Enantioselectivity regiocontrol

The major problem remains control of regioselectivity in favor of the branched regioisomer. While aryl alkenes as well as heteroatom-substituted alkenes favor the chiral branched isomer, for aliphatic alkenes such an intrinsic element of regiocontrol is not available. As a matter of fact branched-selective and asymmetric hydroformylation of aliphatic alkenes stands as an unsolved problem. In this respect regio- and enantioselective hydroformy-... 

Palladium complexes are general and versatile catalysts for allylic amination.1,la lh The palladium-catalyzed allylic aminations of 1,3-symmetrically disubstituted substrates, including enantioselective versions, have been widely studied.1, a h It has been important to control the regioselectivity in allylic amination of unsymmetrical substrates 1 or 2 (Equation (1)). In general, palladium-catalyzed allylic amination gives the ( )-linear product 3Tla lh regiocontrol in amination has recently attracted much attention in approaches toward the branched product 4. 

Control of reaction selectivities with external reagents has been quite difficult. Unsolved problems remaining in the held of nitrile oxide cycloadditions are (a) Nitrile oxide cycloadditions to 1,2-disubstituted alkenes are sluggish, the dipoles undergoing facile dimerization to furoxans in most cases (b) the reactions of nitrile oxides with 1,2-disubstituted alkenes nonregioselective (c) stereo- and regiocontrol of this reaction by use of external reagents are not yet well developed and (d) there are few examples of catalysis by Lewis acids known, as is true for catalyzed enantioselective reactions. 

As with the Aratani catalysts, enantioselectivities for cyclopropane formation with 4 and 5 are responsive to the steric bulk of the diazo ester, are higher for the trans isomer than for the cis form, and are influenced by the absolute configuration of a chiral diazo ester (d- and 1-menthyl diazoacetate), although not to the same degree as reported for 2 in Tables 5.1 and 5.2. 1,3-Butadiene and 4-methyl- 1,3-pentadiene, whose higher reactivities for metal carbene addition result in higher product yields than do terminal alkenes, form cyclopropane products with 97% ee in reactions with d-men thy 1 diazoacetate (Eq. 5.8). Regiocontrol is complete, but diastereocontrol (trans cis selectivity) is only moderate. 

The enantioselective intramolecular C-H insertion is a very general synthetic process [1], The C-H insertion can occur on methyl, methylene and methine sites, but often excellent regiocontrol is achieved by means of the appropriate substrate and tether. Electron-donating groups adjacent to the C-H bond favor C-H insertion whereas electron withdrawing groups disfavor the reaction. A comprehensive review describing the full scope of this chemistry has recently been published [lc]. Only a few representative examples will be discussed here. 

Donor/acceptor-substituted carbenoids are usually much more chemoselective than the more established carbenoids functionalized solely with acceptor groups [lc]. The development of these donor/acceptor-substituted carbenoids has enabled enantioselective intermolecular C-H insertions to become a very practical process. These carbenoids have a strong preference for functionalizing C-H bonds where positive charge build-up at C in the transition state is favored but these electronic effects are counter-balanced by steric factors. Benzylic and allylic sites and C-H bonds adjacent to oxygen and nitrogen functionality are favored but these sites can also be sterically protected if desired. By appropriate consideration of the regiocontrolling elements, effective intermolecular C-H insertions at methyl, methylene, and methine sites have been achieved. 

The development of chiral rhodium (II) catalysts has resulted in major advances in asymmetric cyclopropanation and C-H insertion. High levels of chemoselec-tivity and regiocontrol are easily accessible. Futhermore, control of diastereose-lectivity and enantioselectivity are now standard features of both processes. Catalyst design has provided the key to success in these important appHcations of diazocarbonyl compounds. 

Another example of a pronounced positive pressure effect on enantioselectivity was found by Hillers and Reiser [82] for the Heck reaction of 2,3-dihydrofuran (180) and phenylperfluorobutylsulfonate (phenylnonaflate) (181) in the presence of (R)-BINAP (cf. Chapter 7) Under normal pressure and at 60 °C an enantiomeric excess of 47 % ee for 183 was achieved when 1.0 GPa was applied, the enatio-selectivity for 183 was improved to 89 % ee under otherwise unchanged conditions. On the other hand the ratio of 182 to 183 was only 1 1.6 at high pressure and 182 was obtained with an enantiomeric excess of only 5 % ee. Apparently, a very effective kinetic resolution had taken place under high pressure. It should be noted that the use of new chiral ligands for the described Heck reaction of tetrahydrofuran now allows an enantioselectivity of 96 % ee with complete regiocontrol at atmospheric pressure [83]. 

In instances where the two termini of the allyl moiety possess nonidentical groups, the issues of both regiocontrol and enantiocontrol can become important (Scheme 21). Typically, the nucleophile approaches from the less sterically hindered terminus, and the mechanism proceeds via a double inversion (overall retention) of stereochemistry process. Consequently, the use of a racemic substrate is unlikely to lead to a single regio-isomeric product with high enantioselectivity. 

Butadiene monoepoxide 166 has been used as a substrate for enantioselective allylic substitution reactions. The reaction with phthalimide has been performed with excellent regiocontrol and excellent enantiocontrol. The best results were obtained with a variant 168 of the standard ligand (Scheme 36). ° " ... 

Kraus GA, Li J, Gordon MS, Jensen JH. Regiocontrol by remote substituents. An enantioselective total s3mthesis of fre-nolicin B via a highly regioselective Diels-Alder reaction. J. Am. Chem. Soc. 1993 115 5859-5860. 

---