Asymmetric Synthesis of Drugs and Natural Products

Ahindra Nag, Ahindra Nag

• Publisher: CRC Press
• Year: 2018
• ISBN:
  9781315302294
• Edition: 1
• Topic: Business
• Subtopic: Pharmaceutical, Biotechnology & Healthcare Industry
• Index: Business

This book focuses on different techniques of asymmetric synthesis of important compounds, such as drugs and natural products. It gives insightful information on recent asymmetric synthesis by Inorganic, Organic and Enzymatic combinations. It also emphasizes chiral compounds and design of new catalyst for synthesis of compounds.

1
Basic Stereochemical Approaches to Natural Products and Drugs

Ahindra Nag

CONTENTS

1.1Basic Concept of Chirality

1.2Meso Compounds

1.3Tautomerism and Valance Tautomerism

1.4Conformation

1.5Fischer Projection and Absolute Configuration

1.6Chiral Resolution

1.6.1Crystal Picking

1.6.2Chemical Separation

1.6.3Biochemical Separation

1.6.4Chromatographic Separation

1.7Application of Enantiomers in Drugs and Natural Products

Problems

Answers

References

1.1Basic Concept of Chirality

An asymmetric carbon atom (known as the stereogenic center) is attached to four different groups¹ termed a chiral (pronounced as kiral). The word chiral derives from the Greek word cheira meaning hand, which is closely related to optical activity. For a molecule to have chirality, it must not possess a plane, a center, or a fourfold alternating axis of symmetry. Molecules which are mirror images of each other are termed enantiomers (from the Greek entatios meaning opposite) and need chiral recognition to be separated. Enantiomers react^1,2,3,4,5,6 at different rates with other chiral compounds and may have different solubilities in the presence of an optically active solvent. They may display different absorption spectra under circulatory polarized light. Enantiomers may have different optical rotations, which could be either (+), that is, dextrorotatory (clockwise), or (−), that is, levorotatory (anticlockwise), and can be determined by a polarimeter. The optical purity of a mixture of enantiomers is given by

$$\%\text{Optical}\text{purity}\text{of}\text{sample}=100\ast \frac{\text{Specific}\text{rotation}\text{of}\text{sample}}{\text{Specific}\text{rotation}\text{of}\text{a}\text{pure}\text{enantiomer}}$$

$$\text{Specific rotation}{\left[\mathrm{\alpha }\right]}_{\text{D}}={\mathrm{\alpha }}_{\text{obs}}\text{/c}l$$

where

α_obs is the experimentally observed rotation

c is the concentration in g/mL

l is the path length of the cell used, expressed in dm (=10 cm)

Enantiomeric excess⁷ is one of the indicators of the success of an asymmetric synthesis. The enantiomeric excess (ee_p) of a product is determined by chromatographic methods using the following formula:

$${\text{ee}}_{\text{p}}=\frac{\left[d\right]–\left[l\right]}{\left[d\right]+\left[l\right]}$$

where [d] and [l] are the concentrations of the mixture of the products.

Enantiomeric ratio⁷ (E) is calculated from the extent of conversion (c) and the enantiomeric excess (ee_p) of the product using the following equation:

$$\text{E}=\frac{ln\left[1-\text{c}\left(1+{\text{ee}}_{\text{p}}\right)\right]}{ln\left[1-\text{c}\left(1-{\text{ee}}_{\text{p}}\right)\right]}$$

The stereoisomers of a compound that are not mirror images of each other are termed diastereomers (Figure 1.1). They have different physical characteristics, such as refractive indices, specific rotations, melting and boiling points, crystalline structures, and different solubilities in different solvents. They possess different chemical properties when reacted with chiral and achiral reagents and different rates of reaction due to different values of ΔH. Diastereoselectivity² is the preference for the formation of one or more diastereomers over the other in an orga...