Wittig reaction nonstabilized

Retrosynthetic cleavage of the trans A8,9 disubstituted double bond in intermediate 11, the projected precursor of diketone 10, provides phosphorus ylide 12 and aldehyde 13 as potential precursors. In the forward sense, a Wittig reaction could conceivably achieve a convergent coupling of intermediates 12 and 13 with concomitant formation of the requisite trans C8-C9 olefin. Ordinarily, the union of a nonstabilized ylide, such as 12, with an aldehyde would be expected to afford an alkene with a cis geometry.8 Fortunately, however, the Schlosser modification of the Wittig reaction permits the construction of trans olefins from aldehydes and nonstabilized phosphorus ylides.9... 

Syntheses of (l )-frans-isomers were reported by Crombie [24] and Elliott [25] starting from (1 /t Wran.v-chrysanthemic acid by means of the Wittig reaction. Their method were convenient to obtain (Z)-isomer (Scheme 10, step a) but not appropriate for the synthesis of ( )-isomer because of the (Z)-selective nature of the Wittig reaction in the case of nonstabilized ylides. It was very difficult to separate the pure ( )-isomer out of the (E)- and (Z)-mixture. This problem was overcome by use of the Takai s method (Scheme 10, step b) [26]. The ( )-selectivity of the double bond was fairly high (E Z = 89 11) (Scheme 10). 

The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefms. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes f-olefins instead. 

All P ylides for Wittig reactions are obtained by deprotonation of phosphonium salts. Depending on whether one wants to prepare a nonstabilized, a semistabilized, or a stabilized ylide, certain bases are especially suitable (see Table 11.1 an unusual, i.e., base-free, generation of ylides is described in Side Note 11.1). In stereogenic Wittig reactions with aldehydes, P ylides exhibit characteristic stereoselectivities. These depend mainly on whether the ylide involved is nonstabilized, semistabilized, or stabilized. This can also be seen in Table 11.1. 

Under salt-free conditions, the cw-oxaphosphetanes formed from nonstabilized ylides can be kept from participating in the stereochemical drift and left intact until they decompose to give the alkene in the terminating step. This alkene is then a pure ci.s-isomer. In other words, salt-free Wittig reactions of nonstabilized ylides represent a stereoselective synthesis of cis-alkenes. 

A different reaction mode of lithiobetaines is used in the Schlosser variant of the Wittig reaction. Here, too, one starts from a nonstabilized ylide and works under non-salt-free conditions. However, the Schlosser variant is an olefination which gives a pure frans-alkene rather than a trans.cis mixture. The experimental procedure looks like magic at first ... 

Stereogenic Wittig reactions of nonstabilized ylides of the structure Ph3P+—CH —R2 have been studied in-depth in many instances. They give the cis-configured oxaphosphetane rapidly, with the rate constant kcis, and reversibly (Figure 9.7). On the other hand, the same nonstabilized ylide produces the /ran.v-oxaphosphetane slowly, with the rate constant ktrans, and irreversibly. The primary product of the [2+2]-cycloaddition of a nonstabilized P ylide to a substituted aldehyde is therefore a cis-oxaphosphetane. Why this is so has not been ascertained despite the numerous suggestions about details of the mechanism which have been made. 

The general representation of the classic Wittig reaction is presented in equation (21). The ( )- and (Z)-selectivity may be controlled by the choice of the type of ylide (95), the carbonyl derivative (94), the solvent and the counterion for ylide formation. As a general rule, the use of a nonstabilized ylide (95 X and Y are H or alkyl substituents and is phenyl) and salt-free conditions in a nonprotic, polar solvent favors the formation of the (Z)-alkene isomer (96) in reactions with an aldehyde. A stabilized ylide with strongly conjugating substituents such as an ester, nitrile or sulfone forms predominantly the (f -alkene. 

Mechanistic studies have been the subject of a great deal of recent work." Although at one time the Wittig reaction was thought to occur through the formation of zwitterionic betaine intermediates (100) and (101), the reaction of a nonstabilized triphenylphosphorus ylide (99) with an aldehyde forms observable (by NMR) 1,2-oxaphosphetanes (104) and (105), which eliminate to produce the alkene (102) and phosphine oxide (103) (Scheme 21). "... 

Application of the Wittig reaction of a nonstabilized ylide to the synthesis of an ( )-alkene is practically and effectively carried out by the Schlosser modification. Alternatively, the use of a trialkylphos-phonium ylide can produce high ratios of ( )-alkene." Recently, Vedejs has developed a reagent using dibenzophosphole ylides (110) to synthesize ( )-disubstituted alkenes (111) fixnn rddehydes (equation 24). The initial addition of ylide occurs at -78 C, but the intermediate oxaphosphetane must be heated to induce alkene formation. The stereoselectivity in the process is excellent, particularly for aldehydes with branched substitution a to the reacting center. Both the ethyl and butyl yli s have b n utilized. 

The reactivity and stability of phosphoranes depend on the nature of the substituents at the ylide carbanion carbon. Accordingly, the ylides used in Wittig reactions are divided into nonstabilized and stabilized ylides. 

Schlosser Modification. Almost pure tran -olefins are obtained from nonstabilized ylides by the Schlosser modification of the Wittig reaction (Wittig-Schlosser reaction). For example, treatment of the (cij )-oxaphosphetane intermediate A with n-BuLi or PhLi at -78 °C results in lithiation of the acidic proton adjacent to phosphoras to produce the P"Oxido phosphonium ylide B. Protonation of B with f-BuOH leads to the trans-1,2-disubstituted alkene C. 

Wittig reaction-Schlosser modification One-pot multistep preparation of (E)-alkenes from "nonstabilized" phosphorous ylides and carbonyl compounds by the equilibration of the intermediate lithiobetaines. 488... 

Figure 1. Proposed mechanistic model for the Wittig reaction of nonstabilized and semistabilized ylides with aldehydes in the presence of soluble metal ions. Formation of the metallated betaines represents the step that determines the stereocontrol of the reaction.

In more complex systems the nonstabilized Wittig reaction tends to be less reliable in obtaining exclusively cis double bonds. This may be seen in the Merck Frosst LTB4 synthesis (Scheme 2.6), where as much as 20% trans compound is obtained, which must be separated by HPLC. 

Finally, a most dramatic example of the subtle requirements of the Wittig reaction is seen in the Merck Frosst (5S,12S)-diHETE (LTB ) synthesis (Scheme 2.8). ° Not only does a nonstabilized Wittig not give a predominance of cis olefin, but the (5/ )-substrate 21 produces a 3 2 transl cis ratio, while (5S)-22 affords a 19 1 transl cis selectivity. This remote change in stereochemistry is sufficient to completely alter the course of the reaction. 

Conia7 recommends this base as a substitute for the usually employed phenyllith-ium or n-butyllithium for preparation of nonstabilized phosphonium ylides. The base is soluble in various organic solvents and the /-amyl alcohol formed apparently improves the yields in the Wittig reaction. 

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