Radical stereoselectivity intramolecular reactions

Molander and co-workers have studied the stereoselective intramolecular addition of ketyl radicals to olefins [95JOC872]. The ketyl radicals are generated from ketone by treatment with samarium(II) diiodide. A similar reaction sequence using 61 gave only elimination products. 

Once a chiral silane is synthesized, intramolecular reaction such as the Heck reaction and the radical cyclization reaction with transfer of chirality from the silicon center can be pursued. Other reactions of interest include the stereoselective hydrosilylation of aldehydes and ketones. Our method could be used to tether chiral silanes to solid support for uses in solid support... 

Iminyl radicals are generated by the addition of tributylstannane to N-chloro25 or, more conveniently, A -arylthio imines26,27 , 32. These radicals display considerable reactivity towards unactivated C—C double bonds in intramolecular reactions. 3,4-Dihydro-2//-pyrroles were obtained in good yield with variable stereoselectivity by the slow addition (4-5 h) of tributylstannane to a refluxing cyclohexane solution of suitable unsaturated jV-(2-benzo-thiazolylthio) and Ar-phenylthio imines (Table 2). 

Various methods for the generation of carbon-centred radicals have been described earlier in this chapter and these are generally applicable for subsequent intramolecular reaction. Commonly, tributyltin hydride is used to initiate carbon radical formation. For example, treatment of the bromide 56 with tributyltin hydride and AIBN gave the cyclopentanes 57 and 58 (4.53). In such cyclizations, the 4-substituent plays a dominant role in the stereoselection (to favour the trans arrangement between the substituent at this position and the new chiral centre), although the cyclization of the isomeric -alkene occurs with no diastereosele-ctivity. ... 

Recendy, we described a useful sequence where Michael-acceptor sulfoxides 30 were obtained in two steps from homopropargylic alcohols 29 by radical addition of thiophenol and oxidation with sodium periodate. The unsaturated sulfoxides were used in a highly stereoselective intramolecular oxa-Michael reaction. The sequence provided stereoselective functionalization of the sulfoxide moiety, and the products 31 proved to be useful in the synthesis of modified furanosides 32. This represents a good exanple where sugars are prepared from acyclic precursors. The Michael addition was followed by a hydrolytic Pummerer reaction, yielding protected a-hydroxy aldehydes tScheme 20.8) that upon acidic treatment afforded 3-substituted ribofuranoses. 

In further illustrations of the use of free-radical cyclization reactions in terpene synthesis Snider et al. have described the 5-exo-trig cyclization from the imidazolide (29) to produce both B-copaene (30a) and B-ylangene (30b), Stork and Baine have synthesized seychellene (32) [from (31)], and Ladlow and Pattenden have featured a novel, stereoselective intramolecular radical cyclization step onto an enolic double bond, viz. (33) - (34), in their synthesis of ( )-alliacolide (35). 

PET reactions [2] can be considered as versatile methods for generating radical cations from electron-rich olefins and aromatic compounds [3], which then can undergo an intramolecular cationic cyclization. Niwa and coworkers [4] reported on a photochemical reaction of l,l-diphenyl-l, -alkadienes in the presence of phenanthrene (Phen) and 1,4-dicyanobenzene (DCNB) as sensitizer and electron acceptor to construct 5/6/6- and 6/6/6-fused ring systems with high stereoselectivity. 

Diels-Alder catalysis.1 This radical cation can increase the endo-selectivity of Diels-Alder reactions when the dienophile is a styrene or electron-rich alkene. This endo-selectivity obtains even in intramolecular Diels-Alder reactions. Thus the triene 2, a mixture of (Z)- and (E)-isomers, cyclizes in the presence of 1 to 0° to the hydroindanes 3 and 4 in the ratio 97 3. Similar cyclization of (E)-2 results in 3 and 4 in the ratio 98 2 therefore, the catalyst can effect isomerization of (Z)-2 to (E)-2. Even higher stereoselectivity is observed when the styrene group of 2 is replaced by a vinyl sulfide group (SC6H5 in place of QHtOCT ). 

Anodic C, C-coupling is a very powerful tool to synthesize cyclic compounds with high regio- and stereoselectivity. It involves inter- and intramolecular coupling of arylolefins, dienes, enolethers, phenol ethers, and aromatic amines and often opens a quick entry into complex natural products in a few steps. Although the mechanism is fully established in only a few cases, it does appear to involve the coupling of two radical cations at the site of their highest radical density and is further controlled by steric constraints. This important type of reaction is reviewed in Chap. 5 and in Refs. [89, 90]. 

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 sodium cation chelation by the bis(enone) anion-radicals shown in Scheme 3.52 controls their further transformations although they proceed at the expense of other reaction centers (Yang et al. 2004). This kind of intramolecular cyclobutanation is characterized with the pronounced cis-stereoselectivity. However, this stereoselectivity disappears if the reaction proceeds in the presence of the tetrabutylammonium cation, when such a chelation is impossible. 

Another example of stereoselective radical cation addition was presented by Hirano and co-workers. The reaction of 1,1-diphenyl-l,n-alkadienes employing 1,4-dicyanobenzene as a sensitizer yielded intramolecular tandem cyclization products in up to 60% yield (Scheme 29) [40]. 

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