Retro

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Retrosynthesis, Stereochemistry, and Conformations

1.1.

IntRoduCtIon

Where does one begin a book that will introduce and discuss hundreds of chemical reactions? To synthesize a complex organic molecule many reactions must be used, and the strategy used for that synthesis must consider not only the type of reaction but also the mechanism of that reaction. We begin with abrief introduction to synthetic planning. A full discussion of strategies for total synthesis will be introduced in chapter 10, but surveying the fundamental approach can help one understand how reactions are categorized. The total synthesis of complex natural products usually demands a thorough knowledge of reactions that form carbon-carbon bonds as well as those that change one functional groupinto another. Examination of many syntheses of both large and small molecules, reveals that building up a carbon skeleton by carbon-carbon bond forming reactions is rarely done successfully unless all aspects of chemical reactivity, functional group interactions, conformations, and stereochemistry are well understood. The largest number of actual chemical reactions that appear in a synthesis do notmake carbon-carbon bonds but rather manipulate functional groups.
KOH , EtOH Br 1 2 3 4 OH CrO3 O

Changing one functional group into another is defined as a functional group interchange (FGI). Simple examples are the loss of H and Br from 2-bromo-2-methylpentane (1) to form 2-methyl-2-pentene (2), or oxidizing the alcohol unit in 2-pentanol (3) to the carbonyl unit in 2-pentanone (4).Contrast these reactions with a reaction that brings reactive fragments together to form a new bond between two carbon atoms, such as the condensation of two molecules of butanal (5) under basic conditions to give 6, which is known as the aldol condensation. The aldol condensation forms a carbon-carbon bond but before such a reaction can occur one usually must incorporate or change key functional groups.This observation is an important reason that more functional group exchange reactions are typically required, relative to carboncarbon bond forming reactions. Several different functional groups may also be structural units of the molecule being synthesized.

chapter 1

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Nowadays, the relationship of two molecules in a synthesis is commonly shown using a device known as a transform,defined by Corey and co-workers1 as: “the exact reverse of a synthetic reaction to a target structure”. The target structure is the final molecule one is attempting to prepare. The synthetic transformation that converts butanal (5) to hydroxy-aldehyde 6 via the aldol condensation (see sec. 9.4.A) is an example. The transform for this synthetic step is, therefore, 6 ⇒ 5. Inspection of 6 and 5 revealsthat mentally breaking the highlighted bond (bond a) in 6 (represented by the squiggly line) leads to disconnect fragments 5 and 7 and in this process bond a is said to be disconnected. An elementary disconnection approach quickly becomes an integral part of how one thinks about molecules. The focus here, however, is on how to put molecules together. How does the disconnection approach assist us inthis endeavor? Understanding why bond a is important comes from a thorough knowledge of the chemical properties of compound 6. When we disconnect bond a, we eventually want to make that bond by a chemical reaction. To understand the molecular characteristics of 6 that led us to disconnect bond a, we must understand the chemical reactions required to form that bond.
CHO transform a HO 6 HO • CHOsynthesis 1. NaOEt , EtOH reflux CHO 2. H3O+ CHO HO 6

where

7 indicates a disconnection

5 •

5

Pentanoic acid (8) is a simple target that a OH CO2H illustrates the approach. Disconnection 9 8 of the carbon-carbon bond marked a X + "CO H" 2 leads to 1-butanol (9) as the precursor 10 (the starting material). Analysis of the targeted carboxylic acid as well as the product alcohol...