Asymmetric Alkoxy- and Hydroxy-Carbonylations of Functionalized Alkenes Assisted by β-Carbonyl Groups

Article abstract of DOI:10.1002/anie.202105977

As a fundamental type of carbonylation reaction, the alkoxy- and hydroxy-carbonylation of unsaturated hydrocarbons constitutes one of the most important industrial applications of homogeneous catalysis. However, owing to the difficulties in controlling multi-selectivities for asymmetric hydrocarbonylation of alkenes, this reaction is typically limited to vinylarenes and analogues. In this work, a highly efficient asymmetric alkoxy- and hydroxy-carbonylation of β-carbonyl functionalized alkenes was developed, providing practical and easy access to various densely functionalized chiral molecules with high optical purity from broadly available alkenes, CO, and nucleophiles (>90 examples, 84–99 % ee). This protocol features mild reaction conditions and a broad substrate scope, and the products can be readily transformed into a diverse array of chiral heterocycles. Control experiments revealed the key role of the β-carbonyl group in determining the enantioselectivity and promoting the activity, which facilitates chiral induction by coordination to the transition metal as rationalized by DFT calculations. The strategy of utilizing an innate functional group as the directing group on the alkene substrate might find further applications in catalytic asymmetric hydrocarbonylation reactions.

Full text of DOI:10.1002/anie.202105977

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Asymmetric alkoxy- and hydroxy-carbonylations of functionalized
alkenes assisted by β-carbonyl group
Authors: Kaiwu Dong, Xinyi Ren, Zhen Wang, Chaoren Shen, Xinxin
Tian, Lin Tang, and Xiaolei Ji
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10.1002/anie.202105977
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric alkoxy- and hydroxy-carbonylations of functionalized
alkenes assisted by β-carbonyl group
Xinyi Ren,[a],# Zhen Wang,[a],# Chaoren Shen,[a] Xinxin Tian,[b] Lin Tang,[a] Xiaolei Ji,[a] and Kaiwu
Dong[a],*
Dedicated to Professor Matthias Beller on the occasion of his 60th birthday
[a]
[b]
Chang-Kung Chuang Institute, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200062, China.
Institute of Molecular Science, Key Laboratory of Materials for Energy Conversion and Storage of Shanxi Province, Shanxi University, Taiyuan 030006,
China.
#These authors contributed equally to this work. *E-mail: kwdong@chem.ecnu.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: As a fundamental type of carbonylation reactions, alkoxy-
and hydroxy-carbonylations of unsaturated hydrocarbons constitutes
one of the most important industrial applications of homogeneous
catalysis. Since the birth of asymmetric catalysis, the
enantioselective variant of such transformation has been recognized
as a direct and efficient approach for the synthesis of chiral carbonyl
compounds. However, owing to the difficulties in controlling multi-
selectivities for asymmetric hydrocarbonylation of alkenes, to date
this reaction is typically limited to vinylarenes and analogues. In this
carbonylation of alkenes without aryl-substituent, the alkyl-
palladium intermediate readily undergo reversible β-hydride
elimination and insertion, leading to isomerization of the double
bonds and a mixture of olefins. Although this intrinsic reactivity
has been extensively exploited for the synthesis of linear esters
from internal/mixed alkenes with CO and alcohols,5 this renders
the asymmetric hydrocarbonylation of common olefins
a
daunting challenge. Therefore, so far the scope of this reaction
is typically limited to vinylarenes6 and analogues.7
work,
carbonylations of β-carbonyl functionalized alkenes was developed,
providing practical and ready access to various densely
a
highly efficient asymmetric alkoxy- and hydroxy-
Scheme 1 Asymmetric catalytic alkoxy- and hydroxy-carbonylations
a
functionalized chiral molecules with high optical purity from broadly
available alkenes, CO, and nucleophiles (>90 examples, 84-99% ee).
This protocol features mild reaction conditions and broad substrate
scope, and the products can be readily transformed into a diverse
array of chiral heterocycles. Control experiments revealed the key
role of the β-carbonyl group in determining the enantioselectivity and
promoting the activity, which facilitates chiral induction by
coordination to the transition-metal as rationalized by DFT
calculations. The strategy of utilizing an innate functional group as
the directing group on the alkene substrate might find further
applications in catalytic asymmetric hydrocarbonylation reactions.
Introduction
Precoordination of a transition-metal with functional groups
(FGs) in substrates has been exploited to control
stereoselectivity and promote reactivity in asymmetric catalytic
reactions including hydrogenation,8 epoxidation9 and C-H bond
functionalization10. With this in mind, we envisioned that the
multi-selectivity issues in asymmetric hydrocarbonylation of
multi-substituted alkenes could be alleviated by introducing a FG
into the properly position on olefinic substrate (Scheme 1, c).11 It
was anticipated that the FG may act as a directing group (DG),
which by coordination to the transition-metal would guide the
insertion of the unsaturated bond to palladium-hydride at the
privileged position, and may inhibit β-hydride elimination through
the formation of a more rigid palladacycle. In this way, multi-site
interaction between the catalyst and the substrate would
facilitate chiral induction in the asymmetric carbonylation
process. It is generally accepted that an appropriate DG should
coordinate to the metal not too strong to outcompete ligands for
Transition metal-catalyzed carbonylation reactions are
fundamentally important homogeneous catalysis process.1 Of
growing importance are alkoxy- and hydroxy-carbonylations,
which can convert unsaturated hydrocarbons to backbone-
elongated carboxylic acid derivatives with carbon monoxide
(CO) and nucleophiles. This reaction is characterized by perfect
atom-economy, and has achieved numerous industrial-scale
applications.2 Since the birth of asymmetric catalysis,3 the
enantioselective hydrocarbonylation has been recognized as
one of the most direct and efficient methods for the preparation
of optically active carbonyl compounds.4 Despite extensive
efforts, however, this reaction is generally plagued by difficult
control
of
multi-selectivities
(chemo-,
site-
and
stereoselectivities) as well as harsh reaction conditions
(elevated temperature and high CO gas pressure). For the
1
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10.1002/anie.202105977
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RESEARCH ARTICLE
Table 1 Asymmetric methoxycarbonylation of 1a: Optimization of the reaction
vacant coordination sites, which could be detrimental for
asymmetric catalysis as these background reactions erode
enantioselectivity. An innate FG in the alkene would be
preferable, as the FG might be advantageously utilized in further
reactions by simple functional group interconversion (FGI).
Recent seminal studies have demonstrated that by employing
simple and commonly encountered functional groups as the
coordination sites, the weak coordination between the substrate
and the metal center of catalysts can prompt the reactivity and
control the chemo- and stereo-selectivities. Therefore, we turn
our attention to using weakly coordinating groups, such as
carbonyl groups typically found in ketone and carboxylic acid
derivatives, as the DGs. These moieties represent one sort of
the most versatile handles for further synthetic manipulations,
and can be readily transformed into a diverse range of other
conditionsa
yield
(%)b
ee
entry
solvent
MeOH
L
T (oC)
x/y/z
(%)c
1
2
L1
60
60
60
60
60
60
60
60
60
40
40
rt
10/12/24
10/12/24
10/12/24
10/12/24
10/12/24
10/12/24
10/12/24
10/12/24
2/2.4/24
2/2.4/24
2/2.4/48
2/2.4/48
0.2/0.24/48
10/12/24
2/2.4/48
82
86
70 (+)
79 (+)
87 (+)
-/-
nhexane L1
functionalities.12 Herein, we reported
a
highly efficient
3
toluene
THF
L1
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
79
asymmetric alkoxy- and hydroxy-carbonylations of β-carbonyl
functionalized alkenes, wherein the carbonyl group as the DG
was demonstrated to be crucial for controlling the chemo- and
stereoselectivities, and favourable for catalytic activities
(Scheme 1, c). Such protocol provided a practical and ready
access to various chiral densely functionalized molecules with
high optical purity (>90 examples, 84-99% ee) from alkenes, CO,
and nucleophiles. The reactions were typically performed at
ambient temperatures and tolerated different nucleophiles
(alcohols, water and thiol). Monitoring reaction profiles, control
experiments and DFT calculation confirmed the key role of the
carbonyl group in determining the stereoselectivity, while the
presence of an electron-withdrawing vinyl substituent (e.g., -
CO2H, -CO2Me, -Ts, -CF3) could effectively inhibit the alkene
isomerization via the tertiary carbocation intermediates.
4
0
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
99 (95d)
95 (-)
93 (-)
10 (+)
23 (+)
95 (-)
96 (-)
96 (-)
97(-)
6
85
7
65
8
10
9
99 (94d)
90 (84d)
99 (96d)
72d
10
11
12
13e
14f
15f
60
60
40
86d
94 (-)
86 (-)
93 (-)
87
89
aReaction conditions: 1a (0.2 mmol), Pd(OAc)2 (0.2-10 mol%), ligand (0.24-12
mol%), PTSA·H2O (24-48% mol%), CO (30 bar), MeOH (3 equiv.), solvent (1
mL), rt-60 °C, 24 h. bDetermined by GC analysis using n-decane as the
internal standard. cDetermined by chiral HPLC. dIsolated yield. e1a (4.0 mmol),
toluene (5 mL), 48 h. fReplacing 1a with the corresponding methyl ester.
PTSA·H2O = p-toluenesulfonic acid monohydrate.
Results and Discussion
To examine the feasibility of this idea, α-methylene-γ-keto
carboxylic acid 1a was selected as the benchmark substrate for
the asymmetric methoxycarbonylation, and some privileged
bidentate phosphines were screened as chiral ligands (Table 1).
The reaction was carried out under 30 bar CO in MeOH at 60 oC
for 24 h, with the in situ generated Pd(OAc)2-(R)-BINAP (L1)-
PTSA·H2O catalyst system. Gratifyingly, the desired product 2a
was obtained with 70% enantiomeric excess (ee) and 82% GC
yield (Table 1, entry 1). After varying the reaction solvent, the ee
value was improved to 87% in toluene with 3 equiv. of MeOH
(entry 3). Subsequently, chiral ligands L2-L5 were investigated
in this reaction (entries 5-8), and (S)-DIFLUORPHOS (L2)
turned out to be optimal, giving 2a with excellent activity and
enantioselectivity (entry 5, for the effect of more ligands, see
Table S1 in SI). Further optimization of other reaction
parameters including temperature and catalyst loading (entries
9-12) demonstrated that such methoxycarbonylation preceded
With the optimized conditions in hand, the compatibility and
scope of alkenes 1 and nucleophiles were investigated in the
asymmetric alkoxycarbonylation (Scheme 2). Various functional
groups including both electron-donating (alkyl, methoxyl, and
phenoxy) and electron-withdrawing (fluoro, chloro, trifluromethyl,
and cyano) substitutes on the phenyl ring of the alkenes were
well tolerated, affording the corresponding esters 2b-2t with high
enantioselectivities and moderate to excellent yields (84-98% ee
and 41-95% yields, Scheme 2, a). Generally, higher yields were
observed with electron-rich groups (2c-2f and 2k-2r) than those
with electron-deficient ones (2g-2j and 2s-2t). No influence of
the substitute at the para-, meta- or ortho-position on the phenyl
ring was observed. Naphthyl-based substrates proved to be
suitable, giving 2u and 2v with both 97% ee and good yields.
Asymmetric hydrocarbonylation of substrates 1h, 1q, 1r, and 1u
with the catalyst loading of 0.2 mol% attained the corresponding
products in moderate to good yields and excellent
enantioselectivities. The merit of broader substrate scope was
further manifested by employing various aliphatic ketones
o
well even at 40 C or rt (entries 11 and 12). Notably, reducing
the palladium catalyst loading to 0.2 mol% could still afford 2a
with 86% yield and 94% ee on gram-scale (entry 13). Using the
corresponding methyl ester of 1a as the substrate for the
enantioselective methoxycarbonylation gave lower yield and ee
value of 2a compared with that using substrate 1a (entries 14
and 15 versus 5 and 11, respectively).
t
featured with cyclic (2w and 2x), acyclic (2y and 2z) and butyl
alkyl (2aa) groups, giving the corresponding esters with the
same level of enantioselectivity and activity. Interestingly, tri-
substituted alkenes also underwent the carbonylation well under
modified reaction conditions leading 2ab in acceptable yield with
2
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10.1002/anie.202105977
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RESEARCH ARTICLE
excellent enantioselectivity and diastereoselectivity. For the
asymmetric carbonylation of 1a, more than alcohol and water,
tert-butanol was also suitable nucleophile, proving the versatility
amides were carbonylated enantioselectively with moderate
activity (4z-4ae). The diastereomeric ratios of products 4ad and
4ae demonstrated the stereogenic center on the amide moiety
had no impact on the enantioselective control of this asymmetric
hydrocarboxylation. When N,N-disubstituted amides were
employed as the substrates with MeOH as the nucleophile, the
carbonylation products 4af-4ak were obtained in good yields
and high ee values.
of
this
method
(Scheme
2,
b).
Specially,
the
hydroxycarbonylation of 1a with 3 equiv. of H2O proceeded well,
and the acid 2ac was obtained in quantitative yield with 97% ee.
The absolute configuration of 2ac was confirmed to be (S) by X-
ray diffraction analysis.13 Other oxygen nucleophiles, such as
primary (2ad and 2ah), secondary (2ae), benzyl (2ag), and
cyclohexyl alcohol (2ai) as well as ethylene glycol
monomethylether (2aj), underwent the transformation smoothly
in acceptable to high yields with excellent enantioselectivity. Last
but not the least, some biomass-based and natural alcohols also
showed good reactivity and diastereoselectivity as well. For
instance, nucleophiles derived from furfural (2ak), glycerol (2al),
and fructose (2an) as well as menthol (2am) can be used in this
approach and synthetically useful yields with diastereoselective
ratio of >20/1 were obtained. It is noteworthy that by tuning the
type of the alcohol, the mono-ester products 2am and 2an can
be selectively obtained, respectively. Compared to oxygen
nucleophile, the thiocarbonylation of alkenes employing thiol as
the nucleophile is more challenging due to its strong binding
affinity to late-transition metals that could cause loss of catalyst
activity.14 Such asymmetric carbonylation could proceed with
tert-butyl thiol as the nucleophile and mono-thioester 2ao was
afforded in quantitative yield with 96% ee. When using
Scheme 2 Asymmetric alkoxycarbonylation of β-ketone alkenes: Substrate
scopea
secondary/primary
thiols
including
1-pentanethiol
and
cyclohexanethiol as the nucleophiles for the asymmetric
carbonylation, no desired carbonylation occurred. The
asymmetric methoxycarbonylation of other functionalized
alkenes, in which the -CO2H substituent was replaced by
sulfonyl (-Ts) and trifluoromethyl (-CF3) groups, was also
investigated (Scheme 2, c). After slightly modifying the reaction
conditions, the substrates were transformed well into the
corresponding products 2ap-2av and 2aw-2aab in moderate to
excellent yields with high enantioselectivities. In these examples,
the ketone moiety with (hetero)aryl or alkyl substituent was well
tolerated. The expansion of olefinic substituents from -CO2H/-
CO2Me to -Ts and -CF3 groups further validated the design
principle of using the carbonyl functionality to determine the
enantioselectivity.
Encouraged by these results, we turned our attention to
exploring carboxylic amide as the DG for asymmetric
hydrocarbonylation. After optimizing the reaction conditions
using α-methylene-γ-amide carboxylic acid 3a as the substrate,
the reaction was performed with H2O as the nucleophile under
30 bar CO in a mixed solvent of toluene/CH3CN (1/1 v/v) at 15
oC for 48 h. To our delight, the desired cyclic imide 4a was
attained in 82% yield and 93% ee (Scheme 3). Further
investigating the substrate scope and compatibility revealed that
neither the electron properties nor the position of the substitution
on the phenyl ring of 3 had impact on the reaction performance,
providing the target products 4b-4y in high yields with excellent
enantioselectivities (85-98% ee and 78-99% yields). Various
functional groups, including alkoxy, halide, trifluromethoxy,
hydroxy, and methylenedioxy, were well tolerated in the reaction
systems. The catalyst loading can be reduced to 0.2 mol% for
substrates 3d and 3m, and the same level of activity and
enantioselectivity were kept. The absolute configurations of 4v
and the methyl ester of 4a were both confirmed to be (S) by X-
ray diffraction analysis.13 A series of cyclic and acyclic aliphatic
aReaction conditions: 1 (0.4 mmol), Pd(OAc)2 (2 mol%), L2 (2.4 mol%),
PTSA·H2O (48 mol%), CO (30 bar), NuH (3 equiv.), toluene (1 mL), 40 oC, 24
h. Isolated yields. Ee values were determined by chiral HPLC. Dr values were
determined by 1H NMR analysis. b1 (2.0 mmol), Pd(OAc)2 (0.2 mol%), L2 (0.24
mol%), PTSA·H2O (48 mol%), CO (30 bar), MeOH (3 equiv.), toluene (4 mL),
60 oC, 48 h. cPd(OAc)2 (5 mol%), L2 (6 mol%), 60 oC, 48 h. d1ab (0.2 mmol)，
Pd(OAc)2 (10 mol%), (S)-SEGPHOS (12 mol%), PTSA·H2O (48 mol%), 40 oC,
f
24 h. eThermal ellipsoids set at 50% probability. 1 (0.2 mmol), Pd(acac)2 (10
mol%), (R)-SEGPHOS (12 mol%), PTSA·H2O (25 mol%), toluene (2 mL), 60
oC. g1 (0.2 mmol), Pd(OAc)2 (5 mol%), (R)-DM-SEGPHOS (6 mol%),
PTSA·H2O (48 mol%), MeOH (1 mL), 60 oC. Ts = p-toluenesulfonyl.
3
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RESEARCH ARTICLE
Scheme
3
Asymmetric hydroxyl- and methoxycarbonylation of β-amide
Scheme 4 Large-scale reaction and divergent derivatization of the products
alkenes: Substrate scopea
aReaction conditions: 3 (0.4 mmol), Pd(OAc)2 (2 mol%), L2 (2.4 mmol%),
PTSA·H2O (24 mol%), CO (30 bar), H2O or MeOH (3 equiv.), toluene/CH3CN
(0.5/0.5 mL), 15 oC, 48 h. Isolated yields. Ee values were determined by chiral
HPLC. Dr values were determined by 1H NMR analysis. b3 (2 mmol), Pd(OAc)2
(0.2 mol%), L2 (0.24 mol%), PTSA·H2O (24 mol%), CO (30 bar), H2O (3
equiv.), toluene/MeCN (2.0/2.0 mL), 30 oC, 60 h. c40 oC. d30 oC. eThermal
ellipsoids set at 50% probability. f3 (0.2 mmol), Pd(OAc)2 (5 mol%), L2 (6
mol%).
Reaction conditions: a2a (0.2 mmol), NaBH4 (0.24 mmol), MeOH (1 mL), 0 oC,
1.5 h. b1) 2a (0.2 mmol), NH2OH·HCl (0.3 mmol), NaOAc (0.5 mmol), MeOH
(2 mL), reflux, 8 h; 2) Raney Ni (>90%, 100 mg), H2 (30 bar), MeOH (2 mL), rt,
24 h. c2a (1 mmol), Pd/C (10%, 50 mg), H2 (40 bar), MeOH (5 mL), rt, 24 h.
d4a (0.2 mmol), LiAlH4 (4.0 mmol), THF (4 mL), reflux, 22 h. e4a (0.4 mmol),
NaBH4 (0.96 mmol), I2 (0.4 mmol in 2 mL THF), THF (4 mL), 0 oC to reflux, 18
f
h. 4a (0.2 mmol), L-phenylalanine methyl ester hydrochloride (0.22 mmol), 1-
ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC·HCl, 0.24
To examine the efficiency and practicability of this approach,
multi-gram scale synthesis was carried out for the asymmetric
methoxycarbonylation of 3a. Remarkably, the palladium catalyst
loading could be reduced to 0.05 mol%, which represents the
state-of-the-art activity among the reported enantioselective
alkoxycarbonylation. By removing the catalyst through filtration
and the solvent under reduced pressure, the crude product was
obtained in 87% yield with 87% ee value. Recrystallization of the
solid gave 17.4 g of cyclic imide 4a in 75% yield and 96% ee
indicating the presence of enantiomeric enrichment (Scheme 4,
a). Then, the synthetic utility of our approach was demonstrated
by divergent derivatization of the carbonylation products
(Scheme 4, b). For examples, biologically active γ-lactone 5 and
γ-lactam 6 were prepared conveniently with one-pot manner in
moderate to high yields and excellent diastereoselectivities from
2a by simple reduction-related processes. The oxygen atom of
the ketone group can be readily dismantled by hydrogenation
with palladium-on-charcoal catalyst, giving the succinate 7 in
82% yield and 96% ee. Chiral cyclic imide 4a could be readily
i
mmol), 1-hdroxybenzotriazole (HOBt, 0.24 mmol), Pr2NEt (0.5 mmol), CH2Cl2
(2 mL), 0-23 oC. g2an (0.2 mmol), L-alanine methyl ester hydrochloride (0.22
i
mmol), EDC·HCl (0.24 mmol), HOBt (0.24 mmol), Pr2NEt (0.5 mmol), CH2Cl2
(2 mL), 0-23 oC, 24 h.
To probe the mechanism for this highly efficient asymmetric
alkoxy- and hydroxy-carbonylation, kinetic profile was depicted
and a set of control experiments on the effect of the ketone
group was performed (Scheme 5). By monitoring the compound
distribution for the carbonylation of 1a and 3a with ex-situ NMR,
the kinetic progress of these two-step processes was plotted
(Scheme 5, I). The substrate 1a was quantitatively converted
into the carbonylation mono-ester 2a’ within 2 hours, which was
then esterified with alcohol to give the ester product 2a at a
relatively lower rate. During the reaction course, 2a accumulated
steadily and no direct esterification between 1a and MeOH was
observed. This pattern implied that 2a was formed through
methoxycarbonylation followed by acid-catalyzed esterification
with MeOH, and the rate of hydrocarbonylation was faster than
that of subsequent esterification. Similar reaction profile was
disclosed for the hydroxycarbonylation of 3a, i.e. 3a was initially
converted to the acid 4a’, then the following cyclization of this
compound occurred to give the cyclic imide 4a. The cyclization
of 4a’ is relatively sluggish than the hydrocarbonylation. To get
more insights in the role of the functionalized substituents, a set
of the analogues of 1a, such as 12 without β-ketone group, 13
with longer carbon chain, 14/15 using methyl/phenyl substituent
converted into optically active pyrrolidine
8
and fused
heterocycle 9 in high yields and stereoselectivity. Condensation
of 4a and 2ao with α-amino acids (L-phenylalanine methyl ester,
L-alanine methyl ester) afforded chiral amides 10 and 11 in high
yields and diastereoselectivities. The diversity of these
transformations exemplified the potential utility of our reaction
system in organic synthesis by simple FGI.
4
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10.1002/anie.202105977
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RESEARCH ARTICLE
instead of carboxylic acid group, was prepared and subjected to
the standard reaction conditions (Scheme 5, II). After replacing
1a by 12, the reactivity of desired hydrocarbonylation decreased
significantly and the direct esterification product was obtained in
74% yield. Acrylic acid 13 failed to undergo the
hydrocarbonylation, and the esterification product was detected
in 90% yield. When the carboxylic acid group in 1a was replaced
by methyl or phenyl group, the isomerization of terminal alkene
14/15 turned to be dominated, and less than 5% carbonylation
product was detected. These control results unambiguously
revealed the critical role of the carbonyl group in controlling the
enantioselectivity as well as favoring the activity for asymmetric
hydrocarbonylation, and the presence of electron-withdraw
functional groups could inhibit proton acid-catalyzed alkene
isomerization probably by destabilizing the tertiary carbocation
intermediates. The observed distinct reactivity difference among
the substrates listed in Scheme 2 led us to survey the electronic
effect of substituents at the para position of the phenyl ring in β-
ketone alkene (1a, 1e, 1g, 1h and 1i) on the rate of
methoxycarbonylation in detail. According to the Hammett
equation, the relative rates of the reaction compared to the
unsubstituted compound (k/kH) are plotted against the
substituent constant (σ), yielding ρ value (-1.95, R2 = 0.98,
Scheme 5, III). The negative ρ value indicates the development
of positive charge at the reaction center in the transition state of
the rate-limiting step, which means the reaction rate is
suppressed by electron-withdrawing substituents.
To provide further insights into the origin of enantioselectivity
and the role of β-carbonyl moiety in this asymmetric
hydrocarbonylation process, density function theory computation
was carried out by using the local meta-generalized gradient
approximation M06L functional15, which includes dispersion
correction. To save the computational cost, the combination of
Karlsruhe basis sets16 with Weigend06 density fitting auxiliary
basis set17 was utilized. In previous reports on mechanistic
studies of alkene alkoxycarbonylation, pathway initiating from
palladium hydride is generally accepted, wherein a cationic
palladium hydride phosphine complex is frequently proposed as
the active species of palladium-catalyzed hydrocarbonylation.18
Herein this reaction was assumed to follow this mechanism, and
we also treated the cationic palladium hydride complex as the
active catalyst. Given the similar enantioselectivity produced by
(S)-SEGPHOS and (S)-DIFLUORPHOS, the former ligand was
employed in our computational model and the substrate 1b was
selected as the model olefin. The computed free-energy
changes included the implicit solvation effect of toluene by SMD
model.19
Scheme 5 Mechanistic studies
I. Reaction kinetic profile
The results of DFT computation identified that the molecule
without ketone- or enol-form intramolecular hydrogen bond is the
major state of free 1b in the toluene solution (detailed results
see Figure S6 in SI). Regarding the coordination of 1b with [((S)-
SEGPHOS)PdH]+ (denoted as [(P∩P)PdH]+ in Scheme 6), the
ketone-coordinated cationic palladium hydride complexes As
were relatively more stable than the corresponding alkene-
coordinated complexes Bs by 4.0 kcal/mol (detailed results see
Figure S7 in SI). Thus, the coordination of unsaturated cationic
palladium hydride complex with the ketone site of 1b has priority
over the direct coordination with alkene group, and is regarded
as the starting point of pathway towards hydrocarbonylation
product. Such coordination between the ketone group and PdII
fixes the prochiral face of alkene group towards the PdII-H
moiety of active species [(PP)PdIIH]+. We found that complex
AS with the Si-face of prochiral C=C bond exposed to the PdII
center is more thermodynamically favored by 1.1 kcal/mol than
the diastereomeric complex AR with the Re-face of C=C bond
exposed to the metal center (ball-and-stick structures of AS, BS
and TSBC-S as well as AR, BR and TSBC-R see section 7.4 in SI).
Through intramolecular ligand exchange, the intermediates A
were transformed to the corresponding alkene-coordinated
intermediates B. During this process, the molecular
conformation of 1b remained unchanged. Subsequent insertion
of the coordinated C=C bond into Pd-H afforded Pd-alkyl
II. Control experiments
III. Hammett plot
interemediate
C
bearing intramolecular Pd···H-C agostic
interaction (TSBC). Owing to the presence of carboxylic acid
group, the Pd-alkyl complexes C could be further converted to
the more stable carbonyl-coordinated Pd-alkyl complexes D.
5
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On the basis of the process, the ketone group plays the role of
anchoring the spatial orientation of substrate 1b by the
coordination of oxygen atom with the (S)-SEGPHOS-chelated
Pd(II) center. According to the proposed mechanism, the
enantioselectivity is determined by the insertion of the C=C bond
of the olefin into Pd-H to form alkyl complexes (B→C via TSBC).
For this crucial elementary step, significant difference on the
energy barrier between the channels towards (R)- and (S)-
products is found. The energy barrier for Pd-H insertion on the
route towards (S)-configuration is only 0.9 kcal/mol, while that
towards the (R)-configuration is as high as 3.0 kcal/mol. The free
energy of TSBC-R was 1.9 kcal/mol higher than that of TSBC-S
(Scheme 6), indicating generation of the (S)-configuration is
indeed more kinetically favorable. Derived from this energy
difference with Eyring equation, the theoretical ee value of
product 2b is 92%, which is reasonably in line with the
enantioselectivity of experimental data (2b, 96% ee) shown in
Scheme 2. Thus this computational model well explained the
experimentally observed high enantioselectivity assisted by the
β-carbonyl group of 1b.
becomes the rate-determining step of the overall process. In the
transition state of the rate-determining step, the proton of
hydroxy group in methanol was transferred onto the oxygen
center of carbonyl group in acyl-palladium species, and a
positive charge at the reaction site was built (TSI-S). The
structure and energy pattern of TSI-S well explained the
negative ρ value of the Hammett plot determined by experiments,
which indicates the development of positive charge at the
reaction center in the transition state of the rate-limiting step.
Scheme 6 The solvated free-energy changes of alkene insertion into Pd-H to
generate a chiral center with different configuration
To gain a full understanding of the reaction mechanism, the
overall free-energy changes for the transformation from
substrate 1b to product (S)-2b are depicted by DFT-based
calculation (Scheme 7). After the insertion of alkene into the Pd-
H bond, the generated intermediate DS is transformed to the
more thermodynamically stable intermediatSe ES by establishing
intramolecular seven-membered hydrogen-bond interaction
between the carboxylic acid and ketone carbonyl groups.
Comparing with the scenario without this intramolecular
hydrogen-bond interaction, the presence of such interaction
reduces the free energy of transition state for the endothermic
migratory CO insertion (FS→GS via TSFG-S) by 2.2 kcal/mol (see
Figure S8 in SI). Transforming the intramolecular agostic Pd···H-
C interaction to the coordination of carboxylic group with Pd
center gives more stable species Hs. In the final methanolysis,
the external MeOH coordinates with Pd center instead of the
carboxylic group affords the intermediate IS. This step is
endothermic by 11.8 kcal/mol. Afterwards, the proton and
methoxide of MeOH are respectively transferred onto the
oxygen and carbon centers of carbonyl group respectively in the
concerted mode via the transition state of TSI-S to afford the
chiral product 2b and regenerate [(P∩P)PdH]+. This step needs
to surmount the energy barrier of 30.9 kcal/mol and thus
Scheme 7 The solvated free-energy changes for the process from substrate 1b to the methoxycarbonylation product (S)-2b catalysed by Pd/(S)-SEGPHOS
6
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RESEARCH ARTICLE
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8
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Entry for the Table of Contents
An efficient asymmetric alkoxy- and hydroxy-carbonylation of β-carbonyl functionalized alkenes was developed, providing a practical
and ready access to various densely functionalized chiral molecules with high optical purity. Control experiments revealed the key
role of the β-carbonyl group in determining the enantioselectivity and promoting the activity as rationalized by DFT calculations.
9
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