Asymmetric Palladium-Catalyzed Oxycarbonylation of Terminal Alkenes: Efficient Access to β-Hydroxy Alkylcarboxylic Acids

Article abstract of DOI:10.1002/anie.202104252

A novel Pd^II-catalyzed enantioselective oxycarbonylation of alkenes has been established. The ligand with an ethyl group at the C-6 position of Pyox plays a significant role in the intermolecular oxypalladation process, leading to high reactivity and excellent enantioselective control. Compared to the conventional methods, the reaction itself features alkenes as easily prepared starting materials, mild and operationally simple reaction conditions, and insensitivities to air and water. Moreover, this method allows for broad alkene substrate scope, excellent regio- and enantioselectivities, scalabilities and a wide array of applications, and provides a useful route for the convenient and straightforward synthesis of chiral β-hydroxy alkylcarboxylic acids/esters.

Full text of DOI:10.1002/anie.202104252

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Accepted Article
Title: Asymmetric Palladium-Catalyzed Oxycarbonylation of Terminal
Alkenes: Efficient Access to β-Hydroxy Alkylcarboxylic Acids
Authors: Guosheng Liu, Bin Tian, Xiang Li, and Pinhong Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202104252
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Asymmetric Palladium-Catalyzed Oxycarbonylation of Terminal
Alkenes: Efficient Access to β-Hydroxy Alkylcarboxylic Acids
Bing Tian,a Xiang Li,a Pinhong Chen,a Guosheng Liu*a,b
Abstract: A novel Pd(II)-catalyzed enantioselective oxycarbonyl-
ation of alkenes has been established herein. The ligand with an ethyl
group at the C-6 position of Pyox plays a significant role in the
intermolecular oxypalladation process, leading to high reactivity and
excellent enantioselective control. Compared to the conventional
methods, the reaction itself features alkenes as easily prepared
starting materials, mild and operationally simple reaction conditions,
and insensitivities to air and water. Moreover, this method allows for
broad alkene substrate scope, excellent regio- and enantio-
selectivities, scalabilities and a wide array of applications, and
provides a useful route for the convenient and straightforward
synthesis of chiral β-hydroxy alkylcarboxylic acids/esters.
As our ongoing research interest in the difunctionalization of
alkenes,[7] we reported the first intermolecular oxycarbonylation of
alkenes by using a cooperative system, where Lewis acid BF3·Et2O was
required to promote I(III)-mediated alkene activation, followed by a
palladium-catalyzed sequential ring opening and carbonylation (Scheme
2a).[8] However, this process could be remarkably inhibited by adding
external ligands, making asymmetric oxycarbonylation extremely
challenging. Alternatively, recently we found that the engineering of
chiral pyridinyl-oxazoline (Pyox) ligand by introducing a substituent
into C-6 position could dramatically enhance the electrophilicity of
palladium catalysts,[9] which could promote the initial enantioselective
intermolecular oxypalladation.[10] Inspired by these results, we reasoned
that, if the oxidative system can be compatible with a CO atmosphere,
the alkyl-Pd species generated from enantioselective oxypalladation of
alkene could undergo carbonylation reaction, the asymmetric
oxycarbonylation of alkenes might be expected to deliver
enantiomerically enriched β-hydroxy alkylcarboxylic acid (Scheme 2b).
Herein, we communicate the first example of enantioselective
palladium-catalyzed intermolecular oxycarbonylation reaction, which
offers an efficient and straightforward approach to chiral β-hydroxy
alkylcarboxylic acids from the readily accessible alkenes.
Optically pure β-hydroxy alkylcarboxylic acids (esters) are not only
widely found in bioactive natural products and pharmaceuticals (Scheme
1),[1] but also are frequently employed as important building blocks in
organic synthesis.[2] Therefore, intensive efforts have been paid for their
synthesis by chemists over the past several decades, and some efficient
methods have been developed, including asymmetric hydrogenation of
β-keto carboxylic esters,[3] asymmetric Aldol reactions[4] and others.[5]
Owing to the easy availability of alkenes as feedstocks, asymmetric
oxycarbonylation of alkenes is considered as an efficient and attractive
approach for their synthesis. Although the oxypalladation of alkenes has
been extensively investigated, unfortunately, limited examples of the
asymmetric oxycarbonylation of alkenes were exclusively reported in an
intramolecular manner,[6] and there have been no any documented
examples through an intermolecular process to date. Thus, exploration
of new catalytic systems to address this issue is highly desirable.
Scheme 2. Asymmetric oxycarbonylation.
To survey the aforementioned hypothesis, a series of Pyox ligands
were used to explore our initial investigation, which alkene substrate 1
was treated by Pd(OAc)2, Pyox, and oxidant PhI(OAc)2 under 1 atm of
CO (balloon) (Table 1a). As we expected, the simple Pyox L1 failed to
deliver the desired product. However, we are delighted to find that, when
a substituent was introduced into the C-6 position of Pyox, the
oxycarbonylation reaction indeed occurred, and Pyox L3 bearing an
ethyl group at the C-6 position of pyridine exhibited the best
performance to give the target product 2 in 90% yield with 90% ee.[11]
Further increasing the size of the groups at the C-6 on the pyridyl ring,
such as propyl (L4), benzyl (L5), isopropyl (L6) and diphenylmethyl
(L7) could slightly decreasethe yields and enantioselectivities of the
reactions. Moreover, the Pyox ligand L8 with CF3 at the C-5 position
commonly used in the functionalization of alkenyl-alcohols[12] also
provided the desired oxypalladation product 2, but in low yield (26%)
with moderate ee value (79%).
Scheme 1. β-Hydroxy alkylcarboxylic acids in nature products and drugs.
*a)
Dr. B. Tian, Dr. X, Li, Dr. P. Chen, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry, and Shanghai
Hongkong Joint Laboratory in Chemical Synthesis, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn
b)
Prof. Dr. G. Liu
Chang-Kung Chuang Institute, East China Normal University
3663 North Zhongshan Road, Shanghai 200062, (China)
*** Supporting information for this article is given via a link at the end of
the document.
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Table 1: Optimization of reaction conditions.[a,b]
C12 & C15) broadly exist in nature products, such as Rhamnolipids[13]
and Caprazamycin A,[14] could be easily synthesized by the current
reaction. In fact, we are delighted to find that various terminal alkenes
bearing long carbon chains proven to be good candidates to yield the
desired products (9−12) in excellent results. Moreover, alkenes bearing
aryl rings showed even better performances, and the reactions provided
the products 13−15 in 81−90% yields with 96−97% ee; notably, the
compatible aryl iodide in product 15 allows for the further cross coupling.
Furthermore, abundant functional groups were compatible with the
reaction conditions, such as halides (16−17), allylic ester (18), boron
(19), imide (20), ketone (21), arylsulfonyl (22) and cyano (23), affording
target products in good to excellent yields (55−90%) and excellent
enantioselectivities (86−93% ee). It is worthy of note that alkene
substrates bearing various heterocycles were also suitable for the
reaction, such as pyrrole (24), indole (25), carbazole (26),
(benzo)thiophen (27−29), and (benzo)furan (30−32), providing various
oxycarbonylation products in 70−90% yields with 86−95% ee.
Substrates containing both alkynyl and alkenyl moieties preformed
excellent regioselectivity, and the reaction exclusively occurred on the
double bond to give product 33 in 78% yield with 91% ee. More
importantly, for polyenes, the reaction exhibited an exquisitely site-
selectivity on the mono-substituted terminal alkenes. As depicted in
Table 2, for the terminal substrates bearing astyryl moiety, the reaction
exclusively occurred on the aliphatic alkyl-substituted alkenes to give
34−36 with excellent site-selectivities. Moreover, the oxycarbonylation
reaction was sensitive to the steric effects. For the substrates bearing
mono-, di- and tri-substituted alkenes, the reaction exclusively took
place on the mono-substituted alkenes to deliver enantiomerically
enriched products 37 and 38, respectively.
Finally, substrates derived from bioactive moleculeswere also
investigated. For example, terminal olefins bearing benzbromarone (39),
coumarin (40), estrone (41), isoxepac (42), were demonstrated as the
good candidates to yield the corresponding products in high yields
(71−90%) with excellent enantiomeric excess (84−92% ee or de).
Meanwhile, the reaction of terminal alkene in liquid crystal monomer
(43) also worked very well.
As the oxypalladation process is highly sensitive to the steric
effects, the oxycarbonylation of polyene 44 with two terminal double
bonds only occurred on the less sterically hindered terminal double bond
to afford the corresponding product 45 in 69% yield with excellent
enantioselectivity (91% ee) (Scheme 3a). In contrast, our previous
reported cooperative system by combining iodine(III)-mediated alkene
activation and palladium-catalyzed carbonylation[8] provided poor site-
selectivity in the reaction of 44, where oxycarbonylation occurred in
both double bonds to afford product 46 in 48% yield. From the point of
view of the mechanism, the mode of alkene activation are obviously
different in these two catalytic systems, and the steric hindrance of
alkene was at work on oxypalladation while iodine(III)-mediated alkene
activation was unacted on it.
[a] Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), Ligand (15 mol %),
oxidant (1.2 equiv.), HOAc (0.1 mL) and Et2O (0.1 mL) under CO (1 atm) at rt
for 16 hour; the crude product was treated by TMSCHN2 in MeOH/Toluene; [b]
1H NMR yields using CF3-DMA as an internal standard; enantiomeric excess
(ee) value was determined by HPLC or GC on a chiral stationary phase; [c]
Pd(OAc)2 (5 mol%), L3 (7.5 mol %); [d] Pd(OAc)2 (2 mol %), L3 (3 mol %); [e]
Reaction of 1-hexene was conducted in condition as entry 7 (Table 1b).
As oxidants have a remarkable effect on our previously asymmetric
dioxgenation of alkenes,[10] a series of oxidants were surveyed in the
current oxycarboxylation of alkenes (Table 1b). As shown in Table 1b,
compared to the excellent performance of PhI(OAc)2, oxidants such as
NFSI, H2O2, and Selectfluor proved to be inactive or showed low
reactivity (entries1−3). To our delight, 1,4-benzoquinone (BQ), which
was frequently used as oxidant in palladium catalysis, gave 2 in high
yield and enantioselectivity (92% yield and 89% ee, entry 4). Further
screening revealed that the reaction using 3 equiv. of BQ at 0 oC led to
the best results (92% yield and 94% ee, entries 5−6). In addition,
decreasing the palladium catalyst loading from 10 mol % to 5 mol %
gave a similar result (91% yield, 94% ee), but remarkably decreased
yield was obtained using 2 mol% palladium catalyst (entries 7−8).
With the optimized conditions (entry 7 in table 1b), a series of
carboxylic acids were then investigated, such as acetic acid, propanoic
acid, isobutanoic acid, benzoic acid and 2-ethylbutanoic acid, and the
reactions of 4-phenyl-1-butene 1 performed excellent (89−95% ee, for
details, see SI). However, when these acids were tested for the reaction
of 1-hexene, 2-ethylbutanoic acid gave the best yield and
enantioselectivity (7, 81% yield and 90% ee), much higher than others
(3−6, 50−70% yields and 81−87% ee, Table 1c).
Inspired by the above-mentioned results, 2-ethylbutanoic acid was
employed to examine the alkene scope for the asymmetric
oxycarbonylation. As shown in Table 2, a wide range of alkenes was
tested under the standard conditions on a 0.5 mmol scale, and these
substrates could be successfully transformed into the desired products in
high yields with excellent enantioselectivities. First, simple alkenes such
as 1-hexene and 1-pentene exhibited excellent reactivities to give
products 7−8 in 73−85% yields with 88−91% ee. As we know, the
optically pure β-hydroxy carboxylic acids with a long carbon chain (e.g.
In asymmetric synthesis, chemists would like to control the
diastereoselectivity of reactions by chiral ligands. The oxycarbonylation
of alkenes containing β-oxy- and β-amino-stereocenters was
investigated using this method (Scheme 3b). For alkenes 47 and 50, the
employment of catalysts with either enantiomer of ligand L3 both
resulted in excellent diastereoselectivities (89%−96% de), indicating
that the catalyst control is the primary stereochemical influence on the
oxycarbonylation of chiral substrates. Furthermore, a simple cyclization
of the oxycarbonylation products 51 and 53 could readily lead to the
corresponding chiral piperidinones 52 and 54, respectively. Notably,
substrates bearing two terminal double bonds (55 and 56) also exhibited
high reactivity, yielding dioxycarbonylation
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Table 2: Substrate scope of alkenes.[a,b]
[a] Reaction conditions: alkene (0.5 mmol), Pd(OAc)2 (5 mol%), L3 (7.5 mol %), BQ (3 equiv.), and 2-ethylbutyric acid (5 equiv.) in Et2O (0.25 mL) at 0 oC with CO
balloon; the crude product was stirred in MeOH/Toluene (v/v = 1/1, 2 mL), then treated by TMSCHN2 (1 mL, 2 M in n-Hexane). [b] Isolated yields, and ee values
were determined by HPLC or GC on a chiral stationary phase. [c] Reaction at -10 oC.
products 57 and 58 in good stereoselectivities (94/6 and 87/13) with
excellent yields (90% and 89%) and enantioselectivities (99% and 98%
ee), respectively (Scheme 3c).
To demonstrate the utility and synthetic application of the
asymmetric oxycarbonylation reaction, the reaction on a gram-scale (10
mmol) was firstly conducted with 2 mol% palladium catalyst (Scheme
3d). With standard procedure, the large-scale reaction of 1 provided the
expected ester 13 in an even higher yield (91%) with 96% ee; upon the
treatment of the crude mixture of the reaction by water,the desired
carboxylic acid 65 was easily obtained in 93% yield with 96% ee. The
ester 13 could be readily converted to various synthons, commonly used
in organic synthesis, such as the reduced product 1,3-diol 59, which
could be further transformed into functionalized derivatives 60−62. The
absolute structure of (S)-62 was unambiguously determined by the X-
ray structure analysis.[15] Moreover, deprotection of product 13 led to β-
hydroxy ester 63, an intermediate for the
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Scheme 3. Selectivity and synthetic applications.
Reaction conditions: a) N2H4 H2O (1.1 equiv.), EtOH, reflux. b) Diene (0.5 mmol), Pd(OAc)2 (5 mol%), L2 (7.5 mol%), BQ (6 equiv.), and 2-ethylbutyric acid (10
equiv.) in Et2O (0.8 mL). c) LiAlH4 (4 equiv.), THF, 0 oC-rt. d) Ph3P (1.3 equiv.), DIAD (1.5 equiv.), TMSN3 (1.3 equiv.), toluene, 0 °C, then TBAF, THF, rt. e) TsCl
(1.2 equiv.), Bu2SnO (1.2 mol%), Et3N (2 equiv.), DMAP (0.1 equiv.), 0 oC, then NaN3 (3 equiv.), DMF, 80 oC. f) PPh3 (1 equiv.), NBS (1 equiv.), DCM, 0 oC-rt. g) 4-
Chlorobenzenesulfonic acid (0.2 equiv.), MeOH, 100 oC. h) Et3N (1 equiv.), diphenyl phosphorazidate (1 equiv.), tBuOH, reflux. i) NaOH (10 equiv.), THF/H2O, 100
oC. j) Allylmagnesium bromide (2 equiv.), THF, rt. k) Isobutylamine (4 equiv.), HATU (2 equiv.) DMF, 0 oC-rt. l) 4-Chlorobenzenesulfonic acid (0.2 equiv.), MeOH,
100 oC. m) Pd(OAc)2 (5 mol%), Johnphos (6.5 mol%), Cs2CO3 (2 equiv.), toluene, 65 oC.
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synthesis of natural product (+)-dihydrokavain (64) which possesses
sedative, anti-convulsive, anesthetic, and antifungal properties.[16] Chiral
protected amino alcohol 66 and β-hydroxy alkylcarboxylic acid 67 could
be obtained by Curtius rearrangement and deprotection, respectively.
With this strategy, the readily available alkene 69 derived from
commercially available benzyl bromide 68 could be converted to
biologically active natural product (−)-erythrococcamide B[17] (70) in
four steps via a sequential oxycarbonylation, amidation, deprotection,
and cyclization (Scheme 3e). It was noteworthy that only one column
purification was needed using this route, providing 70 in a total yield of
44% with 90% ee
In summary, we have developed the first intermolecular Pd(II)-
catalyzed asymmetric oxycarbonylation of terminal alkenes. This
method has properties of wide substrate scope, excellent regio- and
enantioselectivity control, mild conditions, and operationally simple
processes which offers an efficient and easy access to β-hydroxy
alkylcarboxylic acids. The strategy by introducing sterically moderate
groups into C-6 position of Pyox ligand palys an important role in the
asymmetric intermolecular oxypalladation process.
[9] a) X. Qi, C. Chen, C. Hou, L. Fu, P. Chen, G. Liu, J. Am. Chem. Soc. 2018,
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[10] B. Tian, P. Chen, X. Leng, G. Liu, Nat. Catal. 2021, 4, 172.
[11] With regard to the convenient detection of ee value, the crude product acid
was treated with MeOH followed by TMSCHN2 to give the corresponding
methyl ester. For details, see SI.
[12] N. J. Race, C. S. Schwalm, T. Nakamuro, M. S. Sigman, J. Am. Chem. Soc.
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[13] C. Buonocore, P. Tedesco, G. A. Vitale, F. Palma Esposito, R. Giugliano, M.
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Miyake, Y. Akamatsu, J. Antibiot. 2005, 58, 327.
[15] Deposition Number 2053659 (for 62) contains the supplementary
crystallographic data for this paper. These data are provided free of charge
by the joint Cambridge Crystallographic Data Centre and
Acknowledgements
We are grateful for financial support from the National Natural Science
Foundation of China (Nos. 21532009, 21971255, 21821002, 21790330
and 21761142010), the Science and Technology Commission of
Shanghai Municipality (Nos. 19590750400 and 17JC1401200), the
Strategic Priority Research Program (No. XDB20000000) and the Key
Research Program of Frontier Science (QYZDJSSW-SLH055) of the
Chinese Academy of Sciences. P.C. also thanks the Youth Innovation
Promotion Association CAS (No.2018292).
Fachinformationszentrum
Karlsruhe
Access
Structures
service
Conflict of interest
www.ccdc.cam.ac.uk/structures.
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[17] Z. Latif, T. G. Hartley, M. J. Rice, R. D. Waigh, P. G. Waterman, J. Nat.
Prod. 1998, 61, 614.
The authors declare no competing financial interest.
Keywords: enantioselective oxycarbonylation • palladium-catalyzed •
terminal alkenes • β-hydroxy alkylcarboxylic acids
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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B. Tian, X, Li, P. Chen, G. Liu*
Page No. – Page No.
Asymmetric Palladium-Catalyzed
Oxycarbonylation of Terminal
Alkenes: Efficient Access to β-
Hydroxy Alkylcarboxylic Acids
A novel Pd(II)-catalyzed enantioselective oxycarbonylation of alkenes has been established herein. The ligand with an ethyl group at
the C-6 position of Pyox plays a significant role in the intermolecular oxypalladation process, leading to high reactivity and excellent
enantioselective control. Compared to the conventional methods, the reaction itself features alkenes as easily prepared starting
materials, mild and operationally simple reaction conditions, and insensitivities to air and water. Moreover, this method allows for broad
alkene substrate scope, excellent regio- and enantio-selectivities, scalabilities and a wide array of applications, and provides a useful
route for the convenient and straightforward synthesis of chiral β-hydroxy alkylcarboxylic acids/esters.
This article is protected by copyright. All rights reserved.