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.