By Xavier Verdaguer1,2I
n the book Alice’s Adventures in
Wonderland, Alice suspected that the
milk on the other side of the look-
ing glass might not be good for the
cat to drink. Perhaps unbeknownst to
the writer Lewis Carroll, this subplot
reflects an important aspect of chemis-
try—that the mirror image of a molecule
is not necessarily the same as the origi-
nal because of a feature known as chiral-
ity. Just like our left and right hands, the
mirrored image of a chiral molecule is not
superimposable to the original. On page
1230 of this issue, Forbes and Jacobsen ( 1 )
describe an approach for the selective syn-
thesis of a single mirror image of
chiral pharmaceutical compounds,
the chirality of which is originated
at a phosphorus atom. The ap-
proach may make the synthesis of
highly desired chiral drugs much
more attainable.
Chirality is essential to life.
Amino acids and sugars are chi-
ral and are found as single right-
handed or left-handed isomers.
Therefore, proteins and most bio-
molecules are intrinsically chiral.
Chirality in molecules most of-
ten originates from carbon atoms
with four different substituents
in a tetrahedral disposition, with
the central atom labeled as “ste-
reogenic” or as a “stereocenter.”
After chemists Jean-Baptiste Biot
and Louis Pasteur discovered and
rationalized the phenomenon of
chirality in organic compounds,
others soon realized that elements
beyond carbon, like phosphorus,
could also be stereogenic, that
is, P-stereogenic. In 1911, chem-
ists Jakob Meisenheimer and Leo
Lichtenstadt were the first to sep-
arate a P-stereogenic compound
into its individual mirror isomers
( 2 ). Although this work initially
seemed like nothing more than
a scientific curiosity, it was a few
decades later when P-stereogenic
phosphorus ligands found appli-
cations in the industrial synthesis
of levodopa (L-dopa), a compound
for treating Parkinson’s disease( 3 ). William S. Knowles received the 2001
Nobel Prize in Chemistry for this discovery.
Nowadays, P-stereogenic compounds
have found their way into numerous drugs.
To make antitumoral and antiviral treat-
ments more effective, nucleoside drugs
are often introduced into the body as pro-
drugs, which are medications that become
active only after entering the patient, and
are used to help improve a medication’s
effectiveness. These phosphorus prodrugs
contain a P-stereogenic atom, as in teno-
fovir alafenamide ( 4 ). Cyclic dinucleotides
like cyclic guanosine monophosphate–ad-
enosine monophosphate (cGAMP), which
are promising candidates for cancer treat-
ments, contain two P-stereogenic phos-phorus atoms ( 5 ). The synthesis of such
phosphorus derivatives in a precise and
stereocontrolled manner is of vital impor-
tance because it will determine the perfor-
mance of the final drug.
Until very recently, the synthesis of
single-handed P-stereogenic compounds
relied on the use of other chiral molecules
known as stoichiometric chiral auxilia-
ries. These are initially attached to the
phosphorus atom but must be discarded
by the end of the synthesis ( 6 , 7 ). An ini-
tial breakthrough in this field came in
2017 when chemists at Merck developed
a highly specific catalyst for the synthesis
of a P-stereogenic prodrug compound us-
ing a dynamic kinetic resolution strategy
( 8 ). Here, a mixture of equal parts
left-handed and right-handed
starting material was used. The
catalyst attaches to the starting
material and exerts two functions:
It provides a bias for the reaction
with the nucleoside such that the
right isomer reacts faster than the
left one, and it interconverts the
two mirror isomers, allowing the
nonreacted left isomer to be con-
verted to the desired right-handed
product. Very recently, a similar
strategy was used in the P(III)
phosphoramidite coupling of oli-
gonucleotides using a chiral phos-
phoric acid catalyst. The approach
allowed the stereocontrolled syn-
thesis of cyclic dinucleotides like
cGAMP ( 9 ). However, both meth-
ods are substrate specific and do
not serve as a general strategy
for the synthesis of P-stereogenic
compounds.
Forbes and Jacobsen describe an
alternative and general approach
based on a symmetrical—that is,
nonchiral—starting material that
is modified to introduce chirality
by using a so-called desymmetriza-
tion reaction (see the figure). The
authors used a starting material(^1) Institute for Research in Biomedicine (IRB
Barcelona), The Barcelona Institute of Science
and Technology (BIST), 08028 Barcelona,
Spain.^2 Departament de Química Inorgà nica i
Orgà nica, Secció Química Orgà nica, Universitat
de Barcelona, 08028 Barcelona, Spain.
GRAPHIC: KELLIE HOLOSKI/ Email: [email protected]
SCIENCE
SCIENCE science.org
CHEMISTRY
Phosphorus through the looking glass
A key building block enables a general synthesis of chiral phosphorus drugs
Merck (2017) Forbes and Jacobsen
O
P Cl
O
P
Cl
O
P
Ar Cl
Cl
O
P
Ar Cl
NR 2
O
P
Ar
NR 2
O
P
Ar
Catalyst Catalyst
- O
P
Nucleoside
O
P
O
P
Catalyst Catalyst
Nucleoside
These symbols represent di erent
chemical groups contained in medicines.
1
Single-handed phosphorus drugs
Merck’s strategy uses a 50/50 mixture of right- and left-handed starting
material. This method is highly substrate specific. Forbes and Jacobsen
use a nonchiral starting material. The key single-handed building block ( 1 )
allows for the synthesis of multiple chiral phosphorus drugs through
sequential substitution.
10 JUNE 2022 • VOL 376 ISSUE 6598 1157