1.2- Oxaphosphetanes synthesis

Scheme 9.1 Stereoisomeric oxaphosphetanes as NMR-detectable intermediates in the Wittig synthesis of alkenes.

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. 

On the other hand, stabilized ylides react with aldehydes almost exclusively via trans-oxaphosphetanes. Initially, a small portion of the cw-isomer may still be produced. However, all the heterocyclic material isomerizes very rapidly to the fnms-configured, four-membered ring through an especially pronounced stereochemical drift. Only after this point does the [2+2]-cycloreversion start. It leads to triphenylphosphine oxide and an acceptor-substituted fnms-configured olefin. This frara-selectivity can be used, for example, in the C2 extension of aldehydes to /ran.v-con figured aj8-unsaturated esters (Figure 9.11) or in the fnms-selective synthesis of polyenes such as /1-carotene (Figure 9.12). 

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. 

Isolable 1,2-oxaphosphetanes as starting materials for the synthesis of olefins 04MI30. 

CNDO-MO calculations suggest that the Wittig olefin synthesis proceeds via 1,2-oxaphosphetans, which undergo P—C bond cleavage considerably in advance of P—O bond cleavage. 

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... 

Ramirez has used the reaction of highly electrophilic carbonyl compounds with a variety of tervalent phosphorus compounds in a general synthesis of 1,2-oxaphosphetans [e. g. (86) ]. 

The observations summarized in Table 8 have important preparative consequences. To achieve the highest possible ( )-alkene selectivity in a system that is capable of stereochemical equilibration, it is essential to provide sufficient time for oxaphosphetane equilibration below the decomposition temperature. This is best done by monitoring the diastereomer mixture using NMR methods to establish the temperature thresholds for diastereomer equilibration as well as for alkene formation from the more reactive cis-diastereomer. Once these temperatures are known, equilibration can be allowed to proceed below the temperature for (Z)-alkene formation until the optimum ratio of trans-cis oxaphosphetanes is obtained. Subsequent warming completes the optimized E-selective alkene synthesis in an equilibrating system (Table 7). 

One other experimental result from the Corey et al. study is important for trisubstituted alkene synthesis. When 55=58 is quenched with formaldehyde, the stereochemistry of C—C bond formation remains the same as before. However, the regiochemistry of the elimination step no longer favors the second aldehyde added, and the major product is now the allylic alcohol 64 (54). This experiment suggests that both oxaphosphetanes 63 and 62 are in equilibrium with the lithium halide adduct 61a. Decomposition is controlled by the nature and degree of oxaphosphetane substitution as well as by stereochemistry. In the formaldehyde reaction, these factors combine to favor the trisubstituted alkene (via 62) over the disubstituted alkene that would be formed via 63 (R"=H). Several examples of trisubstituted alkene synthesis using Corey s method are summarized in Table 10 without further comment because the origins of stereochemistry are not understood in detail, but Corey s model 58 is consistent with the available evidence. 

It has been found that nonstabilized ylides derived from the tetrahydro-phosphole nucleus (90 or 91) afford oxaphosphetanes that decompose at room temperature. Sin( 89, the phosphonium salt precursor of 90, contains only one alkyl group, BTP ylide 90 can be recommended for E-selective alkene synthesis in cases where the alkyl substituent must be used efficiently. Since the phosphorus environment in 90 is relatively expensive, this family of reagents will not provide a practical solution for large-scale synthesis 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. 

The number of publications reporting theoretical studies and those reporting mechanistic studies have increased following the reduction in these numbers last year. One of these reports includes the isolation and separate decomposition of certain oxaphosphetanes and this has allowed the first kinetic study of the second step of the Wittig reaction, albeit for a rather special system. Complex phosphonate carbanions and ylides continue to be widely used in synthesis and the number of reports of the use of the aza-Wittig and related reactions in heterocyclic synthesis remain at last year s high level. 

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