Catalytic Asymmetric Synthesis of the anti-COVID-19 Drug Remdesivir

Article abstract of DOI:10.1002/anie.202011527

The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of the P-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 S_P:R_P). Mechanistic studies showed that this DyKAT is a first-order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10 gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.

Full text of DOI:10.1002/anie.202011527

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Catalytic Asymmetric Synthesis of the Anti-COVID-19 Drug
Remdesivir
Authors: Mo Wang, Lu Zhang, Xiaohong Huo, Zhenfeng Zhang, Qianjia
Yuan, Panpan Li, Jianzhong Chen, Yashi Zou, Zhengxing Wu,
and Wanbin Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011527
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10.1002/anie.202011527
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Asymmetric Synthesis of the Anti-COVID-19 Drug
Remdesivir
Mo Wang,[a,b,†] Lu Zhang,[b,†] Xiaohong Huo,[a,†] Zhenfeng Zhang,[b,†] Qianjia Yuan,[a] Panpan Li,[a]
Jianzhong Chen,[a] Yashi Zou,[a] Zhengxing Wu,[a] and Wanbin Zhang*[a,b]
[a]
Dr. M. Wang, Dr. X. Huo, Dr. Q. Yuan, Mr. P. Li, Dr. J. Chen, Ms. Y. Zou, Dr. Z. Wu, Prof. Dr. W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and
Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
[b]
[†]
Dr. M. Wang, Ms. L. Zhang, Dr. Z. Zhang, Prof. Dr. W. Zhang
School of Pharmacy, Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
M. Wang, L. Zhang, X. Huo, and Z. Zhang contributed equally.
Supporting information for this article is given via a link at the end of the document.
Abstract: The catalytic asymmetric synthesis of the anti-COVID-19
drug remdesivir has been realized via the coupling of the P-racemic
phosphoryl chloride with protected nucleoside GS441524. The chiral
bicyclic imidazole catalyst is crucial for the dynamic kinetic
asymmetric transformation (DyKAT) to proceed smoothly with high
reactivity and excellent stereoselectivity (96% conv., 22:1 SP:RP).
Mechanistic studies showed that this DyKAT is a first-order visual
kinetic reaction dependent on catalyst concentration. The unique
chiral bicyclic imidazole skeleton and carbamate substituent of the
catalyst are both required for the racemization process involving the
phosphoryl chloride and subsequent stereodiscriminating step. A 10-
gram scale reaction was also conducted with comparably excellent
results, showing its potential for industrial application.
in the catalytic asymmetric synthesis of carbon centers,[7]
stereogenic phosphorus groups are still challenging to
construct.[8] Thus, the construction of the phosphorus-based
stereogenic center is a key step in the synthesis of remdesivir.
The first generation of synthetic methods is shown in Scheme
1(Top). The desired enantiopure SP-phosphoramidate is
prepared from the corresponding P-racemic phosphoryl chloride
and GS441524 using stoichiometric amounts of N-methyl
imidazole, followed by separation of the two diastereoisomer
products by chiral preparative HPLC.[5] The second generation
of synthetic methods is shown in Scheme 1(Middle), which
adopted an alternative approach involving the selective
nucleophilic displacement of the enantiopure phosphorylating
agent separated from the additionally prepared mixture of two
diastereoisomer intermediates.[6] Chiral resolution and additonal
synthetic steps in the above-mentioned methods are required for
the preparation of the enantiomerically pure P-stereogenic
intermediates, which inevitably leads to low synthetic efficiency
and a waste of resources. Herein, we describe the first catalytic
asymmetric synthesis of remdesivir via the coupling of the P-
racemic phosphoryl chloride (1) with protected nucleoside (2)
[Scheme 1(Bottom)]. The synthetic methodology is also
promising from an atom-economy and synthetic efficiency
perspective.[9,10]
Organophosphorus(V) compounds provide unique binding
interactions with a target receptor or enzyme because of their
trigonal pyramidal geometry, multiple chelating properties and
potential dual functions as a hydrogen donor and acceptor.[8a]
These characteristics also present a significant challenge for the
construction of P-stereocenters due to the crowded three-
dimensional space[11] and difficult-to-control interactions between
the chiral catalyst and the substrate.[12] Among methodologies
for the construction of P-stereogenic compounds, catalytic
asymmetric substitutions with racemic phosphoryl(V) chloride
provide a simple and economic process in terms of both
operational simplicity and starting material availability. However,
the full conversion of both enantiomers of the racemic starting
material into a single, optically pure product in quantitative yield
is generally challenging.[13] The crux of the problem lies in the
lack of a suitable chiral catalyst that is able to promote the
racemization process (k5/k6) and control the subsequent
stereodiscriminating step (k7/k8, Scheme 2).
Remdesivir (Veklury, GS-5734) has undoubtedly become an
important molecule. It is viewed as one of the world’s most
promising treatments for COVID-19.[1] To date, COVID-19 has
led to approximately 23 millions infections and 800 thousand
deaths since the end of 2019. Furthermore, the numbers and
rates of infections and related deaths are increasing, with 7
million infections and 150 thousand deaths being reported last
month. The urgency of the pandemic has prompted the
governments of the United States, the European Union, Japan,
etc. to approve the remdesivir as a specific treatment for
COVID-19.[2] Recent clinical trial results have shown that it can
effectively shorten the recovery period of hospitalized patients
and reduce the risk of death by 62% in patients with severe
cases of the disease,[3] and so has the potential to greatly lighten
the burden on hospitals and doctors during the pandemic.
Ensuring that there are sufficient supplies of remdesivir is of
paramount importance. Gilead Sciences is striving to provide
almost two million remdesivir treatment courses by the end of
2020 and many millions more by 2021.[4] However, the amount
is far from sufficient to meet clinical needs and so now
remdesivir treatment is rationed due to limited supply. The
development of
a highly effective synthetic approach to
remdesivir is therefore required.
Remdesivir is prepared as a P-stereogenic prodrug of a
parent nucleoside (GS441524) by introducing an amino acid
ester- and aryloxy-substituted phosphoryl group to the hydroxyl
functionality of the nucleoside.[5,6] Unlike the progress achieved
1
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10.1002/anie.202011527
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Top: 1st Generation synthesis of remdesivir. Middle: 2nd Generation synthesis of remdesivir. Bottom: This work: catalytic asymmetric synthesis of
remdesivir.
phosphoric acid derivatives.[14] Their unique bicyclic imidazole
structures provide a good balance between the catalytic activity
of the imidazole skeleton and the stereocontrol property of its
substituent, making the catalyst almost the only one suitable for
asymmetric phosphorylation. This was later confirmed by
research scientists at Merck & Co. and the University of
Wisconsin in their works concerning the asymmetric synthesis of
nucleoside- and glucoside-based phosphoramidate prodrugs,
respectively.[16,17] In order to provide sufficient quantities of
remdesivir for clinical use, and considering the unique
advantages of our chiral bicyclic imidazole catalysts in
asymmetric phosphorylation, herein we developed the first
Scheme 2. Bicyclic imidazole-catalyzed dynamic kinetic asymmetric
transformation (DyKAT) for the synthesis of remdesivir.
highly efficient catalytic asymmetric synthesis of the anti-COVID-
19 drug, remdesivir, using our easily accessible catalysts
[Scheme 1(Bottom)].
We first explored the specific performance of our chiral
bicyclic imidazoles in the catalytic asymmetric synthesis of
protected remdesivir using the P-racemic phosphoryl chloride 1
and nucleoside 2 (Table 1). Initially, we conducted the reaction
in the absence of catalyst and found that only a trace amount of
product 3 with 1.1:1 d.r. (SP:RP) was obtained (Table 1, entry 1).
In the early 2010’s, the catalytic asymmetric conversion of
racemic phosphoryl chloride to phosphoramidate was firstly
realized in our group by using the newly developed chiral
bicyclic imidazole organocatalysts.[14,15] This represented the first
example of the catalytic asymmetric synthesis of P-stereogenic
2
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10.1002/anie.202011527
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COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
imidazole structure appears to have the potential to improve the
reactivity and stereocontrol of this phosphorylation process.
Accordingly, a variety of nucleophilic catalysts bearing a chiral
bicyclic imidazole framework, which was developed by our group,
were screened in this transformation. These catalysts include
those modified with a benzyl ether C1, acetyl ester C2, tert-butyl
carbonate C3, and various carbamates C4-C7 (entries 4-10 and
Table S1-S2 in SI). The catalyst C4 bearing a carbamate group
was identified to be the superior catalyst motif, giving the desired
phosphoramidate product in high conversion (91%) and 9.3:1
selectivity in favor of the desired (S)-configuration at the
phosphorus center. This is consistent with the absolute
configuration of the P-stereocenter in remdesivir (entry 7). The
catalyst C5, bearing a methyl substituent on the carbamate
group, exhibited poorer stereocontrol of the P-stereocenter
(entry 8). Subsequently, the catalysts C6 and C7, bearing
carbamate groups with larger steric hindrance, were synthesized
and applied to this reaction to further improve the
stereoselectivity (entries 9 and 10). To our delight, the catalyst
C7, modified with an adamantinyl group, gave the best results
T
Conv.
[%][c]
[b]
Entry
1
mol% Cat
none
Base
t [h]
16
16
16
16
16
16
16
16
16
16
16
16
16
36
36
48
48
SP:RP
[oC]
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
none
-10
1.1:1
1.1:1
1.5:1
3.2:1
2.6:1
1.9:1
9.3:1
6.2:1
7.4:1
11.2:1
4.3:1
7.8:1
16.6:1
21.8:1
16.4:1
16.4:1
21.6:1
3
2
20% DMAP
20% NMI
20% C1
20% C2
20% C3
20% C4
20% C5
20% C6
20% C7
20% (R)-C7
20% C7
20% C7
20% C7
10% C7
5% C7
-10
-10
-10
-10
-10
-10
-10
-10
-10
-10
-10
-30
-40
-30
-30
-40
33
62
45
63
46
91
47
83
91
81
77
96
96
95
94
96
3
4
(11.2:1 d.r., 91% conv.).
A mismatched relationship was
observed by changing the configuration of the enantiopure C7,
suggesting chiral recognition between the chiral catalyst and the
substrate (entry 11). In the absence of base, the desired product
is obtained in reduced conversion and d.r. (entry 12, 7.8:1 d.r.,
77% conv.). The obvious decrease in reactivity and selectivity
indicated that the base, 2,6-lutidine, may participate in the
transition state of the rate-determining and stereodiscriminating
step. To further improve the diastereoselectivity, the reaction
temperature was reduced to -30 oC and -40 oC, and the
selectivity improved to 16.6:1 and 21.8:1 with comparable
reactivities, respectively (entries 13 and 14). When the catalyst
loading was decreased to 10 mol% and 5 mol%, a longer
reaction time was required but comparable diastereoselectivities
were obtained (entries 13-17). These results suggested that the
d.r. value is not dependent on the concentration of the catalyst.
5
6
7
8
9
10
11
12
13
14
15
16
17
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
Thus, the desired product
3 could be obtained in 94%
conversion with 16.4:1 d.r. and 96% conversion with 21.6:1 d.r.
at 5 mol% (-30 oC) and 10 mol% (-40 oC) catalyst loadings,
respectively (entries 16 and 17).
To further understand the specific role of the base and
catalyst on the reaction process, a detailed mechanistic study
was conducted. At first, the reactions with catalyst loadings of 20
mol% and 10 mol% were monitored over different reaction times
by 31P NMR spectroscopy (Figure 1A). The results showed that
the d.r. values of the product 3 and starting material 1 do not
substantially change as the reaction proceeds, consistent with
the catalyst loading screening results (Figure 1B; Table 1,
entries 13-17). Furthermore, visual kinetic analysis revealed a
first-order dependence on catalyst concentration, which is
different from the second order kinetics reported in previous
work concerning asymmetric phosphorylation (Figure 1C and
1D).[16] In combination with 2,6-lutidine having an integral effect
on the reactivity and stereoselectivity, it was suggested that the
reaction pathway involves the simultaneous activation of the
phosphoryl chloride 1 and nucleoside 2 by catalyst C7 and base
2,6-lutidine, respectively. In order to better understand this dual
activation mode, a computational study was conducted. Relative
transition state energies showed the desired SP configuration to
be favored by 3.5 kcal/mol, in agreement with the experimental
results (Figure 1E).
10% C7
[a] Reaction conditions: P-rac-1 (104.3 mg, 0.30 mmol, 1.5 equiv), 2 (66.3 mg,
0.20 mmol, 1.0 equiv), 2,6-lutidine (46.6 μL, 0.40 mmol, 2.0 equiv), 4Å MS (80
mg), DCM (2 mL). [b] Determined by 31P NMR analysis. [c] Determined by 31
NMR analysis using P(O)(OMe)3 as the internal standard.
P
Next, two achiral nucleophilic catalysts were examined to
explore the inherent substrate induction in the stereochemical
outcome of the P-stereogenic product 3. The desired product
was obtained in only 33% conversion with a 1.1:1 d.r. using the
commonly employed nucleophilic catalyst N,N-dimethylpyridine
(DMAP) (entry 2). Interestingly, by employing N-methyl
imidazole (NMI) as the achiral catalyst, the corresponding
product 3 was obtained smoothly in 62% conversion with a 1.5:1
d.r. (entry 3). These experimental results suggested that: 1) the
nucleophilic catalyst is required for this phosphorylation reaction
to proceed with high reactivity; 2) the chiral nucleoside and
phosphoryl chloride substrates have negligible impact on the
stereochemical induction of the P-stereocenter, thus providing
an opportunity for the use of a chiral nucleophilic catalyst; 3) the
3
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10.1002/anie.202011527
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COMMUNICATION
Scheme 3. The gram-scale catalytic asymmetric synthesis of remdesivir.
adamantinyl-substituted carbamate group of the catalyst are
both required for the DyKAT to proceed smoothly with high
reactivity and excellent stereoselectivity.
A 10-gram scale
reaction was successfully realized, showing its potential for
industrial application.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (Nos. 21991112 and 91856106), National
Key R&D Program of China (No. 2018YFE0126800), Medical-
Engineering
Cross
Research
Foundation
of
SJTU
(YG2020YQ13), and Shanghai Municipal Education Commission
(No. 201701070002E00030).
Conflict of interest
ΔΔG‡ = 0.0 kcal/mol for SP-3
ΔΔG‡ = 3.5 kcal/mol for RP-3
The authors declare no competing interests.
Figure 1. Mechanistic study. A) Temporal concentration profiles for the
standard reaction at two different catalyst loadings. [1]0 = 0.15 M; [2]0 = 0.10
M; [lutidine]0 = 0.20 M; [C7]0 = 0.02 M for 20 mol% and 0.01 M for 10 mol%. B)
Temporal diastereomer ratio of 1 and 3 at two different catalyst loadings. C)
The concentration of product was plotted against a normalized time scale,
t[C7]1. D) The concentration of product was plotted against a normalized time
scale, t[C7]2. E) Transition state model of the stereoselective phosphorylation
with C7. Calculations were performed at the B3LYP-D3(BJ)/6-31G** level of
theory.
Keywords: COVID-19 • antiviral drug • asymmetric nucleophilic
catalysis • phosphoramidates • ProTide technology
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5
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Entry for the Table of Contents
The first catalytic asymmetric synthesis of remdesivir via the coupling of the P-racemic phosphoryl chloride with protected nucleoside
GS441524 has been realized using the chiral bicyclic imidazole catalyst, which is crucial for the racemization process involving the
phosphoryl chloride and subsequent stereodiscriminating step (96% conv., 22:1 SP:RP). Furthermore, a 10-gram scale reaction was
successfully realized, showing its potential for industrial application.
6
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