This module consists of a range of examples exposing the students to sophisticated methods in stereoselective synthesis. Building on previous knowledge, advanced methods for stereocontrol in total synthesis, preparation of enantiomerically pure drug molecules, development of stereoselective rearrangement processes as well as the organic and biological chemistry of carbocations including stereocontrol by enzymes will be the main focus of this module. Throughout, the ability to extract stereochemically relevant information from complex syntheses will be a major focus.

Knowledge

• Appreciate the range of synthetic methods available to prepare enantiomerically pure molecules.
• Know the strategies and reagents required to generate and implement new stereochemical elements within target oriented syntheses.
• Identify key problems in both, small scale academic synthesis and large scale industrial synthesis of stereochemically pure compounds.

Understanding

• Understand the principles and strategies of stereoselective alkene functionalization.
• Understand main principles in pharmaceutical synthesis and related industrial issues together with application to target molecules.
• Recognize where rearrangements can be applied in synthesis and be able to devise retrosynthetic strategies involving rearrangements for all reaction types covered in the course.

This module will be delivered in 10 two-hour lectures, supplemented by 4 1-hour class tutorials, and consists of four blocks, each covering a different aspect of asymmetric synthesis. An initial set of lectures will be used to revise already known principles and reactions and introduce novel methods that can be used to tackle certain problems in asymmetric synthesis together with their theoretical background and any strengths or weaknesses associated with them. These will be followed four units in which such methods are applied to chemical problems.

Ability to analyse stereochemical problems and provide synthetic solutions.

The module will be assessed by a combination of coursework (20%) and written examination (80%). Coursework will be broken down into 2 short, problem-based pieces of work (10% each).

Alkene Functionalisations

Introduction to advanced asymmetric synthesis. Stereoselective functionalisations of double bonds: Briefly revising Sharpless AE and ADH, Jacobsen (year 3), then introduction of other electrophilic reagents including selenium- and iodine-based compounds.

Pharmaceuticals and natural products

Modern pharmaceutical design. Introduction using a representative range of modern pharmaceuticals with a brief discussion of their target areas. A brief outline of how the process moves from discovery through phases 1-3, pilot plant to large-scale manufacture to final marketing; summaries of typical time scales, costs and people involved. The problems associated with Patents and litigation; the constraints of record keeping; the ‘me-too’ factor, illustrated with real examples. Actual examples of drug discovery, with an emphasis on design and how to optimise this.

Rearrangements

The pinacol and semipinacol rearrangement, with a focus on applications to target synthesis. Rearrangements of organoboron compounds, focusing on the migration of alkyl groups from boron to carbon. Migration to electron-deficient nitrogen and oxygen (Baeyer-Villiger, Beckmann, Curtius and related rearrangements).

Carbocations

The organic and biological chemistry of carbocations. How such intermediates can be generated and propagated. Steroid biosynthesis and biomimetic synthetic approaches, focusing on the importance of alkyl migration reactions. Comparing the use of carbocations as versatile intermediates in synthesis and in nature. Use of enzymes as catalysts to generate complex molecules with carbocation intermediates.

An indicative reading and resource list will be provided in the first lecture.