This research is supported by a Marie Curie Action

This research is supported by a Marie Curie Action
This research has received funding from the People Programme (Marie Curie Actions) of the EU (FP7/2007-2013) under REA grant agreement nº PIEF-GA-2013-622413

Saturday, 28 February 2015

How can we prepare a chiral compound? PART IV. Asymmetric synthesis.

In the previous posts, (see how we can prepare a chiral compound? PART I to PART III, from 15 Dec 2014 onwards) I have shown different approaches to access chiral compounds.
Although chiral resolution and chiral pool synthesis have been used or are currently used as efficient methods for preparing chiral compounds there is a high demand of new chiral compounds for pharma, agrochemical, fragrances, fine chemicals and nutrition areas. This means that even chiral pool (chiral compounds from Nature) and/or resolutions are quite limited methods to address new challenging synthesis of chiral compounds. Therefore, innovative approaches to overcome these limitations are desirable.

The asymmetric (or stereoselective) synthesis from prochiral substrates (i.e. substrates that will be chiral after a chemical reaction) is a potent tool that allow the preparation of a broad variety of enantiopure compounds.
In order to fully understand the concept behind asymmetric synthesis we have to review some definitions in organic chemistry related to chirality:

  • Prochiral molecules are those that can be converted from achiral to chiral in a single step (i.e. one single chemical reaction).
  • Stereoisomers are isomeric molecules (from Greek ἰσομερής, isomerès; isos = "equal", méros = "part") that have the same molecular formula and sequence of bonded atoms (constitution), but that differ only in the three-dimensional orientation of their atoms in space. Importantly, we can differentiate between enantiomers and diastereoisomers.
  • Enantiomers are two stereoisomers that are mirror images of each other, which are non-superimposable. Two compounds that are enantiomers of each other have the same physical properties.
  • Diastereomers are stereoisomers that are not mirror images of each other. Diastereomers seldom have the same physical properties.
  • Chemical reactions can be stereoselective which means that can be selectively directed to one stereoisomer (enantio- or diastereoisomer) only.

Once we have a clear-cut picture of these definitions it is important to highlight that asymmetric synthesis involves chemical reactions that introduce one or more elements of chirality in a prochiral substrate generating stereoisomeric compounds (enantio- or diastereoisomers) in unequal amounts. The responsible for the asymmetric induction is the so-called chiral auxiliary (or chiral catalyst in the case of the asymmetric catalysis approach I am going to explain in next posts).

A chiral auxiliary is a chemical compound that is temporarily incorporated into an organic molecule in order to control the stereochemical outcome of the reaction. In simple words, we install a chiral molecule that “help” us to obtain our target compound.
The asymmetric synthesis methods have evolved during the years. Early methods for asymmetric synthesis introduced the chiral auxiliary in the same molecule to be transformed, generating the chiral product permanently attached to the group responsible for asymmetric induction (diastereoselective synthesis). Then, the methods further developed to those that remove the chiral auxiliary from the final chiral product and preferably recover and reuse the chiral auxiliary in future reactions.
The first step involves the incorporation of the chiral auxiliary. From a proquiral compound we move to a stereoisomer. Then, a second chemical reaction is carried out on the stereoisomer. The chirality present in the auxiliary can bias the stereoselectivity of this reaction towards one diastereoisomer only (diastereoselective synthesis). Finally, the chiral auxiliary can then be cleaved from the substrate and is typically recovered for future uses, ideally, without any loss of performance during the diastereoselective reaction.

The next step was to use a chiral reagent (instead of the so-called auxiliary) and directly control the stereochemical outcome of the reaction. Nowadays, it is used a chiral catalyst to control the stereochemical outcome of the reaction.

Aarhus University

Aarhus University
Aarhus University website

Center for Catalysis, AU

Center for Catalysis, AU
Center for Catalysis, AU website

Marie Curie Actions

Marie Curie Actions
Marie Curie Actions website