Alkenes trisubstituted alkene reduction

NaH in the presence of r-butoxide and Ni acetate reduces mono- and di-substituted alkenes. Trisubstituted alkenes do not react. 1-Alkynes are reduced to mixtures of cis- and rranr-alkenes, which undergo competitive, further reduction to alkanes. MgH2, in the presence of Cu iodide or f-butoxide in THF at -78 C, reduces 1-alkynes to 1-alkenes, which are stable toward further reduction. Disubstituted acetylenes are cleanly reduced to ds-alkenes. ... 

Based on information accrued during the stereochemical elucidation, macrolactone 85 was identified as a viable synthetic intermediate (Scheme 12). The authors were cognizant of the potential challenges that could arise. First, the required formation of a trisubstituted alkene in a projected Horner-Emmons macrocyclization was without strong precedent. Also, this strategy would necessitate a stereoselective reduction of the Cl5 ketone, which was predicted to be feasible based on MM2 calculations. 

Exceptions to the generally facile ionic hydrogenation of trisubstituted alkenes include the resistance of both 2-methyl-1-nitropropene (R = NO2) and 3,3-dimeth-ylacrylic acid (R = CO2H) to the action of a mixture of triethylsilane and excess trifluoroacetic acid at 50° (Eq. 85).234 The failure to undergo reduction is clearly related to the unfavorable effects caused by the electron-withdrawing substituents on the energies of the required carbocation intermediates. 

Carbon-carbon double bonds alkene to alkane reductions, trisubstituted alkenes, 40 ketone-alcohol reduction, 77, 86-87 a,p-unsaturated ester reduction, 93-96 Carbonyl compounds ... 

Dicyclohexyl ether [Brpnsted acid promoted ketone reduction, symmetrical ether], 123 Diels-Alder cycloaddition-cycloreversion pathway, alkene to alkane reductions, trisubstituted alkenes, 39-40 3,5-Dimethyl-1 -cyclohexen-1 -yl... 

Further variations on the epoxyketone intermediate theme have been reported. In the first (Scheme 9A) [78], limonene oxide was prepared by Sharpless asymmetric epoxidation of commercial (S)-(-)- perillyl alcohol 65 followed by conversion of the alcohol 66 to the crystalline mesylate, recrystallization to remove stereoisomeric impurities, and reduction with LiAlH4 to give (-)-limonene oxide 59. This was converted to the key epoxyketone 60 by phase transfer catalyzed permanganate oxidation. Control of the trisubstituted alkene stereochemistry was achieved by reaction of the ketone with the anion from (4-methyl-3-pentenyl)diphenylphosphine oxide, yielding the isolable erythro adduct 67, and the trisubstituted E-alkene 52a from spontaneous elimination by the threo adduct. Treatment of the erythro adduct with NaH in DMF resulted... 

Scheme 9 that both the molybdenum and iron complexes can catalyze the allylic amination of nonfunctionalized alkenes with an ene-like transposition of the double bond, but also that the yield of the allyl amine formed, 113, is moderate to high. It is generally found that higher substituted alkenes tend to give the best yields, and un-symmetrical alkenes (trisubstituted) react with virtually complete regioselectivity, as only one isomer is detected. The byproducts are primarily azoxybenzene and aniline, which arise from condensation of nitrosobenzene with phenyl hydroxylamine and reduction of phenyl hydroxylamine, respectively. 

Figure 12.32 shows the second commonly employed method for the generation of dichloroketene, which involves the reductive / -elimination of chlorine from trichloroacetyl chloride by zinc (cf. Sections 4.7.1 and 14.4.1 for mechanistic considerations). The addition of the dichloroketene to the trisubstituted alkene A (Figure 12.32) exhibits ori-... 

The use of NaBH4 as the hydride source appears to have been employed only with Co chloride. Mono- and di-substituted alkenes readily undergo reduction, with dr-alkenes undergoing reduction faster than rranr-alkenes. Trisubstituted alkenes react extremely slowly, while tetrasubstituted alkenes apparently do not undergo reduction. 

The second reduction starts in the same way, though without the preliminary acylation, but — product is a simple enamine and lone pair electrons on nitrogen are now available for protona - j in enamine style. A second reduction can then occur. Notice that the ethyl group keeps the alker itself the weak a conjugation makes a trisubstituted alkene more stable than the disubsti . arf alternatives. The mysterious but necessary weak acid HX could be solvent (EtOH) or protons hvjfj the boron or from the NH. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

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. 

Julia has undertaken studies on the selective reduction of keto sulfones, followed by the trans elimination to the vinyl sulfone. These intermediates can then be reacted with Grignard reagents to produce trisubstituted alkenes. ... 

A serious obstacle to the use of the Julia alkenation for the synthesis of trisubstituted alkenes is illustrated in Scheme 31. Addition of cyclohexanone to the lithiated sulfone (86) gave intermediate (87), which could not be acylated under the reaction conditions because of the sterically hindered tertiary alk-oxide. Owing to an unfavorable equilibrium, (87) reverted back to starting materials. However, by reversing the functionality of the fragments a stable adduct (88) was formed in which the less hindered secondary alkoxide was acylated and the resultant -benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of 3-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

Little is known about the stereochemistry of trisubstituted alkene formation in the Julia alkenation. In a synthesis of milbemycin 33 Barrett and coworkersgenerated intermediate (91 equation 22) as a mixture of isomers (E Z = 5 3) by reductive elimination of a 3-acetoxy sulfone however, a similar reductive elimination on the 3-hydroxy sulfone shown in equation (23) gave a single isomer. The marked difference in the yield of these two transformations reflects the advantage of suppressing the retroaldoliza-tion reaction by acylation. 

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