Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes

Article abstract of DOI:10.1002/anie.202107267

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

Full text of DOI:10.1002/anie.202107267

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-
Hydrogenation of 1,4-Dienes
Authors: Pher G. Andersson, Haibo Wu, Hao Su, Erik J. Schulze, Bram
B. C. Peters, Mark D. Nolan, Jianping Yang, Thishana Singh,
and Mårten S. G. Ahlquist
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202107267
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10.1002/anie.202107267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-
Hydrogenation of 1,4-Dienes
Haibo Wu,[a] Hao Su, [b] Erik J. Schulze,[a] Bram B. C. Peters,[a] Mark D. Nolan,[a] Jianping Yang,[a]
Thishana Singh,[c] Mårten S. G. Ahlquist,[b] and Pher G. Andersson*[a][c]
Dedication ((optional))
[a]
H. Wu, E. J. Schulze, B. B. C. Peters, M. D. Nolan, J. Yang and Prof. P. G. Andersson
Department of Organic Chemistry
Stockholm University
Stockholm SE-10691, Sweden
E-mail: pher.andersson@su.se
[b]
[c]
Dr. H. Su and Prof. M. S. G. Ahlquist
School of Biotechnology
KTH Royal Institute of Technology
Stockholm SE-106 91, Sweden
Dr. T. Singh and Prof. P. G. Andersson
School of Chemistry and Physics
University of Kwazulu-Natal
Private Bag X54001, Durban, 4000, South Africa
Supporting information for this article is given via a link at the end of the document.
Abstract: Transition-metal-catalyzed asymmetric hydrogenation of
olefins is one of the most fundamental transformations for the
production of chiral compounds. However, the control of site
selectivity in asymmetric mono-hydrogenation of dienes or polyenes
remains largely underdeveloped. Herein, we present
a highly
efficient desymmetrization of 1,4-dienes via iridium-catalyzed site-
and
enantioselective
the
hydrogenation.
This
methodology
hydrogenative
demonstrates
first iridium-catalyzed
desymmetriation of meso dienes and provides a concise approach to
the installation of two vicinal stereogenic centers adjacent to an
alkene. High isolated yields (up to 96%) and excellent diastereo- and
enantioselectivities (up to 99:1 d.r. and 99% ee) were obtained for a
series of divinyl carbinol and divinyl carbinamide substrates. DFT
calculations reveal that an interaction between the hydroxyl oxygen
and the reacting hydride is responsible for the stereoselectivity of the
desymmetrization of the divinyl carbinol. Based on the calculated
energy profiles, a model that simulates product distribution over time
was applied to show an intuitive kinetics of this process. The
usefulness of the methodology was further demonstrated by the
synthesis of the key intermediates of natural products Zaragozic acid
A and (+)-Invictolide.
Introduction
Figure 1. (a) Strategies for site-selectivity control in asymmetric mono-
hydrogenation of dienes. (b) Ir catalyzed hydrogenative desymmetrization of
1,4-dienes
Asymmetric hydrogenation of olefins has proved to be a
powerful tool to produce enantiomerically enriched compounds
on both laboratory and industrial scale.1 Meanwhile, olefins are
not only versatile precursors for
a
variety of organic
transformations but also a common functional group ubiquitous
in natural products, pharmaceuticals, and fine chemicals.2 In this
regard, the development of efficient methods to precisely control
the site selectivity in the asymmetric mono-hydrogenation of
dienes and polyenes is highly desirable for its further
applications in organic synthesis.3
Despite significant progress in the field of enantioselective
hydrogenation of different types of single olefins,4 the
discrimination between different olefins in the same molecule
remains a challenging task. Classically, in order to differentiate
one olefin from another, a chelating group such as alcohol,3e
carboxyl acid,3f or amino acid
needs to be present in the
3g
vicinity of the target alkene. This strategy was often used in Rh
1
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10.1002/anie.202107267
Angewandte Chemie International Edition
RESEARCH ARTICLE
and Ru catalyzed hydrogenation of functionalized olefin
substrates. In recent years, Pfaltz-type iridium N, P complexes
have emerged as an efficient catalytic system for asymmetric
hydrogenation of minimally functionalized olefins.5 In this case,
controlling the steric difference has become an alternative
strategy for regio-selective mono-hydrogenation of diene
substrates without chelating groups.3h Nonetheless, the
mentioned strategies require either the chelation or steric
difference between the two olefins. Two enantiotopic olefins
within the same molecule with identical chelating and steric
environments makes the selective mono-hydrogenation even
more challenging. This strategy known as desymmetrization has
been widely applied in asymmetric synthesis,6 however, the
hydrogenative desymmetrization of dienes is so far
underdeveloped.6b Initial work in this area was first reported by
Brown in 2009, wherein moderate selectivities (up to 53% ee)
were obtained for penta-1,4-dien-3-ol and its silyl ether by using
Rh bisphosphine catalysts.7 Later, Vidal-Ferran reported a novel
enantioselective hydrogenation. To the best of our knowledge,
this method represents the first example of Ir catalyzed
hydrogenative desymmetrization of dienes. Moreover, the
desymmetrization of N-containing achiral compounds via
asymmetric hydrogenation is still rare.
Results and Discussion
Our initial investigation began with the attempted
desymmetric hydrogenation of meso divinyl carbinol 1a.
Treatment of 1a with
Table 1. Optimization of the reaction conditions[a]
Rh
P-OP
(phosphine-phosphite)
complex
mediated
hydrogenative desymmetrization of similar substrates with
excellent selectivity (up to 92% ee).8 Recently, the Zhang group
described an elegant nickel catalyzed hydrogenative
desymmetrization of conjugated cyclohexadienones, providing
an efficient access to all-carbon quaternary stereocenters.9
Entry
Cat.
P(bar)/T
Conv.(
%) [b]
2a/2a’(%)
2a
[c]
d.r./ee(%)[c]
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
3 bar/1 h
>99
32
89/11
25/7
96:4/97
68:32/96
99:1/99
69:31/99
N.D.[e]
3 bar/1 h
3 bar/1 h
>99
27
64/36
25/2
6 bar/1 h
6 bar/1 h
<5
N.D.[e]
82/18
63/3
Figure 2. Selected examples of natural products and bioactive compounds
containing an allylic alcohol or allylic amide bearing two contiguous chiral
centers adjacent to an alkene.
3 bar/1 h
>99
66
93:7/99
94:6/95
97:3/99
99:1/99
A
C
C
3 bar/20 min
1 bar/10 min
1 bar/10 min
42
42/0
The products that could be derived from a selective mono-
hydrogenation of a meso diene, chiral allylic alcohols and
amines bearing two vicinal stereocenters adjacent to the olefin,
are important structural units widely present in natural products
and pharmaceuticals (Figure 2).10 Conventional approaches for
the synthesis of this type of complex moieties require multi-
sequence steps and high cost of chiral reagents. The
desymmetric hydrogenation of meso dienes would provide a
straightforward strategy in the installation of two contiguous
chiral centers next to the alkene.
Continuing our interest in practical regio-selective
asymmetric hydrogenations,3h, 11 we sought to develop a general
hydrogenative desymmetrization of non-conjugated 1,4-dienes
bearing different functionalities. Herein, we disclose a highly
efficient desymmetrization of divinyl carbinols and divinyl
carbinamines via iridium catalyzed regio-, diastereo- and
>99
95/5
[a] Reaction conditions: 1a (0.05 mmol), 0.5 mol% catalyst and 10 mol%
K2CO3 in Toluene (1.0 mL) at room temperature. [b] Determined by 1H NMR
spectroscopy. [c] Enantiomeric excesses and diastereomeric ratios were
determined by SFC analysis. [d] 0.2 mol% catalyst was used. [e] N.D.: not
determined
an iridium N,P catalyst (A, 0.5 mol%) bearing a imidazole ligand
and K2CO3 (10 mol%) as the additive in toluene at room
temperature under 3 bar of hydrogen for 1 hour gave the desired
mono-hydrogenated product 2a in 89% NMR yield with 96:4 d.r.
and 97% ee (Table 1, entry 1). Next, a series of Ir N,P catalysts
were screened to evaluate the ligand effect (entries 2-6). It was
found that thiazole catalyst C and oxazoline catalyst F could give
equally promising results as catalyst
diastereoselectivity and enantioselectivity. Notably, high levels of
A
in terms of
2
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10.1002/anie.202107267
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RESEARCH ARTICLE
d.r. and ee were obtained in these cases where the
startingsubstrate was fully converted to the mono-hydrogenated
product (entries 1, 3, 6). This experimental observation was
found to be in good agreement with the mathematical model
developed by Schreiber et al. that illustrates the enhanced levels
of ee and d.r. obtained in a class of reactions that proceed with a
combination of enantiotopic group and diastereotopic face
selectivity.12 In order to compare the initial selectivity of catalyst
A and C, the hydrogenations were performed at lower hydrogen
pressure (entries 7, 8). In these cases, catalyst C showed higher
selectivity than catalyst A. Finally, the best result was achieved
by using catalyst C under 1 bar hydrogen for 10 minutes, where
the desymmetrized product 2a was obtained in 95% NMR yield
with
perfect
d.r.
and
ee.
Table 2. Scope of divinyl carbinol
aReaction conditions: substrate (0.2 mmol), 0.5-1.0 mol% catalyst and 10 mol% K2CO3 in Toluene (1.0 mL) under 1-6 bar H2 at room
temperature for 10 min-1 h. Isolated yield. Enantiomeric excesses and diastereomeric ratios were determined by SFC or GC analysis
(see the SI for details)
3
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RESEARCH ARTICLE
With the optimized conditions in hand, we then examined the
scope of this iridium catalyzed desymmetric hydrogenation of
divinylcarbinols (Table 2). Generally, the aromatic substrates
bearing either an electron-donating or election-withdrawing
group at the para or meta position of phenyl ring underwent the
desymmetrization with excellent diastereoselectivities and
enantioseletivities as well as isolated yields (2a-2g). Substrates
bearing naphthyl, furyl and thienyl moieties were also well
tolerated, and the desired products (2h-2j) were obtained in high
yields with excellent selectivities
Table 3. Scope of divinyl carbinamide.
Next, divinyl carbinols with longer aliphatic sidechains on the
alpha position were tested and the corresponding mono-
hydrogenated products could be obtained with excellent
selectivities (2k, 2l). Remarkably, the divinyl tertiary alcohols
smoothly underwent the desymmetrization to afford the target
products (2m-2o) in high yields with very high
diastereoselectivies and enantioselectivities. This is noteworthy
since the resulting tertiary chiral centers are not accessible via
direct asymmetric hydrogenations, and the current strategy
represents a complementary method to the classical asymmetric
vinylation of ketones to prepare enantioenriched trisubstituted
allylic tertiary alcohols.13
Finally, a series of divinyl carbinols having only aliphatic
substituents were also evaluated. Overall, substrates having
linear, branched or cyclic alkyl substituents on the beta position
were all applicable, good to excellent yields and high level of
selectivities were obtained in these cases (2p-2t). The absolute
configuration of alcohol product 2p was determined by oxidative
cleavage of the olefin and comparison of the hydroxyl ketone
with an isoleucine derivative (see the SI for details). In addition,
substrates bearing highly strained cyclopropyl (2u) and
cyclobutyl (2v) underwent the desired desymmetrization
smoothly without any traces of ring-opening via hydrogenolysis.
Interestingly, other functionalities such as phenyl (2w), chloride
(2x) and silyl ether (2y) were also compatible with the very mild
hydrogenation conditions. A substrate containing cyclohexene
moieties was also tested, the desired enantiomerically pure
product (2z) was produced in 96% yield.
[a] Reaction conditions: substrate (0.2 mmol), 1.0 mol% catalyst and 10 mol%
K2CO3 in Toluene (1.0 mL) under 1-6 bar H2 at room temperature for 10 min-1
h. Isolated yield. Enantiomeric excesses and diastereomeric ratios were
determined by SFC or GC analysis (see SI for details)
were performed to investigate the stereoselectivity of the
desymmetrization process. Divinyl carbinol 1a was chosen as
the model substrate and catalyst ent-C was employed in the
studies. Based on our previous theoretical and experimental
investigations on Ir-catalyzed asymmetric hydrogenation of
olefins,14 the mechanism of desymmetric hydrogenation was
proposed (Figure 3). The computational details and the process
of searching for most stable substrate-catalyst complex are
outlined in the Supporting Information (SI).
Given the success of the current desymmetrization of divinyl
carbinols outlined above, we then decided to explore the
desymmetric hydrogention of divinyl carbinamine derivatives
(Table 3), which are a new class of substrates for hydrogenative
desymmetrization. To our delight, the Boc protected divinyl
carbinamines underwent the desired desymmetrization smoothy
employing the same Ir catalyst. Notably, no base additive was
requried for this transformation. Both electron-withdrawing and
electron-donating groups on the phenyl ring were tolerated (4a-
4c). Significantly,
processed to give the corresponding mono-hydrogenated
products (4d-4h) in high yields and excellent
a series of aliphatic substrates were
diastereoselectivities and enantioselectivities. The absolute
configuration of product 4d was assigned as (4S, 5S) by
comparing its ozonolysis product with natural isoleucine
derivative (see the SI for details).
Figure 3. Proposed hydrogenation mechanism
Considering the unusually high level of ee and d.r. of the
desymmetrized products as well as the very broad substrate
scope that is obtained in the current method, DFT calculations
Since the studied meso compound has two enantiotopic and
two diastereotopic faces, all four individual coordination models
of both the first and the second hydrogenation (Scheme 1) were
tested. The calculated free energies of four different
intermediates and the corresponding olefin insertion transition
states of the first hydrogenation are shown in Figure 4a. The
4
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10.1002/anie.202107267
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RESEARCH ARTICLE
following reductive elimination steps were confirmed to have
lower free energies than the olefin insertions in all cases (SI,
Figure S4).
2a(1_1) increases very fast and is accompanied by the
generation of a small portion of 2a(1_3), which is present as a
minor diastereomer in the mixture. As the hydrogenation
proceeds, the amount of 2a(1_1) remains at a certain high level,
however, the minor diastereomer or enantiomer will be
selectivity consumed by a kinetic resolution
The results indicate that product 2a(1_1) will be the major
product of the first hydrogenation but that significant amounts of
2a(1_3) will also form. The free energy difference between
TS1(1_1) and TS1(1_3) is 1.63 kcal/mol, which suggested that
over 90% diastereoselectivity could be observed in this step.
Due to the very much slower formation of 2a(1_2) and 2a(1_4),
here we only discuss the second hydrogenation of 2a(1_1) and
2a(1_3) as shown in Figure 4b (complete reactions are shown in
SI, Figure S5). We found that the activation free energy for the
reaction of the minor mono-hydrogenated product 2a(1_3) via
TS1(2_3) is very low which will lead to a rapid consumption of
Figure 4. Free energy profile for (a) the first hydrogenation; (b) the second
hydrogenation.
process in the second hydrogenation. As a result, excellent level
of ee and d.r. were obtained in the current desymmetrization
process. Notably, the current model could be also applied in a
generic class of reactions that proceed with a combination of
enantiotopic group and diastereotopic face selectivity.
Scheme 1. Hydrogenative desymmetrization process.
2a(1_3). The hydrogenation of 2a(1_1) is significantly slower
and will therefore be close to the only remaining singly
hydrogenated olefin after some time. All of the predictions from
DFT are consistent with the experimental results. The calculated
free-energy profiles reveal that the hydrogenation of 2a(1_2) and
2a(1_4) is slow due to high activation free energies for the olefin
insertion. By examining the structures, it is clear that 2a(1_2)
and 2a(1_4) have an unfavorable substrate-complex
configuration with the olefin double bond oriented in the plane of
the bidentate ligand (SI, Figure S3), instead of the orientation
along the axial Ir-H bond in 2a(1_1) and 2a(1_3). In all favorable
insertion transition states (TS1(1_1), TS1(1_3) (SI, Figure S7)
and TS1(2_2), TS1(2_3) (SI, Figure S8) we found some
interaction between the hydroxyl oxygen atom and the reacting
hydride, evidenced by O1---Ha distances smaller than the sum of
the van der Waals radii.
Figure 5. Kinetic modeling based on the calculated energy. Concentration in
percent of total reactant and product concentration and time in 10-5 seconds
Using rate constants calculated using transition state theory
(assuming a transmission coefficient of 1) with the calculated
activation free energies, we have simulated the product
distribution over time to give a more intuitive demonstration of
the kinetics of the studied process.15 As shown in Figure 5, in
the early stage of the reaction, mono-hydrogenated product
In order to demonstrate the utility of the current
transformation, we synthesized the side chain fragment of
natural product Zaragozic acid A with this desymmetrization as a
key step (Scheme 2). Firstly, a gram scale hydrogenation was
performed, and the desired optically pure product 2a was
5
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10.1002/anie.202107267
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RESEARCH ARTICLE
under hydrogenation condition with ent-C as the catalyst. We
speculated that the γ-butyrolactone formation could be attributed
to the acidic environment generated during the iridium catalyzed
hydrogenation.19
Conclusion
In conclusion, a highly efficient Ir-catalyzed site-selective
desymmetric mono-hydrogenation of 1,4-dienes has been
developed. This method provides a concise route to chiral allylic
alcohols and allylic amides bearing two vicinal stereogenic
centers adjacent to the alkene. It demonstrates the first Ir-
catalyzed hydrogenative desymmetrization of dienes. Impressive
regio-, diastereo- and enantioselectivities (up to 96% yield, 99:1
d.r. and 99% ee) were obtained for a broad range of divinyl
carbinol (secondary and tertiary alcohols) and divinyl
carbinaimde substrates. DFT calculations indicate that an
interaction between the hydroxyl oxygen atom and active Ir-
hydride is most likely responsible for the stereoselectivities.
Modeling based on the calculated energy profiles was applied to
give an intuitive picture of reaction kinetics, which could be also
Scheme 2. Gram scale desymmetrization and application in the synthesis of
alkyl side chain fragment of Zaragozic acid A.
obtained in an undiminished yield. Then, ozonolysis of the
resulting product afforded the hydroxyl ketone 5, which
underwent bromoform reaction and condensation to give
Weinreb amide 6 in 83% overall yield. Next, the inversion of
alcohol was achieved using a Mitsunobu protocol. Finally, the
PMB protection followed by alkylation furnished the target
molecule 9 with 99% ee. Compound 9 is the enantiomer of
Nicolaou’s intermediate, which was initially synthesized in 12
steps with 81% ee.16
applied for
a class of desymmetrizations with enhanced
diastereo- and enantioselectivities. The utility of this method was
further highlighted by the synthesis of the alkyl side chain of
Zaragozic acid A and the formal total synthesis of (+)-Invictolide.
Acknowledgements
The authors are grateful to the Swedish Research Council (VR),
the Knut och Alice Wallenberg Stiftelsen for funding this
research. T.S. acknowledges the NRF South Africa for the Post-
PhD Track Thuthuka Grant. All calculations were performed on
resources provided by the Swedish National Infrastructure for
Computing (SNIC) at PDC Centre for High Performance
Computing (PDC-HPC) through the project “Small molecule
activation by transition metals in complex environments.” SNIC
2020/6-47, and the National Supercomputing Center under the
project numbers SNIC 2019/3-6 and SNIC 2020/6-47 in
Linköping, Sweden. M.S.G.A. is supported by the Swedish
Research Council (VR) Grant Number 2018-05396, and the
Knut
& Alice Wallenberg (KAW) project CATSS (KAW
2016.0072).
Scheme 3. Synthesis of γ-butyrolactones via a sequential desymmetrization
and tandem hydrogenation and lactonization process: Formal total synthesis
of (+)-Invictolide. Reaction conditions: (a) 0.5 mol% Ir cat., 10 mol% K2CO3, 3
bar H2, Toluene, r.t. 30 min; (b) O3, then DMS, CH2Cl2/MeOH 4:1; (c) Benzene,
reflux, 24 h; (d) 4-Nitrobenzonic acid, DTBAD, PPh3, THF; (e) K2CO3, MeOH,
r.t., 1 h; (f) 1.0 mol% Ir cat., 3 bar H2, Toluene, r.t. 1 h.
Keywords: Site selectivity • asymmetric hydrogenation • 1,4-
diene • iridium catalysis
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For a recent book, see: a) Asymmetric Hydrogenation and Transfer
Hydrogenation, (Eds.: V. Ratovelomanana-Vidal, P. Phansavath),
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To further illustrate the usefulness of this methodology, we
continued to explore its potential in the synthesis of γ-
butyrolactones (Scheme 3), which are important structural units
of
a
wide range of pharmacological active molecules.17
Ozonolysis of the desymmetrized product of 10 followed by
hydroxyl-directed Wittig reaction18 afforded the unsaturated ester
(4S, 5S)-12 as a single isomer with excellent d.r. and ee in 64%
overall yield. Surprisingly, the obtained γ-hydroxyl unsaturated
ester can be transformed into lactone (1’S, 4R, 5S)-13 directly
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RESEARCH ARTICLE
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directly lead to product. Such intermediate would slow down all reaction
7
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10.1002/anie.202107267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
A highly efficient site selective desymmetric mono-hydrogenation of 1,4-dienes was reported. This protocol allows rapid access to a
wide range of chiral allylic alcohols and amides bearing two vicinal chiral centers adjacent to the alkene. The utility of this method
was further highlighted by the synthesis of the alkyl side chain of Zaragozic acid A and the formal total synthesis of (+)-Invictolide.
8
This article is protected by copyright. All rights reserved.