Alkenes synthetic utility

On the whole, the cycloaddition of alkynes to nitrile N-oxides is one of the most important routes to isoxazoles, but in spite of its potentially wide application, its synthetic utility is less than that of the corresponding reaction with alkenes for the following reasons. (1)... 

The synthetic utility of the alkene metathesis reaction may in some cases be limited because of the formation of a mixture of products. The steps of the catalytic cycle are equilibrium processes, with the yields being determined by the thermodynamic equilibrium. The metathesis process generally tends to give complex mixtures of products. For example, pent-2-ene 8 disproportionates to give, at equilibrium, a statistical mixture of but-2-enes, pent-2-enes and hex-3-enes ... 

The blue solutions have been found to catalyse alkene isomerization and hydrogenation and have very considerable synthetic utility (Figure 1.8). 

The catalytic enantioselective addition of vinylmetals to activated alkenes is a potentially versatile but undeveloped class of transformations. Compared to processes with arylmetals and, particularly alkylmetals, processes with the corresponding vinylic reagents are of higher synthetic utility but remain scarce, and the relatively few reported examples are Rh-catalysed conjugate additions. In this context, Hoveyda et al. reported very recently an efficient method for catalytic asymmetric allylic alkylations with vinylaluminum reagents that were prepared and used in Thus, stereoselective reactions... 

Cycloadditions of ketenes and alkenes have synthetic utility for the preparation of cyclobutanones.163 The stereoselectivity of ketene-alkene cycloaddition can be analyzed in terms of the Woodward-Hoffmann rules.164 To be an allowed process, the [2ir + 2-tt] cycloaddition must be suprafacial in one component and antarafacial in the other. An alternative description of the TS is a 2irs + (2tts + 2tts) addition.165 Figure 6.13 illustrates these combinations. Note that both representations predict formation of the d.v-substituted cyclobutanone. 

There are, however, serious problems that must be overcome in the application of this reaction to synthesis. The product is a new carbocation that can react further. Repetitive addition to alkene molecules leads to polymerization. Indeed, this is the mechanism of acid-catalyzed polymerization of alkenes. There is also the possibility of rearrangement. A key requirement for adapting the reaction of carbocations with alkenes to the synthesis of small molecules is control of the reactivity of the newly formed carbocation intermediate. Synthetically useful carbocation-alkene reactions require a suitable termination step. We have already encountered one successful strategy in the reaction of alkenyl and allylic silanes and stannanes with electrophilic carbon (see Chapter 9). In those reactions, the silyl or stannyl substituent is eliminated and a stable alkene is formed. The increased reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions because the reactants are more nucleophilic than the product alkenes. 

The use of Lewis acid catalysts greatly expands the synthetic utility of the carbonyl-ene reaction. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3.35 Sc(03SCF3)3 has also been used to catalyze carbonyl-ene reactions.36... 

Where the nucleophile attacking the substituted alkene is a carbanion (cf. p. 284) the process is referred to as a Michael reaction its particular synthetic utility resides in its being a general method of carbon-carbon bond formation e.g. with (91) ... 

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

Retro-Diels-Alder reactions can be used to regenerate dienes or alkenes from Diels-Alder protected cyclohexene derivatives under pyrolytic conditions144. Most of the synthetic utility of this reaction comes from releasing the alkene by diene-deprotection. However, tetralin undergoes cycloreversion via the retro-Diels-Alder pathway to generate o-quinodimethane under laser photolysis (equation 89)145. A precursor of lysergic acid has been obtained by deprotection of the conjugated double bond and intramolecular Diels Alder reaction (equation 90)146. 

In the second instance, two approaches seem to be worthy of special note. The synthetic utility of elemental phosphorus based on it acting as a radical trap appears to be quite valuable, but additional effort is required to determine the variability of the source of the organic free radicals. (Is there some other, more efficacious, source of organic free radicals that works better with this system than acylated iV-hydroxy-2-pyridones ) The other approach that appears ripe for development is the hydrolysis/elimination with "phosphorates" derived from the oxidative addition of white phosphorus to alkenes. We look forward to the continued development of such facile approaches toward the preparation of fundamental phosphonic acids. 

Metal-catalyzed C-H bond formation through isomerization, especially asymmetric variant of that, is highly useful in organic synthesis. The most successful example is no doubt the enantioselective isomerization of allylamines catalyzed by Rh(i)/TolBINAP complex, which was applied to the industrial synthesis of (—)-menthol. A highly enantioselective isomerization of allylic alcohols was also developed using Rh(l)/phosphaferrocene complex. Despite these successful examples, an enantioselective isomerization of unfunctionalized alkenes and metal-catalyzed isomerization of acetylenic triple bonds has not been extensively studied. Future developments of new catalysts and ligands for these reactions will enhance the synthetic utility of the metal-catalyzed isomerization reaction. 

Negishi reported the hydrogen transfer hydroalumination of alkenes with (/-Bu AKTIBA) and catalytic amounts of palladium and other late transition metal complexes.125 Although uncatalyzed hydroaluminations of alkenes with di-and trialkylalanes at elevated temperatures have long been known, their scope and limitations as well as their synthetic utility have not been extensively explored. 

While transition metal-catalyzed hydroboration is a well-established reaction, the same cannot be said for the transition metal-catalyzed hydroalumination. The synthetic utility of this reaction is only just beginning to emerge. Lautens has led the way in the use of hydroaluminations as the key step in the total synthesis of complex natural products. The synthesis of the anti-depressant sertraline130 involved the formation of the tetrahydronaphthalene core, and this is best achieved using the nickel-catalyzed hydroalumination of oxabicyclic alkenes (Table 16). 

The synthetic utility of the carbonylation of zirconacycles was further enhanced by the development of a pair of selective procedures producing either ketones or alcohols [30] and has been extensively applied to the synthesis of cyclic ketones and alcohols, most extensively by Negishi [22—27,29—33,65,87,131—134], as detailed below in Section I.4.3.3.4. The preparation of unsaturated aldehydes by carbonylation with CO is not very satisfactory. The use of isonitriles in place of CO, however, has provided a useful alternative [135], and this has been applied to the synthesis of curacin A [125]. Another interesting variation is the cyanation of alkenes [136]. Further developments and a critical comparison with carbonylation using CO will be necessary before the isonitrile reaction can become widely useful. The relevant results are shown in Scheme 1.35. 

The reaction is promoted by a variety of bases, usually in catalytic quantities only, which generate an equilibrium concentration of carbanion (92) it is reversible, and the rate-limiting step is believed to be carbon-carbon bond formation, i.e. the reaction of the carbanion (92) with the substituted alkene (91). Its general synthetic utility stems from the wide variety both of substituted alkenes and of carbanions that may be employed the most common carbanions are probably those from CHjfCOjEtlj—see below, MeCOCHjCOjEt, NCCH -COjEt, RCH2NO2, etc. Many Michael reactions involve C=C—C=0 as the substituted alkene. 

The increased reactivity of the silyl- and stannyl-substituted alkenes enhances the synthetic utility of carbocation-alkene reactions. 

However, from the outset of this field, the limitations as well as the potentials of this cycloaddition were also apparent. For instance, the efficiency of this cycloaddition in an intermolecular manner was typically low unless strained olefins were used. Moreover, the use of unsymmetrical alkenes led to a mixture of the cyclopentenone regioisomers. Synthetic utility of this reaction is considerably expanded by the emergency of the intramolecular reaction. Schore introduced the first intramolecular version forming several rings simultaneously, which is now the most popular synthetic strategy in natural product synthesis because of its conceptual and operational simplicity. Additionally, the regiochemistry is no longer the problem in this variation. 

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