Anionic cyclisation stereoselectivity

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The addition of organolithiums to polarised C=X bonds is one of the most widely used ways of making C-C bonds, and (excepting some unusual intramolecular cases) will not be discussed in this book other than to say it is a reliable and successful reaction. With a few exceptions,1 3 stereoselectivity is not a general feature of organolithium addition reactions to C=0 n bonds. Much of this chapter will concern controlled addition of organolithiums to C=C 7i bonds after an overview of carbolithiation, we shall review the development of intramolecular carbolithiation, or anionic cyclisation. 

There is one example, unique for several reasons, of the formation of a four-membered ring by anionic cyclisation onto an oxazoline. Attempted oxazoline-directed lithiation of the styrene 122 gave, instead, the cyclobutane 124 via addition of the alkyllithium to give a benzylic organolithium 123 which cyclises stereoselectively.63 The initial intermolecular carbolithiation proceeds remarkably easily - no additives (such as TMEDA) are required, even with MeLi. 

Anionic cyclisation can be used to form cyclopropanes when the product cyclopropylmethyllithium can undergo an elimination reaction.140111 The simple primary organolithium 270 requires the presence of TMEDA to cyclise, but gives 88% of vinylcyclopropane. 271 cyclises with moderate stereoselectivity. 

Since the sulfide substituents can be removed reductively, the cyclisations of 273 and 276 are synthetically equivalent to cyclisations onto disubstituted double bonds, giving compounds such as 275.142>143 Like the corresponding cyclisations onto monosubstituted alkenes they are highly stereoselective, with the sense of stereoselectivity being solvent-dependent the products 274 and 277 are trans as shown for a cyclisation conducted in THF in pentane complete cis selectivity is obtained. Similar cyclisations onto vinyl sulfides have been used to explore the stereochemical course of the anionic cyclisation reaction, and are discussed below.146... 

The asymmetric cyclisation of achiral olefinic organohthium reagents by a stereogenic alkah metal centre can be modulated by ( )-sparteine, which confers enantiofacial selectivity on the reaction such that the anionic cyclisation process discriminates between the enantiotopic faces of an unactivated C=C bond. Recently, modifications have been made to the well known hthium-ene cyclisation reaction whereby the subsequent expulsion of a thiophenoxide group yields a fused vinylcyclopropane. Moreover, allylic lithium oxyanion-induced reactivity and stereoselectivity in this intramolecular carbometallation has been demonstrated in the highly stereoselective synthesis of a natural bicyclo[3.1.0] hexane. ... 

A-Alkylimides, and the sodium (but not lithium) anions of A-unsubstituted imides (84), behave similarly, and the cyclisations of 84 and 86 provide a stereoselective (with regard to the enamine double bond) route to cyclic acyl enamines 85 and 87 - again, effectively an N —> C acyl transfer.49... 

Anionic cascade cyclisations can be stereoselective (just like their simpler counterparts see below). The cyclisation of 289, for example, gives solely the trans ring-junction product 292 (stereochemistry is determined in the first cyclisation to 290) despite the fact that the cis 5,5-fused system is nearly 30 kJ mol-1 more stable.149 This argues against the reversibility of the cyclisation. Because the cyclisation of 290 is rather slow, trapping the product organolithium 291 with electrophiles other than a proton can pose problems, and considerable amounts of material protonated by the ether solvent are obtained. This can be overcome by decreasing the proportion of ether from 40% to 10% of the solvent volume.150... 

Krief has applied selenium chemistry to some anionic cascade cyclisations.128 For example, 293 can be cyclised in two successive 5-exo reactions to give a mixture of the stereoisomers of 297. If 294 is warmed to 0 °C, an alternative sort of tandem process occurs after cyclisation onto the alkene, the organolithium 295 undergoes an intramolecular displacement, stereoselectively generating the 5,3-fused system of 296. Similar intramolecular cyclopropanations (of a-bromo organolithiums) have been described by Hoffmann151 but are probably mediated by carbenes rather than a sequential cyclisation-substitution sequence. 

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