Room-Temperature Palladium-Catalyzed Deuterogenolysis of Carbon Oxygen Bonds towards Deuterated Pharmaceuticals

Article abstract of DOI:10.1002/anie.202014196

Site-specific incorporation of deuterium into drug molecules to study and improve their biological properties is crucial for drug discovery and development. Herein, we describe a palladium-catalyzed room-temperature deuterogenolysis of carbon–oxygen bonds

Full text of DOI:10.1002/anie.202014196

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Room-temperature Palladium-Catalyzed Deuterogenolysis of
Carbon Oxygen Bonds towards Deuterated Pharmaceuticals
Authors: Wei Ou, Xudong Xiang, Ru Zou, Qing Xu, Kian Ping Loh, and
Chenliang Su
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Room-temperature Palladium-Catalyzed Deuterogenolysis of
Carbon Oxygen Bonds towards Deuterated Pharmaceuticals
Wei Ou,[a] Xudong Xiang,[a] Ru Zou,[a] Qing Xu,[b] Kian Ping Loh,[c] Chenliang Su*[a]
[a]
Dr. Wei Ou, Xudong Xiang, Ru Zou, and Prof. Dr. Chenliang Su
International Collaborative Laboratory of 2D Materials for Optoelectronic Science & Technology, Engineering Technology Research Center for 2D Materials
Information Functional Devices and Systems of Guangdong Province, Institute of Microscale Optoelectronics, Shenzhen University, Shenzhen, 518060,
China
[b]
[c]
Prof. Dr. Qing Xu
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang, China
Prof. Dr. Kian Ping Loh
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Site-specific incorporation of deuterium into drug
deuterated reducing reagents such as NaBD3CN, nBu3SnD,
molecules to study and improve their biological properties is crucial
Hex3SiD etc. (Scheme 1b), which are generally expensive and
highly volatile, causing poor-functionalities tolerance, high costs
and waste production. There is thus a need to develop mild,
selective and direct deoxygenative deuteration strategy that
utilizes readily available alcohols and ketones.
for drug discovery and development. Herein, we describe
palladium-catalyzed room-temperature deuterogenolysis
a
of
carbon-oxygen bonds in alcohols and ketones with D2 balloon for
practical synthesis of deuterated pharmaceuticals and chemicals with
benzyl-site (sp3 C-H) D-incorporation. The highlights of this
deoxygenative deuteration strategy are mild conditions, broad scope,
practicability and high chemoselectivity. To enable the direct use of
D2O, electrocatalytic D2O-splitting is adapted to in-situ supply D2 on
demand. With this system, the precise incorporation of deuterium in
the metabolic position (benzyl-site) of ibuprofen is demonstrated in a
sustainable and practical way with D2O.
Deuterium labeling techniques are widely utilized as efficient
tools in synthetic chemistry, quantitative LC–MS/MS analysis as
well as pharmaceutical discovery and development.[1-3] In 2017,
the first deuterated drug, deutetrabenazine (Austedo, SD-809)
was approved by FDA,[4] which led to a rising demand for the
practical synthesis of deuterated drugs as well as their key
building blocks. Traditional strategies for introducing deuterium to
pharmaceuticals are the stoichiometric alkylation of nucleophilic
N, O with expensive and highly toxic deuterium reagents (such
as CD3I), and the C–H/C–D exchanges promoted by transition
metals, acid/base, N-heterocyclic carbenes, or photocatalysts.[5]
However, site-specific deuterium labeling of pharmaceuticals
with controllable deuterium atoms remains a major challenge.
Defunctionalization-deuteration (DFD) reactions refer to the
conversion of a specific functional group into deuterium by using
a low cost and readily available deuterium source such as D2O,
CD3OD and D2. The advantages of DFD strategy have allowed
the precise deuterium labeling at target sites. Very recently, a
variety of strategies involving the reductive deuteration of halides,
Scheme 1. DFD strategy for deoxygenative reduction of alcohols and ketones.
Herein, we reported the Pd-catalyzed room-temperature
deuterogenolysis of benzylic alcohols and aromatic ketones
using D2 or D2O as the deuterium source (Scheme 1c). This
strategy exhibits broad reaction scopes, excellent functionalities
tolerance, high chemo-selectivity and efficiency. In addition, a
variety of deuterated drug intermediates and drugs including
atomoxetine, tesmilifene etc. are constructed in good-excellent
yields with high D-incorporation at the specific benzyl-site (sp3
C-H). Since D2O is the most ideal deuterium source, an
electrocatalytic D2O splitting coupled with the mild Pd-catalyzed
deuterogenolysis system is designed, in which the D2 gas could
be in-situ generated and supplied on-demand. Gram-scale
production of metabolic position D-labeled ibuprofen has been
achieved, attesting to the practicability of this synergistic system.
Our initial investigations were focused on screening proper
catalysts and additives for hydrogenolysis of aryl alcohol and
optimization of the reaction conditions. We used commercially
available Pd(OAc)2 catalyst, as it could be easily converted to
[6] alkenes and alkynes,[7] unsaturated carboxylic acid derivatives
[9]
[8], deuterium methylation of nitroarenes
etc, have been
developed via DFD strategy by us and other research groups.
Deoxygenation of alcohols, [10] aldehydes or ketones [11] to the
corresponding alkanes is very important in the construction of
drugs, natural products and their key intermediates.
Barton-McCombie
deoxygenation,
Wolff-Kishner-Huang
reduction and their various modifications are the classical
methods for deoxygenative reduction of alcohols and aldehydes
or ketones to synthesize drugs and their intermediates (Scheme
1a).[12] Traditional deoxygenative deuteration of carbon-oxygen
bonds (i. e. alcohols) usually require the use of corresponding
1
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10.1002/anie.202014196
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highly reactive Pd(0) species under reductive atmosphere.
Encouragingly, the hydrogenolysis of 1-phenylethan-1-ol
occurred smoothly in the presence of the Pd(OAc)2 (10 mol %)
under 1 bar H2 at room temperature in chlorobenzene, affording
ethylbenzene product in 61% GC yield in 2 h. Nearly quantitative
yield was achieved in the presence of strong base (t-BuOK, 1.2
yields with moderate to high D incorporation. Deuterogenolysis of
a series of chain or ring (6, 7 or 12 membered) tertiary alcohols
was also smoothly achieved, indicating the little impact of the
steric effect and re-confirming the university of this strategy.
Interestingly, this mild protocol could be further extended to
epoxide substrate, producing the deuterated product 2aa in 94%
yield with excellent D-incorporation under the mild conditions.
Benzyl sites are typical oxidative metabolic positions present
in many important drugs, such as tolbutamide, buprofen etc.,
while the classical iridium-catalyzed H/D exchange method
generally introduce D-atom at the aromatic rings.[13] Deuterium
substitution of groups at benzyl sites is therefore highly desired
to study the metabolic process as an important diagnostic tool,
providing vital information about the drug metabolites. Owing to
the mild process, the protocol enabled facile access to a variety
of benzyl butsite-specifically labeled key intermediates of drugs,
including Lidocaine (2a), Phylloquinone (2g), Gemfibrozil (2l) and
the D-labeled TAK779 (2c). [14] The late-stage functionalization of
complex biologically active molecules such as Adapalene
derivatives (product 2ab), L-Methol (product 2ac), (+)-Fenchol
(product 2ad), and Vitamin E (product 2ae) were also achieved
readily with 83-95% yield with high D incorporations. Next,
gram-scale production of drugs intermediates was evaluated. As
a result, 1.5 g of 2c and 5.0 g of 2g, the building blocks for
construction of TAK779 and Phylloquinone, had been achieved in
98%, 99% yield with uniformly high D-incorporations.
Atomoxetine 5 is an important marketed drug for treatment of
attention deficit/hyperactivity disorder in children. Utilizing our
strategy, a 20 gram-scale production of key intermediate 2af of
deuterated atomoxetine was demonstrated from commercially
available 2-hydroxybenzyl alcohol, allowing the rapid and
low-cost access to deuterated atomoxetine in high overall yields.
equiv.).
Encouraged by
these
results, Pd-catalyzed
deuterogenolysis of benzyl alcohol was performed and optimized
under D2 atmosphere (see SI for detailed). For primary alcohols,
the best conditions is the use of Pd(OAc)2 (10 mol%) in
D2O/PhCl (0.2 mL/1 mL) under 1 atm D2 at room temperature;
For the second and tertiary benzylic alcohols, additional 20 mol%
of t-BuOK is required to achieve good yields.
Scheme 2. Working mechanistic proposal.
Wolff-Kishner-Huang reduction reactions offer
a powerful
The reaction mechanism is currently the subject of detailed
investigation. The reaction-rate analysis conforms that there was
an induction period in the initial stage of the reaction, suggesting
the in-situ generation of reactive Pd(0) species from palladium
acetate under reductive atmosphere (Figure S1). Deuterium
could be easily activated by Pd(0) to form Pd-(D)2 reductive
species. It is believed that the coordination of alcohols with Pd(0)
occurs, followed by C-O cleavage reaction by Pd-(D)2, furnishing
the desired deuterated compounds. A side reaction, -elimination
of benzyl alcohols to produce aldehyde was observed, verifying
the interaction of alcohols with reactive Pd(0) species. The
aldehyde intermediate could be reduced by Pd-(D)2 to form
deuterium-incorporated benzyl alcohols, which underwent
deoxygenative deuteration, furnishing the corresponding product
with two-deuterium atoms on the benzyl site (scheme 2).
approach to methylene from ketones. However, their application
in construction of deuterated building blocks and drugs had been
hindered due to the lack of commercially available deuterated
reagents. We propose that the mechanism in our protocol
involves the Pd-catalysed deuterogenolysis/hydrogenolysis of
aldehydes or ketones that were generated from the -elimination
of substituted benzyl alcohols probably. This was verified by the
more than 100% D-atom incorporation in deuterogenolysis of
several substituted benzyl alcohols. On this basis, we became
interested in the room-temperature Pd-catalytic deuterogenolysis
of ketones for construction of valuable deuterated building blocks
and drugs. To our delight, the use of 10 mol% Pd(OAc)2 and 20
mol% of tBuOK for catalytic deuterogenolysis of acetophenone
with D2 at room-temperature produced the desired product
deuteron-ethylbenzene 7a in almost quantitative yield. Based on
this protocol, we tested a variety of structurally diverse ketones,
affording the corresponding deuterated products (7a-7n) in good
to excellent yields with high D-incorporations. Consistently, this
protocol shows good functionality-tolerance. For example,
Consistently,
a mixture of undeuterated, mono- di- and
trideuterated products (more than 100% D-atom incorporation)
were observed for some special substrates (scheme 3).
Next, the generality and practicality of this strategy was
investigated to synthesize valuable deuterated chemicals and
pharmaceuticals (scheme 3). A wide range of substituted primary
benzyl alcohols were amenable to our strategy, producing the
corresponding deuterated products (2a-2l) in 61-99% yields with
high D incorporation (>90%). This protocol exhibited excellent
functional groups tolerance, including boronic esters (2c),
sulfonyl (2j), ester (2k), hydroxy (2l) as well as heterocycles such
as benzofuran (2h) and indole derivatives (2i). Cyclic or chain
secondary benzyl alcohols were also found to be competent
substrates, providing the deuterated products (2m-2r) in high
aromatic
ketones bearing ester groups (7j, 7k), cyano (7l) and
hydroxyl (7m), furnished the corresponding products with good D
incorporation (59-84%) and in 63-92% isolated yields.
Deuterogenolysis of heteroaromatic ketone deserves comment
as heterocyclic motifs are widespread in many natural products,
medicinal agents and their key intermediates. The room
temperature deuterogenolysis of 1-(benzofuran-2-yl)butan-1-one
was evaluated, affording the corresponding deuterated
2-butylbenzofuran 7n in 93% yield. Here, the H/D exchange on
the side chain of product 7n catalyzed by Pd(0) can be observed,
2
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owing to the reactive -position of ketones. With the deuterated
building-block 7n in hand, we turned our efforts to synthesize
afforded the targeted deuterium-labeled Amiodarone 12 in 64%
total yields with 73% D incorporation.
deuterium-labeled
Amiodarone.
Subjecting
7n
and
Diarylmethane skeletons are ubiquitous in pharmaceutically
important molecules and medicinal agents such as
antihistamines (i. e. Diphenhydramine), anticancer drugs (i. e.
Tesmilifene), hypolipidemic drugs (i. e. Beclobrate), etc. Here,
4-methoxybenzoyl chloride 8 to Friedel-Crafts acylation and
demethoxylation cascade reaction under the AlCl3-Lewis acid
condition successfully afforded the deuterated building block 9 in
67% yield. Subsequently, the iodination of 9 with iodine and
potassium carbonate, followed by alkylation of the phenol unit,
Tesmilifene was selected as
a model drug to test the
effectiveness and practicability of our strategy in construction
Scheme 3. Alcohol scope (see the Supporting Information for detailed reaction conditions). the D content was determined by 1H NMR spectroscopy. [a] GC-MS
yield using anisole as an internal standard. [b] Isolated yield.
3
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Scheme 5. Concept of electrolysis of D2O to provide deuterium source.
incorporation of deuterium in the metabolic position (benzyl-site)
of ibuprofen was performed (scheme 5). Firstly, the
electrocatalytic D2O-splitting occurred at electrochemical
compartment, which continuously supplied D2 gas for the room
temperature deuterogenolysis of 6x. As a result, 5 mmol of 6x
was successfully converted into D-labeled 7b, which further
underwent Friedel-Crafts acylation with acetyl chloride, affording
the key building block 14 in 93% yield with 80% D incorporation
(2 steps). Next, the α-D-labled buprofen could be obtained
smoothly following the literature method. [16] Since α-oxidation is
a key step in ibuprofen metabolism, precise deuteration of the
metabolic position is a useful way to study and improve its
biological properties.
In summary, we have developed
a room-temperature
palladium-catalyzed deuterogenolysis of alcohols and ketones
for the practical synthesis of deuterated pharmaceuticals and
chemicals with benzyl-site D-incorporation. This strategy also
allows the precise-controlling the deuterium atom number at the
benzyl-site by changing the substrates of alcohols and ketones.
The mild conditions, high chemoselectivity and scalability of this
protocol enable its application to the practical construction of
valuable deuterated pharmaceuticals and chemicals for synthetic
mechanism study as well as LC/MS quantification. Further
mechanistic studies are ongoing in our lab.
Scheme 4. Ketone scope (see the Supporting Information for detailed reaction
conditions). the D content was determined by 1H NMR spectroscopy. [a]
GC-MS yield using anisole as an internal standard. [b] Isolated yield. iPr =
Isopropyl, Bn = benzyl.
of deuterated diarylmethane pharmaceuticals. Under the
optimized conditions, diaryl ketone 6j smoothly underwent
deuterogenolysis followed by ester hydrolysis, providing the
corresponding aryl phenol 7m’ in 80% yield (2 steps) with 89% D
incorporation. Alkylation of 10 with aminoalkyl chloride 11 yielded
the desired deuterium-labeled Tesmilifene 13 in 92% yield.
Electrocatalytic water-splitting is a well-established technology
to produce hydrogen from water.[15] Here, to avoid using the
flammable D2 gas, an ideal way is to in-situ supply D2 by
electrocatalytic D2O-splitting. To this end, a reactor consisting of
a chemical compartment and electrochemical compartment
connected with a cannula was designed, in which deuterium
produced at cathode cell could be utilized for Pd-catalytic
deuterogenolysis reaction at the chemical compartment. To test
the practicability of this synergistic system, the precise
Acknowledgements ((optional))
This work was financially supported by the National Natural
Science Foundation of China (21972094 and 21672163),
Guangdong Special Support Program, Pengcheng Scholar
program,
and
Shenzhen
Innovation Program (JCYJ20190808142001745).
Keywords: deoxygenative • deuteration • electrocatalysis •
reduction • drug
4
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Entry for the Table of Contents
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We developed an operationally simple and easily scale-up protocol for deuterogenolysis of carbon oxygen bonds, which leads to a
practical approach to synthetically valuable benzyl-deuterated building blocks and deuterium medicines, including atomoxetine,
tesmilifene, amiodarone, ibuprofen. Combining the in situ electrocatalytic heavy water-splitting, this protocol enables the direct
utilization of D2O for construction of high value-added deuterated chemicals and pharmaceuticals from low cost and easily available
alcohols and ketones.
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