Alkenes, £>selective synthesis trisubstituted

Homer-Wadsworth-Emmons reactions of ketones and aldehydes with phosphono-acetate esters, (R20)2P(=0)CH2C02R1, produce E/Z mixtures of a, /Tunsaturated esters. Use of the conventional reagent, sodium hydride, gives some selectivity. The combination of tin(II) triflate and A -cthylpipcndine enhances—and sometimes also reverses—the selectivity in most cases studied.71 Six-membered oxo-coordinated tin intermediates are proposed to control the selectivities observed. A similarly selective synthesis of trisubstituted exocyclic alkenes from cyclic ketones has been reported.72... 

Fig. 14.48. Ireland-CLaisen rearrangement of two 0-allyl-0-sityl ketene acetals. Trans-selective synthesis of disubsti-tuted and F-selective synthesis of trisubstituted alkenes.

Fig. 11.43. Claisen-Ireland rearrangement of two O-allyl-O-silyl ketene acetals. 7ran.v-sclective synthesis of disubstituted and E-selective synthesis of trisubstituted alkenes.

As noted in the discussion of ( )-selective alkene formation, Kishi has found that a-substituted aldehydes reacted with trimethylphosphonopropionate and KOBu to produce the (Z)-alkene selectively. A strongly dissociating base is critical to this approach. In addition to the examples already presented in the discussion of ( )-alkene formation, the (Z)-selective reaction has recently been applied to the synthesis of macrolide antibiotics. In this example, a trisubstituted alkene was formed and closed to the lactone (148 equation 33). In an application to diterpenoids. Piers encountered an example of how substrate-specific the alkene formation can be. With a-dimethoxyphosphonyl-y-butyrolactone (150), the reactions with simple aldehydes proceeded with very high selectivity [(Z) ( ) = 99 1]. On application of the reaction to the more complex aldehyde (149) the (Z) ( ) stereoselectivity dropped to 3 1 in 58% yield (equation 34). No selectivity was observed on reaction with benzaldehyde. Although for hindered substrates, strongly basic conditions with a dimethyl phosphonate can be a simple and effective method for the synthesis of (Z)-isomers, the reaction is not general. In 1983, Still and coworkers introduced methodology that used bis(trifluoroethyl)phosphonoesters (153) to provide a facile approach to (Z)-aIkenes (154) when reacted with aldehydes (equation 35). " ... 

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. 

Lowenthal and Masamune (44) investigated the cyclopropanation of trisubsti-tuted alkenes leading to a chrysanthemic acid synthesis. They found that ligand 50c provided poor selectivities in this case (24% de for the trans isomer). Substitution in the 5 position of the oxazolines leads to increased selectivities, with excellent results provided by the BHT ester (94 6, 94% ee), Eq. 32. This ligand proved to be applicable to other trisubstituted and several cis-disubstituted alkenes, providing the corresponding cyclopropanes in ee values of 82-95%. These authors note that catalysts generated from CuOTf, CuOf-Bu, and Cu(II) precursors (with activation) provided similar yields and enantioselectivities. 

White peach scale. Several scale sex pheromones have now been elucidated each of them possesses an asymmetric center and usually a trisubstituted alkene link within an isoprenoid framework (43). The structure of the white peach scale pheromone, R,Zb-II (Figure 8), lent itself to synthesis with another chiral starting material, namely limonene (44). Selective ozonlysis followed by workup with dimethyl sulfide-methanol provided a ketoacetal, III. Wittig methylenation followed by hydrolytic cleavage of the acetal gave a dienaldehyde, IV. Conversion of the aldehyde via the acid to an amide (45) with enantiomerically pure ot-methylbenzylamine permitted chromatographic assessment of the purity of the diene aldehyde (and the limonene). The required R-isomer of the diene aldehyde was >48% ee. 

In analogy to the Peterson alkenation, the intermediate hydroxyphosphine oxidn (269) cm be prepared by addition to epoxide derivatives (268 Scheme 36). Overall yields are high for this process, and this sequence can be applied to the synthesis of phosphonate intermediates as well. Warren has studied hydroxy-directed epoxidation. Provided the allylic phosphine oxide is trisubstituted, as is (270) in equation (6S), these oxidations proceed with good selectivity. Ring opening can then be undertaken to generate the hyth-oxyphosphine oxide. 

In Hanessian s approach to avermectin discussed in Section 3.1.11.4.1, the Julia coupling was used for the trisubstituted alkene and the diene portion of the molecule. The sulfone (439) was deprotonated with Bu"Li and the aldehyde (440) added to it to obtain a 47% yield (77% based on recovered sulfone) of -hydroxy sulfones (equation 103). The alcohol was converted to the chloride and the reductive cleavage carried out with sodium amalgam in 35% yield. The desired diene was the only detectable isomer (441). From the examples cited, it is apparent that the synthesis of ( , )-dienes by the Julia coupling is an extremely successful process, in terms of both yield and selectivity. 

In the enantioselective total synthesis of p-lactone enzyme inhibitor (-)-ebelactone A and B, I. Paterson and coworkers constructed seven stereocenters and a trisubstituted alkene plus a very sensitive p-lactone ring. The backbone of their strategy applied an aldol reaction / Ireland-Claisen rearrangement sequence and used minimal functional group manipulation. The Ireland-Claisen rearrangement was performed in the presence of an unprotected ketone moiety and set a precedent for this protocol. The diastereoselectivity was 96 4, indicating highly ( )-selective silylketene acetal formation. 

A simple example of the examination of a proposed structure through synthesis is provided in this section. In 2005, Takita12 proposed the structure of the male-produced aggregation pheromone of the stink bug Eysarcoris lewisi as the sesquisabinene alcohol, ( )-2-methyl-6-(4 -methylenebicyclo[3.1.0]hexyl)hept-2-en-l-ol (8) (Scheme 1). Mori13 synthesized (61 )-8 and (6S)-8 from the enantiomers of citronellal (10). The key steps were the intramolecular addition of an ct-keto carbene to the alkene bond (11—>12) and ( )-selective olefination of 13 to give 14. The 1H- and 13C-NMR spectra of 8 around the trisubstituted double bond at C-2 were different from those of the natural pheromone. 

The synthesis of such eight-membered rings by the nickel-catalysed dimerisation of butadienes, is used here with 2-methylbutadiene. The regio-selectivity and stereo-specificity of the hydro-boration of symmetrical 124 are as expected for a trisubstituted alkene. Conversion of the alcohol 125 into a good leaving group 126 made it reactive enough to carry out electrophilic addition on the other alkene. In aqueous solution, the final nucleophile was water and the product a mixture of diastereoisomers of the tertiary alcohol 127. 

Very recently, cross-metathesis has also been employed for the synthesis of functionalized trisubstituted alkenes.331-335 This method is, however, rather limited and, in general, poor Z/E selectivities are observed (Eq. 173). 

---