Strategies and Tactics in Organic Synthesis provides a forum for investigators to discuss their approach to the science and art of organic synthesis. Rather than a simple presentation of data or a secondhand analysis, this classic provides stories that vividly demonstrate the power of the human endeavor known as organic synthesis and the creativity and tenacity of its practitioners.
Firsthand accounts of each project tell of the excitement of conception, the frustration of failure, and the joy experienced when either rational thought or good fortune gives rise to the successful completion of a project. This book series shows how synthesis is really done. Readers will be educated, challenged, and inspired by these accounts, which portray the idea that triumphs do not come without challenges.
This innovative approach also helps illustrate how challenges to further advance the science and art of organic synthesis can be overcome, driving the field forward to meet the demands of society by discovering new reactions, creating new designs, and building molecules with atom and step economies that provide functional solutions to create a better world.
- Presents state-of-the-art developments in organic synthesis
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- Written by leading experts in the field
- Uses firsthand narrative accounts to illustrate vividly the challenges and joys involved in advancing the science of organic synthesis
Spiroketalization Methods and Synthesis
Barry B. Butler, Jr.; Aaron Aponick1 Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida, USA
1 Corresponding author: email address: firstname.lastname@example.org
This chapter is a review of the literature on a small family of natural products named the acortatarins. Our interest in these compounds is largely due to their unique structure, which is a pyrrole-fused morpholine spiroketal. The isolation, structural assignment and later correction, biological activity, and syntheses of these molecules are presented. Although the compounds are not extremely complex, two structures were nevertheless incorrectly assigned (as well as correctly assigned in a less well-cited isolation paper!). With all the modern analytical tools at our disposal, incorrect assignments can and do still occur, and, this is a modern example of how synthetic chemistry was used to identify the errors and make the correct assignments. The progression of our research program toward the development of metal-catalyzed spiroketalization methods and our work on acortatarin A is described.
Reactive oxygen species
In 2006, I began my independent career at the University of Florida and had to make some strategic choices about the direction I wanted to take my research program. Unfortunately, I arrived to find that my labs were not ready for occupancy. This detail drastically shaped my first (nearly) 10 years of work by influencing what we were able to do at a time when we were able to handle evolving projects in an extremely fluid manner. To set the stage, this was July in Florida and, having moved from California, the humidity was palpable both indoors and out. Without a place for the proper equipment such as a glovebox, my "organometallicy" research plans would have had to either be put on hold or modified. At the time, I viewed the situation as grim but we needed to get a good start and, with an enthusiastic first group of students, we initiated work on several different ideas that would not require glovebox chemistry.
Bearing these limitations in mind, we decided to study a metal-catalyzed alkyne hydroalkoxylation reaction to generate a substrate for Claisen rearrangement that would hopefully proceed under mild conditions (Scheme 1). This would involve addition of an allylic alcohol 2 to an alkyne 1 to form the allyl vinyl ether (or metal-analogue) 3 that was primed for either a thermal or catalyzed Claisen rearrangement to form 4. We felt that the appeal of this reaction would be that, instead of adding H2O across the triple bond, we would instead be adding C, H, and O, forming a new CC bond and therefore increasing the complexity more than was traditionally observed. Catalyst selection here would be key, but a wide variety of different metals were known to catalyze alkyne hydration and it seemed likely that we would be able to find a catalyst for this reaction that fit our needs.1 Scheme 1
Initially proposed hydroalkoxylation/Claisen rearrangement sequence.
At the time, the beginning of the homogeneous gold-catalysis boom had begun2 and numerous examples purported Au-complexes to be air and moisture stable-possibly perfect Florida catalysts. Additionally, Au-catalyzed alkyne hydration was known,3 but more importantly, a report by Teles and coworkers was intriguing to us because they described observation of an enol ether in one of their hydration reactions, essentially an incomplete reaction in their system, but exactly the desired reactivity here.4 Furthermore, a report by He and coworkers described a tandem Au-catalyzed aryl Claisen rearrangement/alkene hydroalkoxylation, whereby both Au(III) and Au(I) salts were ostensibly able to catalyze the reaction.5 Armed with this combination of facts, we set about to test the hydroalkoxylation/Claisen hypothesis. Unfortunately, this idea fell flat and seemed untenable, but through the work of observant and dedicated graduate students that I often witnessed standing shoulder-to-shoulder, four wide at our lone 5-ft fume hood, an understanding of why this reaction was not working was developed.
At the time what we did not know, and probably could not have anticipated, was that the allylic alcohol itself was reactive under the conditions. Instead of acting exclusively as nucleophiles, it was found that allylic alcohols could also act as electrophiles. This became evident when what proved to be a volatile byproduct was identified as diallyl ether 8 under a myriad of Au-catalysis conditions employing both Au(I) and Au(III) salts (Scheme 2).6 Although it took until 2012 before the paper finally appeared, we were able to get the hydroalkoxylation/Claisen sequence to work quite well7 and others followed suit.8 This was an arduous endeavor that ultimately would not have been successful without what came next-scope studies and mechanistic investigation of this unexpected reactivity. Scheme 2
Unexpected ether formation.
2 Evolution of Au- and Pd-Catalyzed Spiroketalization Methods
While trying to use allylic alcohols as nucleophiles in Au-catalyzed reactions, electrophilic reactivity was unexpectedly observed and the potential for a variety of mechanistic pathways responsible for this reactivity was intriguing. Au-complexes are typically reported as soft, carbophilic p-acids,9 but for the observed reaction, it seemed more reasonable that a cationic mechanism whereby the Au-complex functioned as a more traditional oxophilic Lewis acid10 was operative. This piqued our interest, and we decided to change the goals of the project to see where it would take us. Fortunately, pursuing these Au-catalyzed dehydrative transformations developed from a single observation into a research program (vide infra).
2.1 Au-Catalyzed Allylic Substitution
The intermolecular Au-catalyzed reaction to form diallyl ether 8 was mechanistically interesting but not synthetically useful, as the yield was always low and the catalyst loading high. Attempts to optimize the reaction were ultimately unsuccessful, but fortunately it was found that the intramolecular cyclization worked extremely well and could even be categorized as a spot-to-spot reaction. As seen in Scheme 3, with substrates bearing a nucleophilic hydroxyl group tethered to an allylic alcohol, high yields and diastereoselectivities are observed for the tetrahydropyran products.11 The reaction conditions are mild, employing 1 mol% Ph3PAuCl/AgOTf in methylene chloride at room temperature, and the range of substrates tolerated was broad. Both the catalyst loadings and temperature could be reduced, and it is particularly noteworthy that water is the only byproduct. Scheme 3
Au-catalyzed diol cyclization.
Allylic substitution is well known12 and other metal-based complexes have been reported to catalyze reactions with hydroxyl leaving groups.13 Indeed, with homogeneous Au-catalysis, a variety of reactions that proceed via cationic pathways have been reported.14 While discussion is beyond the scope of this chapter, it is worth noting that the mechanism for this reaction has been extensively studied and does not appear to proceed via an allylic cation.15 Further developments in this area have been reported by a variety of groups and now involve the use of nitrogen nucleophiles, carbon nucleophiles, and intermolecular reactions as well as enantioselective variants.16 While many of those reports came from our laboratory, our interests took us in a different direction and we became keen on using modified substrates to develop spiroketalization methods for applications in synthetic schemes.
2.2 Au-Catalyzed Spiroketalization of Propargylic Triols and Acetonides
Spiroketals are quite common in natural products, displaying a wide range of impressive biological activities.17 This importance has prompted investigations into their syntheses, but the most common method used is still the classical acid-catalyzed dehydration of ketodiols.18 A variety of other strategies based on transition metal catalysis have been developed and this work has recently been reviewed.19 These methods feature a variety of advantages, but most importantly they can be used to employ different substrate classes (nonketodiols) with mild conditions, facilitating new synthetic strategies.
To effect spiroketalization, our goal was to employ a propargyl substrate such as 11 (Scheme 4). The central hypothesis was that if propargyl systems behaved similarly to allylic systems, then by analogy the allene 12 should be formed. This substrate should be reactive toward Au-catalysts, and if the R-substituent contained a second nucleophile, the spiroketal 13 should be directly formed under the reactions conditions. The advantages would be that the necessary...