In August of this year, the drug asenapine (sold as Saphris by Shering-Plough) was approved by the FDA for treatment of schizophrenia and manic episodes of biopolar I disorder, according to a recent news article in Nature Reviews Drug Discovery (doi:10.1038/nrd3027). Asenapine is an atypical antispychotic. The tricyclic 6-7-6 ring structure is common to most of the the atypical antispychotics (including clozapine and olanzapine, but not risperidone). What makes them atypical is that they not only treat the "positive" symptoms of schizophrenia (hallucinations, delusions, mania) but the "negative" ones as well (depression, cognitive impairment).
A SciFinder search revealed 3 patents with published syntheses of the drug; surprisingly, no papers so far with SAR studies or anything of the sort, and just enough clinical trials to allow the drug to be marketed. The drug wasted no time getting to the market - at least, according to the literature I looked through - which for a mental disorder like schizophrenia for which there is no truly good treatment, only adequate treatment, is wonderful.
Two patents had two different approaches (and the others were either duplicates or elaborations), and the most recent was an elaboration on one of the others. The first, from 2006, sought to make the trans-pyrrolidine as efficiently as possible to improve upon the former synthesis. The synthesis on a whole, though, is extremely steppy. The second, in 2008 (Int. Pat. #: WO 2008/003460) instead chopped the molecule in two via a cyclization between a stilbene and an in-situ generated azomethine, followed by an Ullman condensation to connect the phenol with the other ring; use of the trans-stilbene naturally leads to the trans-ring juncture.
To make the stilbene, HWE:
You can obviously see where there's room for synthesizing analogues here by using a different benzyl bromide in the first step. The coupling partner used in the next step is activated in-situ by CsF or TFA. I think it looks like a handy synthesis.
A 'just accepted' article in Bioorganic and Medicinal Chemistry (doi:10.1016/j.bmc.2009.10.012) caught my attention because of the number of "anti" activities stated in the title for a particlar 'new' class of compounds, 2-arylazobenzosuberones: "Synthesis, Tautomerism, Antimicrobial, Anti-HCV, Anti-SSPE, Antioxidant and Antitumor activities of Arylazobenzosuberones." From one common precursor, 12 compounds were synthesized with variation of the arene group of the diazonium salt coupling power. Reaction of 1-benzosuberone-2-dimethylaminomethylene with aryl diazonium chloride resulted in the Japp-Klingemann type cleavage of the dimethylaminomethylene group.
The Japp-Klingemann reaction normally involves the reaction of beta-keto esters or acids with aryldiazonium salts in the presence of base to form hydrazones, usually in aqueous medium but in alcohols if solubility is poor:
In this paper, however, an alpha-dimethylaminomethylene group functions as the original ketone in this case, so there's no need for a strong base - the conditions for the reaction are sodium acetate in ethanol at 0-5 °C for 20 minutes, then overnight in a refrigerator to crash out the product.
So for all the anti's - 8 of these compounds were tested for inhibitation of growth of 4 strains of bacteria and 4 strains of fungi using the agar diffusion method. Referenced antibacterial drugs are mentioned, but not identified nor is comparison data for the standard included in the data presented in the form of Minimum Inhibitory Concentration (MIC) values. The paper claimed much better activity of some of the compounds than the standards, but the units of the values are GRAMS per mL. That's HUGE to me... the lowest measured was 0.313 g/mL. The tetra- and pentacyclic compounds below weren't tested, but I would've liked to see them tested, since the heteroarene rings are such great pharmacaphores and they're much different than the rest of the bicyclic azoketosuberones.
Antioxidant activity was assessed with the DPPH radical scavanging test, a colorimetric assay that determines XXX, with ascorbic acid (vitamin C) as a standard. The second test was inhibition of ONOO- (ooohhhhnooooooooooooooooooo!) which can cause tissue damage from oxidation and nitration of lipids, proteins DNA and carbohydrates. These results were in IC50 values, thank goodness, but like all the other biological activity tests, the hydrazones were just as good if only slightly better than the standards, if standard data was even shown. They aren't orders of magnitude different. What did I expect?
When I read these kinds of med chem type papers I take an especially harsh eye to it, definitely not because I'm a scientist and thus am cynical (which I definitely am), but because it's a habit from being a reviewer for a school journal. Everything we got in seemed to me so unimpressive that I finally got fed up and quit being on the board. The biological studies in this paper made me feel like that. Please, please don't talk up your results. Just tell them how they are and let the community decide whether or not your compounds are the shit. When I just now got around to opening the Kürti and Czakó text, I wasn't surprised to see a similar ring system used to make a remarkably similar product by G. Primofiore and co-workers in 1993 (see below, from p.225)... ripoffs! Can't believe I wasted that time. The only thing I liked was that all the compounds were in the yellow/orange range in moderate to good yields... slightly redeeming.
Everyone loves neat tricks in synthesis that are not as easy to spot in retrosynthesis as oxidations or reductions; one of these I came across recently is the conversion of furans to tetrahydropyrans, the Achmatowicz reaction, the seminal publication of which was in 1971 in Tetrahedron:
This reaction was used in a few total syntheses; besides those mentioned in the Wikipedia article, I particularly like O'Doherty's synthesis of the indolizidine (-)-D-Swainsonine published in Org. Lett. The four carbons that will form the five-membered ring of the bicyclic system was formed using the Achmatowicz reaction. 2-Lithiofuran opened the gamma-butyrolactone to install the alpha-oxygen; a TBS protection allowed for asymmetric Noyori reduction of the ketone, installing the necessary stereocenter for the substituent on the tetrahydropuran for the subsequent steps. The Achmatowicz was achieved using NBS.
Other than modifications to the ring's functional groups, the carbonyl was converted to an azide in several steps which was used in the second to last, pivotal step of the synthesis, closing the 5-membered ring via reductive cyclization to complete the indazolidine ring system. (The benzyl group is hydrogenated off, allowing the isomerization to the aldehyde which is then attacked by the nitrogen and the oxygen eliminated.) That makes for two rearrangement-type reactions to form the final product - I won't get into overall strategy and the greater story of the synthesis of the molecule and its enantiomer, but I just wanted to point out how the Achmatowicz was used creatively to make a pretty neat molecule.
