Synthesis of the antiviral cyclobutyl guanosine derivative Lobucavir

Asymmetric Synthesis of Cyclobutanones: Synthesis of Cyclobut-G

Benjamin Darses, Andrew E. Greene & Jean-François Poisson*

J. Org. Chem., 2012, 77 (4), 1710; DOI: 10.1021/jo202261z

A synopsis by Peddabuddi Gopal

Cycloalkanes are less stable than simple (acyclic) alkanes because of bond angle strain, which increases as the number of carbons in a ring decreases. Cyclopropanes (bond strain energy 27.5 kcal/mol) and cyclobutanes (bond strain energy 26.3 kcal/mol) are particularly unstable relative to a cyclohexane ring. Nonetheless, natural products containing the cyclobutane ring have been found to possess significant biological activity with (−)-biyouyanagin A, (+)-kelsoene and (−)-bielschowskysin providing just a few examples. Thus, although developing efficient synthetic protocols for these natural products is very challenging, it shows great potential to improve the quality of our lives.

Therefore four-membered carbocycles are valuable building blocks in synthesis. Piperidines, tetrahydropyrans, cyclohexanones, and oxazepines are some examples that can be efficiently accessed through an approach that uses donor−acceptor cyclobutane derivatives as 1,4-dipole precursors. Cyclobutanes have also been used in transition-metal-catalyzed ring-opening reactions for the construction of larger rings and functionalized non-cyclic products.

In general, the significant protocol to prepare cyclobutane derivatives involves [2 + 2] cycloaddition, intramolecular nucleophilic substitution, and ring contraction/expansion reactions. It should be noted that the reported approaches to four-membered carbocycles are generally limited in scope and few are able to provide enantioselection.

The authors J. F. Poisson et al. established a very efficient strategy for the stereoselective synthesis of cis– and trans-disubstituted cyclobutanones from readily (although non commercially) available alkyl- and functionalized alkylsubstituted enol ethers. On the basis of this methodology they have made an enantioselective synthesis of biologically active cyclobut-G (Lobucavir). This cyclobutyl guanine nucleoside analogue, a derivative of the highly potent anti-HIV natural product, oxetanocin A, was firstly developed by Bristol Myers Squibb some 20 years ago.

In 2008, the J. F. Poisson et al. exploited the diastereoselective [2 + 2] thermal cycloaddition of dichloroketene (DCK) with chiral enol ethers for the enantioselective synthesis of a variety of five-membered ring-containing natural products. In the first step of the sequence, Stericol [(S)-(−)-1-(2,4,6-triisopropylphenyl)ethanol] was treated sequentially with potassium hydride and trichloroethylene, which yielded the corresponding dichloroenol ether. The latter was treated with n-butyllithium followed by methyliodide to form the methylated ynol ether, which was directly hydrogenated to afford the Z enol ether.

Consequently, the authors prepared different types of Z/E ketenophiles using different alkylhalides and polyformaldehyde. However, Z olefins are very useful to prepare both cis and trans cyclobutane derivatives, while E olefins show very poor in stereoselectivity. Based on different types of ketenophiles they made different types of cyclobutane derivatives. In this process they have explained very well about optimization of the most important dechlorination of the unstable α,α- dichlorocyclobutanone intermediates.

Finally, the synthesis of the nucleoside analogue Lobucavir is somewhat related to our research. The author’s stepwise illustration is very good, actually the same work was published in OL, 2008 but in this article, in addition to that article they prepared E alkenes and trans cyclobutane derivatives and also they reported failure reaction in preparation of cyclobut-G.

13 thoughts on “Synthesis of the antiviral cyclobutyl guanosine derivative Lobucavir

  1. These are the kind of articles that you need when you are trying to reproduce a natural synthetized material that are potential drugs for medicine. But also, these kind of modifications are strong tools for synthetic building blocks in supramolecular chemistry. In this article Poisson and coworkers developed an efficient approach to develop cis- and trans- cyclobutanones derivatives. This was a challenge for many researchers in organic synthesis that were limited to design five- and six- membered carbocycles. Other important aspect was the synthesis of a stable monochlorocyclobutanone. Finally, they synthesize cyclobut-G by using this approach. In scheme 11, we can see the effects of working with the “complex” guanine but they figure out how to solve the problem.

    According with the reported results, it’s seems that the “chiral auxiliary” of the protecting group of the C3 plays a role in the amount of obtained chiral cis- or trans- product. It will be interesting how supramolecular chemistry can be incorporated with these kind of reactions or other type of conventional catalysts to see how the enantiomeric excess or product can be changed by adding an extra auxiliary to this kind of reactions. We know that this cycloadditions depends a lot of the orientation of the molecular orbitals of the reacting species before the cycloaddition takes place.

    About the procedure of 18, It was interesting that the crude 18 was washed with aqueous 30% H3PO4 and then purified without problems. I really enjoyed the article because not only deal with a current synthetic challenge, but also we can see the application of this elegant work. Applying these kinds of approaches are promising tools for the design of more complex macromolecules in material science or medicinal chemistry.

    About the synopsis, is well written in terms of the important aspects of this chemistry. Gopal talks more about the development of these reactions and what the research group done, but I was expecting more about the efficiency of these reactions in terms of the desired product and how reliable is this methodology in comparison with other 2 +2. The picture was simple, but I got the message.

  2. In a detour from our usual GQ/Supramolecular related papers, this week’s blog brings us a synthetic methodology paper, presenting the preparation of a variety of substituted cyclobutanone derivatives that could be used as intermediates in multi-step synthesis of further derivatized compounds. .
    The chlorinated cyclobutanone intermediates prove to be quite unstable and the authors had to use a few tricks to learn to work around their instability, modifying solvent acidity, reaction times, reagents, temperatures… The main attraction of the paper is indeed the dichlorination of these highly reactive cyclobutanones… With the help of a chiral auxiliary (S-Stericol) cyclobutanone products were achieved with good stereoselectivity. This auxiliary shows a very good applicability in this article however, interestingly, the epimers were more readily prepared treating the products in basic conditions than by direct synthesis.
    The paper is pleasing to read: easy to follow, tells a nice story, shows good results… Yet if the paper was meant to help us in our synthetic efforts with preparation of deoxyguanosine derivatives, than I see little application in it: the cyclobut-G compound is described in the last two paragraphs, and the only reaction that includes a guanine group is an SN2 reaction between a triflated alcohol and the purin salt. However, as an example of providing tools for organic chemist to facilitate future synthesis, its got good appeal. And I’m really happy to be discussing a synthesis paper, as our group does spend most of it effort in synthetic organic chemistry.
    The synopsis, in my opinion, had too long an introduction, and discussed to little of the real chemistry. Also, it added little analysis to what was already in the paper. I was a little confused as paragraph 5 begins by citing a 2008 OL paper, and then continues describing the 2011 JOC, which is the topic of the blog… I think. The picture could’ve been a little more creative… I don’t know if there’s any deeper meaning, perhaps, to the airplanes used as arrows….

  3. In this article, Poisson and coworkers describe their approach in synthesizing cis and trans disubstituded cylobutanones. They explained the importance of these compounds as building blocks in organic synthesis because of the energy stored in the bond strain of their structures. However, the preparations of these cyclobutane derivatives are very limited, and not many of them can yield the desired product in an antioselective manner. Therefore Poisson and his team synthesized their compounds by using a [2+2] cycloadition/ dechlorination sequence with several enol ethers and dichloroketene. They compared the Z-enol ethers with their E counterparts, and found that, overall the E-enol ethers had lower yields. They explain that this was actually due to the dechlorination and not to the cycloaddition. I’m not sure how to explain this, but I didn’t get this last part, did they try to separate the steps of the synthesis like they were doing at first (form the dichlorobutanone to the disubtituded cyclobutanone) to say that the problem was mainly in the cycloaddition? Or did they do a one-pot synthesis and they figured this out because of the reaction times?
    Another thing they observe was that by taking out the “auxiliary chiral” which protected the C3 carbon, they could obtain 3-hydroxy cyclobutanone. This last step was important, because they were able to use this new derivative (with the proper substituents) to make a guanosine analogue that possessed anti HIV properties, suggesting that this type of synthesis can have great potential for future applications.
    Overall I think this was a good paper. I really don’t remember the last time we read a paper about synthetic methodology, but it’s an interesting change. We deal in our lab with different synthesis so we can really appreciate the importance of these types of papers.
    About the synopsis, it wasn’t that clear to me in some parts, and I would have liked to see more explanation in the synthetic part of the paper rather than the introduction. Although it’s always important to have some background information. I don’t think I got the idea of the picture…

  4. In this week’s other paper, Poisson and coworkers developed a method for the preparation of a variety of substituted (cis and trans) cyclobutanone derivatives. The monochlorocyclobutanone intermediate was highly reactive, but they managed to make it stable by modifying certain aspects of the synthesis. Finally, cyclobut-G was synthetized with the help of the chiral auxiliary (S-Stericol).

    About the paper, I had some trouble with the reading as I’m not use to reading articles that talk about synthesis. However, it did me good, because I had to look up those things I was having particular trouble with; then I completely understood the paper.
    Gopal’s synopsis was good, as it covered the important aspects of the paper. I thought the picture was a little plain for my taste, but I got the message.

  5. The synthesis of cyclobutane rings have always been interesting due to their nature. They have an extremely high ring strain and thus, they are attractive intermediates for the synthesis of many other compounds. The Poisson Group has developed a novel synthetic method for the synthesis of substituted cyclobutanones. They start by preparing a model alkene and testing a variety of conditions for the formation of the cyclobutanone. A nice one pot procedure was found and applied to the synthesis of a variety of cyclobutanones with interesting functionalities, good yields and with enantiomeric purity. Finally to demonstrate the synthetic potential of these products by synthesizing cyclobut-G.

    This is a really nice article that avoids the use of [2+2] photocycloadditons. The rationale behind every step, every reaction and failure was appropriately addressed. I found Gopal’s synopsis lacking in depth, specially when talking about the procedures. He could have been more descriptive of the methodology used and actually tell the story that the article conveys. I don’t think his figure represents the article well. I would have tried a flowchart of some sort. There is definitely room to improvise. The cyclobut-G derivative looks interesting enough… they should add some salt…

  6. Poisson and coworkers describe a stereoselective approach for the synthesis of a chiral cis- and trans-disubstituted cyclobutanones. They explain that the importance of four membered carbocycles in synthesis is because of the energy in their strain. The most common reactions involving these type of compound are the [2+2] cycloadditions, nucleophilic substitutions etc. However, they wanted to create a more efficient method for the synthesis involving enantionselection. The synthesis involved a [2+2] cycloaddition and decholorination procedure. The authors state that dechlorination can be accomplished with several reducing agents, but side reactions were a concern because of the alkoxyl group (C3 group) that can undergo through an acid reaction or an elimination. NH4Cl was used to solve this problem after the cycloaddition. The alkoxyl plays an important role in obtaining the cis or trans product. The compound synthesized eased the synthesis a a new guanosine derivative with anti HIV properties.
    It is interesting to read a synthetic paper because you find out all the work that is need for the synthesis of a compound. A synthetic chemist must always have several alternatives to obtain the final product. If one synthetic route doesn’t work you must try another one to see if it works, if it’s easier and if it’s more efficient.
    The blogger does a good job in introducing the importance of the synthesis done and he also brought past work. On the other hand, I would have liked to see a short summary of the main results of the article. The picture is representing the synthesis and the different routes, I think that is what it means.

  7. Biologically active natural products usually have very peculiar and/or tricky skeletons. Therefore its synthesis is limited by the accessibility of highly efficient methodologies with the potential for their application as large-scale syntheses. Considering that there are various natural products containing a cyclobutane as part of their skeleton it is necessary to develop diverse methods for the synthesis of chiral cyclobutane derivatives. Particularly in this week’s article Poisson and colleagues reported on the stereoselective synthesis of cis- and trans-disubstituted cyclobutanones from a family of alkyl- and functionalized alkyl-substituted enol ethers. I think that the family of enol ethers synthesized included diverse examples which can lead us to a good discussion on the limitations and advantages of their methodology which include first the dechlorination step and the eventual cyclobutanone formation. I particularly like the discussion about the optimization of their dechlorination conditions and that the authors shortly discuss their observations about the monochlorination reaction. Also, because the authors elaborate on the discussion regarding the enol ethers bearing a protected hydroxyl group. It was helpful that the authors include a figure showing a potential Bellus-Claissen rearrangement since this promote a better understanding of their discussion about this possible pathway . And last but not least… it was exciting to see how they incorporate a chiral cyclobotanone on the synthesis of Cyclobut-G which is biologically active.
    In general the article has overall good readability complimented with very appropriate figures and good detailed descriptions for their synthethic methodology which is essential in this type of articles. The beginning of the narrative helps to put in perspective the relevance of the results described in this article and in Gopal’s synopsis he also incorporate some interesting details about the biological activity of Cyclobut-G. His synopsis in general was good, he described the main strategy of the article but I think he could have expand on some details for example a bit about the enol ethers bearing a protected hydroxyl group and in his evaluation of the library of examples evaluated, where those appropriate?, what other example(s) the authors could have tested? Regarding the figure I consider that it highlights going from SM up to Cyclobut-G through a cyclobutane intermediate but the airplanes confuse me a little bit.

  8. Poisson et was work on the stereoselectivity synthesis of chiral cis- and trans cyclobuttanones via a 2+2 cycloadition and decholorinaton. It is a very straightforward article with a general good discussion of results and explaining conditions of the reactions with the rational of why doing it like that in the first place. Got to say it was easy to follow, sometimes synthesis papers can get crowded with acronyms.
    About Gopal’s synopsis I think it drifted off a bit from the main point of the paper yet maintains it a bit interesting.

  9. Poisson and his group present an alternative to reactions such as [2+2] Cycloaddition reactions when synthetizing chiral cis and trans disubstituted cyclobutanones. They propose the use of four membered rings in synthesis because of their versatility. They later proved the use of this approach in the synthesis of a guanosine derivative compound that is relevant due to its applications in HIV treatment.

    I like the paper, the narrative was pretty good and we rarely get to read articles that are more focused on synthesis. I thought it was a very complete article. As for Gopal’s synopsis, I thought maybe he could’ve focused less on the introduction and more on the actual aspects of the whole procedure. And the picture, it does convey kind of the main Idea of the paper, although it was a little confusing to me at first.

  10. This article is an unusual one, it makes me remember the times of undergraduate research and the beginning of graduate school when this was all I was looking for in the literature. It is always good to revise the arrow pushing skills. In this article a bioactive Guanine (G) analogue is synthesis. Interestingly for us, this cyclobut-G analogue is no longer acid sensitive due to the lack of anomeric carbon. The authors emphasized the simplicity and good efficiency of the presented synthetic route, they should send us a few grams of these simple to make G analogue. The synthetic schemes looks straightforward with exception of the few water sensitive reactions, starting with the trichloroacetyl chloride reagent, whose attraction for water will probably be stronger than mine. I guess I’m not in love with synthesis (only at the bench level) any more, but I do like to learn and read about it. To conclude the article, the authors mention the need to find some other application to cyclobut-G. What other possible application does it has? How interesting will be to incorporate it in a G-rich oligo DNA? I am sure we will find some additional application to it if Reek sends us a few grams of this compound.
    The blog synopsis was a good summary of the article in a very concise way keeping it both simple and interesting perhaps it looks too similar to the article. A little bit of more creativity would have being better. The links in the synopsis were very interesting but not very useful. The picture was strange but I have my ideas on what the airplane means. It means that the SM (starting material?) flies to the cyclobutanone and the cyclobutanone gets also converted to the G target as fast and easy as traveling in a airplane.

  11. I guess Reek will never send us a G analogue… It should read Poisson instead of Reek. Sorry for the confusion.

  12. Wow this is really really great!!! I was just checking for my name in prof. Rivera’s web page/pubs and saw this my old presentation article. I missed this great intellectual person, his way of thinking in science field, teaching and research approach was really good, I was not that aware of drug design and delivery, however I learnt so many things from this lab.

    Thanks for prof. Rivera, Maria and other group members

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