Aldehydes Wittig olefination

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

The reaction of an alkylidene phosphorane 1 (i.e. a phosphorus ylide) with an aldehyde or ketone 2 to yield an alkene 3 (i.e. an olefin) and a phosphine oxide 4, is called the Wittig reaction or Wittig olefination reaction. ... 

Whereas the nucleophilic addition of vinylmagnesium bromide to a-alkoxy aldehydes (12, 16) proceeds with a low to moderate chelation-controlled diastereoselectivity, a remarkably high preference for the opposite stereochemical behavior is found with the jS-silyl phosphorus ylide 1477. Due to the electron-donating 4-methoxyphenyl substituents at the phosphorus atom, as well as the /i-methyldiphenylsilyl group, 14 is an excellent vinylation reagent which does not lead to any Wittig olefination products. 

In an alternative approach, the isomeric unsaturated pyrrolidine or piperidine aldoximes 245 a and 245b were prepared and subjected to lOOC reaction affording 246a and 246b, respectively (Eq. 28). Esterification of 240 followed by N-tert-BOC protection and DIBALH reduction provided aldehyde 244 (X = 0) which was subjected to Wittig olefination. Introduction of a two carbon aldoxime chain on N in 244 (X = CH2) was carried out by alkylation with Et a-bromoacetate after deprotection of the N atom in 244. Reduction and oxima-tion led to 245. 

These problems were circumvented by protecting the C(4),C(5) diol prior to Wittig olefination step (Figure 3). Thus, treatment of 10b (a mixture of pyranose and furanose anomers prepared by hydrolysis of 8 with aqueous trifluoroacetic acid) with excess EtSH and concentrated HCI (as solvent) at provided dithioacetal 9 in 50% yield, along with 25% of a mixture of thiopyranosides and thiofuranosides that was recycled to 10b in high yield by treatment with HgCIa and CaCOa in aqueous CH3CN. Finally, the diol unit was protected as a cyclohexylidene ketal, and then the thioacetal was hydrolyzed under oxidative conditions to arrive at the key aldehyde intermediate 3. 

With the fully functionalized heterocyclic core completed, synthetic attention next focused on introduction of the 3,5-dihydroxyheptanoic acid side-chain. This required initial conversion of the ethyl ester of 35 to the corresponding aldehyde through a two-step reduction/oxidation sequence. In that event, a low-temperature DIBAL reduction of 35 provided primary alcohol 36, which was then oxidized to aldehyde 37 with TRAP. Subsequent installation of the carbon backbone of the side-chain was accomplished using a Wittig olefination reaction with stabilized phosphonium ylide 38 resulting in exclusive formation of the desired -olefin 39. The synthesis of phosphonium ylide 38 will be examined in Scheme 12.5 (Konoike and Araki, 1994). 

Retrosynthetic considerations reveal an approach (Scheme 1.2.6) in the first step based on disconnections of the C -Cy and C12-C13 double bonds. Those can be built up using highly B-selective Wittig olefinations between allyltributylphos-phorous ylides derived from the corresponding allylic bromides 29 and 31 [31]. The aldehyde 30 is accessible from the keto ester 33, which can be prepared in high enantiomeric purity by a biocatalytic enantioselective reduction of a... 

Table 5.5. Wittig olefination of support-bound aldehydes and ketones.

This aldehyde intermediate was then olefinated using the Takai olefination.29 This step was also attempted using the Wittig olefination, but the basic conditions lead to retro-Michael side reactions, hence resulting in low yields. The Takai olefination avoids the use of basic conditions and produced 29 and 30 in good yields. 

The total synthesis of (+)-Macbecin I 78 [39] began with aldehyde 73, prepared via the addition of optically pure crotylsilane onto a benzylic acetal, which underwent an SMS reaction to give ester 75 in a 12 1 syn/anti ratio. Oxidative cleavage of the double bond, Wittig olefination of the resulting aldehyde and a reduction-oxidation sequence yielded a,/ -unsaturated aldehyde 76. A second SMS reaction was then performed leading to polyether 77 (dr > 20 1) that contains all the chiral centers of (+)-Macbecin I 78, Scheme 13.31. 

The primary alcohol is first oxidized to an aldehyde, which is then the substrate in a Wittig olefination reaction. Here a stabilized ylide is employed and therefore the E double bond is formed exclusively. (For a detailed description of the Wittig reaction see Chapter 13 the selectivity issues are explained in Chapter 9.)... 

The protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

The ylid character of X5-phosphorins and their Cr(C0)3 complexes again is evident when one or both groups on phosphorus are CHR2 as one can abstract a+ protpn giving a carbanion. Reaction with electrophiles (e.g. D, CH3, and RCHO) causes side chain addition. No Wittig olefination is found with aldehydes. Instead a 1(2 -hydroxy) product 9 is formed which can be dehydrated to the X5-phosphorin derivative 10. 

After successful hydroformylation one may decide to remove the catalyst-directing o-DPPB group, which may be achieved by simple alkaline hydrolysis (syn-6a—>syn-3) [10] or via hydride reduction after transferring the aldehyde e.g. to an alkene via Wittig olefination (syn-6b syn-23) [14]. 

Lactone 7 (derived from D-isoascorbic acid) reacted readily with the aryllithium formed from bromide 8 to produce lactol 9 (Scheme 16.3). The latter underwent a facile ring-opening and Wittig olefination with methylenetriphenylphosphorane to give 6 in excellent overall yield. After 0-trifLation, a two-carbon chain extension was performed on 10 with the azaenolate derived from A-cyclohexylacetaldimine 11 and lithium diisopropylamine (LDA). After acid hydrolysis of the product imine, aldehyde 12 was isolated in 83% yield for the two steps. The (2-azaallyl)stannane 5 was prepared from aldehyde 12 in quantitative yield by treatment with (aminomethyl)tri-n-butylstannane. 

Several variants of the Wittig olefination reaction have been adapted to solid phase (Fig. 8). Williard et al. [43] prepared a series of stilbenes using the Homer-Emmons reaction on resin-bound aldehydes. A route to either substituted or unsubstituted unsatu-... 

Fig. 11.4. Optimum cis-selec-tivities of Wittig olefinations of different aldehydes with nonstabilized ylides under "salt-free" conditions.

Fig. 11.7. trans-Selective Wittig olefination of aldehydes I—Preparation of a trans-configured a,j8-unsaturated ester (preparation of the starting material Figure 17.24). 

Fig. 11.8. trans-Selective Wittig olefination of aldehydes II—Synthesis of /J-carotene from a dialdehyde. The ylide used here is already known from Figure 11.2. In a way, it is "(semi)stabilized" since it is prepared in situ like a semista-bilized phosphonium ylide, but reacts as trans-selectively as a stabilized ylide. 

Ketones are never suited for use in Wittig reactions with Ph3P -CH -C(=0)H since the condensation product would be an aldehyde that would more rapidly undergo a second Wittig olefination than the residual unreacted ketone for the first time. 

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