Month: April 2012

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.