Synthetic Organic Community Research Articles

Synthetic Strategies for the Preparation of Butenolides and Their Transformation into Other Derivatives

Butenolides, five membered α,&946;-unsaturated γ-lactones, are ubiquitous moieties present in the structures of many natural products and synthetic compounds endowed with a large array of biological activities. Butenolides with an γ-alkylidene moiety are termed as γ-alkylidenebutenolides. Because of their chemical structures as well as their biological activities, butenolides have attracted the attention of synthetic organic chemistry community. As a consequence, several methodologies have been developed to synthesize these classes of compounds. The potential use of such substances is expanded due to their easy conversion into lactams and pyridazine derivatives which are also of potential biological interest. Moreover, the chemistry of such compounds is very rich in large extension associated also with the nature of their substituents. Herein, we present some classical and recent methodologies for the synthesis of butenolides and γ-alkylidene butenolides. These methods involve the use of several transition metal reagents, condensation and conjugated addition reactions. Some methods used to convert butenolides and γ-alkylidene congeners into lactams and pyridazines are described. Methodologies for the preparation of oxazolones namely azlactones, compounds which are structurally similar to butenolides and have attracted the attention of synthetic organic chemists due to their versatility as building blocks, are also highlighted. Examples of applications of the methodologies in the synthesis of natural products as well as in the preparation of analogues endowed with biological activities, including some contributions from the author’s groups, are discussed. Keywords: Aldol reaction, Alkylidenebutenolide, Butenolide, Pyridazinone, Butyrolactone, Azlactones.

Alcohols as alkylating agents in heteroarene C-H functionalization.

Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage1. One of the core principles that underlies DNA biosynthesis is the radical-mediated elimnation of H2O to deoxygenate ribonucleotides, an example of ‘spin-center shift’ (SCS)2, during which an alcohol C–O bond is cleaved, resulting in a carbon-centered radical intermediate. While SCS is a well-understood biochemical process, it is underutilized by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylations using alcohols as radical precursors. Considering traditional radical-based alkylation methods require the use of stoichiometric oxidants, elevated temperatures, or peroxides3–7, the development of a mild protocol using simple and abundant alkylating agents would have significant utility in the synthesis of diversely functionalized pharmacophores. In this manuscript, we describe the successful execution of this idea via the development of a dual catalytic alkylation of heteroarenes using alcohols as mild alkylating reagents. This method represents the first broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer (HAT) catalysis. The utility of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.

Synthetic Strategies Towards the Sex Pheromone of Trogoderma Species.

Z-14-methyl-8-hexadecenal and its E-isomer were identified as the essential female secreted sex pheromones of trogoderma species of insects. Since the discloser of its structure in 1969, ( Z )-(-)-14-methyl-8-hexadecen-l-ol and methyl ( E )-(-)-14-methyl-8-hexadecenoate as the sex pheromones have been the subject of intense study by the synthetic organic community. Several strategies have been developed for the total synthesis of these exciting pheromone molecules and they are discussed in detail.

ChemInform Abstract: Synthesis of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids Using Bioinspired Reactions

AbstractReview: 41 refs.+subrefs.

Synthesis of Tryptophan-Based Dimeric Diketopiperazine Alkaloids Using Bioinspired Reactions

Tryptophan-based dimeric diketopiperazine alkaloids such as ditryptophenaline, WIN 64821, naseseazine A, and naseseazine B, exhibit a unique architecture and interesting biological activity. These alkaloids have been the subject of intense study by the synthetic organic chemistry community, and several elegant total syntheses have been discovered, especially using bioinspired strategies. Described herein is a brief overview of these alkaloid syntheses via bioinspired transformations as key steps.

Greener Organic Synthesis

When Bruce H. Lipshutz said he had a goal to help the synthetic organic chemistry community get organic solvents out of organic reactions, he wasn’t kidding. The University of California, Santa Barbara, chemistry professor had been quizzing process chemists in industry about the most common reactions they use and what they would like to do to improve the cost and environmental profiles of the processes—that is, how to make them greener and more sustainable. One of the biggest obstacles, they said, was organic solvents. That bit of information led Lipshutz and his research group to develop a class of low-cost designer surfactants. These amphiphilic molecules form nanomicelles, which act as reaction compartments. They enable common transition-metal-catalyzed organic reactions to run in water at production scale at room temperature. For his efforts, Lipshutz received a Presidential Green Chemistry Challenge Award in 2011. Lipshutz has now moved on to the next phase ...

Design, Synthesis, and Biological Evaluation of Truncated Superstolide A

Design, Synthesis, and Biological Evaluation of Truncated Superstolide A

SynthCon2: A Forum for Australian Organic Chemists

In April 2013, the second biennial SynthCon meeting, SynthCon2, was held in the Yarra Valley at Fergusson’s Winery. Building upon the success of SynthCon1, which had around 45 attendees, 55 delegates attended and presented recent results from their laboratories. SynthCon focuses on the needs of the synthetic organic chemistry community within Australia. Although the tyrannies of distance no longer impede the timely delivery of the latest international discoveries, conducting research in Australia still presents a unique range of challengesyand advantages. A central motivation behind the creation of these meetings was a desire to address the challenge of performing research within smaller institutes, and often in the absence of colleagues working in closely related fields. By providing a meeting focused on academics, without the distractions of international speakers, it was hoped that an environment conducive to the open and frank development of novel ideas could be created. While we have some way to go, our second meeting allowed delegates from the Australian National University, Biota International, CSIRO, Curtin University, Deakin University, Griffith University, Monash University, Queensland University of Technology, University of Adelaide, University of Melbourne, University of New England, University of New South Wales, University of Queensland, University of Sydney, University ofWestern Australia and University ofWollongong to meet and discuss new and unpublished chemistry. This Research Front presents a taste of the chemistry from this meeting, with research papers examining the synthesis and biological activity of Sunitinib analogues, facial selectivity in benzonitrile oxide cycloaddition, the enantioselective synthesis of kopsia and aspidosperma natural products, temperature responsive amphiphiles, and the ozonolysis of endoperoxides. Several highlights focused on emerging areas, such as ionic liquid conjugated proline catalysis, chemical activation of nitrenes and azides, and the role of peptide secondary structure in electron transfer, are presented. Finally, a focus article highlights 1-(acyloxy)benzotriazoles, and examines its utility. SynthCon2, and SynthCon1, was financially supported by Davies Collison Cave, CSIRO, Australian Journal of Chemistry, Biota International and Monash University. Thanks also to Amanda Lee, for her help behind the scenes, and in the creation of the cover art for this issue; Simon Lee, our trusted bus driver; Michael Blair, for the homebrew; and the Lupton doctoral students for venue set-up. Planning is under way for SynthCon3, which will be held in Victoria’s Yarra Valley in 2015. Our chair, Richard Payne, will be in contact in due course. Hopefully, SynthCon3 will see some familiar faces, along with new members of the community, as we continue to foster excellence in organic synthesis within the Australian chemistry community.

ChemInform Abstract: Alkylidene β‐Ketoesters in Asymmetric Catalysis: Recent Developments

AbstractReview: 86 refs.

Alkylidene β-Ketoesters in Asymmetric Catalysis: Recent Developments

Although alkylidene β-ketoesters have been known since the beginning of the 20th century, they have only recently attracted the attention of the synthetic organic community. In these versatile electrophiles, the enone double bond is strongly polarized because of the presence of the ester moiety as a second electron-withdrawing group. The resulting increase in reactivity has recently opened the way to a number of challenging transformations in the field of enantioselective catalysis, but is also responsible for their high sensitivity toward acids, bases, and high temperature, which hampered their application in organic synthesis for a long time. The saturated β-ketoester moiety generated in these reactions has been used for diverse functionalization reactions, some of which lead to quaternary stereocenters. This perspective highlights the origins of alkylidene β-ketoester chemistry and focuses on recent developments of the quickly evolving field of asymmetric catalytic reactions of these substrates. After ...

Copper(II)-Catalyzed Amidations of Alkynyl Bromides as a General Synthesis of Ynamides and Z-Enamides. An Intramolecular Amidation for the Synthesis of Macrocyclic Ynamides

A general and efficient method for the coupling of a wide range of amides with alkynyl bromides is described here. This novel amidation reaction involves a catalytic protocol using copper(II) sulfate-pentahydrate and 1,10-phenanthroline to direct the sp-C-N bond formation, leading to a structurally diverse array of ynamides including macrocyclic ynamides via an intramolecular amidation. Given the surging interest in ynamide chemistry, this atom economical synthesis of ynamides should invoke further attention from the synthetic organic community.