Schlosser Modification
The Schlosser modification of the Wittig reaction is a variation that allows for the selective formation of E-alkenes from nonstabilized phosphorus ylides. This modification addresses the main limitation of the traditional Wittig reaction, which typically leads to the formation of Z-alkenes when nonstabilized ylides are used[1][2][3][5][7][14].
In the traditional Wittig reaction, the geometry of the resulting alkene depends on the reactivity of the ylide. Stabilized ylides, which have an electron-withdrawing group, tend to give predominantly E-alkenes, whereas non-stabilized ylides lead to Z-alkenes[4]. The Schlosser modification overcomes this limitation by converting the erythro betaine intermediate, which leads to the Z-alkene, into the threo betaine using phenyllithium at low temperatures, thus affording the E-alkene[1][7].
The mechanism of the Schlosser modification involves the use of excess lithium salts during the addition step of the ylide and subsequent deprotonation/protonation steps. Lithium salts prevent the intermediate betaines from reacting further, and these lithiobetaines, which are quite stable, may be deprotonated. The use of a sterically hindered proton donor then leads to the trans lithiobetaine, and the reaction proceeds to form the E-alkene[2][3].
An example of the use of the Schlosser modification is in the synthesis of leukotriene A methyl ester. In this synthesis, a stabilized ylide is used in the first step, which unexpectedly gives mainly the cis product. The second Wittig reaction uses a non-stabilized Wittig reagent, and as expected, this gives mainly the cis product[1].
The Schlosser modification is particularly useful when the E-alkene is the desired product, and it has been applied in various synthetic strategies, including the synthesis of trisubstituted E-alkenyl bromides and iodides[2]. It is also noted that the reaction takes a "normal" course if lithium is exchanged by potassium[2].
In summary, the Schlosser modification is a valuable tool in organic synthesis for the selective formation of E-alkenes from nonstabilized ylides, expanding the versatility of the Wittig reaction.
Citations:
[1] https://en.wikipedia.org/wiki/Wittig_reaction
[2] https://www.organic-chemistry.org/namedreactions/schlosser-modification.shtm
[3] https://www.sciencedirect.com/topics/chemistry/schlosser-modification
[4] https://www.organic-chemistry.org/namedreactions/wittig-reaction.shtm
[5] https://link.springer.com/chapter/10.1007/978-3-662-04835-1_252
[6] http://orgsyn.org/demo.aspx?prep=v97p0217
[7] https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_%28Organic_Chemistry%29/Reactions/Organic_Reactions/Wittig_Reaction
[8] https://hwpi.harvard.edu/files/myers/files/19-stereoselective_olefination_reactions.pdf
[9] http://ccc.chem.pitt.edu/wipf/Courses/2320_07_files/Wittig_Reaction.pdf
[10] https://byjus.com/chemistry/wittig-reaction/
[11] https://www.youtube.com/watch?v=oBCT7KiSyUs
[12] https://www.thermofisher.com/io/en/home/chemicals/learning-center/organic-chemistry-resources/carbonyl-compound-reactions/wittig-reaction.html
[13] https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/slct.202002192
[14] https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_%28Organic_Chemistry%29/Alkenes/Synthesis_of_Alkenes/Alkenes_from_Aldehydes_and_Ketones_-_Wittig_Reaction
[15] http://www.orgsyn.org/Content/pdfs/procedures/v97p0217.pdf
[16] https://www.youtube.com/watch?v=IiuOa1pWQCg
[17] https://www.chemie-brunschwig.ch/documents/suppliers-information/Thermofisher/named-reactions-organic-synthesis-ebook-v16.08.pdf