Regioselectivity synthetic applications

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

Scheme 9.3. Synthetic application of alkenyltitanium reagent (yields are based on the parent silylalkyne ratio in square brackets refers to regioselectivity).

Besides the above electrophiles, the acetylene—titanium complexes react regioselectively with other acetylenes providing the corresponding titanacyclopentadienes. An example of a homo-coupling reaction is shown in Eq. 9.11 [30], which also displays some synthetic applications [30,31]. Especially noteworthy is the highly regioselective cross-coupling reaction of unsymmetrical internal and terminal acetylenes, which is illustrated in Eq. 9.12... 

The regioselective formation of Tf-allyltitanocenes is clearly attractive for further synthetic applications. 

If the cycloaddition and cycloreversion steps occurred under the same conditions, an equilibrium would establish and a mixture of reactant and product olefins be obtained, which is a severe limitation to its synthetic use. In many cases, however, the two steps can very well be separated, with the cycloreversion under totally different conditions often showing pronounced regioselectivity, e.g. for thermodynamic reasons (product vs. reactant stability), and this type of olefin metathesis has been successfully applied to organic synthesis. In fact, this aspect of the synthetic application of four-membered ring compounds has recently aroused considerable attention, as it leads the way to their transformation into other useful intermediates. For example aza[18]annulene (371) could be synthesized utilizing a sequence of [2 + 2] cycloaddition and cycloreversion. (369), one of the dimers obtained from cyclooctatetraene upon heating to 100 °C, was transformed by carbethoxycarbene addition to two tetracyclic carboxylates, which subsequently lead to the isomeric azides (368) and (370). Upon direct photolysis of these, (371) was obtained in 25 and 28% yield, respectively 127). Aza[14]annulene could be synthesized in a similar fashion I28). 

Galactose oxidase exhibits a surprisingly low specificity for the primary alcohol but is completely regioselective secondary alcohols are not substrates. This re-gioselectivity suggests potential synthetic applications (117) and has raised interest in the design of small molecule catalysts mimicking GO reactivity. 

There are only a few reactions in which substituted benzenes are constructed in one step and with predictable regioselectivity. Carbene-complex-mediated benzannulations are one of these. Because of the scarcity of reliable benzannulation reactions, the use of carbene complexes for this purpose has become one of the most valuable synthetic applications of these organometallic reagents. 

Synthetic applications involving regioselective or diastereoselective photooxygenation ene reactions, as key steps, are very common in the literature and some examples have already been reported in the previous sections. Additionally, the number of natural products... 

These newly discovered methods have found wide synthetic application. Examples include the generation and cycloaddition of stabilized N-unsubstituted azomethine ylides, nonstabilized N-substituted azomethine ylides, and even the parent azomethine ylides bearing no carbon substituents (19). However, these modem procedures often require severe reaction conditions such as high reaction temperatures, the use of polar solvents, and the use of strong bases, among others. The poor stereo- and regioselectivities that are often observed in the cycloadditions of nonstabilized azomethine ylides have discouraged their use in the stereocontrolled synthesis of complex molecules. 

Titanium ylides are generated from imine esters with titanium isopropoxide chlorides and amines or by transmetalation of the N-lithiated ylides (90,91). The regioselectivity of their reactions with methyl acrylate is opposite to that normally observed (90). A transition state is proposed in Scheme 11.13 to explain this alternative regioselectivity. Intramolecular cycloadditions of the titanium ylides offer a synthetic application of this regioselectivity. 

A chapter written in 1996 covers hydroformylation catalyzed by organometallic complexes in detail,219 whereas a review written 5 years later gives a summary of the advances on hydroformylation with respect to synthetic applications.220 A selection of papers in a special journal issue has been devoted to carbonylation reactions.221 A major area of the research has been the development of fluorous biphasic catalysis and the design of new catalysts for aqueous/organic biphasic catalysis to achieve high activity and regioselectivity of linear or branched aldehyde formation. 

Although almost all kinds of thiocarbonyl compounds are good dienophiles, synthetic applications derived from the Diels-Alder adducts of thioketones, thionesters and dithioesters remain rather rare and focused on specific targets, as in the preparation of a fragment of the antibiotic erythronolide from the cycloadduct formed regioselectively from 2-methyl-l,3-pentadiene and an a-oxodithioester, a particularly efficient dienophile [524]. 

Several interesting synthetic applications of hydroformylation are known. As one example, hydroformylation of enol ethers to afford -hydroxy aldehydes can be extended to catalytic aldol synthesis. The Rh-catalysed hydroformylation of the cyclic enol ether 42 affords the protected. vy -3,5-dihydroxyaldchydc 43 without forming the anti product 44. The regioselectivity of attack on the terminal carbon is also very high [28],... 

Thayumanavan, S. Regioselective, diastereose-lective, and enantioselective lithiation—substitution sequences reaction pathways and synthetic applications. Ace. Chem. Res. 1996, 29, 235... 

---