[ad_1]
We at Prof. Debabrata Maiti’s laboratory have been exploring the reactivity of the carboxylate group in activating sp3 C-H bonds for a number of years now. Whereas we had been exploring the C-H functionalization potentialities within the realm of cyclic aliphatic acids, we discovered this superb response that exhibits reverse site-selectivity and kinds bicyclic lactones with unsaturation within the cyclic ring. We’re gonna speak in regards to the story of this challenge and the journey in between.
How/Why we found this challenge
All of us are conscious of the fantastic thing about lactones. Its ubiquitous affect might be noticed all over the place, from perfume molecules to pharmaceutically related compounds.1,2
However how do chemists put together lactones?
Essentially the most basic textbook response that involves thoughts is intramolecular esterification. This entails the cyclization of a hydroxy acid or hydroxy ester compound with a leaving group, ensuing within the formation of a lactone. Then there are different reactions like Baeyer-Villiger Oxidation and iodolactonization to generate lactones.3
Though there exists plenty of chemical reactions to kind lactones, the route is usually not simple. Both the beginning supplies are extremely designed (not available) or there are a number of steps to kind the product. All of those rely for the decreased atom and step economic system of reactions.
With our exploration of carboxylate-assisted sp3 C-H activation, we realized a fantastic alternative to kind not simply easy lactones however bicyclic lactones. The outstanding problem was to kind lactones in a single step from alkyl carboxylic acid with out having to make use of any exterior coupling accomplice.
Intramolecular lactonization of the aliphatic carboxylic acid is a disfavored course of as evident from the earlier literature.4 We got here up with a cyclic aliphatic acid 3-methyl cyclohexane acetic acid that has equally accessible gamma methyl and gamma methylene teams.
The traditional information would point out that methyl group activation is simpler than methylene. However the catch with this substrate is that the next step reductive elimination following methyl activation might be troublesome (that is precisely what we discovered later in our DFT research) and so it mustn’t proceed.
Whereas methylene activation, although extra strenuous however subsequent organometallic step beta-hydride elimination must be extra favorable (Determine 1). With this speculation, we subjected the substrate to an amenable response situation, and voila! we discovered our thought course of to be true.
Utility of the found response
Some essential benchmarks for testing the effectiveness of a brand new chemical response are its generality, functions, and so forth.
Is the response equally potent for a various class of substrates? Can the response be utilized for accessing essential advanced molecules?
In an effort to discover solutions, we assessed plenty of completely different aliphatic acids which comprise 5, 6, 7, 12, and 15-membered rings. The protocol was discovered to be efficient for all such substrates, albeit, in numerous yields. The fascinating case is with macro ring containing acids (12 and 15 membered). Macro lactonization has been historically thought-about a difficult response because it typically required extremely diluted situations and gradual addition procedures to forestall oligomerization.5 Nonetheless, we may obtain macro lactonization using the identical precise situations as different lessons of substrates.
What intrigued us extra is after we tried to make the response work within the presence of an exterior accomplice. We name it the intermolecular model of the response. In case you do not add something additional (besides the substrate) within the response, it kinds unsaturated lactones (Determine 2), nonetheless, should you add an olefin or an allyl alcohol, it kinds unsaturated lactones containing olefins (Determine 3).
The intriguing half is what number of issues are occurring in a single-pot response. Within the presence of Olefin, listed below are the events-
- gamma-methylene C-H activation
- C-O cyclization
- Unsaturation within the ring
- gamma-olefination
One of many long-standing targets of artificial chemists is to make extra advanced compounds from easier beginning supplies (ideally in a single step). This response exhibits the potential of such approaches. Undoubtedly, we’re going to witness extra such reactions within the coming days the place advanced molecules might be synthesized from one or two-step reactions (e.g., multicomponent reactions).
We portrayed plenty of situations the place the developed protocol might be harnessed to kind varied pure merchandise or bioactive molecules in fewer steps than earlier than (Determine 4).
The thriller of reverse web site selectivity
Reversing the standard web site selectivity is likely one of the main highlights of this response. This was all the time in our minds and so we needed to discover a rationale for this.
We collaborated with Dr. Xinglong Zhang from IHPC, A*STAR, Singapore to unravel the thriller. We discovered the substrate to be in a singular place to command reverse web site selectivity. Though the methyl activation is extra facile on this case, the next organometallic step (after methyl activation) reductive elimination is unfavorable on this case.
Whereas the methylene activation (although a bit of extra strenuous than methyl activation) is accompanied by a extra favorable means of beta-hydride elimination and thus the system favors the methylene activation over methyl (Determine 5). Extra particulars are within the paper. It’s as if the system reveals delayed gratification as a substitute of prompt gratification.
Conclusion
This response is a good instance of the potential of weak coordination in activating inert C-H bonds and thereby beginning a cascade response. Generally a delicate push is more practical than doing it the exhausting means. Whereas robust coordination is taken into account higher for forming organometallic complexes, weak coordination in a response can lead to fruitful finish merchandise.
What about aliphatic ketones, alcohols, esters, and so forth. practical teams? Can we harness the weak coordination of such practical teams for driving reactions?
We anticipate extra exploration in such domains within the coming years, probably resulting in extra thrilling chemical reactions.
Reference:
1. Kreuger, M. R. O., Grootjans, S., Biavatti, M. W., Vandenabeele, P. & D’Herde, Okay. Sesquiterpene lactones as medicine with a number of targets in most cancers therapy Anti-Most cancers Medication 23, 883-896 (2012).
2. Li, G., Kusari, S. & Spiteller, M. Pure merchandise containing ‘decalin’ motif in microorganisms. Nat. Prod. Rep. 31, 1175-1201 (2014).
4. Kao, L.-C.; Sen, A. Platinum (II) catalyzed selective distant oxidation of unactivated C−H bonds in aliphatic carboxylic acids. J. Chem. Soc. Chem. Commun. 18, 1242 (1991)
5. Pressure, G., Perfetto, A., Mayer, R. J., Ciofini, I., Leboeuf, D. MacrolactonizationReactionsDriven by aPentafluorobenzoylGroup. Angew.Chem.Int. Ed., 60, 19843–19851 (2021)
[ad_2]