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 a-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 a-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 a-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 a-cedrene (5) is known [8]. Addition of lithiated compound 7 to enol ether enone 6 gave compound 8. This on DIBAL-H reduction to 9 and regioselective cyclopropanation provided 10. Further Collins oxidation gave ketone 11, which was then subjected to rearrangement to deliver a-cedrene (5).
Scheme 1.2 Corey's synthesis of a-cedrene (5).
Historically, many early syntheses were reported without employment of protecting groups. The targets were simple at that time and had limited functionality, and masking groups was not a necessity. Thus it is rightly said that practicing PGF synthesis is not by synthetic planning but out of choice or necessity. Hence many a time the first synthesis of a newly isolated natural product of reasonable complexity is well praised and has its own charm, even though the second synthesis could be shorter, PGF, and much more efficient. The syntheses of early times could be evaluated for efficiency even though feasibility was what counted the most. The concept of PGF synthesis was not as developed and sought after as it is today. For example, the synthesis of tropinone (21) by Robinson in 1917 is considered as one of the greatest achievements in organic synthesis as it was PGF, and the choice of materials used for its preparation had a natural reactivity that followed a distinct pathway with minimal side reactions (Scheme 1.3) [9]. The synthesis illustrates the genius of Robinson, and it could partly be attributed to the inherent symmetry of the natural product and his knowledge of alkaloid biogenesis. The materials used are succinaldehyde (15), methylamine, and acetonedicarboxylic acid (ADCA, 17) in water as a medium, reacted by a distinct cascade reaction path involving imine formation, Mannich reaction, and, lastly, double decarboxylation during acidic work-up, to provide tropinone in moderate 42% yield. This synthesis has entered in every account reported thereafter based on the concepts, be it PGF syntheses, total syntheses, ideal synthesis, green chemistry, or modern organic synthesis. This synthetic strategy conceptually still poses a challenge to future chemists to find a catalytic system that could make acetone to successfully replace acetonedicarboxylic acid (it is known that this gives very low yields in comparison with ADCA). This would then qualify for a truly ideal synthesis or closer to atom-economic synthesis.
Scheme 1.3 Robinson's synthesis of tropinone (21) in 1917.
Danishefsky's synthesis of (±)-patchouli alcohol (25) in 1968 represents another early example of an efficient PGF synthesis (Scheme 1.4) [10]. The natural product had limited functional groups (only one OH group), which made the design of synthetic strategy simpler. The strategy was based on skeleton-building steps with minimum side reactions. The initial Diels-Alder reaction of 22 with methyl vinyl ketone set the [2.2.2] bicyclic system 23 in place. The remaining steps were toward the construction of the third ring.
Scheme 1.4 Danishefsky's synthesis of (±)-patchouli alcohol.
Greene and coworkers in 1978 reported an efficient conversion of a-santonin (26) to (-)-estafiatin (30; Scheme 1.5) [11]. (-)-Estafiatin was isolated from the bitter herb Artemisia mexicana in 1963 by Sanchez-Viesca and Romo [12]. a-Santonin (26) was converted in three steps to produce compound 27. Further reduction of the enone with NaBH4 in pyridine and elimination of the alcohol in HMPA at 250 °C gave a mixture of di- and trisubstituted olefins from which the latter diene 28 was separated. Further addition of a-selenide to the lactone 28 and elimination gave the exo-methylene compound 29. Selective epoxidation of the triene from the less hindered a-face produced (-)-estafiatin (30) as the major product. The synthesis represented an efficient conversion of one natural product to the other.
Scheme 1.5 Total...
