Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins

Article abstract of DOI:10.1002/anie.201912640

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio- and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio- and diastereoselectivity.

Full text of DOI:10.1002/anie.201912640

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Asymmetric Hydrogenation of Unfunctionalized, Tetrasubstituted,
Acyclic Olefins
Authors: Raphael Bigler, Kyle A. Mack, Jeff Shen, Paolo Tosatti,
Chong Han, Haiming Zhang, Michelangelo Scalone, Andreas
Pfaltz, Scott E. Denmark, Stefan Hildbrand, and Francis
Gosselin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912640
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10.1002/anie.201912640
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Hydrogenation of Unfunctionalized, Tetrasubstituted,
Acyclic Olefins
Raphael Bigler,*[a] Kyle A. Mack,[b] Jeff Shen,[b] Paolo Tosatti,[a] Chong Han,[b] Stephan Bachmann,[a]
Haiming Zhang,*[b] Michelangelo Scalone,[a] Andreas Pfaltz,[c] Scott E. Denmark,[d] Stefan Hildbrand,[a]
and Francis Gosselin*[b]
Abstract: Asymmetric hydrogenation has evolved as one of the most
powerful tools to construct stereocenters. However, the asymmetric
hydrogenation of unfunctionalized, tetrasubstituted, acyclic olefins
remains the pinnacle of asymmetric synthesis and an unsolved
challenge. We report herein the discovery of an iridium catalyst for the
first, generally-applicable, highly enantio- and diastereoselective
hydrogenation of such olefins and the mechanistic insights of the
reaction. The power of this chemistry is demonstrated by the
successful hydrogenation of a wide variety of electronically and
sterically diverse olefins in excellent yield, enantio- and
diastereoselectivity.
1,1-disubstituted and trisubstituted alkenes affords products with
single stereocenter, the asymmetric hydrogenation of
a
tetrasubstituted olefins (AHTO) can generate two vicinal
stereocenters and thus give rise to products of higher
stereochemical complexity. Owing to the aforementioned reasons
and the challenges associated with their steric encumbrance,
unfunctionalized, tetrasubstituted, acyclic olefins arguably
represent the most challenging substrate class for asymmetric
hydrogenation.[4,5]
After an initial report by Buchwald on the asymmetric
hydrogenation of unfunctionalized tetrasubstituted olefins using a
highly electrophilic but sensitive ansa-zirconocene catalyst,[6]
Pfaltz’ application of iridium/phosphinyl oxazoline (PHOX)
complexes[7] paved the way for the development of several related
catalysts.[8,9] In all cases, the investigated substrates were
restricted to simple cyclic 2,3-disubstituted indenes, 3,4-di-
substituted 1,2-dihydronaphthalenes or, if acyclic, trimethyl-
styrenes (Figure 1). In most cases, the iridium catalysts show
variable enantioselectivity and little functional group tolerance.
Thus, while considerable progress has been made for
functionalized analogues,[5,10] the asymmetric hydrogenation of
unfunctionalized, tetrasubstituted, acyclic olefins has remained an
open challenge.
Introduction
Over the past decades, the asymmetric hydrogenation of C=C,
C=O, and C=N double bonds has matured to become one of the
prevalent methods to install stereocenters in organic molecules
with several industrial processes relying on its chemical
prowess.[1] Moreover the awarding of half of the 2001 Nobel prize
in chemistry for asymmetric hydrogenation is testament to its
transformational impact on organic synthesis.[2] Among the most
challenging substrates to date are unfunctionalized olefins, as
they lack both nearby heteroatoms acting as transient
coordinating groups to the metal center or polarity effects
activating the double bond.[3] Whereas the reduction of
[a]
Dr. Raphael Bigler, Dr. Paolo Tosatti, Dr. Stephan Bachmann, Dr.
Michelangelo Scalone, Dr. Stefan Hildbrand
Pharmaceutical Division, Small Molecules Technical Development,
Department of Process Chemistry and Catalysis
F. Hoffmann-La Roche Ltd
4070 Basel, Switzerland
E-mail: raphael.bigler@roche.com
[b]
Dr. Kyle A. Mack, Jeff Shen, Dr. Chong Han, Dr. Haiming Zhang, Dr.
Francis Gosselin
Department of Small Molecule Process Chemistry
Genentech, Inc., 1 DNA Way
South San Francisco, California 94080, United States
E-mail: zhang.haiming@gene.com, gosselin.francis@gene.com
Prof. Dr. Andreas Pfaltz
Department of Chemistry
University of Basel
4056 Basel, Switzerland
Prof. Dr. Scott E. Denmark
Roger Adams Laboratory, Department of Chemistry
University of Illinois
Urbana, Illinois 61801, United States
Figure 1. Commonly investigated substrates and state-of-the-art catalysts. ArF
= 3,5-bis(trifluoromethyl)phenyl; oTol = ortho-tolyl.
[c]
[d]
Recently, we disclosed efficient methods for the
stereoselective synthesis of tetrasubstituted, acyclic olefins,[11]
whose enantioselective reduction would give rise to intriguing
structural motifs inaccessible with state-of-the-art synthetic
methods. In this article, we report the first generally-applicable,
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201912640
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RESEARCH ARTICLE
highly enantio- and diastereoselective hydrogenation of such
unfunctionalized, tetrasubstituted, acyclic olefins.
2aa) and very challenging alkyl-triaryl olefins (2ae–ai) were all
hydrogenated with excellent yield, er and dr. Importantly, catalyst
(R)-1o provided optimal results for all tested substrates, thus
obviating the need to build up large catalyst libraries often
required for other iridium-based catalyst systems.[7a,8a] Low
enantioselectivity was observed only for extremely challenging
substrates, i.e. in which the Re- and Si-faces are differentiated
only by the electronic properties of the aromatic substituents
((Z)-2c and 2ac) or the length of an alkyl substituent (2ab) as well
as for trialkyl-aryl substrate 2ad. In addition, both enantiomers of
the catalyst are readily available. Thus, the application of (R)-1o
and (S)-1o in the asymmetric hydrogenation of 1,1-dialkyl-2,2-
diaryl olefins (E)-2aj and (Z)-2aj allowed access to all four
stereoisomers of the product 3aj with outstanding stereo-
selectivities (Figure 3b).
Results and Discussion
(E)-2,3-Diphenylbut-2-ene ((E)-2a) was chosen as
a
representative starting point for our study (Figure 2). An initial
parallel screening of a subset of 34 iridium catalysts in our catalyst
library (see Figure S1 and Table S1 in the Supporting Information)
led to rapid hit identification. The best-performing PHOX-type
complex (S)-1a[7a] afforded the desired product (2R,3R)-3a in 80%
conversion and a diastereomeric ratio (dr) of 98:2 under relatively
mild conditions (2 mol% catalyst, 50 bar H2, PhCl, 30 °C, 24 h),
albeit with a poor enantiomeric ratio (er) of 80:20. Fortunately, the
modular synthetic approach to catalysts bearing such phosphino-
methyl-oxazoline ligands allowed for efficient structure
optimization and a secondary serial screening of 15 variants (see
Figure S2 and Table S2 in the Supporting Information) identified
(R)-1o as the optimal catalyst, now affording the desired product
(2S,3S)-3a with >99% conversion, 98:2 dr and substantially
improved enantioselectivity (98:2 er).
The reaction was preparatively useful and readily scalable:
the asymmetric hydrogenation of Bpin-containing olefin (E)-2k
occurred with virtually the same efficiency on a gram scale (Figure
3c). This allowed for the preparation of (2S,3S)-3k and its use in
different post-hydrogenation chemical modifications of interest to
medicinal chemists,[13] highlighting the utility of this asymmetric
hydrogenation protocol to introduce vicinal stereocenters in
organic synthesis.
Although similar catalysts to (R)-1o, for example catalyst
(S)-1j bearing a phenyl group instead of the 3,5-bis-tert-
butylphenyl motif, have previously been reported by the Pfaltz
group,[7a] the introduction of two tert-butyl groups has a substantial
effect on the activity and selectivity of the catalyst, which is
particularly pronounced for challenging substrates. For example,
the hydrogenation of (Z)-2aa with (R)-1o occurs in 98% yield with
95:5 dr and 99:1 er. In contrast, its phenyl analogue (S)-1j only
achieves 17% conversion with 91:9 dr and 97:3 er under
otherwise identical conditions. Furthermore, employing analogue
(S)-1c bearing diphenylphosphine and iso-propyl oxazoline
donors failed to give any of the desired product, whereas it was
the catalyst of choice for cyclic tetrasubstituted olefins and
trimethylstyrenes (see Table S3 in the Supporting Information for
additional examples). These results clearly highlight the
challenges associated with the hydrogenation of acyclic,
tetrasubstituted olefins and the substantial improvement achieved
by introducing a 3,5-bis-tert-butylphenyl motif on the oxazoline
donor.
Figure 2. Catalyst screening and optimization for the asymmetric hydrogenation
of (E)-2a (conversion to product is reported). (S)-1a and (R)-1o afford opposite
enantiomers of 3a.
Catalyst (R)-1o proved highly successful in the hydrogenation
of a broad range of substrates (Figure 3a). Both electron-rich and
electron-deficient substituents were well tolerated on the (E)-1,2-
dimethyl-1,2-diaryl olefin core ((E)-2a–f,h). Only the most
electron-deficient alkene (E)-2g bearing two trifluoromethyl
groups on the aryl substituents could not be hydrogenated
successfully. The enantiomeric ratio of the major diastereomer
remained high (>99:1–97:3 er), whereas the minor diastereomer
showed low enantiomeric purity throughout (63:37–50:50 er).
Crucially, several important functional groups such as Cl (2i),
TMS (2j), Bpin (2k), NHCOCF3 (2l), OAc (2m), CO2Me (2n),
OTIPS (2o) and OBn (2p and 2q) were compatible and did not
affect the efficiency of this transformation.
To shed light on the origin of diastereoselectivity, we
conducted the hydrogenation of (E)-2d under D2-atmosphere and
observed incomplete deuterium incorporation at the benzylic
positions as well as partial deuteration of the formerly allylic
positions indicating the possibility of a competing β-hydride
elimination/reinsertion pathway (Figure 4a). This observation is
particularly relevant for the formation of the minor diastereomer,
in which only 55% D-incorporation was observed at both benzylic
positions. Although only a small KIE was observed when
performing the reaction under D2 vs. H2 (kH/kD
= 1.3),
perdeuteration of the methyl groups in (E)-2a led to a consider-
able KIE of 2.0 in a competition experiment (Figure 4b). The
increased KIE is potentially caused by the multiplicative effect of
deuterium atoms,[14] underlining the non-innocence of the allylic
hydrogens in the catalytic cycle. However, hydrogenation of the
The substrate scope is not restricted to the (E)-1,2-dimethyl-
1,2-diaryl substructure: several other (E)-1,2-dialkyl-1,2-diaryl
olefins ((E)-2r–y), but also 1,1-dialkyl-2,2-diaryl olefins (2z and
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10.1002/anie.201912640
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RESEARCH ARTICLE
Figure 3. Ir-catalyzed asymmetric hydrogenation of unfunctionalized, tetrasubstituted, acyclic olefins. The general reaction scheme is shown at the top. a,b) Isolated
yields are reported (except for (2S,3S)-3g); dr and er (major diastereomer) are obtained from the crude reaction mixtures after filtration through silica gel. Absolute
configurations of products are assigned in analogy to (2S,3S)-3k and (1S,2S)-3ah, for which it was determined by X-ray crystallography.[12] c) Scale-up of the
synthesis of (2S,3S)-3k at 1.26 g (3.8 mmol) and post-modifications (see Supporting Information for details) of (2S,3S)-3k. Isolated yields are shown for post-
modification products (dr > 20:1 for all isolated products). Ac = acetyl; Bn = benzyl; pin = pinacolato; TIPS = triisopropylsilyl; TMS = trimethylsilyl.
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Figure 4. Mechanistic experiments. a) Deuterium incorporation in AH of (E)-2d. b) Kinetic isotope effects in AH of (E)-2a. c) AH of isomerized compounds 4a. AH
of (R)-4a and (S)-4a affords (S,S)-3a and (R,R)-3a as the minor diastereomer, respectively.
isomerized olefins 4a favored the formation of meso-3a, thus
showing that non-metal-bound 4a is not an intermediate in the
main catalytic cycle (Figure 4c).
(E)-2a with catalyst (R)-1o, we propose a plausible mechanistic
pathway (Figure 5) with a main Ir(III)/Ir(V) catalytic cycle in which
the resting state of the catalyst is the Ir(III) dihydride species
Ir-I.[15,16] Endergonic coordination of (E)-2a to Ir-I leads to the
formation of Ir-II. Subsequent endergonic coordination of Ir-II and
H2, followed by simultaneous hydride transfer (migratory inser-
On the basis of previous studies on Ir-catalyzed
hydrogenations, our experimental observations, and DFT
calculations for the asymmetric hydrogenation of model substrate
H
H
Ph
Me
Ph
Ph
Me
Ph
Ir-I
H
H
Me
Me
Ph
Me
Ph
Ph
Me
Ph
H
H
(2R,3R)-3a
(2S,3S)-3a
Ir-I
Me
+
Ir
H
H
L*
H
H
H2
meso-3a
H
H
Ir-V
Ph
Me
Ph
H
H
H
H
Ph
Me
Ph
Me
+
Ph
H
Me
Ph
Ph
H
Me
Ph
Ir-I
N
P
H
+
Ir
+
Ir
H
L*
H
Ph
L*
Ph
+
+
+
(R)-4a
H
H
Ir L*
Ir L*
Ir
H
H
H
H
H
H
Ir-I
H
H
Ir-III'
Ir-V'
H
Ir-III
H
Ir-IV
Ph
Me
Ph
L*
Ph
Me
+
Ph
Me
Ph
Me
+
H2
H
H
H2
H2
+
Ir
Ir
H
Ir
H
H2
H
L*
L*
H
Me
Ph
Me
Ph
Me
Ph
Ir-IV'
Ir-II'
(E)-2a
Ir-II
path to minor enantiomer
paths to major enantiomer
path to minor diastereomer
TS3
TS1'
TS1
TS2'
TS2
TS1'
TS1
TS2
TS3
Figure 5. Catalytic cycle, which includes provisions for the formation of (2S,3S)-3a (black and blue), minor enantiomer (2R,3R)-3a (red), and diastereomer meso-
3a (violet). Gibbs free energies for relevant ground state and transition state structures of the proposed catalytic cycle and 3D representations of key transition
states along the reaction coordinate.[17] See Supporting Information for more details.
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10.1002/anie.201912640
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RESEARCH ARTICLE
tion) and oxidative addition of H2 generates Ir(V) intermediate
Ir-III. The enantioselectivity is dictated by the relative barriers of
the hydride transfer/oxidative addition step in accordance with the
alternative Ir(I)/Ir(III) catalytic cycle (see Supporting
Information),[18] which was only +1.1 kcal/mol higher in energy
than the proposed Ir(III)/Ir(V) cycle, exhibited high er (>>99:1) but
Curtin-Hammett principle. For this particular olefin-catalyst pairing, an attenuated difference in energy between reductive elimination
the experimental er (98:2) is in excellent agreement with the
calculated relative energy difference of 2.3 kcal/mol (97:3 er). In
a previous report, Bayer et al. suggested that the stereochemical
outcome of a similar reaction is influenced by a key C–H/π
dispersive interaction between the substrate aryl ring and the
oxazoline moiety.[15e] Comparing TS1 and TS1’ (Figure 5), it is
clear that there is a much more efficient overlap of the aryl ring
with the oxazoline C–H group in TS1. Furthermore, to
accommodate this interaction in TS1’, the 3,5-bis-tert-butylphenyl
group must rotate away from the substrate, which causes a
distortion in the ligand backbone due primarily to steric clash with
the adjacent cyclohexane substituent. These powerful
interactions are particularly prominent in the hydrogenation of
tetrasubstituted olefins where the substrate cannot orient itself to
place a vinyl hydrogen proximal to the oxazoline ring.
and β-hydride elimination (0.5 kcal/mol). Both mechanisms
include intermediate Ir-II (Figure 6). However, while H2
coordination is required in the Ir(III)/Ir(V) cycle, this intermediate
undergoes direct hydride transfer (migratory insertion) in the
Ir(III)/Ir(I) cycle to give Ir(III) intermediate Ir-VI, which can
reductively eliminate to give product and Ir(I) species Ir-VII. Given
these results, it is likely that a H2 pressure-dependent shift in
mechanism from Ir(III)/Ir(V) at high pressure to Ir(I)/Ir(III) at low
pressure is operative, accounting for the reduced dr at lower
pressure.
Conclusion
Asymmetric hydrogenation of olefins has been a heavily studied
area for decades. However, despite recent advances, a general
method for highly selective asymmetric hydrogenation of
unfunctionalized, tetrasubstituted, acyclic olefins has remained
elusive. In this report, we have developed a catalyst which allows
for the first time to successfully hydrogenate these challenging
substrates and we have also demonstrated its generality,
scalability and selectivity. We believe that this advance will have
an important impact in catalysis and synthesis as it allows rapid
access to complex structural motifs inaccessible with other state-
of-the-art methods.
Reductive elimination of intermediate Ir-III affords the hydro-
genated product (2S,3S)-3a and regenerates the Ir(III) dihydride
catalyst Ir-I. Intermediate Ir-III may also undergo a competitive β-
hydride elimination and simultaneous reductive elimination of H2
to give intermediate Ir-IV. The calculated energy barrier
corresponds to a 98:2 preference for reductive elimination over
the β-hydride elimination. Complex Ir-IV undergoes either H2
coordination and oxidative addition/migratory insertion to produce
Ir-V, which reductively eliminates leading to product formation of
(2S,3S)-3a, or exchange of Re- and Si-bound olefin complexes
by decomplexation/recomplexation to arrive at Ir-IV′.[15c] From
Ir-IV′, a related sequence produces the minor diastereomer
meso-3a.
Experimental Section
Interestingly, performing the reaction with (E)-2a under 2 bar
of H2 (instead of 50 bar) still leads to full conversion and high er
(99:1) but with significantly eroded dr (78:22). Calculations on an
A representative procedure for the asymmetric hydrogenation of
unfunctionalized, tetrasubstituted, acyclic olefins is as follows. In
a glove box, (E)-2a (20.8 mg, 100 μmol) and (R)-1o (3.3 mg, 2.00
μmol) are added to a 30 mL autoclave with glass inset. PhCl (1.0
mL, degassed under Ar) is added to the mixture and the autoclave
is sealed and removed from the glove box. The autoclave is
connected to a H2 line, flushed three times with H2 (3 × 20 bar)
and sealed under H2 (50 bar). The autoclave is placed in a pre-
heated metal block and stirred at 30 °C for 24 h. The pressure is
released and the solvent is removed under reduced pressure. The
crude product is dissolved in TBME (1 mL) and filtered through a
pad of silica gel with TBME (5 mL). The solvent is removed under
1
reduced pressure and the product is analyzed by H NMR, GC
and chiral HPLC. Full experimental details and characterization of
the compounds are given in the Supplementary Information.
Acknowledgements
We thank A. Alker, R. Santillo, P. Schmitt, A. Becht Joerger, I.
Duffour, O. Fuchs, M. Buerkler, P. Cron, I. Plitzko, C. Wyss
Gramberg, C. Bartelmus, S. Brogly, O. Scheidegger and N.
Valente for experimental and analytical support. We are grateful
to the Roche technology, innovation and science committee for
funding.
Figure 6. Pressure-dependent shift of mechanism.
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Keywords: asymmetric catalysis • hydrogenation •
tetrasubstituted olefins • iridium • N,P ligands
[16] We also surveyed alternative mechanisms including Ir(I)/Ir(III) and
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[12] Details of the crystallographic analyses are given in the Supporting
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10.1002/anie.201912640
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
RESEARCH ARTICLE
Ligand optimization enables the
asymmetric hydrogenation of
unfunctionalized, tetrasubstituted,
acyclic olefins, which installs two
vicinal stereocenters with excellent
stereoselectivies.
Dr. Raphael Bigler, Dr. Kyle A. Mack,
Jeff Shen, Dr. Paolo Tosatti, Dr. Chong
Han, Dr. Stephan Bachmann, Dr.
Haiming Zhang, Dr. Michelangelo
Scalone, Prof. Andreas Pfaltz, Prof.
Scott E. Denmark, Dr. Stefan Hildbrand,
Dr. Francis Gosselin
Page No. – Page No.
Asymmetric Hydrogenation of
Unfunctionalized, Tetrasubstituted,
Acyclic Olefins
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