 94:6 rr, 97% ee). 4-Methoxyphenylethanone with an
electron-donating group reacted smoothly, and good results
(6g; 89% yield and 97% ee) could be obtained with an
extended reaction time. Notably, a methylthio group, a
strongly coordinating moiety which could impair the activity
of the metal catalyst, had a negligible effect on the reaction,
and 4-methylthiophenylethanone could be transformed
efficiently into the desired product 6h. 2-Acetonaphthone
was also suitable for this reaction, and an excellent yield (6i;
98%) with high regioselectivity (92:8 rr) and enantioselectivity
(90% ee) were achieved. For heteroaryl-substituted ketones,
equally good yields with high regioselectivity (6j,k; >95:5 rr)
and ee values (92% and 96% ee, respectively) were obtained.
Unsaturated α-methyl ketones, for instance, (E)-4-phenyl-
butenone and 4-phenylbutynone, were applicable substrates in
the current reaction, and the desired products 6l,m were
afforded with good outcomes.47 Interestingly, acetone can also
undergo homologation with α-diazo ester 2d, yielding the
desymmetrization product 6n in high yield (90% yield) but
very low enantioselectivity (39% ee). To our delight, the
reaction of propiophenone with 2d took place with the use of
the less bulky ligand L2-RaEt2 instead, and the desired ethyl-
shift product 6o was isolated in moderate yield (54% yield)
and ee value (75% ee). Other alkyl-substituted ketones, for
instance, 1-phenylbutan-1-one, were investigated as well;
a
Unless otherwise noted, all reactions were performed with Sc(OTf)3
(11 mol %), L2-RaPr3 (10 mol %), 5 (0.10 mmol), and 2d (0.11
mmol) in CH2Cl2 (0.5 mL) at 30 °C for the indicated time. Isolated
yields of a mixture of 6 and 7 are given . The rr was determined by a
1H NMR analysis, and ee value was determined by HPLC analysis on
b
a chiral stationary phase. Acetone 5n (50 μL) and 2d (0.1 mmol).
c
L2-RaEt2 (10 mol %) was used.
however, most of them exhibited extremely low reactivity
(for more details, see page S7 in the Supporting Information).
We envisaged that this dramatic effect could be attributed to
steric repulsion. The modulation of the ligand might provide a
potential solution to this issue, as indicated in the reaction with
propiophenone (6o).
2.3. Homologation of Unsymmetrical Cyclic Ketones
with α-Diazo Esters. Encouraged by the above results, the
enantioselective ring expansion of unsymmetrical cyclic
ketones and α-diazo esters was investigated. Initially,
benzocyclobutenone (8a) and ethyl α-benzyl-α-diazoacetate
(2s) were selected as the model substrates. In the presence of
Sc(OTf)3−L2-RaPr2, the reaction occurred smoothly, generat-
ing the alkyl-shift product 9a in 55% yield with 63% ee (Table
4, entry 1). The NMR spectrum of the crude reaction mixture
indicated that the regioisomer 10a formed via competitive aryl-
shift process as well. However, the purification of regioisomer
10a was unsuccessful due to the other undefined and
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in moderate yields with good ee values (21−51% yield, 89−
92% ee).
Table 4. Optimization of the Homologation of
Benzocyclobutenone 8a with α-Diazoester 2
a
Then, the representative cyclic ketones 11 were tested
(Table 5). The reactions with 6-alkoxybenzocyclobutenone
derivatives were smooth, yielding the desired products 12a−d
in acceptable yields (50−64% yield) with excellent ee values
(90−97% ee). For the reaction of 5,6-dimethoxybenzocyclo-
butenone, the ligand L2-PiPr3 was used instead of L4-PiPr3 to
afford a moderate yield and enantioselectivity (12c). Five-
membered cyclic ketones are more challenging substrates
according to the literature.51 To our delight, 1-indanone can
also undergo ring expansion smoothly with L2-PiPr3 as the
ligand, forming the substituted 1-tetralone 12e in good yield,
regioselectivity, and enantioselectivity (60% yield, 91:9 rr, 88%
ee). It should be noted that the α-amination product of 1-
indanone was not detected at all,52 which probably results from
the change in ligand as well as the basic conditions in our
previous study. In addition, 3-phenylcyclobutenone trans-
formed into 12f in moderate yield and ee (60% yield, 52% ee).
Furthermore, the desymmetrization of cyclobutanone occurred
under the standard conditions, generating the corresponding
cyclopentanone derivative 12g in high yield (86%) but with
poor ee. Unfortunately, 1-tetralone, cyclopentanone, and
cyclooctenone were sluggish in the current catalytic system
(for more details, see the Supporting Information).
9
10
b
entry
L*
yield (%)
ee (%)
yield (%)
ee (%)
1
2
3
4
L2-RaPr2
L2-PiPr3
L3-PiPr3
L4-PiPr3
L4-PiPr3
55
57
54
34
52
63
82
85
90
92
<30
<30
<39
<43
<40
33
68
87
94
95
c
5
a
Unless otherwise noted, all reactions were performed with Sc(OTf)3
(10 mol %), ligand (10 mol %), 8a (0.10 mmol), and 2s (0.10 mmol)
in CH2Cl2 (0.5 mL) at 30 °C for 20 h. Isolated yields are given. The
ee values were determined by HPLC analysis on a chiral stationary
phase. The regioisomer 10 was mixed with other undefined
byproducts. Sc(OTf)3 (11 mol %), 8a (1.5 equiv), and 2a (0.10
b
c
mmol) were used.
2.5. Mechanism Studies. To gain insights into the
reactivity and the origin of enantioselectivity of the
homologation of ketones, we carried out DFT calculations
using the ligand L2-RaPr2. The discussion here is based on the
data calculated on CPCM (dichloromethane) at the M06L/
Def2-TZVP//B3LYP-D3/6-31G(d,p), SDD(Sc) level of
theory. All of the calculations were performed using Gaussian
09 software; see the Supporting Information for details.53
Although a water-bonded Sc(III) complex was crystallized
(Figure 2, left),29 the calculation result suggests that
replacement of water by acetophenone gives a more stable
species that can be considered as a reactive species for
mechanistic investigations (for more details, see the Support-
ing Information). Next we examined the complexation of one
acetophenone molecule to a chiral tetradentate N,N′-dioxide
ligand bonded to Sc(III) (Figure 2). Two complexes, Add and
Add′ (Figure 2), are nearly energetically degenerate with a 0.8
kcal/mol difference. As such, both conformers were considered
in the following steps. In addition, indirect evidence for the
binding of TfO− on Sc(III) is presented in the Supporting
Information. Moreover, the coordination of an ester on Sc(III)
was ruled out; see the Supporting Information for details.
Second, α-diazo ester nucleophilically adds to Add and
Add′. Diverse intermediates were formed via the correspond-
ing transition states TS1 (Figure 3 and the Supporting
Information). Finally, the carbon−nitrogen bond of the
intermediates is cleaved (TS2), leading to the simultaneous
release of N2 and alkyl migration for the resulting products.
This step is shown to be the rate-determining step (Figure 3).
This is in agreement with the influence of the electronic nature
of the substituents on acetophenone, where an electron-
withdrawing substituent did not accelerate the reaction due to
the instability of the corresponding intermediates, although the
nucleophilic addition step might be easier.
inseparable byproducts (for details, see the Supporting
Information). Moreover, switching the ligand to L2-PiPr3 led
to an enhancement of enantioselectivity of the alkyl-migration
product 9a (entry 2, 85% ee). When the length of the carbon
tether in the chiral N,N′-dioxides was increased, a higher
enantiomeric excess was afforded but with the decrease in yield
(entries 2−4). The use of L4-PiPr3 gave the product 9a in 34%
yield with 90% ee (entry 4). Finally, by utilizing methyl α-
benzyl-α-diazoacetate 2a, 1.5 equiv of ketone 8a, and 11 mol %
Sc(OTf)3, the ring expansion product 9b was generated in 52%
yield with 92% ee (entry 5).50 There was no better result after
further investigation of other reaction parameters (for details,
see the Supporting Information).
2.4. Substrate Scope. After establishing the optimized
conditions (Table 4, entry 5), we first examined the generality
of α-diazo esters in the reaction with benzocyclobutenone (8a)
(Table 5). Due to the polarity of aryl-shift products being
similar to that of other byproducts, only alkyl-shift products 9
were isolated in most cases (for details, see the Supporting
Information). A 2-fluorophenyl-bearing α-diazo ester showed a
lower reactivity, affording a slight decrease in yield and ee value
(9c; 39% yield, 85% ee). Meanwhile, in this case, pure
regioisomer 10c could be obtained in 46% yield with 91% ee.
The absolute configuration of the corresponding products 9c
and 10c were determined to be R via an X-ray crystallographic
analysis, and most of the others had Cotton effects in the CD
spectra similar to that of 9c (for details, see the Supporting
Information). For other substituted α-benzyl α-diazo esters,
the electronic properties of a substituent at the meta or para
position of the phenyl ring had a negligible effect on the
enantioselectivity, generating the alkyl-shift products (9d−m)
in modest yield and high ee value (37−47% yield, 90−92%
ee). A 2-naphthyl-substituted α-diazo ester was well tolerated
in the reaction (9n). Other α-diazo esters with unsaturated
moieties, such as allyl or alkynyl, were compatible with this
catalytic system (9o,p). Ethylphenyl-, dodecyl-, and methyl-
substituted α-diazo esters showed higher reactivity, and the
corresponding ring-expansion products (9q−s) were isolated
The main product 3a is given by the transition state TS2R, in
which the leaving N2 is antiperiplanar to a migrating alkyl (or
aryl) group of diazo for a concerted process, and steric
repulsion between the bulky −CO2Me and −N2 of α-diazo
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a
Table 5. Scope of α-Diazo Esters 2 with Cyclic Ketones
a
Unless otherwise noted, all reactions were performed with Sc(OTf)3 (11 mol %), L4-PiPr3 (10 mol %), 8a or 11 (0.15 mmol), and 2 (0.10 mmol)
in CH2Cl2 (0.5 mL) at 30 °C for the indicated time. Isolated yields are given. The ee values were determined by HPLC analysis on a chiral
stationary phase. The absolute configuration was determined by a comparison of the optical rotation with the corresponding literature value.48,49
b
c
d
1
L2-PiPr3 (10 mol %) was used. The rr was determined by a H NMR analysis.
Figure 2. Two binding modes of ketone to Sc(III).
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Figure 3. Free energy profile for R-3a, R-4a, and S-3a (3a′) calculated using CPCM (dichloromethane) at the M06L/Def2-TZVP//B3LYP-D3/6-
31G(d,p), SDD(Sc) level of theory.
ester with the aryl on the chiral N,N′-dioxide ligand is
prevented. Also, the phenyl migration product (R)-4a is
generated via TS2PhR, in which the N2 extrusion directionality
points toward the metal−ligand complex and steric repulsion
between −CO2Me and the aryl of the dioxide ligand is present
(2.6 kcal/mol higher in energy than TS2R). However, 3a′ with
an S configuration as a minor product is given by the transition
state TS2S derived from Add′. Moreover, other high energy
transition states for N2-release/methyl (or phenyl)-migration
processes are shown in the Supporting Information as well.
reactivity and enantioselectivity. Moreover, the ring expansion
of benzocyclobutenone derivatives with α-diazo esters to
deliver various cyclic β-keto esters was compatible under
slightly modified conditions, and a number of enantioenriched
cyclic β-keto esters were readily afforded. In addition, DFT
calculations were conducted to understand the activation mode
and the origin of regioselectivity and enantioselectivity. Further
application of this reaction in organic synthesis and the
exploration of other reactions with α-diazo esters are ongoing
in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12683.
■
3. CONCLUSION
sı
In summary, the efficient catalytic asymmetric intermolecular
homologation of acetophenone derivatives with α-diazo esters
was accomplished under mild conditions. The key to success is
the use of a chiral N,N′-dioxide−Sc(OTf)3 complex as the
chiral Lewis catalyst, which enabled the activation of
acetophenone derivatives and precisely controlled the stereo-
selectivity of the addition/rearrangement process. This
protocol provided a rapid and facile route to chiral acyclic β-
keto esters with a quaternary carbon center in high yield with
excellent regioselectivity and enantioselectivity. This trans-
formation could be scaled up to gram scale without erosion of
Detailed experimental procedures, characterization data
for all new compounds, 1H, 19F{1H}, and 13C{1H} NMR
and HPLC spectra, and computational studies (PDF)
Accession Codes
CCDC 1951827, 1951831, and 1959085 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
2400
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J. Am. Chem. Soc. 2021, 143, 2394−2402

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pubs.acs.org/JACS
Article
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
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AUTHOR INFORMATION
■
Corresponding Authors
Xiaohua Liu − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, People’s Republic of
China; orcid.org/0000-0001-9555-0555; Email: liuxh@
scu.edu.cn
Yun-Dong Wu − Shenzhen Bay Laboratory, Shenzhen
518055, People’s Republic of China; Lab of Computational
Chemistry and Drug Design, State Key Laboratory of
Chemical Oncogenomics, Peking University Shenzhen
Graduate School, Shenzhen 518055, People’s Republic of
China; orcid.org/0000-0003-4477-7332; Email: wuyd@
pkusz.edu.cn
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, People’s Republic of
China; orcid.org/0000-0003-4507-0478;
Email: xmfeng@scu.edu.cn
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University, Chengdu 610064, People’s Republic of China
Maoping Pu − Shenzhen Bay Laboratory, Shenzhen 518055,
People’s Republic of China; orcid.org/0000-0002-0745-
9549
Jun He − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, People’s Republic of China
Jinzhao Li − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, People’s Republic of
China
Jian Yang − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, People’s Republic of
China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12683
Author Contributions
∥F.T. and M.P. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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The authors acknowledge financial support from the National
Natural Science Foundation of China (grant nos. 21890723
and 21625205). We thank Dr. Yuqiao Zhou (Sichuan
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