Efficiency in Natural Product Total Synthesis

Pei-Qiang Huang, Zhu-Jun Yao, Richard P. Hsung, Pei-Qiang Huang, Zhu-Jun Yao, Richard P. Hsung

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9781118605400
• eBook ISBN: 9781118940211
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Biochemistry

Uniting the key organic topics of total synthesis and efficient synthetic methodologies, this book clearly overviews synthetic strategies and tactics applied in total synthesis, demonstrating how the total synthesis of natural products enables scientific and drug discovery.

•Focuses on efficiency, a fundamental and important issue in natural products synthesis that makes natural product synthesis a powerful tool in biological and pharmaceutical science
•Describes new methods like organocatalysis, multicomponent and cascade reactions, and biomimetic synthesis
•Appeals to graduate students with two sections at the end of each chapter illustrating key reactions, strategies, tactics, and concepts; and good but unfinished total synthesis (synthesis of core structure) before the last section
•Compiles examples of solid phase synthesis and continuing flow chemistry-based total synthesis which are very relevant and attractive to industry R&D professionals

1
Principles for Synthetic Efficiency and Expansion of the Field

Pei‐Qiang Huang

Fujian Provincial Key Laboratory of Chemical Biology, Department of Chemistry and iChEM, Xiamen University, Xiamen, China

Today, the field of natural product total synthesis, which was once a dominant sub‐discipline of organic chemistry, has lost its prime position. Even with the renaissance of natural products as drug candidates, and the recent recognition of the value and contribution of natural product‐based drugs to societies by the Nobel Prize in Physiology or Medicine 2015, the situation has changed. As we have mentioned in the Introduction, “it is estimated that half of the top 100 best‐selling medications will soon be biologics.” According to Dirk Trauner, “the field is currently under fire, at least in societies that have traditionally supported it.”^1a To address these challenges, we need to significantly improve efficiency of the synthesis,^1b expand the field of total synthesis, and address the concerns of society. In this chapter, the efforts by chemists from these dimensions will be summarized with a focus on concepts.

1.1 Concepts for Efficiency in the Total Synthesis of Natural Products

As we have pointed out in the previous sections, the total synthesis of natural products is facing with many challenges. The key to tackle these problems is to improve the synthetic efficiency, which involves selectivity, economy of synthesis, and green chemistry. Over the last five decades, many concepts have been advanced by the leading scientists in the field. It is expected that the new concepts will become new criteria for total synthesis.

1.1.1 Ideal Synthesis

1.1.1.1 Hendrickson’s Definition (1975)

The concept of ideal synthesis was first advanced by J. B. Hendrickson in 1975:

The synthesis would start from available small molecules so functionalized as to allow constructions linking them together directly, in a sequence only of successive construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also its correctly placed functionality. If available, such a synthesis would be the most economical, and it would contain only construction reactions.²

1.1.1.2 Wender’s Definition (1996)

A more comprehensive definition of ideal synthesis was given by P. A. Wender in 1996.^3a

An ideal (the ultimate practical) synthesis is generally regarded as one in which the target molecule (natural or designed) is prepared from readily available, inexpensive starting materials in one simple, safe, environmentally acceptable, and resource‐effective operation that proceeds quickly and in quantitative yield.³

Wender also indicated two general ways^3a for approaching the ideal synthesis (i.e., achieving maximum relevant complexity increase while minimizing step count):

1. The use of strategy‐level reactions such as the Diels–Alder reaction or multistep processes such as tandem and domino sequences that allow for a great increase in target‐relevant complexity in one operation.
2. The design and development of new reactions and reaction sequences that allow for a great increase in ...

Table of contents

• Cover
• Table of Contents
• Foreword
• Preface
• Introduction
• 1 Principles for Synthetic Efficiency and Expansion of the Field
• 2 Selected Procedure-Economical Enantioselective Total Syntheses of Natural Products
• 3 Diels–Alder Cascades in Natural Product Total Synthesis
• 4 Organometallics-Based Catalytic (Asymmetric) Synthesis of Natural Products
• 5 C–H Activation-Based Strategy for Natural Product Synthesis
• 6 Recent Applications of Kagan’s Reagent (SmI2) in Natural Product Synthesis
• 7 Asymmetric Organocatalysis in the Total Synthesis of Complex Natural Products
• 8 Multicomponent Reactions in Natural Product Synthesis
• 9 Renewable Resource-Based Building Blocks/Chirons for the Total Synthesis of Natural Products
• 10 Natural Product Synthesis for Drug Discovery and Chemical Biology
• 11 Modern Technologies in Natural Product Synthesis
• 12 Concluding Remarks and Perspectives
• Index
• End User License Agreement