Tetrasubstituted alkenes, synthesis

The cyclization to form very congested quaternary carbon centers involving the intramolecular insertion of di-, tri-, and tetrasubstituted alkenes is particularly useful for natural products synthesis[l36-138], In the total synthesis of gelsemine, the cyclization of 166 has been carried out, in which very severe steric hindrance is e.xpected. Interestingly, one stereoisomer 167... 

The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et al. synthesized 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts <06JHC781>. The PEG-bound pyridinium salts 53 were reacted with alkenes or alkynes in the presence of Et3N, via 1,3-dipolar cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of the heterocycle with KCN/MeOH afforded 1,2,3,7-tetrasubstituted indolizines 56 and 57 in good to excellent yield. 

Trost reported the synthesis of 1,4-dienes with ruthenium catalysis through regioselective carbometallation of alkynes with alkenes.51 Di- and trisubstituted olefins can also be obtained with arylboronic acids through an intermolecular process under rhodium,30 52 55 nickel,56 and palladium catalysis.57 Recently, Larock has reported an efficient palladium-catalyzed route for the preparation of tetrasubstituted olefins.58,59... 

The regioselectivity of palladium-catalyzed additions of organoboronic acids to unsymmetrical alkynes is strongly dependent on steric and electronic effects (Scheme 12).62 Multi-component reaction has been reported for the synthesis of tetrasubstituted alkenes.58 The aryl group from an aryl iodide is generally added to the less hindered... 

Dipolar cycloaddition. Arylthiomethyl chlorides (1) in the presence of a Lewis acid can undergo a [4 + 2]cycloaddition to a tetrasubstituted alkene. They can be prepared by reaction of thiophenol with BrCH2Cl in the presence of DBU in CH,CN. C2H5A1C12 is preferred over A1C1, SnCl4, or TiCl4 as the Lewis acid. This reaction provides a short synthesis of cuparene (2). 

Analogous chemistry has been reported with a-chlorosulfoxides, though much less studied. Initial y-dehydrochlorination yields thiirane S-oxides, but from these intermediates two alternative pathways can occur leading to sulfenales and/oi alkenes. The method was shown to be efficient for the synthesis of tetrasubstituted alkenes [417]. 

These methods were mainly used in the synthesis of crowded tetrasubstituted alkenes (in search of tetra(t-butyl)ethylene). 

Various aspects of this reaction have been summarized by Kocienski.2 It is particularly useful for synthesis of disubstituted alkenes and conjugated dienes and trienes. It fails with some trisubstituted alkenes and most tetrasubstituted. alkenes because the precursors are unstable. One advantage of this route is that rra/is-alkenes are formed preferentially or exclusively. Yields are highest when the eliminated groups can adopt a /rons-coplanar arrangement. 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

Cyanosilylation of alkynes with Me3SiCN is effectively catalyzed by a PdCl2 complex.263 Its intramolecular version is valuable for the stereo-defined synthesis of tri- and tetrasubstituted alkenes.264 A Pd-catalyzed system effects an efficient three-component coupling of Me3SiCN, highly electron-deficient alkenes, and allyl chlorides (Equation (69))/ 3 The... 

The strategy described here should find considerable use as a method for the stereoselective synthesis of alkenes. Although this olefination strategy involves one more step than the classic Wittig reaction, in many cases it may prove to be the more practical method. Finally, the scope, overall efficiency, and stereoselectivity of the 0-lactone route compares favorably to the Wittig, Julia-Lythgoe, and related established strategies for the synthesis of tri- and tetrasubstituted alkenes. 

Alkene synthesis," Diphosphorus tetraiodide [or phosphorusflll) iodide] converts di- and trisubstituted /3-hydroxy sulfides into alkenes. The reaction is conducted for 2-6 hours in refluxing methylene chloride. The reaction is regiospecific, and involves anfi-elimination of the OH and RS groups. Yields are 80-90%. Thionyl chloride is the preferred reagent for a similar reaction with tetrasubstituted )S-hydroxy sulfides. 

The carbometallation of alkynes is also unique in its stereochemical pattern, since it is executed as an exclusive cis addition. For example, the stereoisomeric purity of pheromone 104, prepared as shown, is higher than 99.9% This feature is of special importance in the synthesis of natural pheromones, as the biological activity of these compounds is dramatically affected by the presence of an even negligible amount (less than 0.5% ) of the undesirable stereoisomer. Not surprisingly, this reaction has found numerous areas of application, especially in the stereospecific synthesis of the tri- and tetrasubstituted alkenes, a goal difficult to achieve by other methods. To illustrate the effectiveness of this approach, the synthesis of faranal 105, the trail-marking pheromone of the ant species Monomoriumpharaonis, is shown in Scheme 2.33. 

The reaction is effective with electron-rich carbonyls such as trimethylsilyl esters and thioesters, as Table 20 indicates. Lactones ate substrates for alkylidenation however, hydroxy ketones are formed as side products, and yields are lower than with alkyl esters. Amides are also effective, but form the ( )-isomer predominantly. This method has been applied to the synthesis of precursors to spiroacetals (499) by Kocienski (equation 115). ° The reaction was found to be compatible with THP-protected hy- oxy groups, aromatic and branched substituents, and alkene functionality, although complex substitution leads to varying rates of reaction for alkylidenation. Kocienski and coworkers found the intramolecular reaction to be problematic. As with the CrCb chemistry, this reaction cannot be used with a disubstituted dibromoalkane to form the tetrasubstituted enol ether. Attempts were made to apply this reaction to alkene formation by reaction with aldehydes and ketones, but unfortunately the (Z) ( )-ratio of the alkenes formed is virtu ly 1 1. ... 

The reductive desulfurization of thiiranes has been accomplished with Raney nickel, Li in EtNHa, Zn in HOAc, BusSnH, and P2I4 in DMF but the reaction has seldom been applied to organic synthesis. A noteworthy procedure for preparing moderately hindered tetrasubstituted alkenes, which proceeds via a thiirane intermediate, was developed independently by Barton and Kellogg. The procedure, illustrated in Scheme 14 for the preparation of (34), involved reaction of thiocamphor (30) with diazoalkane... 

The anions of nitroalkanes (nitronates) can be used as precursors in a connective and regiospecific synthesis of tetrasubstituted alkenes. They are easily formed on reaction with LiOMe and undergo oxidative dimerization in the presence of bromine. The resultant 1,2-dinitroalkanes (Scheme 37) participate in a reductive elimination involving an rc1 radical chain mechanism when irradiated in the presence of Na2S, PhSNa or the lithium nitronate derived from 2-nitropropane. 

An alternative procedure (Scheme 38) affords a connective synthesis of unsymmetrical tetrasubstituted alkenes. In this case the lithium nitronate reacted with a 1,1-dinitroalkane to give the 1,2-dinitroalkane intermediate. Reductive elimination was effected by Ca(Hg) in DMF-HMPA. 

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