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Escaping from flatland: asymmetric synthesis for medicinal chemistry

Key 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

pharmaceutical drugs are 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 positive 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-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

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.

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.

Escaping from flatland: asymmetric synthesis for medicinal chemistry Questions

1. What is a chiral molecule? [1 mark]

2. Draw the skeletal structure of the amino acid phenylalanine and circle the chiral centre. [2 marks]

3. Draw the skeletal structure of thalidomide and circle the chiral centre. For a bonus 1 mark identify the function groups of thalidomide [1 mark]

4. What is a catalyst? [3 marks]

5. What is an agonist? [1 mark]

6. List 3 other natural products or natural product derivatives that have been synthesised for medicinal purposes? [2 marks]

Extension Question

Why is it important to know and have selectivity over the chirality of a pharmaceutical molecule? [4 marks]

Escaping from flatland: asymmetric synthesis for medicinal chemistry Questions

1. What is a chiral molecule? [1 mark]

2. Draw the skeletal structure of the amino acid phenylalanine and circle the chiral centre. [2 marks]

3. Draw the skeletal structure of thalidomide and circle the chiral centre. For a bonus 1 mark identify the function group that appears twice in thalidomide [2-3 marks]

4. What is a catalyst? [3 marks]

5. What is an agonist? [1 mark]

6. List 3 other natural products or natural product derivatives that have been synthesised for medicinal purposes? [2 marks]

Extension Question

Why is it important to know and have selectivity over the chirality of a pharmaceutical molecule? [4 marks]