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	Tuesday 07th February 2012 12:35

	Wittig Reaction: The Schlosser Modification The preparation of (E)-alkenes from non-stabilised phosphorous ylides and carbonyl compounds via lithiobetaines is known as the Schlosser modification of the Wittig reaction. This reaction is a one-pot synthesis named after Manfred Schlosser (a former PhD student of Georg Wittig) who first reported the strategy in 1966. This is a modification of the Wittig reaction, and requires an understanding of the classic reaction to appreciate the benefits and nuances.
	1. General Scheme
	Scheme S1: The Schlosser modification of the Wittig reaction
	2. Mechanism
	The Schlosser modification is a particularly elegant piece of synthetic chemistry, which overcomes the likelihood of mixed products, and in fact inverts the expected product. Under the standard Wittig reaction, non-stabilised phosphorous ylides yield the (Z)-isomer in high selectivity. Using the Schlosser modification, non-stabilised phosphorous ylides yield the (E)-isomer in high selectivity. Scheme S2 should be familiar from the classical Wittig reaction. The Schlosser modification cannot alter the rates of formation of the oxaphosphetane, and so the cis oxaphosphetane dominates.
	Scheme S2: Formation of the oxaphosphetane
	The addition of the lithium halide prevents the oxaphosphetane from undergoing the normal Wittig reaction by the ionic binding to the oxygen (cleaving the phosphorous-oxygen bond) to form a lithiobetaine. At this point, there is a large excess of the cis- form of the reagents (which lead to the (Z) isomer) vs. the trans form (leading to the (E)-isomer). However, the addition of phenyl lithium as a base removes an acidic hydrogen from the carbon attached to the phosphorous, which allows bond rotation to occur. As a result, the ß-oxido phosphorous ylides interconvert between the trans and cis. This equilibrium is heavily weighted towards the trans product as it is not sterically hindered as the cis ylide is (the trans isomer is thermodynamically favourable).
	Scheme S3: Formation of ß-oxido phosphorous ylides.
	The trans ß-oxido P ylide is then taken back to the oxaphosphetane (an acid is used to protonate the carbon attached to the phosphorous, which renders the trans lithiobetaine. Removal of the lithium attached to the oxygen allows the Wittig reaction to proceed as normal, via the trans betaine and trans oxaphosphetane to give the pure (E)-alkene.
	Scheme S4: Conversion from ß-oxido phosphorous ylide to (E)-alkene.
	3. Control / Isomerism
	Using the Schlosser modification of the Wittig reaction, non-stabilised phosphorous ylides yield the (E)-isomer in high selectivity due to the equilibrium between the cis- and trans- ß-oxido phosphorous ylide largely favouring the trans isomer.

	4. Reaction Notes
	The Schlosser modification allows almost exclusive (E)-selectivity in conditions which normally give high (Z)-selectivity. The reaction with phenyl lithium to form the the ß-oxido P ylide needs to be conducted at low temperature so as to be only capable of removing the acidic proton at the carbon on the C-P bond, otherwise it can remove other hydrogens.
	5. Further Reading
	Kürti and Czakó; Strategic Applications of Named Reactions in Organic Synthesis. 1st edn., 488-489. (Elsevier Academic Press, 2005) Schlosser, M., Christmann, K.F., Angew. Chem., Int. Ed. Engl. 1966, 5, 126 Schlosser, M., Christmann, K.F., Liebigs Ann. Chem. 1967, 708, 1-35

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