Figure 1. Taken from [1].
Just a quick one here. This is a paper from Organic Letters,
where the researchers have made some fluorinated analogues of an inhibitor
against Hepatitis C virus. An interesting aspect is that the chemical structure
contains a triangle – no, I mean cyclopropyl, the 3-membered carbon ring.
Recently, it becomes known that a major strategy against
Hepatitis C virus was to target a protease (NS3/4A), which is involved in the
replication of the virus. A known inhibitor of this enzyme is the compound 2 in Figure 1. Not only this peptidomimetic have a di-peptide backbone, it also
consists of a cyclopropyl-amino acid functionality. That is why if we want to
start making analogues resembling this compound, we have to start with the
cyclopropyl core.
The researchers of this paper decided to go one step further
- they want to test whether the inclusion of a fluorine atom, bonding directly
to the carbon atom in the cyclopropyl core, would lead to any improvement of
the inhibitor.
The reason why this paper caught my attention was because I
was fascinated by the cyclopropyl type structure, an also its synthesis,
nevertheless we will not miss any other details.
Figure 2. Synthesis of the fluorinated cyclopropyl amino
ester building block. Taken from [1].
The first stage is to make the protected, fluorinated
cyclopropyl amino ester 8 (Figure 2). Using ethyl dibromofluoroacetate, they carried out
a cycloproponation with the aminoacrylate 7, with Zn/LiCl at low temperature,
with dropwise addition. Indeed, LiCl can accelerate many organozinc and also
organomagnesium (Grignard reaction), but one thing important about LiCl (which
I can convince you because I have done some related experiments). LiCl is
really hygroscopic, so you have to heat it up and dry it under vacuum before
use. Except this precaution, LiCl really helps to promote the reaction, and literature
abounds with its use. The resulting
cyclopropyl amino ester was stable to column chromatography, and they got that
with a reasonably great yield. Their next key challenge was to install the
exocyclic double bond, sort of conjugated to the cyclopropyl ring. That involved
a series of steps, and the pen-ultimate step involved a Wittig reaction to put
in the double bond. After an acidic hydrolysis, they get the amino ester
hydrochloride salt 6.
Figure 3. Completion of Synthesis. Taken from [1].
The reason why they made the compound 6 was because they
wanted to develop a strategy to make a fluorinated version of Simeprevir, and
compound 6 was actually one of the 4 building blocks they are going to put
together at the end. Indeed, their synthesis indeed exposed some of the
chemical properties of the building blocks, including compound 6, from the
side-reactions they encountered throughout the optimization (Figure 3). For example, a relative
higher temperature led to the ring-opening of the cyclopropyl, and indeed they
can monitor this because of the distinct 19F NMR shifts of the fluorine atoms in the decomposition products and the cyclopropyl fluorine (Figure 4). They counteracted the problem by
lowering the temperature to -15 Celsius. The other key reactions to join the
fragments together included a Mitsunobu, a ring-closing metathesis and a mixed
anhydride coupling reaction. So, they have devised a novel strategy towards
fluorinated analogues and they have also submitted their compounds to some
preliminary antiviral activities studies.
Reference:
1. Toward
the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors
Using Methyl α-Amino-β-fluoro-β-vinylcyclopropanecarboxylate
as Key Intermediate
G.
Milanole, F.
Andriessen, G.
Lemonnier, M.
Sebban, G.
Coadou, S. Couve-Bonnaire,
J.-F. Bonfanti, P.
Jubault, and X. Pannecoucke
Org. Lett., 2015,
asap
DOI:
10.1021/acs.orglett.5b01216
