Halogenation halocyclization

Transfer of a halonium ion to l,o)-alkenols or l,co-alkenoic acids which are capable of undergoing halocyclization is a key method to generate 4-, 5- and 6-membered heterocyclic rings via the so-called halocyclization processes 1,2,3,4,5,6,7). This synthetic method would be far more valuable if the halogen transfer to an achiral alkene could be conducted in a chiral fashion (exemplified in Figure 1) as it would produce optically active heterocycles that could be further functionalized through manipulation of the halomethyl group. 

The important role played by the conditions of the halocyclization, and by the halogen employed, is evident in the cyclization of 2-hydroxy-6-[( )-l-propcnyl]cyclohexanecarboxylic acid (5), a precursor in the total synthesis of ( )-ramulosin2. When the iodolactonization is conducted with iodine and potassium iodide in aqueous sodium hydrogen carbonate, a mixture of 6/7/8 (X = 1) in a 14 57 29 ratio is obtained in 91 % yield, whereas a mixture of 6/7 in a 60 40 ratio and 86% yield is observed when the reaction is performed with iodine in diethyl ether/tetrahy-drofuran/aqueous sodium hydrogen carbonate. By contrast, the bromolactonizalion, carried out with bromine in methanol6, affords a 78 22 mixture of 6 and 7 (X = Br) in 88% yield. 

Intramolecular participation of an appropriately placed nucleophile promises to be a useful strategy for the stereocontrolled synthesis of acyclic systems. Thus, halocyclization of unsaturated carboxylic acids, alcohols and functionalized alcohols (123) can be effected by a variety of electrophilic halogenating... 

The first report of a polycyclization organocascade is dedicated to the enantioselec-tive halocyclization of polyprenoids mediated by chiral phosphoramidites catalysts with A-iodosuccinimide as halogen source (Scheme 7.35) [53]. The corresponding iodinated polycyclic products are then obtained with excellent enantiomeric excesses and moderate yields. 

Halocyclization reactions are valuable transformations since they often impart chirality while incorporating the halogen. A host of these reactions have been reported, and new... 

Instead, it is more likely that the N-X-bond is cleaved heterolytically, resulting in an equilibrium with the adduct [Nu-X]" (Scheme 12, right Nu=nucleophilic activator). The latter then reacts with the nucleophilic compound to be halogenated. As the N-X bond is likely broken, these reactions are not directly relevant in the specific context introduced above, and only a few illustrative cases will be mentioned (for recent events [122]). One impressive example is the enantioselective halocyclization of polyprenoids which is carried out under addition of 1 equiv. of a chiral nucleophilic phosphoramidite. This nucleophilic phosphoramidite abstracts halenium ions from NIS or NBS via the phosphor atom to form a tight ion pair which then initiates the cyclization reaction by coordination to a double bond in the substrate [123]. 

The electrophilic addition of a halogen to an olefin usually proceeds via cyclic halonium (halirauium) ion intermediates [39]. Brown s group investigated the reaction mechanism of halocyclization. They demonstrated that Br and B transfer rapidly from the haliranium ions of adaman-tylidene adamantine to other olefins [40]. Calculations of bromiraninm ion transfer between two ethylenes revealed the reaction mechanism illustrated in Scheme 9.25. 

Until recently the catalytic asymmetric halocyclization remained a long-standing problem. Applications of these methods are sparse, and the halogens are often substituted at the later stages. A brief description will be presented here. 

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