Diastereo- And Enantioselective Synthesis of Structurally Diverse Succinate, Butyrolactone, and Trifluoromethyl Derivatives by Iridium-Catalyzed Hydrogenation of Tetrasubstituted Olefins

Article abstract of DOI:10.1021/acscatal.9b01508

A highly efficient iridium N,P-ligand-catalyzed asymmetric hydrogenation of functionalized tetrasubstituted olefins lacking a directing group has been developed. Various structural diverse chiral succinate derivatives were obtained in high yields and exce

Full text of DOI:10.1021/acscatal.9b01508

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Article
Diastereo- and Enantioselective Synthesis of Structurally
diverse Succinate, Butyrolactone, Trifluoromethyl Derivatives
by Iridium Catalyzed Hydrogenation of Tetrasubstituted Olefins
Sutthichat Kerdphon, Sudipta Ponra, jianping yang, Haibo Wu, Lars Eriksson, and Pher G. Andersson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01508 • Publication Date (Web): 30 May 2019
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Diastereo- and Enantioselective Synthesis of
Structurally diverse Succinate, Butyrolactone,
Trifluoromethyl Derivatives by Iridium Catalyzed
Hydrogenation of Tetrasubstituted Olefins
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Sutthichat Kerdphon, ‡[a] Sudipta Ponra,‡[a] Jianping Yang,‡[a] Haibo Wu,[a] Lars Eriksson[b] and
Pher G. Andersson*[a][c]
[a]Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 106
91, Stockholm, Sweden; E-mail: pher.andersson@su.se
[b]Department of Materials and Environmental Chemistry, Stockholm University, Svante
Arrhenius väg16C, SE-10691, Stockholm, Sweden
[c]School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa.
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Abstract: A highly efficient iridium N,P-ligand catalyzed asymmetric hydrogenation of
functionalized tetrasubstituted olefins lacking a directing group, has been developed.
Various structural diverse chiral succinate derivatives were obtained in high yields and
excellent enantio- and diastereoselectivities (up to 99% ee) using 0.5 - 1.0 mol% catalyst
loadings. This stereoselective reaction is applicable for synthesis of chiral acyclic
molecules (up to >99% ee) having two contiguous stereogenic centers and is compatible
with various aromatic, aliphatic and heterocyclic systems, a variety of functional groups
of different electronic nature. Furthermore, this asymmetric protocol allows a short
enantioselective route to the butyrolactone building block, an intermediate in the
synthesis of anticancer agent BMS-871 and pharmaceuticals (2S)-(-)-Verapamil, (2S)-(-)-
Gallopamil.
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Keywords: tetrasubstituted olefin, asymmetric hydrogenation, iridium catalysis,
enantioselective, diastereoselective.
INTRODUCTION
Succinic acid derivatives are important building blocks in both organic and medicinal
chemistry. For instance, these derivatives are employed as inhibitors of renin1 and
matrix metalloproteinases2. Moreover, succinates are used mainly as non-phthalate
plasticizers3 in the cosmetic industry4 and agricultural chemistry, and in material
science as monomers for polymers and dendrimers.5 Substituted butyrolactones are also
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common structural motifs in a wide range of complex natural products (Figure 1. A)
and serve as chiral building blocks in the synthesis of biologically active compounds
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(Figure 1. B).6 Consequently, numerous methods and strategies have been developed
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for the synthesis of succinate derivatives.7,
However, efficient catalytic and
enantioselective synthesis8 of these important building blocks containing two
contiguous stereocenters are unexplored and the general catalytic asymmetric synthesis
of these derivatives still presents a major challenge.8f
Figure 1. A. Natural products containing butyrolactone motif. B. Bioactive molecules
derived from butyrolactone or chiral succinate compounds.
Asymmetric hydrogenation of tetrasubstituted olefins (AHTOs) possesses
tremendous potential in stereoselective synthesis since it enables the introduction of
two vicinal stereocenters in one single step. Despite this, progress in this area has grown
at a relaxed pace,9 partly because of the difficulties in differentiation of the prochiral
faces of a fully substituted olefin, and partly the steric hindrance of the four different
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substituents, which results in a slow rate of hydrogenation of these substrates in
comparison to the di- and tri-substituted olefins. Highly enantioselective hydrogenation
of olefins lacking a coordinative group is even more difficult as the coordinating group
assists in the transfer of the chiral information from the catalyst to the product.10 The
limited number of reports in literature on the AHTOs without a coordinating group
compared to the AHTOs with a coordinating group, further proves these difficulties.9a
To date, the catalytic system that has been reported was successful for only a few
special types of substrates. Also, each class of olefins requires a special catalytic
system.11 Examples of AHTOs a lacking coordinating group is still limited12 for cyclic
olefins12a-e, 12g, 12h and for acyclic olefins are very rare (Scheme 1).12c, 12f-h The reported
methods require either high catalyst loadings,12a-e a mixture of catalysts,12e or
sophisticated reaction conditions.12e Furthermore, there are only a few methods
available for the hydrogenation of tetrasubstituted non-chelating olefins having
functional groups that are able to create useful building blocks for further synthesis.12e
Thus, development of a catalyst having a wide substrate scope for AHTOs to access
versatile building blocks is still a very challenging task in asymmetric hydrogenation.
Here we report our work to develop a general, simple, and efficient atom-economical
protocol for the highly enantioselective synthesis of different chiral building blocks
containing two stereogenic centers.
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Scheme 1. Asymmetric hydrogenation of tetrasubstituted olefins without coordinating
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group.
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RESULTS AND DISCUSSION
Initially, (Z)-diethyl 2-methyl-3-phenylmaleate 1a was chosen as test substrate for
asymmetric hydrogenation by using iridium-N,P complex as the catalyst. Normally,
acyclic tetra-substituted olefins containing non-chelating groups12a specially two ester
groups12f are notoriously difficult substrates since these olefins are both electron
deficient and lack chelating groups that would facilitate binding to the catalyst as well
as discrimination between the two enantiotopic faces.
It was found that olefin 1a could be hydrogenated in good yield using imidazole N,P-Ir
complex A but with poor enantioselectivity (Table 1). Subsequently, several chiral
iridium Crabtree-type catalysts having thiazole and oxazoline N,P-ligands were
evaluated using 0.5 mol% of catalyst loading. The catalyst containing a thiazole ligand B
resulted in poor conversion and enantioselectivity. Catalyst C, containing a bicyclic
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thiazole led to an improved enantioselectivity (72%). Interestingly, the bulkier iridium
N, P-catalyst D having a di-phenyl substituted oxazoline led to a much higher
enantiomeric excess, 96% ee. The promising result obtained for catalyst D prompted us
to further modify the catalyst structure by varying the substituents on the phosphine
and phenyl of the oxazoline ring. Changing the ortho-methyl group to an ortho-ethyl
substituent on phosphine for catalyst E did not improve the efficiency nor the selectivity
of the hydrogenation reaction. Catalyst F with the more electron-rich di(2,4-
dimethylphenyl)-phosphine group, resulted in a higher reactivity (78% conversion, 95%
ee) compared to catalyst E. The introduction of electron-rich substituents on the two
phenyl groups on the oxazoline ring, (4-Me-Ph and 4-OMe-Ph, catalyst G and H),
further improved the yield of hydrogenation products. Amongst the newly developed
catalysts (Table 1), the highest reactivity for substrate 1a was recorded with catalyst H
which afforded 96% ee with full conversion using a catalyst loading of only 0.5 mol%.
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Table 1. Evaluation of N,P-iridium catalysts in the asymmetric hydrogenation of 1aa
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aReaction conditions: 0.05 mmol substrate, 0.5 mol% catalyst, 0.5 mL CH2Cl2.
Conversions were determined by 1H-NMR spectroscopy. Enantiomeric excess
determined by HPLC and SFC-HPLC analysis using a chiral stationary phase.
Having identified suitable catalysts and establishing the optimized conditions,
different ester groups were screened in the hydrogenation (Table 2). The possibility to
have two ester groups possessing orthogonal reactivity would enable one to
differentiate between them and render them more useful in further synthesis. Ester
groups had proved to have significant influence on the reactivity and on
enantioselectivities (see Supporting Information for details) and changing from the
diethyl ester to benzyl-ethyl ester 1b was found to be best both in terms of
enantioselectivity (99% ee) and conversion (99%). The other benzyl-ethyl ester 1c also
provides high conversion (99%) but in slightly lower ee (95%). Based on the high
reactivity and enantioselectivity for substrate 1b it was chosen as the suitable substrate
class for further studies on the efficacy of this reaction.
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Table 2. Optimization of reaction conditions for the hydrogenation of
tetrasubstituted maleate olefinsa
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a0.5 mol% catalyst H, 0.5 mL CH2Cl2. Conversion determined by 1H-NMR spectroscopy.
Enantiomeric excess determined by HPLC and SFC-HPLC analysis using a chiral
stationary phase.
A series of di-ester derivatives were successfully hydrogenated using newly
synthesized catalyst H to give the products in excellent yield, complete
diastereoselectivity and high to excellent enantioselectivities (Table 3). First, substrates
bearing different alkyl groups, ranging from short to longer aliphatic chain substituents
on the olefin (1b-1f), were evaluated and all the substrates were hydrogenated
efficiently (2b-2f) in excellent yield (96-99%) and enantioselectivities (90-99% ee). The
maleate derivatives bearing either electron-donating or electron-withdrawing
substituents gave good to excellent isolated yield (60-99%) with excellent
enantioselectivity (91-98% ee). The reaction also allowed several electron-donating
group (Me or OMe) on the aromatic ring and smoothly afforded 2m-2o in high yields
and enantiomeric excess. The maleate 1p with the bulkier 2-naphthyl substituent gave
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the product 2p in good yield and excellent enantioselectivity of 98%. A number of
heterocyclic compounds with different substitutions were also evaluated in the
hydrogenation using both catalysts H and D with promising results. Interestingly,
challenging substrates having aliphatic substituents (1v and 1w) were hydrogenated (E-
isomer) in high levels of reactivity (99% yield), and good enantioselectivity (81% and
84% ee respectively).
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Table 3. Asymmetric hydrogenation of tetrasubstituted maleate olefins.
aReaction conditions: 0.1 mmol substrate, 0.5 mol% catalyst H, 0.5 mL CH2Cl2. bReaction
conditions: 0.2 mmol substrate, 1.0 mol% catalyst D, 2.0 mL Benzene. c2.0 mol% catalyst
d
H. 130 bar H2. Enantiomeric excess was determined by SFC-HPLC analysis using a
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chiral stationary phase. All yields are isolated yield. Conversions were determined by
1H-NMR spectroscopy.
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To investigate the substrate scope of this atom-economical process in addition to the
di-esters, several mono-functionalized olefins were also investigated (Table 4). Catalyst
I was found to hydrogenate , -unsaturated ester 3a to give 4a in high yield (99%) and
excellent 90% ee. For ester 3b catalyst D provides best result in 50% yield with
enantioselectivity of 94% ee. Similarly, , -unsaturated sulfone 3c was successfully
hydrogenated using catalyst J with high level of enantioselectivity (90% ee) but in only
22% isolated yield. Chemoselective hydrogenation of the olefin for , -unsaturated
ketone 3d was also successful under optimized reaction condition in high 90% yield
with excellent 95% ee.
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Table 4. Asymmetric hydrogenation of mono-functionalized tetrasubstituted olefins.
Reaction conditions: 0.05 mmol substrate, 1.0 mol% catalyst, 0.5 mL CH2Cl2. The
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conversions were determined by H-NMR spectroscopy. Catalyst I, catalyst D,
ccatalyst J, catalyst D in benzene. Enantiomeric excess determined by SFC-HPLC
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analysis using a chiral stationary phase and GC analysis using a chiral stationary phase.
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The trifluoromethyl group (-CF3) by virtue of its special properties provides a pivotal
role in pharmaceuticals, agrochemicals and material chemistry such as liquid crystals.13
To further study the boundaries of this highly stereoselective hydrogenation process,
we also evaluated a number of tetrasubstituted trifluoromethyl olefins that results in
synthetically useful chiral trifluoromethyl molecules with two contiguous stereogenic
centers (Table 5). Optimization using (E)-ethyl trifluoromethyl-3-phenylbut-2-enoate 5a
as the standard substrate proved that catalyst B is most suitable (see Supporting
Information for optimization details). Both E- and Z-isomer of trifluoromethyl
containing , -unsaturated ethyl ester could be hydrogenated in good to excellent
enantioselectivity. E-isomer 5a provides 98% yield and 97% ee, whereas the opposite Z-
isomer 5b resulted in product 6b with 84% ee albeit in only 13% conversion. The
established catalytic system proved effective for a large variety of different esters (5c-5f)
and produced the desired products in good to excellent yield (48-99%) and high
enantioselectivities (91->99% ee). Weak electron-donating (Me) substituent on the
aromatic ring 5g was well tolerated and the best result of 68% yield and 97% ee was
obtained by using catalyst D. Another significant advantage of the reaction is that
substrates (5h and 5i) having aliphatic substituents can be hydrogenated in high yields
(99%) and good levels of stereoselectivity (88% ee and 82% ee respectively). The fruitful
examples of this reported reaction conditions to synthesize chiral trifluoromethyl
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molecules with two contiguous stereogenic centers in mostly good to excellent yield,
with exceptional diastereoselectivities (>99%) and enantioselectivities (up to >99%)
again underlines that this catalytic system is very general for tetrasubstituted
trifluoromethyl-olefins.
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Table 5. Asymmetric hydrogenation of CF3 containing tetrasubstituted olefins.
2
Ir-N,P catalyst (1 mol%)
R2
F3C
* * R
F3C
R1
H2 (100 bar)
R1
CO2R
CO2R
CH2Cl2, r.t., 22 h
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6
F3C
CO2Et
F3C
Me
F3C
Me
F3C
Me
* *
Me
CO2Me
CO2H
CO2Et
6da
6ba
6ca,b
6aa
88% yield
93% ee
13% conv.
84% ee
99% yield
96% ee
98% yield
97% ee
X-ray structure
F3C
F3C
Me
F3C
nBu
F3C
Me
Me
F3C
Et
Me
CO2Et
6gc
CO2Et
CO2Ph
Me
CO2Et
CO2Et
6hd
6id
6fa
6ea
99% yield
88% ee
99% yield
82% ee
68% yield
97% ee
Me
60% yield
>99% ee
48% yield
91% ee
Reaction conditions: 0.05 mmol substrate, 1.0 mol% catalyst, 0.5 mL CH2Cl2. a1.0 mol%
catalyst B. bCorresponding tBu ester was used as starting material for compound 6c and
c
used for absolute configuration determination (CCDC 1907708). 1.0 Mol% catalyst D.
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d1.0 Mol% catalyst C, The conversion was determined by H-NMR spectroscopy.
Enantiomeric excess determined by SFC-HPLC analysis using a chiral stationary phase
and GC analysis using a chiral stationary phase.
The practicality of this Ir-catalyzed hydrogenation reaction was confirmed for the large
scale production of chiral succinate derivative. A gram-scale set-up using for 1.0 g of
starting material 1b, 0.5 mol% of catalyst H produced the desired compound 2b in
excellent 96% yield and >99% ee. Hydrogenolysis using Pd-C in EtOH under 1 bar
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hydrogen pressure resulted in the desired 4-ethoxy-3-methyl-4-oxo-2-phenylbutanoic
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acid 7 in 98% isolated yield with 99% ee (Scheme 2).
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Scheme 2. Gram-scale production of chiral succinate derivative
Having two different ester groups in the hydrogenated product 2b is very useful since
they can be easily differentiated by an orthogonal deprotection (Scheme 3). Lactone 8
was prepared via selective reduction of the ethyl ester group of 7 using LiBH4 to
generate 4-hydroxy-3-methyl-2-phenylbutanoic acid. Under acidic conditions this
intermediate cyclized to produce lactone 8 in 61% isolated yield in 98% ee. The regio-
isomeric cis-lactone 9 was prepared in 78% isolated yield with excellent 99% ee via a
divergent route using a one-pot, chemo-selective reduction of the carboxyl acid group
using BH3.SMe2 followed by cyclization in the presence of PTSA. Both the selective
reduction and cyclization reaction proceeds with excellent preservation of
stereochemistry.
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Scheme 3. Derivatization of enantiomeric compounds from hydrogenation reaction via
chemoselective reduction.
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To demonstrate the synthetic utility of the developed methodology, the reaction was
successfully applied for the formal synthesis of anticancer agent BMS-871 and calcium
channel-blockers Verapamil and Gallopamil (Scheme 4). Hydrogenated product 2f was
efficiently converted to the butyrolactone 10a in 87% yield and 91% ee using the two-
step strategy of hydrogenolysis and selective reduction of the carboxylic acid, followed
by cyclization as discussed in the reaction sequence of Scheme 3. Similarly, succinate
derivatives 2n and 2o were converted to corresponding butyrolactones 10b or 10c in
good yields and excellent ee. Butyrolactone 10a, 10b or 10c are precursors for the formal
synthesis of aforesaid bioactive molecules.6d, h
Scheme 4. Enantioselective formal synthesis of BMS-871, (2S)-(-)-Verapamil, (2S)-(-)-
Gallopamil.
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Reaction condition (a) H2 (1 bar), Pd/C (10 mol%), EtOH, r.t., o.n. (b) BH3.SMe2 (3
equiv.), THF, r.t., o.n.; PTSA (1.0 equiv.), THF, r.t., 24h. (c) LiBH4 2M in THF (10 equiv.),
THF, reflux, 7h.
CONCLUSION
A variety of tetrasubstituted, acyclic olefins have been successfully evaluated in
asymmetric hydrogenation using catalytic amounts of new N, P-iridium catalysts (0.5-1
mol%). Two adjacent stereogenic centers were introduced during the asymmetric
hydrogenation with complete diastereoselectivity and excellent enantiomeric excess (up
to >99%). The enantiomerically enriched succinate derivatives were converted to chiral
building block butyrolactones by simple and easy reaction condition via hydrogenolysis
followed by chemoselective reduction and lactonization, respectively. The feasibility
and the utility of this protocol were finally confirmed by the gram-scale synthesis of
useful building blocks and by the formal stereoselective synthesis of anticancer agent
BMS-871 and pharmaceuticals (2S)-(-)-Verapamil, (2S)-(-)-Gallopamil.
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The Supporting Information is available free of charge on the ACS Publications website.
Experimental procedures, crystallography reports, and analytical data (PDF)
Crystallographic data for 6c (CIF)
AUTHOR INFORMATION
Corresponding Author
*Pher.Andersson@su.se
Author Contributions
‡ S.K., S.P. and J.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The Swedish Research Council (VR), Stiftelsen Olle Engkvist Byggmästare, Knut and
Alice Wallenberg Foundation (KAW 2016.0072 and KAW 2018:0066) supported this
work. We thank Dr. Thishana Singh, School of Chemistry and Physics, University of
Kwazulu-Natal, South Africa, for proof reading and editing the manuscript.
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SYNOPSIS
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A
HO
MeO
O
O
H
O
O
H
H
H
H
O
H
O
H
H
H
O
O
N
O
O
N
O
H
O
H
N
H
O
HO
H
H
O
Stemonine
tuberostemonol
B
Cinnamomumolide
Stenine
R
Me
NC
Ar
Me
Me
O
O
COOH
COOH
OMe
N
NH2
N
OMe
N
H
N
O
N
H
Ar = 3,4-(MeO)2Ph;
[(2S)-(-)-Verapamil]
Ar = 3,4,5-(MeO)3Ph;
[(2S)-(-)-Gallopamil]
R = OMe ;
Methoxyphenylkainic acid
R = H ;
CF3
BMS-871
anticancer agent
Phenylkainic acid
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O
LiBH4 2M in THF
(10 equiv.)
O
O
2M HCl
r.t., o.n.
HO
OH
THF, reflux, 7h
Me
Me
O O
8
HO
OEt
61% yield
98% ee
Me
O
PTSA
(1.0 equiv.)
O
O
BH3.SMe2
(3 equiv.)
7
HO
OEt
99% ee
THF, r.t., 24h
Me
THF, r.t., o.n.
Me
9
78% yield
99% ee
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