Design and Synthesis of antiviral Molnupiravir analogues
Qi Chen*, Jarod M. Marasco, Jenna N. Kriley
Department of Chemistry, Slippery Rock University, Slippery Rock, PA 16057

Introduction:
Viral infectious diseases have been proved to be a major threat to our public health, including the ongoing
COVID-19 pandemic. Two pillars of fighting viral infectious diseases are vaccines and antiviral drugs.
Despite the immense achievements of our COVID-19 vaccines, yet the pace of antiviral drug development is
dreadfully slow. Besides Remdesivir, only two more compounds (currently under development by Pfizer and
Merk respectively), are showing significant progress in treating COVID infections. Two of three (Remdesivir
from Gilead and Molnupiravir from Merck) (Figure 1) are nucleosides analogues, which indicate the
importance of nucleosides analogues in the field of antiviral research. Their antiviral mechanism could be
rather varied despite the chemical structure similarity among the nucleoside analogs. Such as Redemisvir
stops the viral replication by halting the RNA-dependent RNA polymerase (an RNA assembling machine). In
contrast, Molnupiravir, an RNA mutagen, causes the virus to accumulate replicating errors, thus leading to
viral death. Sometimes, structure differences as minor as changing one atom could respond to the diverse
antiviral mechanism. And diversity is the key to battling viral resistance to the exiting antiviral drugs.

Figure 1 The structures of Molnupiravir and Remdesivir
NH2
N

O

N

HO

O

N

O

O
C

O
HO

OH

Molnupairavir

O

HO

N

N

OH

Remdesivir

OH
N

O
N

O

O

O

HO

O

HO

OH

OH

N

2

1

O

Chemistry:

O

The designed synthesis of target compounds 1 and 2 includes three major
synthetic challenges we presented here as three core steps in synthesis (Scheme
1). The first challenge (core step I) involves establishing the 5’-side chain via a
1,4-Michael addition of a vinyl group to the key intermediate enone 9, obtained
through a 6-step synthesis by the undergraduate researcher (Scheme 2).
OH

HN

O

Nucleobase

N

O

Side chain
Natural Nucleosides

N

N

O

OH

HO

O

OH

1

N

O

O

O

2

O

O

O

7
5’

O

N

Figure 1. Nature and Carbocyclic nucleoside

O
OH

O

O

O

O

O
8

9

N

+

O

N
H

7

Bz

N

Coupling
reaction
O

O

Bz
O

5

Core Step-II

HN

Scheme 1: Retrosynthesis design for target compounds
O

O
OH

HO

a

D-Ribose

c
O

O

O

OCH3

I

b
O

OH

HO

HO

OH

HN

F
B F K
F

O
8b

O

O

O

O

N

HO

1

N

O

N

O

O

OH

O

O

O

O

Bz
O

O

O

18

12

N

NH

O
OH

O

O

OH
N

HO
HO

11

10

O

O
8

N
N

O

OCH3

OH

The 1,4-addition of the 5’ side-chain was successful installed by a in situ formed Gilman reagent transformed from a lithium reagent.
The 1HNMR below shows the achieved pure compound 22. The reduction using the LiAlH4 gave a mixture of diastereomers of the
hydroxyl group on the 1’ position. The condition will be modified to use less reactive NaBH4 to ensure the enantiomeric pure
compound 23.

O

6

Core Step-I

Figure 4:Structures for the reagents in a. condition 2

5

O

+

Cond.1 under higher T

O

The new synthesis strategy (Scheme 5) is pursued to optimize the 5’ side chain construction (Core step-I). The protected alkoxyl group
is chosen as the nucleophile, which will shorten the synthesis route by two steps (oxidative cleavage and reduction) compared with the
old design (Scheme 1).

O

O

O

Scheme 4. Synthesis condition for compound 5: a. condition 1: vinylmagnesium bromide,CuBr.Me2S, TMSCl, HMPA, THF, -78oC;
condition 2: acetylacetonatobis(ethylene)rhodium (I), (R)-MonoPhos, potassium vinyltrifluoroborate, EtOH, reflux; b. LiAlH4, THF, 0oC; c.
compound 6, DIAD, PPh3, 60oC.

Bz
O

Carbocyclic Nucleosides
5’

O

8

a

4

Core Step-III

O

c

O

O

O

O

3

Side chain

The presented study is the first in the line to pursue a series of chemically modified compounds designed
based on the antiviral drug Molnupiravir (EIDD-2801, MK-4482), currently finished phase II/III clinical trials
with a promising positive result and was granted an emergency use authorization by U.S. FDA. The newly
designed targets adopted the carbocyclic sugar framework to improve the antiviral activity by increasing the
cyto-stability compared to the parent compound. Carbocyclic nucleosides (Figure 2) are also known for their
prominent board-spectrum antiviral activities with distinct drug action mechanisms. Their antiviral activity
stems from inhibition of a host enzyme Adenosylhomocysteine (AdoHcy) hydrolase, then consequentially
stop the “capping” progress, a major step in forming the mature viral mRNA (Figure 3). The designed
compounds (Figure 4) combine the features of Molnupiravir (nucleobase) with the carbocyclic rings to pursue
a class of dual antiviral mechanism drug candidates. Potential pro-drug structures are also included to test the
pharma kinetic properties. The proposed synthesis strategy successfully achieves the key intermediate via a
Mitsunobu coupling reaction. Optimization of the reaction conditions for the critical synthesis steps is detailed
in the following discussion.

O

9

HO

O

O
HO

Side Chain

Side Chain

O

HO

N

NH

N

OH

b

Cond.1 and 2

O

N

Bz

O

O

OH

O

Nucleobase

O

9

N

H2
C

5’
a

Figure 2. Naturally Occurred and Carbocyclic Nucleosides

N
N

HN

N

NH2

Ph
O O
P
O
HN

OH

HN

HN

O

The first attempt to construct the 5’-side chain is to use the in-suit formed Gilman reagent under the low temperature to facilitate the 1,4addition of unsaturated ketone 9. No reaction under -75oC, even after stirring overnight. After rising the temperature to -20oC, compound
8 was formed, accompanied by the 1,2-addition by-product 8b (Scheme 4). The other condition (cond. 2) was also tried using less reactive
vinyltrifluoroborate as a nucleophile with rhodium catalyst. Compound 8 was achieved with a low yield (27%). After reduction (b) and
Mitsunbu coupling (c) compound 5 was obtained as a low quantity mixture and difficult to carry on for the later synthesis.

Figure 3. Designed Target Compounds, Carbocyclic Molnupiravir

a

O

O

O

O

O

9

OH

f

O

OH

O

O

O

O

e

O
15

Figure 3. Antiviral Mechanism of AdoHcy Hydrolase inhibitors

9

14

13

The second challenge (core step II) is to combine nucleobase 6 with pseudo sugar 7
via a coupling reaction. Two main components in this step (6 and 7) are synthesized
parallelly to improve success rate. The strategy is known as convergent synthesis in
comparison with linear synthesis. The synthesis of nucleobase coupling precursor 7
is shown below in scheme 3.
O
NH
N
H
16

O

a

N
N
Bz
17

O

N

b
N
H

Bz
O

6

Scheme 3. Synthesis condition for compound 6: a. Benzoyl chloride, acetonitrile/pyridine (5:2, v/v);
b. K2CO3, dioxan/H2O (1:1, v/v), CH2Cl2, 77% in two steps.

O
O
22

Revised Core Step-I

O

N

O

O

OH
O

O

23

O

N
H

21

6

O

N

d

O
N

+

O

NH
N

Bz
O

O

Bz

O

O

O

O

O

25

24

Core Step-II

Scheme 5. Revised Retrosynthesis design for the target compound 1.

Scheme 4. Synthesis condition for compound 22: a) tBuOK, tBuOMe,
sec-BuLi, CuBr.SMe2, diisopropyl sulfide, THF. B) LiAlH4, THF 0oC.

Acknowledgements:
We are grateful to the FSRG Research Grant fund from Slippery Rock University for their support of this research.

References:
1.

O
Bz

O

O

Scheme 2. Synthesis of intermediate 15: a.(MeO)2CMe2, MeOH, HCl, acetone, rt., 72%; b.
PPh3, I2, imidazole, 86%; c. Zn, MeOH, 96%; d. vinylmagnesium bromide, THF, 78%; e.
Grubbs catalyst, CH2Cl2; f. PDC, CH2Cl2, 90%.

O

O

O

O

O

O

d
O

OH

c

Coupling
reaction

Core Step-III

O

22

20

19

b

2.
3.
4.
5.
6.
7.
8.
9.

(a) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Smpeck, R.; Andrei, G.; Bbalzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35,
3372; (b) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem.
1994, 37, 551; (c) Yang, M.; Schneller, S. W. Bioorg. Med. Chem. Lett. 2005, 15, 149; (d) Yang, M.; Schneller, S. W.; Korba, B. J.
Med. Chem. 2005, 48, 5043.
Schneller S. W. Rec Adv. Nucleotides. 2005; 24:1395.
Liu C.; Chen Q.; Schneller S. W. Bioorg. Med. Chem. Lett. 2016, 26, 928.
Schneller S. W.; Liu C.; Chen Q.; Ye. W. PCT Int. Appl. 2016, WO 2016022563 A1; US 9,657,048.
Chen Q.; Davidson A. Bioorg. Med. Chem. Lett. 2017, 4436.
(a) De Clercq, E. Nucleotides Nucleic Acids 2005, 24, 1395. (b) Liu, C.; Chen, Q.; Schneller, S. W. Bioorg. Med. Chem. Lett.
2012, 22, 5182.
(a) DeClercq, E. J. Clin. Virol. 2004, 30, 115. (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.;
Guedj, R. Tetrahedron 1994, 50, 10611. (c) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
Liu C.; Chen Q.; Yang M.; Schneller S. W. Bioorg. Med. Chem. 2013, 21, 359.
Liu C.; Chen Q.; Schneller S. W. Bioorg. Med. Chem. Lett. 2012, 22, 5182.