Stereospecific oxaphosphetane

Single alkene diastereomers are accessible through a Wittig-Homer reaction only if it is performed in two steps (Figure 11.10). A 1 1 mixture of the phosphorylated lithium alkoxides syn- and anti-D is still formed but if the mixture is protonated at this point, the resulting phosphorylated alcohol diastereomers C can usually be separated without difficulty. The suitable diastereomer will be deprotonated with potassium-ferf-butoxide in the second step and then be converted into the stereouniform trans- or cis-alkene E via stereospecific oxaphosphetane formation and fragmentation. 

Vedejs, E., Marth, C. F., Ruggeri, R. Substituent effects and the Wittig mechanism the case of stereospecific oxaphosphetane... 

To explain this phenomenon, there are two seperate processes to consider. The first and most important one for this reason is the formation of the oxaphosphetane. The addition of the ylide to the aldehyde can, in principle, produce two isomers with either a Z or E substituted double bond. The following elimination step is stereospecific, with the oxygen and phosphorus departing in a syn-periplanar transition state. With unstabilized ylides the syn diastereomer of the oxaphosphetane similar to 61 is formed preferentially. This step is kinetically controlled and therefore irreversible, and predominantly the Z-alkene 62 that results reflects this. 

We have a fairly detailed knowledge of the mechanism of the Wittig reaction (Figure 11.3). It starts with a one-step [2+2]-cycloaddition of the ylide to the aldehyde. This leads to a heterocycle called an oxaphosphetane. The oxaphosphetane decomposes in the second step—which is a one-step [2+2]-cycloreversion—to give triphenylphosphine oxide and an alkene. This decomposition takes place stereoselectively (cf. Figure 4.44) a cw-disubstituted oxaphosphetane reacts exclusively to give a cis-alkene, whereas a fraws-disubstituted oxaphosphetane gives only a trans-alkene. The reaction is stereospecific. 

The stereochemistry of the alkene product in Wittig reactions is thought to be influenced by the reversibility of formation of the isomeric threo and erythro oxaphosphetanes (or betaines) which undergo stereospecific loss of triphenyl-phosphine oxide to give the trans (E) and cis (Z) alkenes, respectively (Scheme 4). Factors that enhance the reversibility of this initial step favour the threo intermediate and hence the (E) alkene. Stabilized phosphoranes give a predominance of the (E) alkene while non-stabilized phosphoranes give the (Z) alkene. In general, stabilized phosphoranes react readily with aldehydes (see Protocol 4) while non-stabilized phosphoranes will react with aldehydes, hemiacetals (see Protocol 5) and ketones.2,3... 

Generally, oxaphosphetanes are thermodynamically unstable and fragment into alkenes and triphenylphosphine oxide. This elimination step is stereospecific with oxygen and phosphorus departing in a 5jn-periplanar mode to produce (Z)-alkenes, the driving force being formation of the very stable P = O bond (130-140 kcal/mol, 544-586 kJ/mol bond dissociation energy). 

If the syn oxaphosphetane 69 is favoured, the Z-alkene 70 must be formed. And it is The formation of the oxaphosphetane is syn selective and the elimination step is stereospecific. The selectivity varies, but with R=Alkyl it is usually quite good. Here is an example - the synthesis of the sex attractant 75 of the Gypsy moth. This is the epoxide of a long chain cis alkene Z-74 easily made by a Wittig reaction with excellent Z-selectivity.11... 

The phosphine 286 is easily alkylated to provide the Wittig intermediate 287 that eliminates in the usual stereospecific manner via the oxaphosphetane 288 and must therefore give the strained frans-cyclo-octene E-284, the smallest trans cycloalkene that is stable. It is also chiral.58... 

Oxaphosphetanes are obligatory intermediates in all known aldehyde Wittig reactions (19, 22b). If they decompose stereospecifically to alkenes, then the... 

Several tests are available to determine whether equilibration of stereochemistry occurs in the course of oxaphosphetane decomposition (methods A-E, Scheme 7), but each method has some limitations. In method A, oxaphosphetane diastereomers are prepared independently by deprotonation of the )S-hydroxyphosphonium salts 27 or 28 with base (NaHMDS, NaNHj, KO-tert-Bu, etc.) (20). If each isomer affords a distinct oxaphosphetane 31 or 32 according to NMR analysis (usually, or H), then the solutions are warmed up to the decomposition temperature. Kinetic control is established if stereospecific conversion to the alkenes can be demonstrated from each diastereomer. A less rigorous version of this test is to perform the experiment only with isomer 27, the precursor of the cis-disubstituted oxaphosphetane 31 (21c). All known examples of significant (> 5%) stereochemical equilibration involve 31 and not the trans-disubstituted isomer 32 (20, 21c). A negative equilibration result with the cis diastereomer 31 can be assumed to apply to 32 as well. 

Reversal correlates with the presence of lithium ion and also with the involvement of betaine species. These two risk factors are interrelated because lithium halides rapidly cleave oxaphosphetane 31 or 32 (Scheme 8) at — 70°C resulting in the reversible formation of the betaine lithium halide complexes 40 or 41, respectively (18b). Donor solvents shift the equilibrium toward the oxaphosphetane by coordinating the lithium halides and thereby promote stereospecific decomposition to the alkenes. If the solvent is not an effective lithium coordinating agent, then 40 and 41 decompose slowly, and the risk of... 

It is likely that the ( )-alkene selective reactions of anionic ylides are due to equlibration of the betaine lithium halide adduct as discussed earlier. However, the balance is delicate and small structural changes can have surprising consequences. Thus, Corey s stereospecific trisubstituted alkene synthesis via /3-oxido ylides (Table 10) is clearly under dominant kinetic control, even though lithium ion is present and aromatic aldehydes can be used as the substrates (54,55). The only obvious difference between the intermediates of Table 10 and oxido ylide examples such as entry 11 in Table 21 is that the latter must decompose via a disubstituted oxaphosphetane while the stereospecific reactions in Table 10 involve trisubstituted analogues. Apparently, the higher degree of oxaphosphetane substitution favors decomposition relative to equilibration. There are few easy and safe generalizations in this field. Each system must be evaluated in detail before rationales can be recommended. 

How can the Z selectivity in Wittig reactions of unstabilized ylids be explained We have a more complex situation in this reaction than we had for the other eliminations we considered because we have two separate processes to consider formation of the oxaphosphetane and decomposition of the oxaphosphetane to the alkene. The elimination step is the easier one to explain—it is stereospecific, with the oxygen and phosphorus departing in a syn-periplanar transition state. Addition of the ylid to the aldehyde can, in principle, produce two diastereo-isomers of the intermediate oxaphosphetane. Provided that this step is irreversible, then the stereospecificity of the elimination step means that the ratio of the final alkene geometrical isomers will reflect the stereoselectivity of this addition step. 

When R is not conjugating or anion-stabilizing, the syn diastereoisomer of the oxaphosphetane is formed preferentially, and the predominantly Z alkene that results reflects this. The Z-selective Wittig reaction therefore consists of a stereoselective first step, to form the syn oxaphosphetane, followed by a stereospecific elimination from this intermediate to give a Z alkene. 

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