E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing.

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ).

Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome proliferator-activated receptor γ (PPARγ). Based on known PPARγ ligands (MDG548, GW1929, and rosiglitazone), we have designed and synthesized azobenzene derivatives, termed AzoGW1929 and AzoRosi, which were confirmed to be active in cell-based assays. Subsequent computer-aided optimization of AzoRosi resulted in the photohormone AzoRosi-4, which bound and activated PPARγ preferentially in its light-activated cis-configuration.

Different Strategies for Designing Dual-Catalytic Enantioselective Processes: From Fully Cooperative to Non-cooperative Systems.

An emerging area of research in chemistry requires that we learn how to manage the characteristics of a pair of co-catalysts so that a transformation proceeds as we wish it to. These are processes during which one catalyst first generates a non-isolable intermediate, which then in situ undergoes a reaction that is promoted by a different catalyst. This scenario raises several design issues. Since co-catalysts often have overlapping functions, what if there is an exchange of ligands between two organometallic catalysts? How can we be certain that a co-catalyst reacts specifically with a particular intermediate? What if the less reactive co-catalyst must engage first, and the one that is more active needs to wait its turn? How might we orchestrate the proper sequence of events? While many dual-catalytic processes have been introduced and reviews are available, there are subtle yet crucial distinguishing attributes that remain unappreciated. While the terms "dual-catalysis" and "cooperative catalysis" are often used interchangeably, on many occasions the catalysts are not entirely cooperative. Here, we will discuss how chemists have been able to harmonize the opposing functions of catalysts to achieve high efficiency and/or stereoselectivity. We will show that the progress achieved thus far is likely the preamble to the future development of non-orthogonal multi-catalytic processes (i.e., transformations involving several catalysts that are not inherently cooperative) where the order with which each catalyst enters the fray will demand additional innovative strategies.

Reversible optical control of F1 Fo -ATP synthase using photoswitchable inhibitors.

F1 Fo -ATP synthase is one of the best studied macromolecular machines in nature. It can be inhibited by a range of small molecules, which include the polyphenols, resveratrol and piceatannol. Here, we introduce Photoswitchable Inhibitors of ATP Synthase, termed PIAS, which were synthetically derived from these polyphenols. They can be used to reversibly control the enzymatic activity of purified yeast Yarrowia lipolyticaATP synthase by light. Our experiments indicate that the PIAS bind to the same site in the ATP synthase F1 complex as the polyphenols in their trans form, but they do not bind in their cis form. The PIAS could be useful tools for the optical precision control of ATP synthase in a variety of biochemical and biotechnological applications.

Total Synthesis of Lycopladine A and Carinatine A via a Base-Mediated Carbocyclization.

A concise, enantioselective synthesis of lycopladine A and carinatine A is presented. Our synthetic approach hinges on the recently developed mild carbocyclization of ynones to furnish the hydrindane core of the alkaloids. Their pyridine ring was efficiently installed using the Ciufolini method. Both heterocycles of carinatine A, a rare naturally occurring nitrone, were formed in a single operation.

A Conia-Ene-Type Cyclization under Basic Conditions Enables an Efficient Synthesis of (-)-Lycoposerramine†R.

An enantioselective total synthesis of the Lycopodium alkaloid lycoposerramine R is presented. It relies on a base-mediated cyclization that resembles the Conia-ene reaction of ynones and gold-catalyzed variants thereof. Thus, hydrindanones and other functionalized ring systems bearing an exocyclic alkene can be rapidly accessed at room temperature without noble metal catalysis or substrate preactivation.