Protecting-Group-Free Organic Synthesis

Improving Economy and Efficiency

Rodney A. Fernandes

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9781119295204
• eBook ISBN: 9781119295228
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Physical & Theoretical Chemistry

Presents a comprehensive account of established protecting-group-free synthetic routes to molecules of medium to high complexity

This book supports synthetic chemists in the design of strategies, which avoid or minimize the use of protecting groups so as to come closer to achieving an "ideal synthesis" and back the global need of practicing green chemistry. The only resource of its kind to focus entirely on protecting-group-free synthesis, it is edited by a leading practitioner in the field, and features enlightening contributions by top experts and researchers from across the globe.

The introductory chapter includes a concise review of historical developments, and discusses the concepts, need for, and future prospects of protecting-group-free synthesis. Following this, the book presents information on protecting-group-free synthesis of complex natural products and analogues, heterocycles, drugs, and related pharmaceuticals. Later chapters discuss practicing protecting-group-free synthesis using carbohydrates and of glycosyl derivatives, glycol-polymers and glyco-conjugates. The book concludes with a chapter on latent functionality as a tactic toward formal protecting-group-free synthesis.

• A comprehensive account of established protecting-group-free (PGF) synthetic routes to molecules of medium to high complexity
• Benefits total synthesis, methodology development and drug synthesis researchers
• Supports synthetic chemists in the design of strategies, which avoid or minimize the use of protecting groups so as to come closer to achieving an "ideal synthesis" and support the global need of practicing green chemistry
• Covers a topic that is gaining importance because it renders syntheses more economical

Protecting-Group-Free Organic Synthesis: Improving Economy and Efficiency is an important book for academic researchers in synthetic organic chemistry, green chemistry, medicinal and pharmaceutical chemistry, biochemistry, and drug discovery.

1
Introduction: Concepts, History, Need, and Future Prospects of Protecting‐Group‐Free Synthesis

Rodney A. Fernandes

Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India

“There is excitement, adventure and challenge, and there can be great art in organic synthesis. These alone should be enough, and organic chemistry will be sadder when none of its practitioners are responsive to these stimuli.”

– R. B. Woodward, 1956

For “ideal synthesis” “– a sequence of only construction reactions involving no intermediary refunctionalizations, and leading directly to the target, not only its skeleton but also its correctly placed functionality.”

– Hendrickson, 1975

1.1 Introduction, Concepts, and Brief History

Nature, an architect par excellence, produces hundreds of compounds beautifully crafted and is the master chemist of all. These intriguing molecules have challenged many practitioners of organic synthesis as how to achieve an ideal synthesis that closely resembles nature’s creation. The design of a synthetic strategy for a complex molecule from simple synthons and achieving it is an amalgamation of ingenuity, creativity, and determination. Organic synthesis has evolved from the beginning of this century, and chemists have mastered the art of building molecules using the arsenal of reactions, reagents, and analytical methods. The astonishing progress in the last few decades in new methods development, availability of new reagents, and powerful techniques for reaction analysis have changed the dimension and image of the art of organic synthesis. Hence it is rightly said today that with reasonable effort and time, any isolated compound from natural sources with any level of complexity can be synthesized. The remarkable synthetic accomplishments over the years should be considered among the top achievements of human genius.

In organic synthesis, of the three challenges – chemoselectivity, regioselectivity, and stereoselectivity – the most demanding and strenuous to achieve is chemoselectivity [1]. How to differentiate functional groups without selective masking (chemoselectivity) has always been a concern while designing synthetic strategies. A target‐oriented synthesis often demands completion of synthesis with many closely placed similar functional groups involving a high level of selectivity, and hence, synthetic strategies, though not desirable, inevitably need to use protecting groups. Hence, most total synthesis chemists invariably follow the commonly available books on various protecting groups and the ways to introduce and also to remove them [2]. A given molecule can be synthesized in many ways by strategic deconstruction reactions or retrosynthesis, which allows many possible options to build the molecule [3]. It is this scope that results in different ways of functional group modifications, some of which may be far from ideal construction reactions, straying away from an ideal synthesis. Hendrickson developed a rigorous system of codification of construction reactions to build a complex molecule [4]. It can be inferred from his paper that an “ideal synthesis” would require “– a sequence of only construction reactions involving no intermediary refunctionalizations, and leading directly to the target, not only its skeleton but also its correctly placed functionality.” Thus there exists a need for truly constructive or skeleton‐building reactions in total synthesis. Although this concept has inspired many minds to design efficient strategies, the practice of total synthesis may need a long way to go to achieve an ideal protecting‐group‐free (PGF) synthesis, the nature’s way [5]. There are many complex molecules with multiple functionalities, and their synthesis inevitably necessitates protecting groups due to the close similarity of functional groups reactivity. In many cases, cascade reactions and rearrangements are sought after to achieve a PGF‐based close to an ideal synthesis. Many syntheses are biomimetic and therefore based closer to the biosynthesis pathway and use the natural reactivity of functional groups. This sounds good when complex molecules have an all‐carbon framework and/or minimal functional groups. This can be exemplified by Anderson’s synthesis of α‐cedrene (5; Scheme 1.1) [6]. A pentane solution of nerolidol (1) was treated with formic acid and then with trifluoroacetic acid (TFA) for 2 h to obtain α‐cedrene (5) in about 20% yield. This synthesis involving the bisabolene to spirane intermediates (type 2 and 3, respectively) closely mimics the parallel biogenetic pathway.

Scheme 1.1 Anderson’s synthesis of α‐cedrene (5).

Another closely related synthesis by Corey and Balanson [7] involved the ring opening of cyclopropane 12 generating a carbonium ion and subsequent incipient carbanion 13, which triggers two ring closures giving cedrone 14 (Scheme 1.2), from which the synthesis of α‐cedrene (5) is known [8]. Addition of lithiated compound 7 to enol ether enone 6 gave compound 8. This on DIBAL‐H...

Table of contents

• Cover
• Table of Contents
• Foreword by Prof. W. Hoffmann
• Foreword by Prof. G. Mehta
• Preface
• 1 Introduction
• 2 Protecting‐Group‐Free Synthesis of Natural Products and Analogs, Part I
• 3 Protecting‐Group‐Free Synthesis of Natural Products and Analogs, Part II
• 4 Protecting‐Group‐Free Synthesis of Natural Products and Analogs, Part III
• 5 Protecting‐Group‐Free Synthesis of Heterocycles
• 6 Protecting‐Group‐Free Synthesis of Drugs and Pharmaceuticals
• 7 Protecting‐Group‐Free Synthesis in Carbohydrate Chemistry
• 8 Protecting‐Group‐Free Synthesis of Glycosyl Derivatives, Glycopolymers, and Glycoconjugates
• 9 Latent Functionality
• Index
• End User License Agreement