Iridium-catalyzed acid-assisted asymmetric hydrogenation of oximes to hydroxylamines

Article abstract of DOI:10.1126/science.abb2559

Asymmetric hydrogenations are among the most practical methods for the synthesis of chiral building blocks at industrial scale. The selective reduction of an oxime to the corresponding chiral hydroxylamine derivative remains a challenging variant because of undesired cleavage of the weak nitrogen-oxygen bond. We report a robust cyclometalated iridium(III) complex bearing a chiral cyclopentadienyl ligand as an efficient catalyst for this reaction operating under highly acidic conditions. Valuable N-alkoxy amines can be accessed at room temperature with nondetected overreduction of the N-O bond. Catalyst turnover numbers up to 4000 and enantiomeric ratios up to 98:2 are observed. The findings serve as a blueprint for the development of metal-catalyzed enantioselective hydrogenations of challenging substrates.

Full text of DOI:10.1126/science.abb2559

RESEARCH
◥
strate (~5 orders of magnitude less basic than
an imine) is protonated, activating it toward
hydride addition; (ii) the conjugated base dis-
sociates from iridium, facilitating dihydrogen
coordination and its subsequent heterolytic
cleavage into a proton and a hydride source
(20); and (iii) N-protonation of the basic hy-
droxyl amine product prevents catalyst poi-
soning (Fig. 1D). The need for stoichiometric
amounts of a strong acid severely complicates
the use of chiral proton sources (e.g., chiral
phosphoric acids). We hypothesized that chi-
ral cyclopentadienyl (Cpx) ligands, which have
emerged as powerful ligands for transition
metal–catalyzed C-H functionalizations (21),
constitute a potential entry point for enantio-
selective oxime hydrogenation. Although
transient cyclometalated species of Cpx metal
complexes are frequent intermediates in C-H
functionalizations (22), their use as stable
cyclometalated complexes for catalytic pur-
poses has been far less explored.
REPORT
ORGANIC CHEMISTRY
Iridium-catalyzed acid-assisted asymmetric
hydrogenation of oximes to hydroxylamines
Josep Mas-Roselló1, Tomas Smejkal2, Nicolai Cramer1*
Asymmetric hydrogenations are among the most practical methods for the synthesis of
chiral building blocks at industrial scale. The selective reduction of an oxime to the
corresponding chiral hydroxylamine derivative remains a challenging variant because of
undesired cleavage of the weak nitrogen-oxygen bond. We report a robust cyclometalated
iridium(III) complex bearing a chiral cyclopentadienyl ligand as an efficient catalyst for this
reaction operating under highly acidic conditions. Valuable N-alkoxy amines can be accessed
at room temperature with nondetected overreduction of the N‒O bond. Catalyst turnover
numbers up to 4000 and enantiomeric ratios up to 98:2 are observed. The findings serve
as a blueprint for the development of metal-catalyzed enantioselective hydrogenations
of challenging substrates.
Oxime substrates 1 were typically obtained
as E/Z-diastereomeric mixtures. When required
(see below), separation by silica gel column
chromatography delivered the pure bench-
stable E and Z isomers. Air- and moisture-
stable iridium(III) complexes Ir1 to Ir4 were
accessed in a straightforward two-step se-
quence. Their subsequent evaluation as selec-
tive catalysts in the reduction of oxime E-1a
to N-tert-butoxylamine 2a is summarized in
Fig. 2 and fig. S2. The hydrogenation tests
were conducted with 1 mol % of the iridium
complex, 1.5 equivalents of methanesulfonic
acid (MsOH), and 50 bar of H2 at 23°C in
2-propanol (16). Exposure of E-1a to achiral
complex Ir1, bearing an acetophenone imine
as the lower chelate portion, resulted in quan-
titative formation of 2a with no detected
overreduction by nuclear magnetic resonance
(NMR) analysis. Using (S)-Ir2 where the Cp*
unit was replaced by our chiral binaphthyl-
derived Cpx ligand (23) gave (S)-2a in 41%
yield and 70:30 enantiomeric ratio (e.r.). En-
couraged by this proof of principle, we tailored
the lower chelating C,N-ligand architecture for
the transformation resulting in Ir3. Additional
3,5-dimethyl groups of the aniline unit and a
cyclic rigid tetralone backbone with an ethyl-
ene glycol ether adjacent to the iridium boosted
the catalyst performance, giving 2a in >99%
yield and improved 89:11 e.r. In particular, the
proximal (2-methoxyethyl) ether substituent
rendered the complex more robust toward
deactivation. In addition, the oxygen atoms
of the tail might engage in hydrogen-bonding
interactions with the substrate (24). The enantio-
selectivity of the hydrogenation was further
improved by retaining the optimal C,N-ligand
and tuning the capping chiral Cpx ligand, re-
sulting in Ir4, which has the Cpx methoxy units
replaced by phenyl groups (25). Using Ir4 as
the precatalyst produced 2a in >99% yield and
symmetric hydrogenation with homoge-
neous transition metal catalysts is one
of the most efficient methods for the
preparation of single enantiomers at in-
dustrial scale (1, 2). The enormous pro-
oxazaborolidine borane adducts was shown to
yield hydroxylamine products in an enantio-
selective fashion. However, those reactions
suffer as well from undesirable primary amine
by-products, depending on the oxime struc-
ture (10, 11) (Fig. 1C). Moreover, costs and
waste build-up make this method difficult to
scale. Here, we present cyclometalated chiral
iridium(III) complexes bearing a chiral cyclo-
pentadienyl ligand (Fig. 1D, purple) and an
achiral aryl imine C,N-chelate (Fig. 1D, green).
We apply them for the enantioselective hydro-
genation of protonated oximes to hydroxyl-
amine derivatives, showcasing their potential
in asymmetric catalysis. Related C,N-chelated
half-sandwich Ir(III) complexes (12) have al-
ready found diverse applications in catalysis,
including hydrogenation, dehydrogenation,
oxidation, and hydrofunctionalization, among
other transformations (13–15).
A
gress in highly enantioselective reduction of
prochiral olefins and ketones is tightly linked
to the development of new chiral ligand archi-
tectures (3, 4). In the context of chiral amine
synthesis, the catalytic asymmetric hydrogen-
ation of imine or enamine precursors is a well-
established method and is frequently used
industrially (5). In stark contrast, related metal-
catalyzed hydrogenations of oximes to pro-
duce chiral hydroxylamines have proven elusive
(Fig. 1B). These substrates are often inert,
and when reactivity is observed, undesired re-
ductive cleavage of the labile N–O bond leads
to primary amines (6). Therefore, the devel-
opment of a complementary homogeneous
hydrogenation mode is required.
The N-alkoxy amine group is an increasingly
common motif in agrochemicals and pharma-
Preliminary studies revealed that cyclo-
metalated Cp*-iridium complex Ir1 (Fig. 2)
engages in highly efficient homogeneous oxime
hydrogenations in the presence of stoichiomet-
ric amounts of a strong Brønsted acid (16). The
reaction is fully chemoselective toward reduc-
tion of the C=N bond of oxime, showing no
ceuticals, with the N–O bond offering favorable
physical and biological properties (7). Com-
pared to the related, more abundant, chiral
amine moieties in drugs (8), current bioactive
N–
O compounds either lack chirality or are
reductive cleavage of the N–O bond. The re-
marketed as racemates (Fig. 1A). A practical
asymmetric synthesis would facilitate incor-
poration of chiral three-dimensional hydrox-
ylamine scaffolds as design elements in drug
discovery (9). So far, only the use of substoi-
chiometric to stoichiometric amounts of chiral
quired acid assistance in the reaction sug-
gests an ionic hydrogenation mechanism (fig.
S1), whereby a protonated substrate receives
a hydride from a metal complex via an outer-
sphere mechanism (17). The enantiodetermining
facial-selective hydride delivery to the non-
coordinated substrate is often the slowest step
(18). This is distinct from classical homoge-
neous hydrogenation, where the substrate is
bound to a metal center and subsequently
receives the two hydrogen atoms from the
same catalyst entity (19). The strong Brønsted
acid fulfils a triple role: (i) The oxime sub-
1Ecole Polytechnique Fédérale de Lausanne (EPFL), School of
Basic Sciences, Institute of Chemical Sciences and
Engineering, Laboratory of Asymmetric Catalysis and
Synthesis, BCH 4305, CH-1015 Lausanne, Switzerland.
2Syngenta Crop Protection AG, Process Chemistry Research,
4332 Stein AG, Switzerland.
*Corresponding author. Email: nicolai.cramer@epfl.ch
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Fig. 1. Relevance of hydroxylamines and strategies for their enantioselective
production by oxime reductions. (A) Marketed biologically active compounds
containing N‒O bonds either lack chirality or are sold as racemates. (B) Metal-
catalyzed asymmetric oxime hydrogenations lead to undesired primary amine
products. (C) Asymmetric reductions with stoichiometric chiral oxazaborolidine
reagents proceed with partial cleavage of the N‒O bond, are expensive, and
are difficult to scale up. (D) Iridium(III) complexes enable the enantioselective
hydroxylamine synthesis via the developed asymmetric hydrogenation platform.
94:6 e.r. 1H-NMR analysis of Ir4 in tetrahydro-
furan (THF)–d8 revealed a 70:30 diastereomeric
mixture provided by the iridium stereogenic
center. Upon in situ hydride incorporation,
complex Ir4-H was detected in 96:4 dia-
stereomeric ratio (d.r.) (fig. S3). This likely
represents the ceiling of achievable selectiv-
ity. X-ray crystallographic analysis of related
complex Ir3b-I provided additional struc-
tural insights of the complex in the solid state
(fig. S4).
The hydrogenation proceeds in a variety of
solvents. However, the catalyst reactivity and
selectivity were lower in aprotic solvents such as
toluene and THF (Fig. 2, entries 4 and 5). Among
alcoholic solvents, tert-amyl alcohol (tAmylOH)
was superior, giving excellent levels of enantio-
selectivity (97.5:2.5 e.r.) and conversion (98%)
for the reduction of E-1a to 2a (entry 3), where-
as the reduction of Z-1a under otherwise iden-
tical conditions resulted in a modest conversion
and modest enantioselectivity (entry 7). In
line with previous reports (26), this indicates a
strong impact of the oxime E/Z stereochemistry
on the reaction outcome, with E-1a providing
superior reactivity and selectivity. Because pro-
tonated oximes can isomerize by nucleophilic
addition/elimination to the C=N double bond,
was maintained at 0.25 mol % catalyst load-
ing (entry 10) or with lower hydrogen pres-
sure (1 bar H2) (entry 11). With lower loadings,
the risk of catalyst deactivation by chloride
anion contamination increases. The chloride
analog of (S)-Ir4 was completely catalytically
incompetent as a result of the high Cl-Ir
binding affinity (entry 12). The absolute con-
figuration of 2a was confirmed by single-crystal
x-ray analysis of its 4-nitrobenzenesulfonic
acid salt.
Using the optimized conditions with a slow
E/Z-oxime equilibration regime, the acid-
assisted enantioselective reduction was ap-
plicable to a variety of oximes 1, producing the
corresponding alkoxy amines 2 in excellent
yields and enantioselectivity (Fig. 3). Contrast-
ing the reported racemic B(C6F5)3-catalyzed
oxime hydrogenation (27), the bulky tert-butoxy
group of 1a is not mandatory. Substrates with
O-methyl as well as other primary and sec-
ondary O-alkyl substituents were quantitatively
hydrogenated in high enantioselectivities, up
to 97:3 e.r. Even free oximes were smoothly
reduced to the corresponding hydroxylamine
the choice of the alcoholic solvent and the
Brønsted acid is key to achieving high selec-
tivity by tuning the substrate E/Z equilibration
rate versus the hydrogenation rate. Pure E-1a
isomer equilibrates to an 80:20 E/Z-mixture
in the absence of Ir4 (entry 6). Using the cat-
alyst in tAmylOH produced 2a in 97.5:2.5 e.r.,
irrespective of the reaction time (4 or 20 hours);
this indicates that the hydrogenation is faster
than oxime isomerization (entries 3 and 9).
Performing the reduction in methanol (MeOH),
which triggers a faster oxime isomerization,
caused a drop in selectivity to 80:20 e.r. (entry 2).
In contrast, 1.0 equivalents of MsOH, the mini-
mum required amount of acid, in tAmylOH
afforded 2a in 98:2 e.r., although this was
accompanied by incomplete conversion of
E-1a (entry 8). 2,2,2-Trifluoroethanol dis-
rupted essential interactions for stereocon-
trol and yielded 2a in modest 54:46 e.r.
(entry 1). Additional experiments showing
the impact of the acid strength and stoichi-
ometry on the reaction outcome are sum-
marized in fig. S4. A high enantioselectivity
products without any detectable N–O bond
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Fig. 2. Development of the iridium precatalyst and reaction optimization. Conditions: E-1a, 1 mol % Ir, 50 bar H2, 1.5 equiv MsOH, 0.5 M in iPrOH, 23°C,
1
20 hours, basic work-up to free 2a. *Determined by H-NMR with internal standard; yield of 2a virtually identical to the consumption of 1a. †e.r. determined by
chiral HPLC. ‡Isolated yield. §>99% of 1a recovered (4:1 E:Z).
scission, as exemplified by 2b. Despite the
acidic reaction conditions, an acid labile acetal
moiety (2c) and O-benzyl group susceptible to
hydrogenolysis (2d, 2e) did not interfere and
remained intact. Substrate selectivity control
by existing stereocenters at the ether oxygen
atom, as exemplified by 1e with the (S)-a-
methylbenzyl group, could be overridden
by the iridium catalyst. Product 2e was ob-
tained either in a 4:1 d.r. for the mismatched
case with (S)-Ir4 or in a 7:93 d.r. using the
matched catalyst isomer (R)-Ir4. In general,
the enantiomeric purity of products 2 could be
upgraded by simple recrystallization of their
salts, as shown for compound (S)-2g (from
93:7 e.r. to 99:1 e.r. with 81% recovery). When
starting from pure Z-1g isomer, the antipode
(R)-2g was formed in 20:80 e.r. Dialkyl oximes
1l and 1m bearing 2° and 3° alkyl substituents
were equally well reduced, giving for instance
N-2m, the N-methoxy derivative of rimanta-
dine (28) in 93:7 e.r. Related substrates with
adjacent hydroxyl or tosylate groups at the
a-carbon atom were compatible, affording
reduced products 2n and 2o in excellent
yields and high selectivities. Another salient
application is the access to N-alkoxy amino
acid derivatives, as shown for valine analog
2p formed in 98% yield and 90:10 e.r. The
protocol works with D2 generated by Skrydstr-
up’s two-chamber setup, thus qualifying
for practical deuterium isotopic labeling of
valuable hydroxylamine scaffolds. Accord-
ingly, benzoxazine 2q-d1 was synthesized in
80% yield and 97:3 e.r. with 92% deuterium
incorporation.
We next targeted the synthesis of N-alkoxy
derivatives of valuable chiral a-branched ben-
zylamines (29). No stereocontrol was achieved
with 4-methoxy acetophenone derived oxime
E-1j, which equilibrates to a 9:1 E:Z isomeric
mixture under the reaction conditions. Steri-
cally more demanding Z-1k, with a locked
Z-configuration due to the tert-butyl substitu-
ent, gave 2k in 92:8 e.r. To further investigate
the impact of the aryl oxime stereochemistry
on the reaction, we individually subjected the
separated isomers Z-1rc and E-1rc to condi-
tions for fast hydrogenation (3 mol % Ir4)
and slow isomerization (iPrOH, 1.0 equiv of
MsOH, 2 hours) (Fig. 3B). The diastereoisomer
having the N-OR moiety trans to the large
substituent (here Z-1rc) reacted much faster
and more selectively to 2rc (99%, 97:3 e.r.)
than did E-1rc (22%, 70:30 e.r.), which suggests
that actually only ~7% of isomer E-1rc was
reduced. Given this behavior, we hypothesized
that using conditions with a fast E/Z equili-
bration regime would be most beneficial. In-
deed, hydrogenation of a 1:1 E:Z mixture of
1rc under equilibrating conditions [ethanol
(EtOH), 1.5 equiv of MsOH] formed 2rc in
quantitative yield and 92:8 e.r.
A variety of substrates 1ra to 1rk were con-
veniently hydrogenated as the unresolved 1:1
E/Z mixtures, forming the corresponding N-
methoxy amines in excellent yields and com-
parably high enantioselectivities. This substrate
type allowed the demonstration of the unique
chemoselectivity and functional group toler-
ance of the acid-assisted reduction method.
Whereas most transition metal–catalyzed hy-
drogenation methods frequently reduce aro-
matic bromo, vinyl, and nitro as well as azido
groups, these remarkably remained untouched
under our reaction conditions. Moreover, the
pinacol boronate group of 2rk survived, serving
as a potential handle for subsequent cross-
coupling reactions. Nitrogen and sulfur het-
eroarenes 2re and 2rf were also compatible.
(See fig. S6 for tests of additional functional
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Fig. 3. Substrate
scope of the oxime
hydrogenation.
Isolated yields; e.r.
determined by chiral
HPLC. (A) Hydrogena-
tion of pure E-oximes.
(B) Hydrogenation
of E/Z oxime mixtures.
(C) Natural product hy-
droxylamine derivatives.
*In iPrOH. †2 mol %
Ir4. ‡5.0 equiv of TFA
instead of MsOH.
§Recrystallized as its
p-nitrobenzenesulfonate.
¶In MeOH. #In EtOH.
**Ex situ generation
of D2 using COware.
††3 mol % Ir4, 1.0 equiv
MsOH, iPrOH, 23°C,
2 hours. ‡‡94:6 e.r.
at 1 mol % Ir4.
§§20 bar H2, 5 hours.
¶¶From (bS)-1rl: (aS,bS)-
2rl 99%, 77:23 d.r.
##1 mol % Ir1.
Mas-Roselló et al., Science 368, 1098–1102 (2020)
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groups.) Enzyme inhibitor 1rg (30) could be
reduced in quantitative yield and 93:7 e.r.,
illustrating the applicability of the method
for late-stage derivatization. Existing stereo-
genic centers adjacent to the C=N bond ex-
hibit a strong substrate control. For instance,
(R)-1rl possessing a b-methyl stereogenic cen-
ter yielded cis-isomer (R,R)-2rl in 97:3 d.r. and
93:7 e.r. In contrast, b-ester analog ( )-1rm
gave trans-isomer 2rm in 98:2 d.r., likely by
cis-hydrogenation followed by acid-promoted
epimerization of the ester to the thermodynam-
ically more stable product. N-methoxy deriva-
tives of norephedrine 2s and estrone 2t were
formed in highly diastereoselective fashion, the
former after double hydrogenation of 1s. Fi-
nally, a 25-g batch of E/Z-1rb was hydrogenated
with a reduced 0.05 mol % catalyst loading
to (R)-2rb in a quantitative manner (turnover
number 4000) in 93:7 e.r., supporting the
scalability of the method. Overall, our find-
ings serve as a blueprint for further asymmetric
transition metal–catalyzed ionic hydrogena-
tions of challenging substrates, and highlight
the yet untapped potential of cyclometalated
chiral Cpx metal complexes in catalysis.
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ACKNOWLEDGMENTS
We thank R. Scopelliti and F. Fadaei Tirani for x-ray
crystallographic analysis of compounds Ir3b-I and (S)-2a-H+,
C. J. Cope and S. Masala for technical support, and V. Grushin
and A. Robinson for insightful discussions. Funding: Supported
by Syngenta Crop Protection AG and EPFL. Author
contributions: T.S. conceived the project. N.C. conceived
and supervised the project. J.M.-R. performed the experimental
work. All authors designed the experiments, analyzed the
data, and drafted the manuscript. Competing interests: The
authors have filed a patent application (GB 1818117.2) for
the described iridium-catalyzed asymmetric ionic oxime
hydrogenation. Data and materials availability:
Crystallographic data for compounds Ir3b-I and (S)-2a-H+
are available free of charge from Cambridge Crystallographic
Data Centre under reference numbers CCDC 1973002 and
1973003, respectively. All other characterization data and
detailed experimental procedures are available in the
supplementary materials.
SUPPLEMENTARY MATERIALS
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Materials and Methods
Figs. S1 to S6
HPLC Traces
NMR Spectra
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11 February 2020; accepted 17 April 2020
10.1126/science.abb2559
Mas-Roselló et al., Science 368, 1098–1102 (2020)
5 June 2020
5 of 5

Iridium-catalyzed acid-assisted asymmetric hydrogenation of oximes to hydroxylamines
Josep Mas-Roselló, Tomas Smejkal and Nicolai Cramer
Science 368 (6495), 1098-1102.
DOI: 10.1126/science.abb2559
Hydrogenations that tolerate N−O bonds
Catalysts that add hydrogen to carbon-carbon, carbon-nitrogen, and carbon-oxygen double bonds are among the
most widely used in synthetic chemistry. They are particularly adept at delivering just one of two mirror-image products.
However, they may also target adjacent bonds in the compound that would be better left intact. Mas-Roselló et al. report
that an iridium catalyst paired with a strong acid can hydrogenate C=N bonds without disturbing a weak N−O bond on the
same nitrogen center. The reactions proceed at room temperature with high enantioselectivity.
Science, this issue p. 1098
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REFERENCES
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