Wittig intermediates, stereochemical

V. Boundary Conditions for Stereochemical Equilibration of Wittig Intermediates... 

V. BOUNDARY CONDITIONS FOR STEREOCHEMICAL EQUILIBRATION OF WITTIG INTERMEDIATES... 

Several puzzling entries in Table 14 remain to be explained, including reactions where hydroxylic solvents or alkoxide bases are used (entries 11-14). Betaine reversal was demonstrated under hydroxylic conditions in the original Trippet-Jones experiment (Scheme 4) (13), and it is conceivable that interconversion between oxaphosphetanes and betaines could be fast enough in hydroxylic solvents to allow significant betaine reversal to the ylide and aldehyde in some cases. However, there is no clear evidence to implicate stereochemical equilibration of benzylide-derived Wittig intermediates in ether solvents. 

The stereochemical outcome of the Wittig reaction can depend on the presence or absence of lithium salts. This may be due to a betaine intermediate stabilized by lithium cation. A stable adduct of this type has now been observed during a Wittig reaction. When Ph3P=CH2 is treated with 2,2 -dipyridyl ketone, P NMR shows the formation of an oxaphosphetane (72) and addition of lithium bromide gives the chelation-stabilized betaine lithium adduct (73). 

Beware of thinking that the occurrence of the lithiobetaines A and B must have stereochemical implications. Until fairly recently, lithium /ree betaines were incorrectly considered intermediates in the Wittig reaction. Today, it is known that lithima-containing betaines are formed in a dead-end side reaction. They must revert back to an oxaphosphetane—which occurs with retention of the configuration—before the actual Wittig reaction can continue. 

These two versions of the HWE are close to stereochemical control the formation of either isomer (E or Z) at will from (more or less) the same starting materials. The next two reactions achieve this aim. By purification of Wittig-type intermediates the stereospecific elimination gives a single isomer of the alkene. 

The reduction of a-phosphorus-substituted ketones of the general form 7 has also been quite thoroughly researched (Table 7 84i -84s. The product alcohols arc intermediates in Horner -Wittig type alkene syntheses, and can be induced to undergo stcreospecific syn elimination on conversion to the corresponding sodium or potassium (but not lithium) alkoxides. It is often possible to purify the alcohols by crystallization, allowing the synthesis of stereochemically homogeneous alkencs. 

Methods A, D, and E suffer from the inherent limitation that they deliberately generate a betaine as the precursor of the oxaphosphetane. Since there is no assurance that the reaction of an ylide with an aldehyde would involve the same ionic intermediate (19,21) these control experiments may provide opportunities for stereochemical equilibration that may not be available to the corresponding Wittig reactions. If the oxaphosphetane generated by methods A or E is stable enough to observe directly, then it is usually possible to distinguish between oxaphosphetane equilibration, betaine equilibration, and other mechanisms for loss of stereochemistry (21 c). However, this is not possible for oxaphosphetanes that contain unsaturated substituents at Cj because oxaphosphetane decomposition is fast at — 78°C (21c). In these examples, method A (like method D or E) can only establish an upper limit for equilibration of all of the conceivable intermediates betaines, betaine lithium halide adducts, oxaphosphetanes, and so on. 

Tables 6 and 7 summarize results from stereochemical equilibration studies performed over the past decade by MaryanofT et al. (22,23), and Vedejs et al. (20, 21c, 39-42). A few other convincing examples are included to expand the scope of the systems covered. Table 6 lists those examples where control experiments establish at least 90% retention of stereochemistry from intermediates-to alkene products. As already discussed, the percentage of equilibration represents the upper limit for loss of stereochemistry from all possible pathways in the control experiments. No attempt has been made to determine whether the minor levels of stereochemical leakage in Table 6 occur at the stage of oxaphosphetanes, betaines, or other potential intermediates. Table 6 includes entries corresponding to all of the principal families of Wittig reagents nonstabilized ylides (entries 1-12, 24, 25, 29, and 30), benzylic ylides (entries 13-17 and 28), allylic ylides (entries 22, 23, 26, and 27), and ester-stabilized ylides (entries 18-21). The corresponding Wittig reactions must take place under dominant kinetic control.

There are also some examples where significant reversal and stereochemical equilibration of intermediates has been demonstrated in aldehyde Wittig reactions (Table 7, subset 1). Several additional examples of reversal from betaine generation experiments may also be relevant, depending on whether the same betaines play any role in the Wittig process (Table 7, subset 2). The following generalizations follow from the comparison of Tables 6 and 7. 

To summarize the material presented so far, there are four distinct, but mechanistically interrelated pathways for the stereochemical modification of Wittig reaction intermediates ... 

If ET intermediates play any role in representative aldehyde or ketone Wittig reactions, they are too short-lived for detection by the fastest available radical or radical anion clocks. This is conceivable if the geometry of the radical ion pair resembles that of an oxaphosphetane with partially developed bonds (223c). Such a scenario fits within the broad definition of a four-center mechanism and allows little (if any) distinction between the geometry of stereochemistry-determining TS that invoke ET versus those that do not. More precise distinctions may have theoretical significance, but they will not influence the stereochemical issues that are of concern in this review. 

The intermediacy of the betaines used in the mechanistic discussions of the Wittig reaction has been questioned and Vedejs has proposed an alternative explanation. The Wittig reaction is subject to solvent effects that indicate a nonpolar transition state for stabilized ylids.There appears to be no direct evidence for the presence of betaines, and none have been isolated. Alternatively, Vedejs and Snoble detected oxaphosphetanes as the only observable intermediates in several Wittig reactions of nonstabilized ylids, using 3Ip NMR. In more recent work, Vedejs devised a test for the betaine mechanism based on changes in phosphorus stereochemistry in the proposed intermediates (betaine vs. oxaphosphetane). The results of this test suggested that "the conventional betaine mechanism l can play at most a minor role in the Wittig reaction".Vedejs points out that the "stereochemical test does not necessarily disprove mechanisms via intermediates with lifetimes that are short compared to the time scale of bond rotation. "494... 

The synthesis of these isomers was guided by a strategy of using only stereochemically pure phosphonium salts and polyene aldehydes as intermediates. To show the importance of various chromatographic and spectroscopic methods for the analysis of such intermediates, the preparation of the (7Z)-isomer of lycopene (31), is briefly considered in Scheme 5. This isomer is a major component of the mixture of (all- )-, (7Z)- and (7Z,7 Z)-lycopene formed in the Wittig reaction of geranyltriphenylphosphonium bromide with crocetindialdehyde [10] in the presence of NaOMe in dichloromethane [18]. 

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