Intramolecular reactions regiocontrol

The inclusion of a separate chapter on catalysed cyclopropanation in this latest volume of the series is indicative of the very high level of activity in the area of metal catalysed reactions of diazo compounds. Excellent, reproducible catalytic systems, based mainly on rhodium, copper or palladium, are now readily available for cyclopropanation of a wide variety of alkenes. Both intermolecular and intramolecular reactions have been explored extensively in the synthesis of novel cyclopropanes including natural products. Major advances have been made in both regiocontrol and stereocontrol, the latter leading to the growing use of chiral catalysts for producing enantiopure cyclopropane derivatives. 

The regiocontrol that results from using an allyl silane to direct the final elimination is illustrated by this example of an intramolecular reaction on to an acetal promoted by tin tetrachloride. The same reaction can be run in the absence of silicon but the intermediate cation can then lose a range of protons to produce five different products ... 

The Alder-ene reaction has traditionally been performed under thermal conditions—generally at temperatures in excess of 200 °C. Transition metal catalysis not only maintains the attractive atom-economical feature of the Alder-ene reaction, but also allows for regiocontrol and, in many cases, stereoselectivity. A multitude of transition metal complexes has shown the ability to catalyze the intramolecular Alder-ene reaction. Each possesses a unique reactivity that is reflected in the diversity of carbocyclic and heterocyclic products accessible via the transition metal-catalyzed intramolecular Alder-ene reaction. Presumably for these reasons, investigation of the thermal Alder-ene reaction seems to have stopped almost completely. For example, more than 40 papers pertaining to the transition metal-catalyzed intramolecular Alder-ene reaction have been published over the last decade. In the process of writing this review, we encountered only three recent examples of the thermal intramolecular Alder-ene reaction, two of which were applications to the synthesis of biologically relevant compounds (see Section 10.12.6). 

Regiocontrol in intramolecular cyclopropanation is mainly dependent on the site of the unsaturated centre related to the carbenoid centre. In other words, ring size of the bicyclic or polycyclic systems which derive from the cyclopropanation is the key to regiocontrol of this type of reaction. The regioselectivity is independent of the catalyst employed, Five-membered ring formation is favoured over the production of six- or seven-membered rings... 

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. 

Iyengar, R., Schiidknegt, K., Aube, J. Regiocontrol in an Intramolecular Schmidt Reaction Total Synthesis of (+)-Aspidospermidine. Org. Lett. 2000, 2,1625-1627. 

An intramolecular version of this acylation of homoallylsilanes leads to 2-cyclopropylcycloal-kanones 10. This reaction gives five-, six-, seven- and even eight-membered ring systems in a highly regiocontrolled manner. In all these cases, the 2-cyclopropyl ketones 7 were isolated as the sole product of intramolecular acylation. . 2-Cyclopropylcyclobutanones were not ob-... 

The intramolecular DOtz reaction, in which the alkyne is tethered to the carbene, improves synthetic efficiency and regiocontrol, although internal alkynes work better than terminal alkynes [30], Such cycloadditions provided the kqr to a synthesis of the antibiotic deoxy-frenolicin [Eq. (12)] [31] and played a role in work aimed toward the synthesis of the ben-zofuran angelicin, in which a 3-furylcarbene complex aimulates toward C2 of the furan, avoiding forming an isobenzofuran structure [Eq. (13)] [32]. 

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