An unexpected journey

I was intrigued by Tian’s report of a palladium-catalyzed formation of allyl sulfones from hydrazines. Upon exposure to Pd(0), the allyl amine you see ought to ionize and undergo straightforward allylic substitution with the hydrazine derivative depicted. However, Tian and co-workers found that under oxidative conditions, the Pd-bound hydrazide ligand undergoes oxidation followed by extrusion of nitrogen and incorporation of the “rebound” sulfone unit. I am drawing this reaction as if it were a reductive elimination, but it is, of course, more likely that the soft sulfone-derived nucleophile attacks the Pd center of the corresponding pi-allyl complex. The authors have considered both of these possibilities, I am just showing one. mmm!divAbstract

This paper also brought back some memories. My lab has published quite a bit on the subject of ionization of allylic amines under palladium catalysis. For example, about six years ago we found that N-protonation of allylic amines leads to rapid ionization and formation of palladium pi-allyl complexes. Thanks to Iain Watson in my lab, we have used this chemistry on a number of occasions. Here is a link to a representative paper, where my former students Igor Dubovyk and Iain showed that synthetically useful outcomes can also be secured by preventing proton-promoted ionization of allyl amines.

Bent out of shape

I got acquainted with Professor Jasti on a recent trip to Boston University. His lab is pushing the frontiers of cycloparaphenylenes (CPP’s), which are warped carbon-rich molecules that are not only aesthetically pleasing, but might one day act as useful precursors to carbon nanotubes and a myriad other applications (some are yet-to-be identified). Previously, the Jasti lab reported their synthesis of [6] and [7] CPP’s. Many of you know that Professor Itami of Nagoya University, Japan, has also been quite active in this area. The latest contribution from the Jasti lab deals with the [5]CPP nanohoop fragment of buckminsterfullerene. The remarkable room-temperature synthesis of this molecule was reported in Nature Chemistry not long ago. The target molecule forms brilliant-red needles and has been characterized by a range of spectroscopic methods. The compound is soluble in many organic solvents and is highly strained, which is not surprising considering how warped the rings are (the strain energy of [5]CPP is 119 kcal/mol…). The proton NMR of the newly minted member of the [5]CPP class of compounds showcases only one singlet at 7.68 ppm, which means that there are no rotational isomers at room temperature. The synthesis takes only 3 steps and I encourage you to take a look at it (not surprisingly, the Suzuki coupling features prominently in this approach). I am showing only the final step that leads to the formation of the target molecule. For me, the most intriguing aspect of this paper is the extent to which chemists can push the concept of aromaticity. I consider it quite fascinating that aryl rings can get bent out of shape in such a dramatic fashion, while retaining their core aromatic character.


Let’s talk about alternatives

I am in New York City today and tomorrow, having a bit of a vacation with my wife. Well, it’s more like she needs some much needed rest and I am keeping her company. I do stay a bit too long at the hotel doing some grant-related work, much to her chagrin. Earlier today we went to the David Letterman show and I think if some of you want to find me in the audience (perhaps my students want to make fun of my giggling face), it might be too late as the show is probably on right now. It was a lot of fun. What fascinated me the most was the attention to detail by those running the telecast. It is quite an astounding display of efficiency: everyone knows exactly what she/he needs to do at a given time.

It is also fun to think about amides, especially about some of the more heretical considerations, if you will. My lab has been tackling the physical organic fundamentals of amide bond formation and extracted some much-needed new value out of this linchpin of synthesis (you can see my post of February 27). It is remarkable how many tricks we can teach this old dog. I will talk at length about some additional underappreciated aspects we currently find rather exciting, but this will happen after we publish our next piece of this saga. As I was watching David Letterman, I kept comparing his well-greased show business machine to some of the mechanisms of chemistry. I refer to the ones where everything happens for a good reason and under “spatiotemporal” control (in other words, at the right place and at the right time). It occurred to me today that I might not have a good answer to the collapse of the tetrahedral intermediate, which is central to understanding amide bond formation. Take a look at the graphic below. Let’s not worry too much about pH and where our protons are supposed to be. These are finer details. For the time being, I am just going to illustrate the collapse using anionic oxygen center that is part of the well-known tetrahedral intermediate (it can also be OH, you know). Here comes the $64,000 question… When we discuss amide bond formation, we teach it in terms of the “blue arrows” you see here. For the life of me, I cannot think of a study (either theoretical or experimental) that has seriously considered an alternative shown in red. This really bugs me and those of you who are of the opinion that this “red” idea is pure heresy, please direct me to the primary literature. Dear undergraduate students: please do not get all flustered and confused, I am certainly hopeful that there is a solid study illuminating the overall process so that we can sleep well tonight. I just can’t think of it.


Bad Behaviour

In my lab we do a lot of peptide work with a particular emphasis on structure determination. This is a multistage and complex process that requires our utmost attention to detail, and is subject to many stumbling blocks of highly technical nature. The often capricious and solvent-dependent solubility and aggregation of peptides are enough to make me cringe. I can recall a number of occasions where we fell victims to this trap: we would change one amino acid in a sequence and record some utterly unanticipated behavior. For instance, one sequence would be soluble and well-behaved, whereas its close relative would be a complete “dud”. Welcome to the world of peptides! No wonder there is American Peptide Society out there… Have you heard of American Alkene Society? Or American Bromine Society? Nope, me neither. It tells you that peptide chemistry, as a field, is in a class of its own.

But let’s go back to some tangible ways of tackling peptide behavior, in particular peptide aggregation and solubility. I was reading a 5-year old paper by Geyer and colleagues in OBC, and came across the use of SDS in order to prevent self-aggregation of peptides. One of the sequences reported in this manuscript corresponded to a ten amino acid peptide with a high antiparallel amphipathic beta-sheet content. This peptide was inclined to self-aggregate in aqueous solution. Fortunately, this undesired behavior was effectively countered by adding perdeuterated sodium dodecyl sulfate to the aqueous phosphate buffer. Under these conditions, the precipitation was prevented, allowing the authors to study their molecules using NMR. I am going to discuss this property with my lab and see how SDS might help with some of our intractable cyclic peptide NMRs that occasionally raise their ugly heads. I think we need to compile a list of the magical additives that help avoid the pitfalls of peptide self-association. If you are aware of tricks along these lines, please let me know.


Science blogging, the way I see it

Hello everyone. Many of my friends, students, and colleagues have been asking me about how I feel about this whole blogging thing. I like it, that’s for sure. A more detailed set of reasons why I think it is worth my time is outlined in the following article that I put together. It just came out yesterday on the Chemical and Engineering News website (thanks a lot, Carmen Drahl, for making it happen!):

Have a great weekend.

In praise of C1 stitching units

When it comes to the so-called “C1 building blocks” (in other words, building blocks that lead to straightforward transfer of one carbon unit), formaldehyde is on the very top of my list. This simple chemical acts as a direct precursor to the methylamine fragment that can be put together using a range of condensation reactions. Formaldehyde-derived iminium ions are fantastic starting materials for the Mannich reaction and are known to partake in cascade processes driven by the incipient primary amine units. In this regard, I enjoyed reading the total synthesis of lyconadins A and C by the Dai group of Purdue University. The cornerstone of their synthesis (shown below) demonstrates how formaldehyde takes on a scaffold containing a ketone and an alpha,beta unsaturated ketone, and stitches a complex multi-ring system in one pot. There are three distinct mechanisms one can propose for this process. One of them – the aza-Michael/Mannich sequence – can be safely ruled out because the control experiment using the secondary amine intermediate shown below, failed. This leaves two possibilities, neither of which can be ruled out at this point of time. Overall, this gram-scale route opens doors towards libraries of lyconadin derivatives and their evaluation as anti-neurodegenerative agents.


Get your rings in order

The title of the paper by Richard Taylor and colleagues speaks for itself: “Rings in Drugs”. Below you can see the top 6 rings from marketed pharmaceuticals. I am also showing a morpholine (number 29) and a beta-lactone (the last ring on the list of top 100). Macrocycles were not considered in this study as maximum single ring size was set at 9. There are several interesting “ring” anecdotes in this paper. For instance, approximately six new ring systems enter drug space annually. Here is a somewhat surprising fact for those of us who are interested in asymmetric synthesis: 40% of drugs do not contain any sp3 carbons in a ring system.


In my view, this paper provides a compelling rationale for going after novel heterocycles. In this regard, I recalled an interesting study published by Erick Carreira’s lab several years ago. In it, the authors made a point about a novel spirocyclic ring that had subtly perturbed the established electronic structure of morpholine. In the graphic below, you can see the relative orientation of the oxygen lone pairs that is clearly different in the two structures. Due to the fact that biological activity of a small molecule can often be traced back to the vectorial relationship of electron pairs on heteroatoms at key positions, the oxetane unit has been employed to expand the chemical space around morpholine. Because morpholine is common (number 29 in the Taylor study), its oxetanyl analogues have found wide use. And so shall many other, yet to be identified, heterocycles that are “vectorially challenged”!