Diastereoselectivity cyclic radicals

The problem of diastereoselectivity in additions to cyclic radicals arising from the opening of bi- or tricyclic epoxides, e. g. cycloheptene oxide or norbornene oxide, has been addressed only recently [32], In the former case, reasonable selectivities can be obtained with titanocene dichloride (trans cis = 76 24), but excellent selectivities are observed with bis(tert-butyl)titanocene dichloride (transxis = 94 6), as shown in Scheme 12.17. 

Intermolecular free radical reactions. Giese notes the diastereoselectivity of reactions of acrylonitrile with cyclic 5- and 6-membered ring radicals can be controlled by adjacent substituents. Thus an axial 3-substituent can favor axial attack, whereas an equatorial 3-substituent favors equatorial attack in the case of 6-membered cyclic radicals. Glucosyl radicals, regardless of the precursor, yield a-substi-tuted products (88 12). 

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. 

The use of radical translocation to generate cyclic radicals which can then add intramolecularly in a stereoselective manner to give addition products has been reported. The diastereoselective addition at C(4) of 1,3-oxazolidinones was examined using this approach. Thus, 1,5-hydrogen translocation from the aryl radical generated from (51) gives the C(4) radical, which can undergo radical addition to acrylate to furnish a 3 1 mixture of diastereomers (52). ... 

In a reaction closely related to the latter, pyranylidene derivatives are obtained by the intermolecular radical coupling of alkynyl- or alkenylcarbene complexes and epoxides. Good diastereoselectivities are observed when cyclic epoxides are used. Moreover, the best results are reached by the generation of the alkyl radical using titanocene monochloride dimer [90] (Scheme 43). 

Chiral l,3-dioxin-4-ones photochemically react intermolecular with (cyclic) ethers, acetals, and secondary alcohols to give the addition products in reasonable yields. The radical addition was completely stereoselective at C-6 of the heterocycle <1999EJO1057>. The exocyclic diastereoselectivity, where relevant, was about 2 1 (Equation 30). In analogy, an intramolecular cascade reaction of a 1,3-dioxin -one derived from menthone was used to get a terpenoid or a steroid framework in optically active form <1997JA1129, 1999JA4894>. 

Free-radical cyclization of phenyl selenide 15 to indolizidinone 16 represented a key step in the total synthesis of (—)-slaframine (equation 52). The two pairs of diastereomers were first separated and then hydrolyzed to the corresponding alcohols in 76% overall yield77. (TMS)3SiH-mediated acyl radical reactions from phenylseleno esters 17 have recently been utilized for the stereoselective synthesis of cyclic ethers78. In fact, the experimental conditions reported in equation 53 are particularly good for both improving cis diastereoselectivity and suppressing decarbonylation. 

TMS)3SiH-mediated acyl radical reactions of phenylseleno esters have been utilized for the diastereoselective synthesis of cyclic ethers by Evans s group. Equation 44 shows that the acyl selenide 83 affords the cA-disubstituted tetrahydrofuran 84 in good yield on exposure at room temperature to (TMS SiH and the Et3 B/02 combination as the initiator via a 5-exo-trig cyclization97 98. 

Beckwith has observed moderate diastereoselectivity in this reaction involving cyclic systems. The cyclizations of allyl and homoallyloxycarbonyloxy radicals are potentially useful as radical based alternatives for an overall oxidation or hydrolysis of a double bond, and also various further transformations of the cyclic carbonates can lead to synthetically useful products.62b In contrast, simple alkoxycarbonyloxy radicals 91a add intermolecularly to ethyl vinyl ether to give, ultimately, carbonates of glycoaldehyde derivatives 91b, Scheme 37.62a... 

Reductive alkylations via a radical pathway have been performed on enamines of cyclic215,216 and acyclic217 ketones. In both cases the diastereoselectivity was high, leading to cis products preferentially in the case of the cyclic derivatives and to ul substituted amines in the case of linear systems (Scheme 143). 

Highly diastereoselective 7-rro/o-radical cyclization of (bromomethyl)dimethylsilyl ethers 150, derived from ethyl y-hydroxy-a-methylenecarboxylates, bearing a bulky y-substituent such as isopropyl, cyclohexyl, and tert- mty in THF gave cyclic silyl ethers 151 bearing preferentially the ethoxycarbonyl group anti to the y-substituent (Equation 28) <2004TL4329>. 

Allylic azides, e.g., 1, were produced by treatment of the triisopropylsilyl enol ethers of cyclic ketones with azidotrimethylsilane and iodosobenzene78, but by lowering the temperature and in the presence of the stable radical 2,2,6,6-tetramethylpiperidine-/V-oxyl (TEMPO), 1-triso-propylsilyloxy-l,2-diazides, e.g., 2, became the predominant product79. The radical mechanism of the reaction was demonstrated. A number of 1,2-diazides (Table 4) were produced in the determined optimum conditions (Method B 16h). The simple diastereoselectivity (trans addition) was complete only with the enol ethers of unsubstituted cycloalkanones or 4-tert-butylcy-clohexanone. This 1,2-bis-azidonation procedure has not been exploited to prepare a-azide ketones, which should be available by simple hydrolysis of the adducts. Instead, the cis-l-triiso-propylsilyloxy-1,2-diazides were applied to the preparation of cw-2-azido tertiary cyclohexanols by selective substitution of the C-l azide group by nucleophiles in the presence of Lewis acids. 

More complex cyclic systems, such as steroids, also react with high 1,2-stereoinduction. The radical reduction of ethyl 3/ -(/er/-butyldimethylsilyloxy)-20-phenylseleno-5-prcgnen-21-oate shows a diastereoselectivity of 7 1 [(20/ )/ (20S)]23. 

Evans and Roseman [40] explored the 1-exo trig acyl radical cyclization for the generation of cyclic ethers 161 and 162 starting from the selenoesters 160. The efficiency and the diastereoselectivity of these reactions were found to increase when tristrimethylsilylsilane was used instead of BusSnH. The generality of this reaction was further established with the corresponding vinylsulfones (instead of acrylates) and also with the corresponding vinyl bromides (instead of selenoesters). 

The resulting nucleophilic alkoxymethyl radical may be trapped by an electron-deficient alkene. Reduction of the adduct radical (3 by DCA radical anion and protonation of the resulting anion, confirmed by deuterium incorporation from methanol-OD, gives the final product (3%). The diastereoselectivity shown has its origin in a preference for protonation, under kinetic control, from the less hindered side. For acyclic alkenes such as methyl 2-cyanocrotonate or dimethyl maleate, free rotation within (395) results in a low cisJrans ratio of 1.8-2.5 1 whereas for cyclic alkenes such as N,3-dimethylmaleimide or 3-methylmaleimide the cisitrans ratio is considerably higher at 86 14. ... 

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