Modern Organic Synthesis

An Introduction

George S. Zweifel, Michael H. Nantz, Peter Somfai

• Publisher: Wiley
• Year: 2017
• ISBN:
  9781119086765
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

This book bridges the gap between sophomore and advanced / graduate level organic chemistry courses, providing students with a necessary background to begin research in either an industry or academic environment.

•Covers key concepts that include retrosynthesis, conformational analysis, and functional group transformations as well as presents the latest developments in organometallic chemistry and C–C bond formation
•Uses a concise and easy-to-read style, with many illustrated examples
•Updates material, examples, and references from the first edition
•Adds coverage of organocatalysts and organometallic reagents

1
Synthetic Design

In character, in manners, in style, in all things, the supreme excellence is simplicity.

Henry Wadsworth Longfellow

Chemistry touches everyone's daily life, whether as a source of important drugs, polymers, detergents, or insecticides. Since the field of organic chemistry is intimately involved with the synthesis of these compounds, there is a strong incentive to invest large resources in synthesis. Our ability to predict the usefulness of new organic compounds before they are prepared is still rudimentary. Hence, both in academia and at many chemical companies, research directed toward the discovery of new types of organic compounds continues at an unabated pace. Also, natural products, with their enormous diversity in molecular structure and their possible medicinal use, have been and still are the object of intensive investigations by synthetic organic chemists.

Faced with the challenge to synthesize a new compound, how does the chemist approach the problem? Obviously, one has to know the tools of the trade, their potential and limitations. A synthetic project of any magnitude requires not only a thorough knowledge of available synthetic methods, but also of reaction mechanisms, commercial starting materials, analytical tools (IR, UV, NMR, MS) and isolation techniques. The ever-changing development of new tools and refinement of old ones makes it important to keep abreast of the current chemical literature.

What is an ideal or viable synthesis and how does one approach a synthetic project? The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps), selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). Furthermore, the experimental ease of the transformations and whether they are environmentally acceptable must be considered.

Synthesis of a molecule such as pumiliotoxin C involves careful planning and strategy. How would a chemist approach the synthesis of pumiliotoxin C?¹ This chapter outlines strategies for the synthesis of such target molecules based on retrosynthetic analysis.

E. J. Corey (Nobel Prize, 1990) introduced and promoted the concept of retrosynthetic analysis, whereby a molecule is disconnected leading to logical precursors.² Today, retrosynthetic analysis plays an integral and indispensable role in research.

1.1 Retrosynthetic Analysis³

The following discussion on retrosynthetic analysis covers topics similar to those in Warren's Organic Synthesis: The Disconnection Approach^3a and Willis and Will's Organic Synthesis.^3g For an advanced treatment of the subject matter, see Corey and Cheng's The Logic of Chemical Synthesis.^3b

Basic Concepts

The construction of a synthetic tree by working backward from the target molecule (TM) is called retrosynthetic analysis or antithesis. The symbol ⇒ signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C–C bonds, and functional group interconversions(FGI).

Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and FGI. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Synthons are fragments resulting from disconnection of carbon–carbon bonds of the TM. The actual substrates ...