Enantioselectivity radical cyclization

The neuroexcitatory amino acid a-kainic acid, a popular testing ground for new pyrrolidine syntheses, has been prepared by a number of routes that involve free-radical cyclization reactions. Bachi has reported two approaches that involve iminoyl radical cyclizations. One enantioselective route is described in Scheme 6 [35]. Isonitrile 48 was prepared in 4 steps from 4-bromo-3-methyl-2-butenal dimethyl acetal, the key reaction being an enantioselective addition of tert-butyl oc-isocyanoacetate to an aldehyde mediated by Hiyashi s catalyst. Treatment of 48 with a catalytic... 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

Scheme 3.20. Mn(OAc)3-mediated chiral auxiliary-assisted enantioselective domino radical cyclization in the total synthesis of (+)-triptocallol (3-79).

Scheme 3.33. Lewis acid-promoted free radical domino cyclization reaction and enantioselective approach.

When the nucleophile bears an appropriately unsaturated chain, these enantioselective cyclizations can be used to advantage in tandem processes leading to bicyclic systems (Scheme 42) [131,141,142], The greater enantios-electivity observed with the mesylate group in this example may be due to the lower degree of stabilization of the alkene radical cation in the looser ion pair, which leads to more rapid cyclization. 

An interesting intramolecular radical cyclization followed by enantioselective hydrogen atom transfer has recently been reported (Scheme 11) [40]. This reaction is carried out in the presence of a chiral complexing agent 38, which... 

Another report by Rychnovsky et al. explored the potential of chirality transfer in the transannular cyclization of cyclodecene 45 [42], They proposed a radical deoxygenation of 45, which produces an intermediate cyclodecenyl radical that can cyclize in a 5-exo fashion to yield 5,7-fused bicycle 48 (Scheme 13). The potential for the optically enriched radical precursor 45 to undergo enantioselective cyclization is dependent on the rate of transannular cyclization. That is, if the radical generated from optically pure... 

Highly enantioselective atom transfer radical cydization reactions catalyzed by chiral Lewis acids have been reported by Yang et al. [80]. Two main advantages of these enantioselective cyclizations include installing multiple chiral centers and retaining a halogen atom in the product, which allows for further functionalization. 

Scheme 24 shows the atom transfer radical cyclizations of unsaturated /3-keto esters 94 using MgfCKLh and chiral ligand 96. It was found that toluene as a solvent generally gave higher enantioselectivities than CH2CI2... 

The aldol reaction is one of the most important reactions in synthetic organic chemistry. Many traditional ionic routes are currently available for diastereo- and enantioselective aldol reaction [97-99]. In contrast to highly basic ionic processes, development of radical methods for preparation of aldols using neutral conditions is attractive [100-102]. With the exception of intramolecular cyclization reactions, radical approaches towards aldol products remain largely unexplored [103-109]. 

Other examples include the intramolecular radical cyclization of 3-bromoaIkyl-2(3fl)-oxazolones 192 and 196 with tributyltin hydride/azobisisobutyronitrile to give the pyrrolooxazolidinones 194,198, and 199. The 2,5-disubstituted pyrrolidine derivatives 195 are produced enantioselectively (Fig. 5.49). 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

Enantioselective synthesis of 2-substituted piperidines with 60% ee has been reported via radical precursors being trapped in an intramolecular reaction (Scheme 17) <2003OL3767>. These cyclizations were rationalized in terms of chair-like transition states, with the maximum number of pseudoequatorial substituents, in which the nucleophilic amine attacks the alkene radical cation on the face opposite to the phosphate anion. 

Under oxidative conditions, treatment of chiral menthyl (3-ketoesters (55) with Mn(OAc)3/Yb(OTf)3 (Lewis acid) in CF3CH2OH generates the corresponding cyclized products with high diastereoselectivity. Eq. 10.26 shows the treatment of chiral menthyl (3-keto esters (55) with Mn(OAc)3-mediated oxidative free radical cyclization to form a single isomer (56a) predominantly. This method can be applied to the enantioselective synthesis of (+)-triptophenolide with 90%e.e., which is a biologically active natural product. 

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