Enantioselective radical chemistry

Radical chemistry has seen tremendous progress in the past two decades and can now be considered as an eminent sub discipline in synthetic organic chemistry [1-6]. Diastereoselective radical chemistry is well established and many examples of enantioselective radical reactions have appeared in the recent literature. For reviews on diastereoselective radical chemistry see [7-11] for reviews on enantioselective radical chemistry see [12-16] and for reviews on conjugate additions, see [17,18]. This review will detail different ways to introduce asymmetry during a radical reaction. These transformations can be broadly classified into atom transfer reactions, reductive alkylations, fragmentations, addition and trapping experiments, and electron transfer reactions. 

Very recently, Gualtieri reported the preparation of chiral, C2-symmetric binaphthyl-substituted germaues (8, 9) coutaiuing S—Ge bonds (equation 9) and their application to enantioselective radical chemistry . These compounds are reported to exhibit superior stability properties than the corresponding tin compounds which could not be isolated (see later) . 

The Schiesser group also recently described the preparation of some stannanes (24-27) derived from cholestanol (Scheme 4), cholic acid (Scheme 5) and lithocholic acid (equation 14), and their application to enantioselective radical chemistry . ... 

Since its publication many more new and exciting examples of enantioselective radical chemistry have been reported. The previous examples as well as the most recent will be covered comprehensively in the following section. 

Enantioselective free-radical chemistry has benefited through the development of chiral, non-racemic stannanes. Despite having been prepared on a limited number of occasions prior to 1996, the use of chiral stannanes in enantioselective free-radical chemistry was only reported on one occasion31. The field effectively lay dormant until Nanni and Curran reported the preparation and uses of (6,)-4,5-dihydro-4-methyl-3//-dinaphtho[2,l-c l/,2/-ejstannepin (11) prepared from (S)-2, 2/-bis(bromomethyl)-l,l,-binaphthyl (equation 11)32 and a few years later Curran and Gualtieri reported the preparation of C2-symmetric... 

Their syntheses are described above. Some stannanes have been modified to improve their physical (solubility/separation/reactivity) properties ° ° °", while others have been tailor-made to aid in chirality transfer and to effect enantioselective outcomes during free-radical chemistry . ... 

Lastly, Gualtieri reported the use of binaphthyl-substituted germanes (8, 9) in enan-tioselective radical chemistry . For example, an enantioselectivity of 59% was reported for the reaction of 126 with 8 at —60° (equation 127). To the best of our knowledge, this represents the first account of the use of a chiral germanium hydride in free-radical reduction chemistry. 

Work in our laboratories has demonstrated that free-radicals can be harnessed to provide beneficial products and chemical technologies. This paper highlights some of our recent quests for the Holy Grail of free-radical chemistry and includes the preparation of selenium-containing antibiotics, carbohydrates, antioxidants and anti-inflammatory agents and the development of reagents for use in enantioselective synthesis. 

Drinking from the Cup - enantioselective free-radical chemistry... 

Within the past decade, diastereosolective radical reactions have become feasible and the factors contolling selectivity defined. Chiral auxiliaries for radical reactions have been recently developed in analogy to those developed for carban-ion chemistry in the 1970s and 1980s. The first example of stoichiometric use of a chiral ligand for enantioselective radical additions was recently reported by Porter and coworkers [59,60,61]. Reaction of the amide 14 with allyltrimethyl-silane at -78 °C, initiated by triethylborane, in the presence of 1 equiv. each of zinc triflate and the chiral bidentate ligand 15, provided the allylated product in a yield up to 88% and ee of 90%, Eq. (18). The presumed intermediate is the a-keto radical complexed to the chiral Lewis acid. 

Until the end of the 1980s it was believed that the high reactivity and flexibility of acyclic radicals prevent stereoselective reactions. This opinion changed in 1991 when the review of Porter, Giese, and Curran appeared [1], In the middle of the 1990s, it became obvious that in most cases acyclic radicals follow the same rules of stereoselectivity as non-radicals [2]. This chapter describes diastereoselective, substrate-controlled reactions of acyclic radicals. The chemistry of cyclic radicals, the influence of chiral auxiliaries and of Lewis acids as well as enantioselective radical reactions are reviewed in Chapters 4.2-4.5. Actually, radicals are suitable intermediates for an understanding of stereoselectivity because (a) their conformation can be determined by ESR spectroscopy, and (b) the transition states of synthetically relevant radical reactions are very early on the reaction coordinate. The present ehapter makes use of these features. 

In closing, it has been proven that radical chemistry can indeed be performed enantioselectively. In fact in certain systems they even rival results obtained using well-established ionic chemistry while still reaping the benefits of radical reactions including mild reaction conditions and water tolerance in most cases. This short review of current enantioselective methods for carbon-carbon bond construction, however, shows that there remains quite a range of chemistry to be discovered in this still emerging field. 

Sibi MP, HasegawaM. Organocatalysis in radical chemistry. Enantioselective a-oxyamination of aldehydes. J. Am. Chem. Soc. 2007 129(14) 4124-A125. 

Sibi and co-workers explored the power of the radical chemistry through a terminal proton abstraction to achieve the enantioselective proton transfer (Scheme 31.31). Indeed, the formation of a bidentate complex by coordination of a chiral Mg complex to a Michael acceptor bearing an achiral template can promote the 1,4-radical addition followed by an enantioselective hydrogen transfer. This strategy is believed to form a bidentade complex aimed to control the enolate geometry, which is a key point of the enantiodetermining step of the reaction. 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Pa]ladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natmal Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

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]. 

Bertrand, S., Hoffmann, N., and Pete, J.P. (2000) Highly efficient and stereoselective radical addition of tertiary amines to electron-deficient alkenes-application to the enantioselective synthesis of necine bases. European Journal of Organic Chemistry, 82, 2227—2238. 

Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. It 155-171 Normant JF (2003) Enantioselective Carbolithiations. 5 287-310... 

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