Chem 125. Advanced Organic Chemistry. 20. Enamines, the Wittig Reaction, and Cyclopropanation.

The lecture begins with an overview of Chapter 7, which covers a variety of carbon-carbon bond forming reactions. The instructor plans to discuss these reactions in the context of the chapter, highlighting the central role of the carbonyl group in these processes. The focus will be on reactions such as the addition of organometallic reagents to carbonyl compounds, enolate chemistry, and Michael acceptors. The instructor also mentions the potential inclusion of metallic chemistry and Grubbs' chemistry in future lectures. The relationship between nitrogen and oxygen in the context of carbonyl compound reactivity is introduced, with a comparison between enols and their nitrogen analogs, enamines (ENA).

This section delves deeper into the chemistry of enamines, emphasizing their stability and nucleophilicity compared to enols. The instructor discusses the historical context, noting Gilbert Stork's work in the late 1950s and early 1960s, which popularized enamines as reagents. The process of forming enamines from secondary amines and ketones is described, along with their use in alkylation and conjugate addition reactions. The mechanism of these reactions is explored, highlighting the formation of iminium ions and subsequent hydrolysis to yield the alkylated compound. The versatility of enamines in carbon-carbon bond formation is underscored, with examples provided to illustrate their utility.

The instructor compares enamines with enolates, discussing their use in synthesis and the advantages of enamines, particularly in avoiding self-condensation issues that can plague aldehyde reactions with LDA (lithium diisopropylamide). The use of enamines in controlled nucleophilic reactions is emphasized, with a focus on their efficiency and scalability. The section also touches on the practical aspects of enamine chemistry, such as the use of different amines and the conditions required for optimal results.

This paragraph introduces the concept of metallo enamines, specifically focusing on their use in asymmetric alkylation chemistry. The instructor discusses the development of this chemistry by Dieter Enders, who utilized chiral amines to generate metallo enamines for enantioselective reactions. The example of using a derivative of proline to generate a specialized amine, called a hydrozone, is provided. The process involves the formation of a metallo enamine, alkylation, and subsequent cleavage with ozone to yield the alkylated carbonyl compound with high enantiomeric excess. The importance of controlling the stereochemistry in drug synthesis is highlighted.

The lecture shifts focus to the Wittig reaction, a method for converting aldehydes and ketones into alkenes using phosphorus ylides. The instructor discusses the reaction's mechanism, involving the formation of an oxyphosphorane intermediate, and its breakdown to yield triphenylphosphine oxide and the alkene. Emphasis is placed on the reaction's utility in building complex molecules from simpler ones, with a specific example involving the reaction of bromopentane with a phosphorus ylide. The stereoselectivity of the Wittig reaction is also explored, with a focus on the conditions required for cis- or trans-selective alkenes.

This section continues the discussion on the Wittig reaction, focusing on the use of phosphorus ylides in stereoselective synthesis. The instructor explains the concept of unstabilized ylides and their tendency to form cis-alkenes under 'salt-free' conditions, which avoid lithium salts that can reduce stereoselectivity. The use of stabilized ylides, which form trans-alkenes, is also discussed, with examples provided. The practical considerations in choosing bases and conditions for optimal stereoselectivity are highlighted.

The lecture introduces the concept of carbenes, divalent carbon species that can react with alkenes in a cyclopropanation reaction. The instructor discusses the reactivity of carbenes, which are typically highly reactive and cannot be isolated. The reaction of alkenes with carbenes to form cyclopropanes is described, emphasizing the stereospecificity of the reaction. The historical context of the development of this chemistry by Corey and the use of dichlorocarbene and dibromocarbene in practical reactions is provided.

This section wraps up the lecture by discussing the Simmons-Smith reaction, a variant of the cyclopropanation reaction that uses methylene (CH2) as the carbene source. The instructor explains the challenges in generating methylene due to its reactivity and the solution developed by Simmons and Smith, which involves the use of diiodomethane and a zinc-copper couple. The reaction mechanism is described, highlighting the formation of a 'carbeneoid' species that reacts with alkenes to form cyclopropanes. The practical utility of this reaction in generating cyclopropanes without substituents is emphasized.