Diastereoselective radical reaction

D. Crich and L. B. L. Lim, Diastereoselective radical reactions /1-face selective quenching of the l,2-0-isopropylidene-3,4,6-tri-0-benzyl-D-glucopyranos-l-yl radical, Tetrahedron Lett., 32 (1991) 2565-2568. 

Radical reactions have been recognised only recently for the construction of enantiomerically pure compounds (Renaud and Sibi 2001 Zimmerman and Sibi 2006). In addition to substrate- or auxiliary-induced diastereoselective radical reactions, and in addition to the use of chiral Lewis acids, chiral hydrogen atom donors or chiral transition metal complexes, template molecules can be used to generate a chiral environment and induce chirality to the substrate. With the chiral complexing agent 12, enantioselective radical reactions were achieved with enantiomeric excesses up to 99% ee. 

Lewis Acid-Mediated Diastereoselective Radical Reactions... 

These selected examples show the importance of Lewis acid in diastereoselective radical reactions. Complexation with Lewis acid, in an endocyclic manner or by using extremely bulky metal complexes such as MABR or MAD, reduces the conformational flexibility of intermediate radicals resulting in an improved facial bias. Lewis acid has been shown to effectively enhance facial selectivity by making a temporary ring a to the radical, thus mimicking the exocyclic effect. Radical reactions involving chiral auxiliaries have also benefited from the use of Lewis acid. 

Although viewed with skepticism ten years ago, the use of Lewis acid to influence stereoselective radical processes is now well established. However, considerable work remains to be done in this area of research. While the perception of complexity in diastereoselective radical reactions involving Lewis acids has in the end proven valid, the richness of the resulting chemistry has been delightfully rewarding. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

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. 

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. 

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). 

Since Et3B-initiated radical reactions with Bu3SnH under aerobic conditions, can be carried out at 0 °C or lower temperature, stereoselective reduction of reactive a-haloesters or a-haloketones can be performed. Eq. 10.1 shows Et3B-mediated Bu3SnH reduction of p-methoxy-a-bromo ester in the presence and absence of MgBr2 (Lewis acid) at 0 °C. Anti/syn diastereoselectivity depends on the absence or presence of a Lewis... 

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

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. 

While high stereoselection has been achieved in radical reactions which occur in a-position146 to a center substituted with a chiral auxiliary, diastereofacial control in the addition of achiral radicals to the P carbon is, in general, difficult to achieve.147 In connection with this, Toru et al. reported extremely high P-stereoselection in the addition of tertiary, secondary, and even primary alkyl radicals to chiral a-sulfinyl cyclopentanones in 1993.148 The effectiveness of the diastereoselective addition of achiral radicals has been shown to depend on the size of the substituent at the sulfmyl sulfur. Bulky chiral arylsulfmyl groups show excellent diastereoselectivi-ties (> 98 < 2). 

The most remarkable feature of this method is that even acyclic enamines undergo reductive alkylation with good diastereoselectivity. The reaction of propiophenone enamines 31-33 with primary carbon-centered radicals substituted by different electron-... 

---