Post on 24-Apr-2020
Escaping from flatland: asymmetric synthesis for Medicinal Chemistry V1.1Key words: biochemistry, asymmetric synthesis, chirality, catalysis, medicinal chemistry, nicotinic acetylcholine receptors (nAChRs), high-impact diseases.
General introductionChirality is a geometric property of some molecules (and ions). A chiral molecule is non-
superimposable on its mirror image. Such molecules contain at least one carbon atom bonded to 4
different atoms or groups of atoms. Most amino acids have an asymmetric carbon and are chiral. The
non-superimposable molecules are called optical isomers or enantiomers. Each enantiomer is
considered left or right handed. Many drugs are only one of two possible enantiomers, the other
potentially having harmful side-effects.
Figure 1 Optical isomers of 2-hydroxypropanoic (lactic) acid. https://en.wikipedia.org/wiki/File:Milchs%C3%A4ure_Enantiomerenpaar.svg
Modern medicinal chemistry requires more efficient and diverse methods for the asymmetric synthesis
of chiral molecules. Over 60% of the world’s top selling small molecule drug compounds are chiral
and, of these, approximately 80% are marketed as single enantiomers. There is a compelling
correlation between drug candidate “chiral complexity” and the likelihood of progression to the
marketplace. Accordingly, it is estimated that over 80% of all drugs entering clinical development are
now chiral entities.
Surprisingly, and despite the tremendous advances made in catalysis1 over the past several decades,
the “chiral complexity” of drug discovery libraries has actually decreased, while, at the same time, for
the reasons mentioned above, the “chiral complexity” of marketed drugs has increased. Since the
mid-1990s, there has been a widespread adoption of a technique called Pd-catalysed aryl cross-
11Catalysis: increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst, which lowers the activation energy, is not consumed in the reaction and can continue to act repeatedly.
coupling, which provide easy access to libraries of “flat” (i.e. not chiral) aromatic compounds.
Consequently, there is now an urgent need to provide efficient processes that directly access
privileged chiral scaffolds (Figure 2). In this regard, new methods for the modular synthesis of
nitrogen-containing scaffolds, especially N-heterocyclic ring systems, are likely to be good starting
points. Molecules of this type are attractive for pharmaceuticals as they are “rule of three” (RO3)
compatible for lead-like compounds. Briefly, the RO3 is a rule that evaluates the druglikeness of a
compound, that is, it describes molecular properties important for a drug, including their absorption,
distribution, metabolism, and excretion. Despite the fact that this rule does not predict if a compound
is pharmacologically active, it is important to keep it in mind during the drug discovery process.
60% of the world’s top selling smallmolecule drug compounds are chiral.
80% of chiral drugs are marketed assingle enantiomers.
Pd-catalysed aryl cross-couplingmethods provide easy access tolibraries of “flat” aromatic compounds
Novel methodologies in asymmetric synthesis
Figure 2. There is now an urgent need to provide efficient processes that directly access privileged
chiral scaffolds.
The biochemistryPhantasmidine is a natural compound (a tetracyclic alkaloid) isolated from the frog Epipedobates
anthonyi, which has been characterized as an agonist of nicotinic acetylcholine receptors (nAChRs), a
ligand-gated ion channel (Figure 3). An agonist is a molecule or ion that binds to a receptor causing
the receptor to produce a biological response via, for example, a shape change.
Mammalian nAChRs are composed of five subunits (- and/or -type) arranged around a water-filled
pore and they share the general functional property of being permeable to small monovalent and
divalent cations (positively charged ions) (Na+, K+, and Ca2+). Agonists, such as the body’s own
acetylcholine (ACh) stabilize the open conformation of the nAChR channel that transiently permeates
small cations for several milliseconds before closing back to a resting state or closing to a
desensitized state that is unresponsive to agonists. These receptors are expressed in the central
nervous system (CNS), peripheral nervous system and skeletal muscles, and they have been the
focus of attention of many drug discovery programmes trying to obtain agonists for the treatment of a
wide variety of high-impact diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) or
epilepsy (Figure 3).
HN
O N Cl
HH
Phantasmidine
nAChRagonist
Alzheimer’s disease
Parkinson’s disease
EpilepsyEpipedobates anthonyi
Figure 3. Phantasmidine, isolated from the frog Epipedobates anthonyi, is a promising nAChR
agonist for the treatment of AD, PD or epilepsy.
The chemical challenge aheadPhantasmidine and its derivatives have been considered as promising nAChR agonists to become
drug candidates. Thus, the development of a new way for the preparation of its enantiopure form as
chiral scaffold and its application for the asymmetric synthesis of the natural product phantasmidine
and derivatives (molecules based on the original molecule) will be of great value, since they may
represent promising candidates to address major unmet medical needs.
Dr. Javier García-Cárceles is a postdoctoral research assistant. He
completed his PhD working as an Organic Chemist in the Medicinal
Chemistry field (Universidad Complutense de Madrid). He did a
predoctoral stay at Stanford University in Brian Kobilka’s lab (Nobel
Prize in Chemistry of 2012). He is currently working in the Bower
Group at the University of Bristol where he is developing novel
methods for C-C bond activation.