Practical Remdesivir Synthesis through One-Pot Organocatalyzed Asymmetric (S)-P-Phosphoramidation

Article abstract of DOI:10.1021/acs.joc.0c02888

Remdesivir, an inhibitor of RNA-dependent RNA polymerase developed by Gilead Sciences, has been used for the treatment of COVID-19. The synthesis of remdesivir is, however, challenging, and the overall cost is relatively high. Particularly, the stereoselective assembly of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety of chiral bicyclic imidazoles were synthesized as organocatalysts for stereoselective (S)-P-phosphoramidation employing a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived carbamate was utilized in the reaction at -20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an excellent opportunity for industrial production of remdesivir.

Full text of DOI:10.1021/acs.joc.0c02888

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Article
Practical Remdesivir Synthesis through One-Pot Organocatalyzed
Asymmetric (S)‑P-Phosphoramidation
Veeranjaneyulu Gannedi, Bharath Kumar Villuri, Sivakumar N. Reddy, Chiao-Chu Ku,
Chi-Huey Wong,* and Shang-Cheng Hung*
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ABSTRACT: Remdesivir, an inhibitor of RNA-dependent RNA
polymerase developed by Gilead Sciences, has been used for the
treatment of COVID-19. The synthesis of remdesivir is, however,
challenging, and the overall cost is relatively high. Particularly, the
stereoselective assembly of the P-chirogenic center requires
recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate
mixture several times to obtain the desired diastereoisomer (39%)
for further coupling with the D-ribose-derived 5-alcohol. To
address this problem, a variety of chiral bicyclic imidazoles were
synthesized as organocatalysts for stereoselective (S)-P-phosphor-
amidation employing a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the
other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the
(S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-
cinnamaldehyde-derived carbamate was utilized in the reaction at −20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-
phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7
d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an
excellent opportunity for industrial production of remdesivir.
such as glycosylation followed by assembly of all components
form viral vesicles for transport and release.14,15
INTRODUCTION
■
The respiratory disease COVID-19 caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently
the most severe global health catastrophe of the century.1−3
SARS-CoV-2 consists of four structural proteins: spike (S),
nucleocapsid (N), envelope (E), and membrane (M) proteins,
which play significant roles in virus maturation and infection.4
The S-proteins are richly glycosylated and are presented as a
trimer on the viral surface with a characteristic bulging
appearance5 for interaction with human angiotensin-converting
enzyme 2 (ACE2) receptor on airway epithelial cells during
the initial step of infection.6−9 Further cleavage of the S-
proteins by human transmembrane protease serine 2
(TMPRSS2) initiates the viral fusion and endocytosis
process.10 Once the RNA genome is released, it hijacks the
cell machinery and translates into polyprotein 1a (PP1a) and
polyprotein 1ab (PP1ab), which are subsequently cleaved by
viral 3C-like (3CL) and papain-like (PL) proteases to generate
16 nonstructural proteins (NSP) as a replication-transcription
complex (RTC).11 Replication of the viral RNA by the RNA-
dependent RNA-polymerase (RdRp, NSP12)12 and tran-
scription of the viral RNA into mRNA by RTC enable the
next translational process to produce the S-, N-, E-, and M-
proteins as well as others.13 Post-translational modifications
Remdesivir 1 (GS-5735, Figure 1) is a broad-spectrum
antiviral compound that was developed by Gilead Sciences for
the treatment of hepatitis C and Ebola virus infections.16,17
The phase III clinical trials of the drug, conducted in The
Democratic Republic of Congo, showed insignificant effect
Figure 1. Structure of remdesivir 1.
Received: December 4, 2020
Published: February 26, 2021
https://dx.doi.org/10.1021/acs.joc.0c02888
© 2021 American Chemical Society
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against Ebola virus.18 Remdesivir 1 is a prodrug of nucleotide
(ProTide) with high cell permeability and is a promising
therapeutic agent against SARS, MERS, and SARS-CoV-
2.19−21 It is metabolized inside the host cell to the
corresponding nucleotide triphosphate (NTP) and targets
the RdRp enzyme to inhibit viral replication within the cell.15
The (S)-P-1 isomer plays a crucial role in RdRp inhibition in
comparison with its (R)-P-isomer with respect to potency,
toxicity, rate of metabolism, and phosphorylation in vivo.22
The synthesis of remdesivir 1 has been developed by Gilead
Sciences.16,17 Scheme 1 describes the key step of (S)-P-
Coupling of 6 with the D-ribose-derived 5-alcohol 7 in the
presence of MgCl2 and diisopropylethylamine afforded the
(S)-P-phosphoamidate 8 (70%), which underwent acidic
cleavage of the isopropylidene group to provide remdesivir 1
(69%).
However, there are some drawbacks in this synthetic route:
(1) an additional nucleophile, such as p-nitrophenol, must be
employed for the stabilization of phosphoramidoyl chloridate
4, (2) the corresponding diastereomeric mixture 5 has to be
purified by silica gel column chromatography before
crystallization, (3) multiple crystallization steps of the 1/1
diastereomeric mixture 5 are necessary to isolate the desired
pure diastereomer 6, resulting in a significant wastage of
materials (61%), (4) the products require purification by
column chromatography in the last two steps, respectively, and
(5) the overall yield for the last two steps is 48.3%, which may
not be considered economic-friendly. Therefore, developing an
efficient methodology to improve the (S)-P-phosphoamidation
step is important for the practical synthesis of remdesivir.
We report here a one-pot catalytic asymmetric phosphor-
amidation method to improve the overall synthesis. This work
is inspired by the mechanism of histidine-dependent glucose 6-
phosphatase catalyzed hydrolysis of glucose 6-phosphate
through intermediates 9, 10, and 11 (Scheme 2) and the
Scheme 1. Stereoselective Phosphoamidation in Gilead’s
Synthesis of Remdesivir
Scheme 2. Mechanism of Glucose 6-Phosphatase
imidazole residues of His119 and His176 as proton donor and
acceptor, respectively.23 The aforementioned mechanism
prompted us that chiral imidazole-derived compounds may
serve as potential catalysts for stereoselective phosphoramida-
tion. Toward our survey in this direction, we have come across
few reports that the chiral bicycloimidazole-based catalysts had
gained a proven ability to be employed as tailor-made motifs
and can impart promising levels of stereoselectivity at
phosphorus.24,25 The desired (R)-stereochemistry at phospho-
rus had been achieved by DiRocco and co-workers, employing
these kinds of chiral catalysts, which also possess (R)-
stereochemistry.26 On the basis of this clue, we envisioned
that for the synthesis of remdesivir 1, the need of a potential
strategy to acquire the desired (S)-stereochemistry at
phosphorus is in high demand, and we hypothesized that
this could be achieved by employing the chiral (S)-
bicycloimidazole-based catalysts as tools.
phosphoamidation, which requires high diastereomeric purity
at the phosphorus center. Coupling of 2-ethylbutyl-L-alanine 2
with PO(OPh)Cl2 3 in Et3N and CH2Cl2 yielded the
phosphoramidoyl chloridate 4, which was directly treated
with p-nitrophenol in one pot to give the 1/1 mixture of
diastereomers 5 (80%) after column chromatography
purification. The diastereomeric mixture 5 was initially
separated by HPLC using a chiral column to deliver a small
amount of optically pure 6, which was used as a seed for
further resolution of 5 through selective crystallization in
diisopropyl ether several times to furnish 6 in 39% yield.
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The strategies for the assembly of P-chirogenic phosphor-
amidates are depicted in Scheme 3. Path A describes Gilead’s
Zhang’s group.27 Unlike earlier described protocols, we report
herein the discovery of chiral imidazole-cinnamaldehyde-
derived structures as improved catalysts for the efficient
synthesis of remdesivir via asymmetric (S)-phosphoramidation
and acidic hydrolysis in a one-pot manner.
Scheme 3. Strategies for the Synthesis of P-Chirogenic
Phosphoramidate
RESULTS AND DISCUSSION
■
A series of chiral bicyclic imidazoles and bis bicyclic imidazoles
proposed for use are summarized in Figure 2. Reaction of
imidazole with acrolein or cinnamaldehyde furnished a racemic
mixture of bicyclic alcohols, which were separated by MPLC
chiral column to yield the optically pure compounds 20−25,
respectively. The detailed synthetic procedures and purification
methods are described in the Supporting Information. The
absolute configuration of 22 was determined by X-ray single
crystal analysis of its (+)-O-acetyl-L-mandelate derivative 26
(see the Supporting Information). Coupling of the alcohols
20−25 with commercially available t-butyl isocyanate gave the
carbamates 27−32, respectively. Consecutive Curtius rear-
rangement of the dicarboxylic acid 33 followed by coupling
with the alcohols 20−25 delivered the bis-carbamate
derivatives 34−39, respectively. Benzylation and silylation of
alcohol 22 provided the ether derivatives 40 and 41,
respectively.
Having the chiral catalysts in hand, the catalytic stereo-
selective assembly of the 1:1 phosphoramidoyl chloridates 4
with the D-ribose-derived 5-alcohol 7 in the presence of 2.0
equiv of 2,6-lutidine was systematically investigated, and the
results were summarized in Table 1. In entry 1, when 20 mol %
of the (S)-carbamate 27 was used in the reaction at −20 °C for
24 h, a mixture of the diastereomers 8 and 42 was obtained in
94% yield with 14.6/1 d.r. ratio (determined by HPLC). In
contrast, the (R)-carbamate 28 gave 64% yield with 1.9/1 d.r.
ratio (entry 2). Obviously, the (S)-configuration of 27 favored
the formation of (S)-P-diastereomer with high selectivity and
yield. We then tried the (S)-carbamate 29 having an extra
phenyl group with (R)-configuration under similar conditions
(entry 3), and the d.r. ratio (24.6/1) and yield (97%) were
approach to convert the racemic phosphoramidoyl chloridate
12 into a 1:1 mixture of 13 and 14 for further resolution to
obtain enantiomer 14 for the SN2-like coupling with alkoxide
(R1O−) to afford the expected phosphoramidate 15.16,17 In
Path B, employment of the chiral imidazole-derived
nucleophile (Nu*) as catalyst to couple the racemic
phosphoramidoyl chloridate 12 with R1OH would give 15
through an intermolecular equilibrium of the intermediates 16
and 17. The formation of the preferred intermediate 17 was
stereoselectively controlled by the chiral environment of the
catalyst. Alternatively, a chiral bis-imidazole catalyst, proposed
in Path C, would offer an intramolecular equilibrium of
intermediates 18 and 19. Very importantly, both Path B and
Path C utilize racemic mixture 12 as the coupling reagent
without further resolution. Most recently, an imidazole-
acrolein-based adamantyl-(S)-carbamate was developed by
Figure 2. Structures of the imidazole-derived chiral alcohols and various chiral catalysts.
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Table 1. Results of Various Chiral Bicyclic Imidazoles as Catalysts for Stereoselective Coupling of Compounds 4 and 7
a
a
entry
catalyst
mol %
T (°C)
t (h)
yield (%)
d.r. ratio (8/42)
1
2
3
4
5
6
7
8
27
28
29
30
31
32
34
35
36
37
38
39
40
41
26
29
29
29
29
29
29
29
29
29
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
2
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−10
−40
−78
−20
−20
−20
−20
−40
−40
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
48
55
24
30
12
24
24
94
64
97
65
79
42
94
88
96
96
93
92
68
61
67
90
92
0
14.6/1
1.9/1
24.6/1
1.2/1
14.6/1
0.9/1
11/1
0.1/1
24.6/1
0.4/1
5.5/1
0.2/1
4.9/1
4.1/1
3/1
17.1/1
30.3/1
0/0
4.4/1
6.2/1
22.8/1
33.5/1
36/1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
79
64
93
93
95
95
10
15
50
50
100
42.4/1
a
The percentage (%) and ratio were determined by HPLC analysis.
slightly increased in comparison with 27. On the other hand, in
entry 5, when the (S)-carbamate 31 with an extra (S)-phenyl
group was tested, a decrease in yield (79%) and 8.9/1 d.r. ratio
was observed. The configuration of this extra phenyl group is
important for the asymmetric phosphoramidation. We next
examined the (R)-carbamates 30 [entry 4, (S)-Ph] and 32
[entry 6, (R)-Ph], and similar results were found as compared
to 28 (entry 2). Regarding the use of bis-bicyclic imidazoles as
catalysts, the d.r. ratios of 8/42 obtained were 11/1 (entry 7,
94% yield), 24.6/1 d.r. (entry 9, 96% yield), and 5.5/1 d.r.
(entry 11, 93% yield) using the dimeric (S)-carbamates 34, 36,
and 38, respectively. Interestingly, the dimeric (R)-carbamates
35 (entry 8), 37 (entry 10), and 39 (entry 12) furnished the
undesired diastereomer 42 as a major product in much better
yields and ratios in comparison with the monomeric (R)-
carbamates 28, 30, and 32, respectively. In addition to the
carbamate moiety, the (S)-benzyl ether (40, entry 13), (S)-silyl
ether (41, entry 14), and (S)-ester (26, entry 15) were further
investigated for the reaction to provide 8/42 with d.r. ratios in
4.9/1 (68%), 4.1/1 (61%), and 3/1 (67%), respectively.
Since compound 29 provides the best results in our catalyst
screening in terms of yield and selectivity, we continued to
study its catalytic properties as well as temperature effect.
When the reaction was carried out at −10 °C (entry 16), the
yield (90%) and selectivity (17.1/1) slightly decreased,
whereas at a lower temperature (−40 °C), little improvement
in selectivity (30.3/1) was observed (entry 17). However, the
reaction required 48 h for completion due to the decrease of
catalytic activity. Moreover, no reaction was observed at −78
°C (entry 18). In entries 19−24, various catalyst concen-
trations were studied. When the catalyst 29 was reduced to 15
mol % (entry 21), 10 mol % (entry 20) or 2 mol % (entry 19),
both selectivity and yield decreased correspondingly. When 50
mol % of 29 was used at −20 °C (entry 22), the selectivity
slightly increased from 24.6/1 to 33.5/1 and the reaction was
completed in 12 h. By lowering the temperature to −40 °C
(entry 23), a selectivity ratio of 36/1 was obtained. A similar
result was observed by employing 100 mol % of 29 (entry 24),
which gave a selectivity ratio of 42.4/1.
In order to avoid the purification of the mixed diastereomers
8 and 42, a one-pot synthesis of remdesivir was investigated
(Scheme 4). In a 1-g scale synthesis, compounds 4 and 7 were
coupled in the presence of catalyst 29 followed by acidic
hydrolysis in p-TSA and methanol at room temperature to
remove the isopropylidene group in the same reaction flask to
furnish a mixture of 1 and its (R)-diastereomer in 96.1/3.9 d.r.,
which was further purified via recrystallization to give
remdesivir 1 (73%) in 99.4/0.6 d.r. The catalyst 29 was
recovered in 82% yield for reuse with similar efficacy. A 10-g
scale synthesis was then performed with the same protocols,
and consistent results were obtained to give 1 and 29 in 70%
(99.3/0.7 d.r.) and 83% yields, respectively.
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using an HPLC system (HP-2100, Agilent), consisting of a quaternary
gradient pump (Agilent 1100), conductivity detector (PROD,
AERS500, 4 mm, Thermal), reagent-free controller (PROD.
RFC10) and autosampler (Agilent 1260 infinity) system with and
acetonitrile−water mobile phase and UV detection.
Scheme 4. One-Pot Synthesis of Remdesivir
Synthesis of Compounds 20 and 21.28 To a mixture of
imidazole (50.0 g, 0.74 mol) and acetic acid (2.9 mL, 0.051 mol) in
dioxane (500 mL) was added acrolein (73.0 mL, 1.09 mol) at room
temperature. The resulting solution was then refluxed on oil bath for
36 h. After cooling to room temperature, the mixture was
concentrated under reduced pressure, and the crude residue was
subjected to flash column chromatography on silica gel by using ethyl
acetate/CH2Cl2/hexane (5/1/5 → 7/2/1) to give an enantiomeric
mixture, which was purified by MPLC chiral OD-H column to yield
20 (37.0 g, 40.5%) and 21 (37.0 g, 40.5%).1H NMR (600 MHz,
CDCl3) δ 7.04 (s, 1H), 6.82 (d, J = 6.0 Hz, 1H), 5.18−5.16 (m, 1H),
4.18−4.14 (m, 1H), 3.90−3.86 (m, 1H), 2.93−2.88 (m, 1H), 2.57−
2.52 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 156.5, 132.8,
114.7, 64.2, 43.5, 36.5.
Synthesis of Compounds 22−25. To a solution of cinnamalde-
hyde (25.0 mL, 0.19 mol) and imidazole (40.5 g, 0.57 mol) in dioxane
(250 mL) was added acetic acid (6.0 mL, 0.105 mol) at room
temperature. The reaction mixture was vigorously refluxed on oil bath
for 72 h. After cooling to room temperature, the solvent was
evaporated under reduced pressure. The crude residue was dissolved
in CH2Cl2, and washed with saturated NaHCO3 solution. The organic
layer was dried over MgSO4, filtered, and concentrated in vacuo. The
crude residue was treated with 80% ethyl acetate in hexane and
sonicated for 30 min. The resultant solids were filtered and washed
with cold ethyl acetate. The solids were purified through the silica gel
column chromatography by using ethyl acetate/dichloromethane/
hexane (5/1/4) as the eluent to afford the trans-isomers (18.2 g,
46.2%) and cis-isomers (9.8 g, 23.8%), respectively. Both isomers
were identified by the NOESY spectra.
CONCLUSION
■
In conclusion, the chiral carbamate 29, derived from imidazole
and cinnamaldehyde in two steps, was successfully developed
as an efficient catalyst for the stereoselective (S)-P-phosphor-
amidation in excellent yield and selectivity. The 1/1 mixture of
phosphoramidoyl chloridates 4 could be directly used as the
coupling reagent, avoiding a waste of the other diastereomer.
In addition, a high yielding combination of (S)-P-phosphor-
amidation and isopropylidene-deprotection successfully pro-
vided remdesivir in a one-pot manner. The organocatalyst 29
could be recovered in good yield, and similar results were
obtained using the recovered catalyst. This one-pot process is
relatively easy to scale up, and is expected to have a great
potential for industrial development.
trans-isomers: 1H NMR (600 MHz, CDCl3) δ 7.38−7.36 (m, 2H),
7.33−7.30 (m, 3H), 7.11 (s, 1H), 6.66 (s, 1H), 5.37−5.35 (m, 1H),
5.17−5.15 (m, 1H), 3.47−3.40 (m, 1H), 2.58−2.54 (m, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 156.6, 140.4, 133.5, 129.2,
128.6, 126.9, 114.0, 64.5, 59.8, 46.5.
1
cis-isomers: H NMR (600 MHz, CDCl3) δ 7.38−7.32 (m, 3H),
7.15 (d, J = 6.0 Hz, 2H), 7.09 (s, 1H), 6.66 (s,1H), 5.51(t, J = 6.8 Hz,
1H), 5.42 (d, J = 6.0 Hz, 1H), 3.05−3.01 (m, 1H), 2.82−2.77 (m,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 156.6, 140.2, 133.1, 129.2,
128.5, 126.4, 114.1, 64.5, 60.0, 48.1.
Separation and Identification of trans-Enantiomers 22 and
23. The enantiomers 22 and 23 were separated by MPLC Chiral OD-
H column using IPA/hexane (3/7) as an eluent. To identify the
stereochemistry of the separated enantiomers 22 and 23, their
enantiomeric mixture was subjected to resolution by using (+)-O-
acetyl-L-mandelic acid.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under an
atmosphere of nitrogen/argon in flame-dried glassware. Solvents were
distilled in the standard way, and commercial reagents were used
without any purification unless otherwise stated. Anhydrous solvents
like CH2Cl2, Et2O, DMF, and Et3N were dried in a standard way.
TLC was performed on glass plates precoated with Silica Gel 60 F254
(0.25 mm, E. Merck). TLC plates were visualized by exposure to
ultraviolet light (UV-254 nm) and/or submersion in aqueous
potassium permanganate solution (KMnO4) followed by heating on
a hot plate (120 °C). Flash column chromatography was carried out
on Silica Gel 60 (230−400 mesh, E. Merck) or MPLC
(INTERCHEM250). Crystal structure was recorded on single-crystal
X-ray diffractometer (Brucker CCD). 1H NMR spectra were recorded
on 600 MHz instrument at ambient temperature. Data were recorded
as follows: chemical shift in ppm from the solvent resonance
employed as the internal standard (CDCl3 at 7.26 ppm, and CD3OD
at 3.35 and 4.78 ppm), multiplicity (s = singlet, d = doublet; t =
triplet; q = quartet; st = septet; m = multiplet; br = broad), coupling
constant (Hz), integration. 13C NMR spectra were measured on 150
MHz spectrometer. Chemical shifts were recorded in ppm from the
solvent resonance employed as the internal standard (CDCl3 at 77.23
ppm, and CD3OD at 49.3 ppm). Mass spectra were obtained with ESI
Finnigan LCQ mass spectrometer (Thermo Finnigan), performed at
Genomics Research Center. Chiral HPLC analysis were performed
To a solution of the enantiomers 22 and 23 (1.0 g, 4.99 mmol) and
(+)-O-acetyl-L-mandelic acid in CH2Cl2 (10 mL) was sequentially
added EDC·HCl (1.43 g, 7.40 mmol) and DMAP (0.61 g, 4.99
mmol) at 0 °C under N2 atmosphere. After removing the ice bath, the
mixture was continuously stirred at room temperature for 3 h. The
reaction mixture was concentrated, and the crude residue was
dissolved in ethyl acetate (20 mL). The mixture was washed with
saturated NaHCO3 solution, and the organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The crude mixture was
subjected to silica gel column chromatography using ethyl acetate/
hexane (1/3) as eluent to afford 26 (820 mg, 44%) as a semi solid and
26A (790 mg, 42%) as a gummy solid.
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Compound 26: 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 4.3 Hz,
2H), 7.44−7.36 (m, 6H), 7.22 (s, 1H), 7.15 (d, J = 6.7 Hz, 2H), 6.78
(d, J = 0.6 Hz, 1H), 6.10 (d, J = 6.5 Hz, 1H), 5.87 (s, 1H), 5.47 (t, J =
6.9 Hz, 1H), 3.11 (dd, J = 14.7, 6.8 Hz, 1H), 2.91 (dt, J = 13.9, 6.8
Hz, 1H), 2.23 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.0,
168.8, 150.3, 139.3, 135.4, 133.0, 129.7, 129.4, 129.1, 128.9, 127.9,
126.5, 115.4, 75.0, 68.9, 59.6, 46.1, 20.9. HRMS m/z (ESI, M + Na+)
calcd for C22H20N2O4Na+ 399.1321, found 399.1330.
using EtOAc/hexane (3/1) to afford 29 as a white solid (66 mg,
89%). H NMR (600 MHz, CDCl3) δ 7.40−7.36 (m, 3H), 7.24 (s,
1
1H), 7.14 (d, J = 6.1 Hz, 2H), 6.78 (s, 1H), 6.03 (d, J = 5.7 Hz, 1H),
5.44 (t, J = 6.0 Hz, 1H), 4.81 (s, 1H), 3.08−3.04 (m, 1H), 2.92−2.87
(m, 1H), 1.34 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.9,
151.8, 139.6, 135.1, 129.4, 128.8, 126.4, 115.1, 67.2, 59.6, 50.7, 46.6,
+
29.0. HRMS m/z (ESI, M + H+) calcd for C17H22N3O2 300.1707,
found 300.1712.
Compound 26A: 1H NMR (600 MHz, CDCl3) δ 7.44 (dd, J = 6.5,
2.9 Hz, 2H), 7.39−7.36 (m, 3H), 7.35−7.29 (m, 3H), 7.20 (s, 1H),
7.05−6.99 (m, 2H), 6.71 (d, J = 0.6 Hz, 1H), 6.10 (dd, J = 6.5, 1.8
Hz, 1H), 5.15 (t, J = 6.9 Hz, 1H), 2.77 (dt, J = 13.6, 6.7 Hz, 1H), 2.70
(dd, J = 14.7, 6.9, 1.8 Hz, 1H), 2.15 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 170.3, 168.5, 150.4, 139.1, 135.5, 133.8, 129.6, 129.4,
129.1, 129.0, 128.0, 126.4, 115.4, 74.6, 68.7, 59.5, 45.9, 20.9. HRMS
m/z (ESI, M + Na+) calcd for C12H12N2ONa+ 399.1321, found
399.1329.
Compound 30. Compound 30 was prepared according to the
general procedure (B) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 30 as a white solid (62 mg,
1
87%). H NMR (600 MHz, CDCl3) δ 7.38−7.32 (m, 3H), 7.21 (s,
1H), 7.18 (d, J = 6.0 Hz, 2H), 6.77 (s, 1H), 5.98−5.97 (m, 1H),
5.23−5.20 (m, 1H), 4.79 (s, 1H), 3.60−3.55 (m, 1H), 2.49−2.47 (m,
1H), 1.29 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) δ 154.0, 151.8,
140.5, 135.4, 129.3, 128.7, 126.4, 115.0, 67.2, 59.3, 50.8, 45.7, 29.8,
+
29.0. HRMS m/z (ESI, M + H+) calcd for C17H22N3O2 300.1707,
The compound 26 was subjected to crystallization by using vapor
diffusion method (CHCl3/Hexane) and crystal growth is in
monoclinic form (Table S1). The crystal structure of compound 26
has revealed that its corresponding precursor after treating with
sodium hydroxide in methanol is compound 22, which is the peak-2
in the MPLC chromatogram. The other peak should be compound
23.
Separation and Identification of cis-Enantiomers 24 and 25.
The enantiomers 24 and 25 were separated by employing the MPLC
Chiral OD-H column using IPA/hexane (3/7) as an eluent. The
separated cis-enantiomers 24 and 25 were subjected to Mitsunobu
reaction followed by saponification to furnish the epimers 23 and 22,
respectively.
General Procedure (A) for the Synthesis of Compounds 27
and 28. To a solution of an alcohol (50 mg, 0.40 mmol) in THF (1.0
mL) was added sodium hydride (60% in mineral oil, 19 mg, 0.48
mmol) in portions. After 30 min, tert-butylisocyanate (40 mg, 0.40
mmol) was added dropwise. After 16 h, the reaction was quenched by
water (2.0 mL), and the mixture was then partitioned between water
(2.0 mL) and i-PrAc (4.0 mL). The organic layer was washed with
brine (4.0 mL), dried over MgSO4, filtered, and concentrated to yield
a pale orange semisolid. The residue was dissolved in MTBE (2.0 mL)
with gentle heating on water bath, and heptane (2.0 mL) was added
to the mixture over 10 min. After 2 h, the mixture was filtered, and the
filtrate was washed with 1/1 MTBE/heptane (2 mL) and dried under
nitrogen stream to yield the desired compound.
found 300.1706.
Compound 31. Compound 31 was prepared according to the
general procedure (B) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 31 as a white solid (62 mg,
1
87%). H NMR (600 MHz, CDCl3) δ 7.40−7.36 (m, 3H), 7.24 (s,
1H), 7.14 (d, J = 6.0 Hz, 2H), 6.78 (s, 1H), 6.03 (d, J = 5.2 Hz, 1H),
5.42 (t, J = 6.0 Hz, 1H), 4.80 (s, 1H), 3.08−3.04 (m, 1H), 2.92−2.87
(m, 1H), 1.34 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.96,
151.85, 139.70, 135.254, 129.36, 128.79, 126.37, 115.11, 67.23, 59.64,
50.78, 46.66, 29.02. HRMS m/z (ESI, M + H+) calcd for
+
C17H22N3O2 300.1707, found 300.1715.
Compound 32. Compound 32 was prepared according to the
general procedure (B) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 32 as a white solid (61 mg,
1
85%). H NMR (600 MHz, CDCl3) δ 7.38−7.33 (m, 3H), 7.26 (s,
1H), 7.21−7.17 (m, 2H), 6.77 (s, 1H), 5.97 (dd, J = 12.2, 6.8 Hz,
1H), 5.21 (dd, J = 12.0, 6.0 Hz, 1H), 4.78 (s, 1H), 3.59−3.56 (m,
1H), 2.48 (dd, J = 12.0 Hz, 6.0 Hz, 1H), 1.30 (s, 9H). 13C{1H} NMR
(151 MHz, CDCl3) δ 154.0, 151.8, 140.5, 135.4, 129.3, 128.7, 126.4,
115.0, 67.3, 59.3, 50.8, 45.7, 29.8, 29.0. HRMS m/z (ESI, M + H+)
+
calcd for C17H22N3O2 300.1707, found 300.1702.
General Procedure (C) for the Synthesis of Compounds 34−
39. 4,4′-(1,3-Phenylene)dibutanoic acid (200 mg, 0.80 mmol) and
triethylamine (0.25 mL, 1.80 mmol) were dissolved in THF (4.0 mL)
under N2 atmosphere. After cooling to 0 °C, ethyl chloroformate
(0.17 mL, 1.80 mmol) was added, and the mixture was stirred for 30
min. To this mixture was added a solution of sodium azide (0.26 g,
4.0 mmol) in water (3.4 mL). After 30 min, toluene (10 mL) and
water (10 mL) were added, and the organic layer was separated. The
aqueous layer was extracted with toluene (3 × 10 mL), and the
combined organic layers were dried over MgSO4, filtered, and
concentrated to ∼50% of the original volume. The crude solution of
the acyl azide was then heated to 90 °C on oil bath for 30 min, then
concentrated to yield the diisocyanate (195 mg, 90%) as a yellow oil.
THF (4.0 mL) was added to dissolve the residue, and the
corresponding starting material among (20−25) (1.6 mmol) and
sodium hydride (60% suspension in mineral oil, 14 mg, 0.36 mmol)
were sequentially added to the mixture. An additional portion of
sodium hydride was added to complete the reaction. After 30 min, a
few drops of water were added to quench the reaction, and the solvent
was removed in vacuo. The crude residue was purified by silica gel
chromatography using EtOAc/hexane (3/1) as the eluent to provide
the desired product.
Compound 27. Compound 27 was prepared according to the
general procedure (A) as a white solid (77 mg, 86%). 1H NMR (600
MHz, CDCl3) δ 7.17 (s, 1H), 6.93 (s, 1H), 5.87 (d, J = 4.8 Hz, 1H),
4.75 (s, 1H), 4.04−4.10 (m, 1H), 3.98−3.94 (m, 1H), 3.08−3.02 (m,
1H), 2.61−2.57 (m, 1H), 1.30 (s, 9H). 13C{1H} NMR (151 MHz,
CDCl3) δ 154.1, 151.8, 135.0, 115.6, 67.3, 50.7, 43.1, 35.6, 29.0.
+
HRMS m/z (ESI, M + H+) calcd for C11H18N3O2 224.1394, found
224.1398.
Compound 28. Compound 28 was prepared according to the
general procedure (A) as a white solid (79 mg, 88%). 1H NMR (600
MHz, CDCl3) δ 7.18 (s, 1H), 6.93 (s, 1H), 5.87 (d, J = 5.4 Hz, 1H),
4.75 (s, 1H), 4.14−4.10 (m, 1H), 3.98−3.94 (m, 1H), 3.07−3.02 (m,
1H), 2.61−2.57 (m, 1H), 1.30 (s, 9H). 13C{1H} NMR (151 MHz,
CDCl3) δ 154.1, 151.8, 135.0, 115.6, 67.3, 50.8, 43.1, 35.6, 29.8, 29.0.
+
HRMS m/z (ESI, M + H+) calcd for C11H18N3O2 224.1394, found
224.1398.
General Procedure (B) for the Synthesis of Compounds 29−
32. To a solution of an alcohol (50 mg, 0.25 mmol) and tert-
butylisocyanate (25 mg, 0.25 mmol) in THF (3 mL) was added
sodium hydride (60% in mineral oil, 7.2 mg, 0.30 mmol) at room
temperature under N2 atmosphere. After 30 min, the reaction was
quenched by water (2 mL), and the mixture was concentrated in
vacuo to give a pale orange semisolid. The crude residue was purified
by silica gel chromatography using EtOAc/hexane (3/1) as the eluent
to provide the desired product.
Compound 34. Compound 34 was prepared according to the
general procedure (C) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 34 as a white solid (299 mg,
1
76%). H NMR (600 MHz, CDCl3) δ 7.17−7.15 (m, 3H), 7.0−6.93
(m, 5H), 5.90−5.87 (m, 2H), 5.17−4.95 (m, 2H), 4.14−4.09 (m,
2H), 3.98−3.95 (m, 2H), 3.24−3.12 (m, 4H), 3.08−3.00 (m, 2H),
2.61−2.57 (m, 6H), 1.83−1.77 (m, 4H). 13C{1H} NMR (151 MHz,
CDCl3) δ 155.9, 151.7, 142.1, 141.6, 135.0, 134.8, 128.9, 128.8, 126.3,
126.3, 115.6, 67.9, 43.1, 40.7, 39.8, 35.5, 35.4, 33.1, 32.9, 31.9, 31.6,
Compound 29. Compound 29 was prepared according to the
general procedure (B) and purified by column chromatography by
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+
31.4. HRMS m/z (ESI, M + H+) calcd for C26H33N6O4 493.2558,
found 493.2556.
71.5, 71.0, 59.9, 47.0, 29.9. HRMS m/z (ESI, M + H+) calcd for
C19H19N2O+ 291.1492, found 291.1493.
Compound 35. Compound 35 was prepared according to the
general procedure (C) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 35 as a white solid (295 mg,
75%). 1H NMR (600 MHz, CDCl3) δ 7.20−7.15 (m, 3H), 7.0−6.93
(m, 5H), 5.90−5.89 (m, 2H), 4.97 (bs, 2H), 4.14−4.10 (m, 2H),
3.98−3.94 (m, 2H), 3.25−3.13 (m, 2H), 3.08−3.02 (m, 2H), 2.62−
2.57 (m, 6H), 1.84−1.77 (m, 4H). 13C{1H} NMR (151 MHz,
CDCl3) δ 155.9, 151.7, 141.6, 134.9, 128.8, 126.3, 115.6, 77.4,
77.2,77.0, 67.9, 43.1, 40.7, 35.5, 33.1, 31.6. HRMS m/z (ESI, M + H+)
Compound 41. To a solution of the alcohol 22 (100 mg, 0.51
mmol) and 2,6-lutidine (80.4 mg, 0.75 mmol) in CH2Cl2(1.5 mL)
was added TBDMSOTf (0.11 mL, 0.5 mmol) at 0 °C under N2
atmosphere. The mixture was warmed to room temperature and
continuously stirred for 12 h. After concentration in vacuo, the
residue was subjected to silica gel chromatography by using EtOAc/
hexane (1/9 → 1/1 → 3/1) to afford the desired compound 41 as a
colorless liquid (99 mg, 63%). 1H NMR (600 MHz, CDCl3) δ 7.36−
7.33 (m, 3H), 7.17 (s, 1H), 7.10 (s, 2H), 6.67 (s, 1H), 5.44 (s, 1H),
5.21 (s, 1H), 2.88−2.86 (m, 1H), 2.71−2.68 (m, 1H), 0.92 (s, 9H),
0.22 (s, 3H), 0.13 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
155.2, 140.4, 134.4, 129.3, 128.6, 126.5, 114.2, 66.3, 59.4, 49.8, 26.1,
18.5, −4.3, −4.6. HRMS m/z (ESI, M + H+) calcd for C18H27N2OSi+
315.1887, found 315.1889.
+
calcd for C26H33N6O4 493.2558, found 493.2560.
Compound 36. Compound 36 was prepared according to the
general procedure (C) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 36 as a white solid (278 mg,
1
54%). H NMR (600 MHz, CDCl3) δ 7.38−7.34 (m, 6H), 7.26 (bs,
2H), 7.11 (bs, 4H), 7.01(bs, Hz, 3H), 6.74 (s, 2H), 6.02 (s, 2H), 5.40
(bs, 1H), 5.04 (bs, 2H), 3.20−3.18 (m, 4H), 3.05−3.02 (m, 2H),
2.89−2.85 (m, 2H), 2.62 (t, J = 6.2 Hz, 4H), 2.47 (t, J = 5.7 Hz, 4H).
13C{1H} NMR (151 MHz, CDCl3) δ 155.8, 151.7, 141.7, 139.7,
135.3, 129.4, 128.8, 128.79, 128.7, 126.4, 126.3, 115.1, 67.9, 59.6,
46.6, 40.8, 33.1, 31.6. HRMS m/z (ESI, M + H+) calcd for
Catalytic Asymmetric Phosphoramidation and One-Pot
Synthesis of Remdesivir. Compound 4. Compound 4 was
prepared by following the reported literature.29 1H NMR (500
MHz, CDCl3) δ 7.40 (td, J = 8.2, 2.6 Hz, 2H), 7.28 (dd, J = 14.0, 7.5
Hz, 3H), 4.48−4.31 (m, 1H), 4.28−4.09 (m, 3H), 1.62−1.53 (m,
4H), 1.42−1.35 (m, 4H), 0.92 (dd, J = 13.2, 7.3 Hz, 6H). 31P NMR
(242 MHz, CDCl3) δ 8.05 and 7.74.
+
C38H41N6O4 645.3184, found 645.3173.
General Procedure for the Catalytic Asymmetric Phosphor-
amidation. In a flame-dried round-bottom flask, a mixture of the 5-
alcohol 7 (10.0 mg, 0.03 mmol) and catalyst (mol %, according to the
Table 1) was coevaporated with anhydrous toluene (1.0 mL, 2 times),
and dried under high vacuum for 2 h. The mixture was dissolved in
dry CH2Cl2 (1.0 mL) under N2 atmosphere, and freshly activated 4 Å
molecular sieves (20 mg) and 2,6-luditine (7.0 μL, 0.06 mmol) were
sequentially added to the solution. The resulting mixture was stirred
at room temperature for 10 min, and then cooled to −20 °C. After 10
min, a solution of the phosphoramidoyl chloridates 4 (15.7 mg, 0.05
mmol) in dry CH2Cl2 (0.5 mL) was added, and the reaction mixture
was continuously stirred at same temperature for 24 h. The reaction
was monitored by TLC analysis until the complete consumption of
the starting material 7. The whole reaction mixture was filtered
through a pad of Celite, and the filtrate was concentrated in vacuo.
The crude residue was dissolved in methanol and filtered off. The
filtrate was subjected to HPLC analysis.
Compound 37. Compound 37 was prepared according to the
general procedure (C) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 37 as a white solid (288 mg,
56%). 1H NMR (600 MHz, CDCl3) δ 7.38−7.34 (m, 6H), 7.26 (d, J
= 5.9 Hz, 2H), 7.11 (d, J = 6.0 Hz, 4H), 7.01(d, J = 6.0 Hz, 4H), 6.75
(s, 1H), 6.02 (d, J = 5.2 Hz, 2H), 5.40 (t, J = 6.1 Hz, 2H), 4.94 (bs,
2H), 3.25−3.18 (m, 4H), 3.05−3.02 (m, 2H), 2.89−2.85 (m, 2H),
2.62 (t, J = 6.2 Hz, 4H), 2.47 (t, J = 5.7 Hz, 4H). 13C{1H} NMR (151
MHz, CDCl3) δ 155.8, 151.7, 141.7, 139.7, 135.3, 129.4, 128.8, 128.8,
128.7, 126.4, 126.3, 115.1, 67.9, 59.6, 46.6, 40.8, 33.1, 31.6. HRMS
+
m/z (ESI, M + H+) calcd for C38H41N6O4 645.3184, found
645.3177.
Compound 38. Compound 38 was prepared according to the
general procedure (C) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 38 as a white solid (293 mg,
1
57%). H NMR (600 MHz, CDCl3) δ 7.34−7.33 (m, 6H), 7.25 (s,
2H), 7.20−7.15 (m, 5H), 6.96 (bs, 3H), 6.77 (s, 2H), 5.99 (s, 2H),
5.20 (s, 2H), 4.98 (s, 2H), 3.56−3.55 (m, 2H), 3.20−3.14 (m, 4H)
2.58−2.47 (m, 6H), 1.8 (bs, 4H). 13C{1H} NMR (151 MHz, CDCl3)
δ 155.8, 151.7, 141.7, 139.7, 135.2, 129.4, 128.8, 128.8, 126.4, 126.2,
115.1, 67.8, 59.6, 46.5, 40.8, 33.1, 31.6. HRMS m/z (ESI, M + H+)
One-Pot Synthesis of Remdesivir 1 in a 1.0 g Scale. In a
flame-dried round-bottom flask, a mixture of the 5-alcohol 7 (1.0 g,
3.02 mmol) and the catalyst 29 (180 mg, 0.62 mmol) were
coevaporated with anhydrous toluene (20 mL, 2 times) and dried
under high-vacuum for 2 h. The mixture was dissolved in anhydrous
CH2Cl2 (50 mL) under N2 atmosphere, and freshly activated 4 Å
molecular sieves (1.5 g) and 2,6-luditine (700 μL, 6.04 mmol) were
sequentially added to the solution. The reaction mixture was stirred at
room temperature for 10 min, and then cooled to −20 °C. After 10
min, a solution of the phosphoramidoyl chloridates 4 (1.57 g, 4.53
mmol) in CH2Cl2 (5 mL) was added, and the reaction mixture was
stirred at the same temperature for 24 h. Dichloromethane was then
evaporated through the needle under reduced pressure. The crude
material was treated with p-TSA (5.74 g, 30.2 mmol) in methanol (50
mL), and the resulting solution was continuously stirred at room
temperature for 24 h. The reaction mixture was filtered through a pad
of Celite to remove 4 Å molecular sieves, quenched by adding
triethylamine, and concentrated in vacuo. The crude residue was
dissolved in EtOAc (100 mL), and the mixture was washed with
saturated NaHCO3. The aqueous layer was extracted with EtOAc (3
× 50 mL), and the combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. The crude residue was subjected
to silica gel column chromatography by using EtOAc/hexane (1/9 →
1/1 → 3/1 → 1/0) to afford the catalyst 29 (148 mg, 82%) and a
mixture of the diastereomers, which was further purified by
recrystallization from CH3CN and CH2Cl2 to afford remdesivir 1
+
calcd for C38H41N6O4 645.3184, found 645.3190.
Compound 39. Compound 39 was prepared according to the
general procedure (C) and purified by column chromatography by
using EtOAc/hexane (3/1) to afford 39 as a white solid (283 mg,
1
55%). H NMR (600 MHz, CDCl3) δ 7.34−7.33 (m, 6H), 7.25 (s,
2H), 7.20−7.15 (m, 5H), 6.96 (bs, 3H), 6.77 (s, 2H), 5.99 (s, 2H),
5.20 (s, 2H), 4.98 (s, 2H), 3.56−3.55 (m, 2H), 3.20−3.14 (m, 4H)
2.58−2.47 (m, 6H), 1.8 (bs, 4H). 13C{1H} NMR (151 MHz, CDCl3)
δ 155.8, 151.7, 141.7, 139.7, 135.2, 129.4, 128.8, 128.8, 126.4, 126.3,
115.1, 67.9, 59.6, 46.5, 40.8, 33.1, 31.6. HRMS m/z (ESI, M + H+)
+
calcd for C38H41N6O4 645.3184, found 645.3176.
Compound 40. To a solution of the alcohol 22 (100 mg, 0.51
mmol) and benzyl chloride (104 mg, 0.75 mmol) in anhydrous THF
(2.0 mL) was added NaH (9.0 mg, 0.37 mmol) at 0 °C under N2
atmosphere. After the ice-bath was removed, resulting solution was
continuously stirred at room temperature for 8 h. The mixture was
quenched with ice-cold water and extracted with EtOAc (3 × 5 mL),
and the combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude residue was subjected to silica gel
column chromatography by using EtOAc/hexane (1/9 → 1/1 → 3/
1
1) to afford the benzyl ether 40 (99 mg, 68%) as a colorless oil. H
NMR (600 MHz, CDCl3) δ 7.41−7.34 (m, 7H), 7.30−7.27 (m, 1H),
7.20 (s, 1H), 7.15−7.13 (s, 2H), 6.74 (s, 1H), 5.46 (dd, J = 12.0, 6.0
Hz, 1H), 4.95−4.90 (m, 2H), 4.75−4.73 (m, 1H), 3.06−3.02 (m,
1H), 2.73−2.69 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.6,
139.9, 138.0, 134.2, 129.3, 128.7, 128.6, 128.3, 127.9, 126.6, 114.7,
1
(1.39 g, 73% yield, 99.4/0.6 d.r.) as a white solid. H NMR (600
MHz, CD3OD) δ 7.87 (s, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.21−7.14
(m, 3H), 6.91 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 4.79 (d, J
= 5.4 Hz, 1H), 4.42−4.35 (m, 2H), 4.28 (dt, J = 10.5, 5.1 Hz, 1H),
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4.17 (t, J = 5.6 Hz, 1H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.90 (ddd, J
= 23.7, 12.7, 6.4 Hz, 2H), 1.45 (dt, J = 12.3, 6.2 Hz, 1H), 1.34−1.28
(m, 7H), 0.85 (t, J = 7.5 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3)
δ 175.15, 175.1, 157.4, 152.3, 152.3, 148.4, 130.9, 126.2, 125.7,
121.51, 121.5, 118.1, 117.7, 112.5, 102.8, 84.44, 81.4, 84.4, 75.9, 71.8,
68.2, 67.3, 67.27, 41.8, 24.4, 24.3, 20.7, 20.6, 11.5, 11.4.
Sivakumar N. Reddy − Genomics Research Center, Academia
Sinica, Taipei 11529, Taiwan
Chiao-Chu Ku − Genomics Research Center, Academia Sinica,
Taipei 11529, Taiwan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02888
One-Pot Synthesis of Remdesivir 1 in a 10.0 g Scale. In a
flame-dried round-bottom flask, a mixture of the 5-alcohol 7 (10 g,
30.2 mmol) and catalyst 29 (1.8 g, 6.2 mmol) were coevaporated with
anhydrous toluene (100 mL, 2 times) and dried under high-vacuum
for 2 h. The mixture was dissolved in anhydrous CH2Cl2 (500 mL)
under N2 atmosphere, and freshly activated 4 Å molecular sieves (15
g) and 2,6-luditine (7.0 mL, 60.4 mmol) were sequentially added to
the solution. The reaction mixture was stirred at room temperature
for 10 min, and then cooled to −20 °C. After 10 min, a solution of the
phosphoramidoyl chloridates 4 (15.7 g, 45.2 mmol) in anhydrous
CH2Cl2 (5 mL) was added, and the reaction mixture was stirred at the
same temperature for 24 h. Dichloromethane was then evaporated
through the needle under reduced pressure. The crude material was
treated with p-TSA (57.4 g, 0.3 mol) in methanol (500 mL), and the
resulting solution was continuously stirred at room temperature for 24
h. The reaction mixture was filtered through a pad of Celite to remove
4 Å molecular sieves, quenched by adding triethylamine, and
concentrated in vacuo. The crude residue was dissolved in EtOAc,
and the mixture was washed with saturated NaHCO3. The aqueous
layer was extracted with EtOAc (3 × 250 mL), and the combined
organic layers were dried over MgSO4, filtered and concentrated in
vacuo. The crude residue was subjected to silica gel column
chromatography by using EtOAc/hexane (1/9→ 1/1 → 3/1 → 1/
0) to afford the catalyst 29 (1.5 g, 83%) and a mixture of the
diastereomers, which was further purified by recrystallization from
CH3CN and CH2Cl2 to afford remdesivir 1 (13.3 g, 70% yield, 99.3/
0.7 d.r.) as a white solid.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science and
Technology of Taiwan (MOST 108-2639-M-001-001-ASP),
and the Academia Sinica (AS-KPQ-109-BioMed and AS-
SUMMIT-109).
REFERENCES
■
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AUTHOR INFORMATION
Corresponding Authors
■
Chi-Huey Wong − Genomics Research Center, Academia
Sinica, Taipei 11529, Taiwan; The Scripps Research
Institute, La Jolla, California 92037, United States;
orcid.org/0000-0002-9961-7865; Email: chwong@
gate.sinica.edu.tw, wong@scripps.edu
Shang-Cheng Hung − Genomics Research Center, Academia
Sinica, Taipei 11529, Taiwan; Department of Applied
Science, National Taitung University, Taitung 95092,
Taiwan; orcid.org/0000-0002-8797-729X;
Email: schung@gate.sinica.edu.tw
Authors
Veeranjaneyulu Gannedi − Genomics Research Center,
Academia Sinica, Taipei 11529, Taiwan
Bharath Kumar Villuri − Genomics Research Center,
Academia Sinica, Taipei 11529, Taiwan
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