Enantioselective Carboetherification/Hydrogenation for the Synthesis of Amino Alcohols via a Catalytically Formed Chiral Auxiliary

Article abstract of DOI:10.1021/jacs.0c09177

Chiral auxiliaries and asymmetric catalysis are the workhorses of enantioselective transformations, but they still remain limited in terms of either efficiency or generality. Herein, we present an alternative strategy for controlling the stereoselectivity of chemical reactions. Asymmetric catalysis is used to install a transient chiral auxiliary starting from achiral precursors, which then directs diastereoselective reactions. We apply this strategy to a palladium-catalyzed carboetherification/hydrogenation sequence on propargylic amines, providing fast access to enantioenriched chiral amino alcohols, important building blocks for medicinal chemistry and drug discovery. All stereoisomers of the product could be accessed by the choice of ligand and substituent on the propargylic amine, leading to a stereodivergent process.

Full text of DOI:10.1021/jacs.0c09177

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Enantioselective Carboetherification/Hydrogenation for the
Synthesis of Amino Alcohols via a Catalytically Formed Chiral
Auxiliary
‡
‡
‡
̌
Luca Buzzetti, Mikus Puriņs, Phillip D. G. Greenwood, and Jerome Waser*
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ABSTRACT: Chiral auxiliaries and asymmetric catalysis are the workhorses of enantioselective transformations, but they still
remain limited in terms of either efficiency or generality. Herein, we present an alternative strategy for controlling the
stereoselectivity of chemical reactions. Asymmetric catalysis is used to install a transient chiral auxiliary starting from achiral
precursors, which then directs diastereoselective reactions. We apply this strategy to a palladium-catalyzed carboetherification/
hydrogenation sequence on propargylic amines, providing fast access to enantioenriched chiral amino alcohols, important building
blocks for medicinal chemistry and drug discovery. All stereoisomers of the product could be accessed by the choice of ligand and
substituent on the propargylic amine, leading to a stereodivergent process.
scope of these transformations remains limited, and auxiliaries
available from the chiral pool are generally required.
urrently, most enantioselective transformations rely on
1
Ctwo strategies: (i) the use of chiral auxiliaries and (ii)
asymmetric catalysis.2 The former allows the development of
general and robust processes, but requires stoichiometric
amounts of enantiopure precursors and multistep procedures.
By contrast, asymmetric catalysis relies only on substoichio-
metric amounts of enantiopure molecules, but it generally
requires an intensive optimization at the expense of robustness
and generality. To overcome these limitations, we envisioned a
catalytic enantioselective method, which would introduce a
chiral auxiliary on the substrate from a cheap nonchiral tether
in a synthetic useful step (Scheme 1A). This process would
require only a catalytic amount of enantiopure species while
providing a robust platform for further diastereoselective
functionalizations, benefiting from the best aspects of the two
traditional strategies. To the best of our knowledge, such an
approach has not yet been realized, although different methods
for improving asymmetric synthesis have been developed. A
seminal work based on the formation of chiral aminals is the
“self-reproduction of chirality” reported by Seebach for the
stereoselective synthesis of amino acids. In this work, the
existing stereocenter on the amino acid first controls the
diastereoselective formation of the aminal by condensation
with an aldehyde. The latter then shields one face of the
enolate.3,4 As another example based on an internal chirality
transfer, Maulide and co-workers recently reported a redox-
neutral coupling of alkenes and aldehydes via a “catch−release”
tethering approach (Scheme 1B).5 However, the resulting
functional group (a ketone) remains in the product. Other
researchers have worked on the concept of “transient chiral
auxiliaries/tethers”, which are easy to install and remove.6−10
For example, Beauchemin and co-workers have used chiral
aldehydes in substoichiometric amounts for the Cope-type
hydroamination of allyl amines (Scheme 1C).11 However, the
To implement our concept, we considered the palladium-
catalyzed carboetherification of propargylic amines,12 based on
the use of trifluoroacetaldehyde-derived tethers (Scheme
1D).13−15 The stereocenter formed in this step could direct
a subsequent functionalization of the double bond, acting de
facto as a chiral auxiliary. The rigid nature of the oxazolidine
scaffold containing the stereocenter should secure a high level
of diasteroselectivity to the following transformations.
Concerning the following diastereoselective functionaliza-
tion, we found the hydrogenation of the formed double bond
particularly attractive. By comparison, the enantioselective
hydrogenation of alkyl- or heteroatom-tetrasubstituted olefins
is highly challenging, with only few limited catalytic
enantioselective systems reported.16−18 After removal of the
tether molecule, this process would provide amino alcohols,
key building blocks in synthetic and medicinal chemistry,
which have been the focus of intensive methodology
development recently.19−26 In particular, the diaryl-substituted
amino alcohols obtained using this strategy can be found in
antidepressants27,28 and have served as intermediates for the
synthesis of antimycotic, antibacterials29 and antiviral mole-
cules.30,31 However, the selective synthesis of one of the four
possible stereoisomers of the amino alcohols generally requires
multistep processes.
To make this process successful, an enantioselective
carboetherification step had to be developed. The reversible
Received: September 1, 2020
https://dx.doi.org/10.1021/jacs.0c09177
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© XXXX American Chemical Society
A

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Scheme 1. (A) Our Concept: Catalytically Formed Chiral
Auxiliaries; (B) Chirality Transfer via Tethering; (C)
Transient Chiral Auxiliaries Introduced from Chiral Pool;
(D) Implementation for the Stereodivergent Synthesis of
Amino Alcohols
Table 1. Optimization Studies
a
entry
Conditions
4 yield (%)
e.e. (%)
1
2
3
4
5
6
7
8
9
Ligand L1, L2 or L3
Ligand L4
Ligand L5
Ligand L6
Ligand L7
Ligand L8
Ligand L9
L9, EtOAc instead of Et2O
L9, MTBE instead of Et2O
L9, Toluene instead of Et2O
<5
44
33
72
49
45
>95
80
89
91
−
20
30
40
64
74
90
84
89
91
94
10
11
b
L9, 0.40 mmol of 1
>95
a
b
NMR yields. Reaction performed using 1.25 mol % of Pd2(dba)3·
CHCl3 and 3.5 mol % of (S,S)-ligand.
stereoinduction in the process (for details, see SI, section
C). Commonly used bidentate BINAP L1 and Josiphos ligands
L2 and L3 were not competent for this reaction (entry 1). The
P,N ligands L4 and L5, derived from the corresponding Ugi’s
amines,36 delivered 4 in moderate yield and enantiomeric
excess (entries 2 and 3), nevertheless demonstrating that a
DYKAT was possible. However, higher asymmetric induction
could not be achieved with this class of ligands. The P,N ligand
S-iPrPhox L6 yielded the desired product in 72% yield and
40% e.e. (entry 4). Promising results were obtained evaluating
the Trost type ligands, commonly used for palladium catalyzed
asymmetric allylation reactions.37,38 In particular, the com-
mercially available DACH-phenyl Trost ligand L7 delivered
product 4 in 49% yield and 64% e.e. (entry 5). Having in mind
the previous positive results obtained with P,N ligands, we
substituted the 2-(PPh2)-aryl fragment with a 2-pyridine.39
This change increased the e.e. to 74% (entry 6). Surprisingly,
the best results were finally obtained employing the benzamide
derived L9 lacking a second strongly coordinating site, which
delivered quantitatively 4 with 90% e.e. (entry 7). To the best
of our knowledge, ligand L9 has been reported only twice in
the literature,40,41 and it was not suitable for imparting high
stereocontrol, as two strong coordinating sites were required
for asymmetric induction. We developed a robust and
operationally simple route for accessing both enantiomers of
L9 on multigram scale (SI, section B4). Demonstrating the
process’s robustness, the reaction could be performed in more
“industrially preferred” solvents42 (ethyl acetate, methyl tert-
butyl ether and toluene, entries 8, 9 and 10), without loss of
yield and enantioselectivity, except for ethyl acetate (entry 8).
Finally, the reaction could be scaled up to a 0.40 mmol scale,
reducing the catalyst and ligand loading to 1.25 and 3.5 mol %,
formation of the hemiaminal I from the propargylic amine
prevents asymmetric induction at this stage (see Supporting
Information (SI), section E for more details). Therefore, a
dynamic kinetic asymmetric transformation (DYKAT) needs
to take place: in the presence of a chiral catalyst, one
enantiomer of I should react preferentially to give oxazolidine
II enantioselectively. Although palladium-catalyzed DYKATs
have been reported,32 the envisaged process is highly
challenging, due to the large distance between the chiral
metal complex and the stereocenter. To the best of our
knowledge, such a DYKAT process has never been realized in
the palladium-catalyzed functionalization of alkynes. If
successful, the selection of the substitution pattern on the
alkyne and on the aryl electrophile, together with the choice of
the suitable enantiomer of the chiral ligand on the palladium
catalyst would provide a simple enantio- and diastereodiver-
gent access to all four stereoisomers of the amino alcohol. This
is especially attractive for medicinal chemistry, as each
stereoisomer may have different bioactivity, and the develop-
ment of stereodivergent methods has been the topic of
intensive research in asymmetric catalysis recently.33−35
We tested the feasibility of our plan by examining the
palladium-catalyzed tethered carboetherification of the readily
available propargylic amine 1 with iodotoluene 2 to access
tetrasubstituted olefin 4 bearing a chiral oxazolidine fragment
(Table 1). 1-Ethoxy trifluoroethanol 3, a commercially
available ethyl hemiacetal of trifluoroacetaldehyde, was chosen
as the electrophilic molecular tether, and Pd2(dba)3·CHCl3, as
the palladium source.12 We first focused on the identification
of a suitable ligand that could secure a high level of
B
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resulting in an improved stereoselectivity of 94% e.e. (entry
11).
The structure of 4, obtained by X-ray single-crystal analysis
(Scheme 2A), shows that the trifluoromethyl group is
diastereoisomer in 79% yield and 94% e.e. (Scheme 2B). The
use of Pearlman’s catalyst also allowed simultaneous removal
of the benzyl protecting group.
Various aryl propargylic amines were well tolerated in the
reaction, regardless of the position of the substituents on the
phenyl ring, as well as their electronic and steric properties
(Scheme 3, 4, 6−14). The geometry of the olefin can be
switched by just exchanging the aryl group on the alkyne and
the aryl iodide (4 vs 6). The reaction tolerates heterocycles
such as pyridine and thiophene on the alkyne, although an
erosion of the enantioselectivity was observed (15 and 16).
Alkyl propargylic amines delivered products 17−19 bearing a
methyl, a benzyl, and a cyclopropyl group. The reaction could
be performed on a 5 mmol scale providing 2.0 g of 4
(quantitative yield) without erosion of the optical purity. The
absolute configuration of the products were assigned by X-ray
analysis of 4, confirming in addition that the aryl group coming
from the iodide is incorporated in trans position to the oxygen.
The investigation of the scope of the iodoarene showed that
numerous synthetically useful functional groups, including
ethers, amines, halogens, esters, nitriles or aldehydes, are well
tolerated independently from their electronic and steric
properties or position on the benzene ring (20−30). 2-
Iodothiophene and 3-iodopyridine delivered products 31 and
Scheme 2. (A) X-ray Crystal Structure of the Product 4; (B)
Optimized Conditions for the Diastereoselective
Hydrogenation
efficiently shielding one of the two enantiotopic faces of the
olefin, setting the stage for the stereospecific hydrogenation.
Indeed, when we submitted 4 to classical conditions for
heterogeneous hydrogenation using Pearlman’s catalyst,43 the
desired hydrogenated product 5 was obtained as a single
a
Scheme 3. Scope of the Enantioselective Carboetherification
a
Reactions performed on a 0.40 mmol scale using 1.3 equiv of aryl iodide and 1.4 equiv of 1-ethoxy trifluoroethanol (3). Isolated yields and HPLC
b
c
d
enantiomeric excess are given. Dichloroethane (DCE) instead of Et2O. Using 2.5 mol % of Pd2(dba)3·CHCl3 and 7 mol % of ligand. DCE at 60
°C.
C
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a
Scheme 4. Scope of the Stereoselective Hydrogenation
a
Reactions performed on a 0.2 mmol scale using Pd(OH)2/C (∼20 wt %). Isolated yields and HPLC enantiomeric excess are given. Product 56
was obtained after treating 5 with TsOH·H2O (7 equiv) in a 2:1 THF/H2O mixture at room temperature for 16 h, the trifluoroacetate salt was
b
obtained after purification by reversed phase preparative HPLC. Pd/C (∼5 wt %) was used instead of Pd(OH)2/C.
32 in good yields. Finally, N-methyl, N-phenyl and N-para-
methoxybenzyl (PMB) propargyl amines delivered products
33−35 in 52−58% yield and 54−92% e.e.
Scheme 5. Diastereo- and Enantiodivergent Access to Chiral
Aminoalcohol Precursors
a
The obtained enantioenriched tetrasubstituted olefins were
then submitted to the optimized conditions for the
diastereoselective hydrogenation (Scheme 4). Products 36−
55 were all obtained as single diastereoisomers, confirming the
robustness of our approach. Scale-up was straightforward and
compound 5 could be obtained in 72% yield on 1.2 mmol scale
without erosion of stereoselectivity. Heterocycles and func-
tional groups containing coordinating N or S atoms and
chlorides were not tolerated in the hydrogenation step (for
details, see SI, Section D5). The nitrile and the carbonyl group
within 25 and 27 were reduced to the corresponding amine 48
and alcohol 50.44 Interestingly, 5, 36, 45, 46, 47 and 54 are
precursors of bioactive compounds with antidepressive
activity,27,28 while the amino alcohols derived from 36 and
47 are intermediates for the synthesis of patented antiviral
drugs candidates.30 Remarkably, our method provides a high
level of asymmetric induction even in the presence of sterically
and electronically similar aryl substituents on the olefin, thus
overcoming a common obstacle in the development of catalytic
asymmetric reactions. Finally, to confirm the traceless nature of
our strategy, we performed a mild acidic hydrolysis of the
hemiaminal in 5. The enantioenriched amino alcohol 56 was
obtained in 76% yield without loss in optical purity.
a
See SI for detailed reaction conditions.
diastereoselective hydrogenation leads to all the stereoisomers
of the desired products 5 and 36. Permuting the iodoarenes in
the cross-coupling and in the carboetherification steps allows
the tuning of the E,Z geometry of the double bond. This
selective process, combined with the choice of the enantiomer
of the ligand, and the diasteroselectivity of the hydrogenation
provide a selective access to the four stereoisomers of the
diaryl amino alcohol precursors.
We then demonstrated that this strategy provides a simple
stereodivergent access to the four possible stereoisomers of
chiral diaryl aminoalcohols by a judicious selection of the
substrates and the ligands (Scheme 5). Starting from the
benzyl propargyl amine 57, a sequence of (i) Sonogashira
coupling, (ii) enantioselective carboetherification and (iii)
D
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In summary, we have developed an innovative strategy to
control the stereoselectivity of asymmetric transformations.45
Our approach first capitalizes on the tools of asymmetric
catalysis to forge a chiral oxazolidine from broadly available
propargylic amines. This stereogenic element is then used to
control the selectivity of the asymmetric hydrogenation of the
tetrasubstituted double bond, giving access to valuable chiral
amino alcohol precursors. The key for success was the first use
of a “truncated” monophosphine Trost-type ligand to induce
high enantioselectivity in an unprecedented DYKAT process.
Combined with a Sonogashira cross-coupling, our approach
gives a stereodivergent access to the four stereoisomers of
protected diaryl amino alcohols in high yield and enantiose-
lectivity. New opportunities for the design and development of
asymmetric functionalizations of olefins can be expected based
on the combination of the enantioselective introduction of a
transient chiral auxiliary followed by a diastereoselective
transformation. Such processes are currently under inves-
tigation in our laboratory.
ACKNOWLEDGMENTS
■
This work is supported by the European Research Council
(ERC Consolidator Grant SeleCHEM, No. 771170 and EPFL.
We thank Dr. R. Scopelliti from ISIC at EPFL for X-ray
analysis. This publication was created as part of NCCR
Catalysis, a National Centre of Competence in Research
funded by the Swiss National Science Foundation.
ABBREVIATIONS
■
Me, Methyl; Bu, Butyl; Pr, Propyl; Cy, Cyclohexyl; Ph, Phenyl;
Bn, Benzyl; p-Tol, p-Tolyl; EtOAc, Ethyl acetate; MTBE,
Methyl tertbutyl ether; Et2O, Diethyl ether; MeOH, Methanol;
AcOH, Acetic acid; dba, Dibenzylideneacetone.
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ASSOCIATED CONTENT
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* Supporting Information
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reaction mechanism; copy of HPLC and NMR spectra
(PDF)
Crystallographic data for the product 4 (CIF)
Crystallographic data for the product 5 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
Jerome Waser − Laboratory of Catalysis and Organic Synthesis,
́
́
Ecole Polytechnique Federale de Lausanne, EPFL, 1015
Lausanne, Switzerland; orcid.org/0000-0002-4570-914X;
Email: jerome.waser@epfl.ch
Authors
Luca Buzzetti − Laboratory of Catalysis and Organic Synthesis,
́
́
Ecole Polytechnique Federale de Lausanne, EPFL, 1015
Lausanne, Switzerland
̌
Mikus Puriņs − Laboratory of Catalysis and Organic Synthesis,
́
́
Ecole Polytechnique Federale de Lausanne, EPFL, 1015
Lausanne, Switzerland
Phillip D. G. Greenwood − Laboratory of Catalysis and
́
́
Organic Synthesis, Ecole Polytechnique Federale de Lausanne,
EPFL, 1015 Lausanne, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09177
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‡L.B., M.P., and P.D.G.G. contributed equally.
Notes
The authors declare no competing financial interest.
Crystallographic data for the product 4 and 5 have been
deposited at the Cambridge Crystallographic Data Centre,
accession numbers CCDC 2020478 and 2020479, respectively.
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