Oxaphosphetanes formation

The preferential formation of ( )-alkene on Wittig reaction of phenyl 3-pyridyl ketones (bearing an oxazole carboxamide group at the / -position of the phenyl ring) with Ph3P=CH(CH2)4C02 K+ has been attributed to interaction between the amide (rather than oxazole) moiety and the carboxyl terminus during oxaphosphetane formation. ... 

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. 

Protic solvents or the addition of proton-active compounds after oxaphosphetane formation shift the stereoselectivity of the reaction in the direction of the ( )-form. If the Wittig reaction is carried out in C2HsOD or if the oxaphosphetane solution, prepared at —75 °C in an aprotic solvent, is treated with deuterated ethanol, then deuterium is incorporated in high yield into the ( )-olefm formed, and the degree of deuterium labelling of the coexisting (Z)-olefin is lower. On the basis of these findings the mechanism discussed below has been established (Scheme 5). 

The [2+2]-cycloaddition between P ylides and carbonyl compounds to give oxaphosphetanes can be stereogenic. It is stereogenic when the carbanionic C atom of the ylide bears—besides the P atom—two different substituents and when this holds true for the carbonyl group, too. The most important stereogenic oxaphosphetane formations of this type start from monosubstituted ylides Ph3P+—CH—X and from substituted aldehydes R—CH=0 rather than formaldehyde. We will therefore study this case in Figure 9.7. 

Schlosser modification of Wittig reaction The presence of soluble metal salts such as lithium salts decreases the aVfrans-selectivity. The normal Wittig reaction of non-stabilized ylides with aldehydes gives Z-alkenes. The Schlosser modification of the Wittig reaction of non-stabilized ylides furnishes -alkenes. In the presence of lithium halides oxaphosphetanes can often be observed, but betaine-lithium halide adducts are also formed. If lithium salts are added to the equilibrium, oxaphosphetane formation and elimination of... 

Figure 2 illustrates several reaction coordinate diagrams that allow exothermic oxaphosphetane formation. Option a (four-center process) and the kinetically equivalent b (transient betaine precursor of the oxaphosphetane two-step mechanism) are consistent with the observation that oxaphosphetanes are formed rapidly and decompose slowly when R = alkyl. Since the barrier AGjJgc decomposition to the alkene is smaller than AGJ y, there will be little reversal or loss of stereochemistry in option a. Reversal should become less likely if the a-substituent R is unsaturated (CH=CH2 or aryl), a situation that would decrease AG g by weakening the P—Cj bond (reaction profile c). If substituents are present that retard the rate of decomposition relative to reversal (as in options d or e), then oxaphosphetane reversal and equilibration of stereochemistry become possible, as discussed in a later section. However, this behavior has not been demonstrated for members of the Ph3P=CHR ylide family in the absence of lithium salts. 

Schlosser et al. found that the ElZ) selectivity can be controlled by manipulating the solvent and the concentration of salt and rationalized his observations in terms of a betaine intermediate. Betaine 535 can react with unreacted n-butyllithium to form a dilithio species (536), which rapidly establishes an equilibrium with 537.488 If lithium salts are added to this equilibrium, oxaphosphetane formation and elimination from the kinetic syn betaine 535 is inhibited. Further addition of excess butyllithium leads to 536 and 537. This equilibrium favors the anti species 537. Protonation leads to betaine 539 (or the potassium salt, 538) and thereby to an oxaphosphetane which collapses to the anti aUcene. This study suggests that excess base and excess salt promotes equilibration and formation of the anti (E) alkene. 

The detection of oxaphosphetanes as relatively stable Wittig intermediates led to revision of the reaction mechanism theory. An asynchronous cycloaddition between ylide and carbonyl component was proposed for the oxaphosphetane formation a transition state resembling the starting material in the case of reactive ylides and a transition state resembling oxaphosphetane in the case of moderate and stable ylides can explain the different (E/Z)-selectivities of the different ylide types [44]. 

In addition to the ionic mechanism [45], a diradical [46-48] or a single-electron-transfer mechanism [49-50] for the oxaphosphetane formation have also been discussed. 

The fZj-selectivity has been attributed to be due to a propeller-like conformation of the stationary phenyl groups which, in the transition state, favours cw-oxaphosphetane formation [51]. Introducing 6>rr/io-substituents in the phenyl groups increases the steric pressure in the transition state and thus the fZj-selectivity. However, the sterically less restricting tris-furyl substituted phosphorus ylides also lead to high fZj-selectivities (see Section C.2.a) obviously, in addition to purely steric effects, polarity effects are also important. 

Extensive research has also been carried out to determine whether oxaphosphetanes are formed irreversibly or can decompose via a retro-Wiiiig reaction to form ylide and carbonyl component or can equilibrate via heterolytic P-C bond cleavage [5,52]. Although oxaphosphetanes undergo ring opening in the presence of Li salts to form betaine adducts [40], the reversibility of oxaphosphetane formation from reactive ylides and aliphatic aldehydes, under salt-free conditions, must be excluded. 

Addition of the nucleophilic ylide to the carbonyl group is followed by oxaphosphetane formation. Elimination of PhjP = 0 (very stable P = 0 bond) then gives the alkene product, which in this case is an enol ether. 

The mechanism of the Horner-Wadsworth-Emmons reaction of the lithium enolate derived from trimethyl phosphonoacetate with acetaldehyde has been investigated by ab initio calculations. Oxaphosphetane formation is rate determining, both in the gas phase and with one ether moleeule solvating. The transition state leading to trans-alkene is more stable than that giving the cis form. 

Ab initio calculations (RHF/6-31 -1- G ) have revealed that the Horner-Wadsworth-Emmons reaction of (Me0)2P0CHLiC02Me with ethanal occurs by carbonyl addition, rate-determining (in the gas phase or in the presence of one molecule of Mc20) oxaphosphetane formation, pseudorotation, P—C bond cleavage, and then O-C bond cleavage. The observed preference for rranx-relative to cts-alkene formation is consistent with the predicted transition-state stabilities. 

It is now accepted that the oxaphosphetane intermediate is formed directly by a [2-1-2] cycloaddition of the phosphonium ylide with the aldehyde (or ketone) through a four-center transition state, in which the formation of the carbon-carbon bond is more advanced than that of the phosphorus-oxygen bond (Scheme 2, Path b). Although there are some exceptions [25, 26], the oxaphosphetane formation step is generally nonreversible [27, 28] and decides the stereoselectivity. 

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