Radical stereoselectivity reductive alkylation

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Nilsson, L., Rappe, C. Alkylation of enamines. A convenient route to 1,4-dicarbonyl compounds. Acta Chem. Scand. 1976, B30,1000-1002. Schubert, S., Renaud, P., Carrupt, P. A., Schenk, K. Stereoselectivity of the radical reductive alkylation of enamines importance of the allylic 1,3-strain model. Helv. Chim. Acta 1993, 76, 2473-2489. 

Cyclopentyl radicals substituted in the /1-position relative to the radical center are formed during the solvomercuration/reductive alkylation reaction of cyclopentene34. The organomer-curial produced in the first solvomercuration step is reduced by sodium borohydride and yields free cyclopentyl radicals in a radical chain mechanism. Addition of alkenes can then occur tram or cis to the / -alkoxy substituent introduced during the solvomercuration step. The adduct radical is finally trapped by hydrogen transfer from mercury hydrides to yield the tram- and ris-addition products, The transicis ratio depends markedly on the alkene employed and it appears that the addition of less reactive alkenes occurs with higher trans selectivity. In reactions of highly substituted alkenes, this reactivity control is compensated for by steric effects. Therefore, only the fnms-addition product is observed in reactions of tetraethyl ethenetetracarboxylate. The choice of alcohol employed in the solvomercuration step has, however, only a small influence on the stereoselectivity. 

The stereoselectivity has been studied more systematically for the reductive alkylation of maleic anhydrides or maleimides1 20. In these reactions, the initial radical addition step is followed by trapping of the adduct radical, which can occur cis or trans relative to the initial addition step. For addition reactions to methylmaleic anhydride, the final hydrogen abstraction step occurs preferrentialy trans to the substituent introduced in the addition step (R1). cis Selectivity increases with the size of this substituent18. 

Guindon Y, LavaUee JP, Boisvert L, et al. Stereoselective radical-mediated reduction and alkylation of a-halo esters. Tetrahedron Lett. 1991 32 27-30. 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Selective ring closure of cyclic secondary alkyl radicals onto the central carbon atom of allenes have been investigated in the course of pyrrolizidine alkaloid syntheses [69]. Thus, reduction of the phenylselenyl-substituted N-(l,2-buten-4-yl)pyrroli-done 42 with Bu3SnH via a radical chain mechanism provides 51% of target compound 44 as a 78 22 mixture of diastereomers (Scheme 11.14). The stereoselectivity... 

The reductive radical alkylation of oxazines using triethylborane as reagent or catalyst (Scheme 8) is also applicable to dihydrooxazines, and can be performed stereoselectively <2003CC426, 2005jOC3324>. This gives the reaction importance in the synthesis of enantiomerically pure amino acids, and it is discussed further in Section 8.06.11.3. 

Homoallylic alcohols are also suitable for controlling the introduction of an alkyl chain, as shown by the synthesis of the diterpenoid atractyligenin61, The starting tricyclic alcohol is converted to the selenocarbonate, a suitable radical precursor. Treatment with tributyltin hydride initiates the stereoselective cyclization which affords the bridged lactone system, an intermediate in the diterpenoid synthesis. Due to the low cyclization rate, tributyltin hydride is added slowly to suppress the formation of noncyclized reduction products. 

In non-polar solvents a decrease in yield was observed in the reactions with N-bromosuccinimide, and a loss of stereoselectivity in the reaction of the exo-isomer with bromine. The inversion of configuration in the reaction with N-bromosuccinimide was explained by direct electrophilic displacement (Scheme 5), but the reaction with bromine was considered to proceed by an initial electron-transfer step, followed by nucleophilic attack of bromide ion on the resulting organopentafluorosilicate radical-ion (Scheme 6). Steric constraints or a reduction in the polarity of the solvent would allow dissociation of the radical ion to a free alkyl radical, and loss of stereoselectivity, as observed (Scheme 7). 

Reductive lithiations of substituted tetrahydropyrans are often highly stereoselective reactions as a direct consequence of the anomeric radical intermediates involved. The mechanism involves one-electron reduction of a thiophenyl ether (or an equivalent reactive functional group) to generate an axial anomeric radical that is reduced by a second electron to form an axial a-alkoxylithium species, which can then be alkylated or protonated. Thus the high selectivities observed in reductive lithiations are a direct reflection of the axial preference for a-oxygenated radicals. 

An alkylation/reductive decyanation method was developed for the efficient synthesis of xjn-l,3-diols [9, 10]. Cyanohydrin acetonides are rapidly deprotonated by amide bases and alkylated with suitably reactive electrophiles to yield diaste-reomerically pure coupled products. Subsequent exposure to Li/NHa affords exclusively xy -l,3-diol acetonides (see above). Although the alkylation itself is stereoselective, it is noteworthy that the, 2>-syn stereochemistry is ultimately set in the reductive decyanation by virtue of the anomeric axial radical intermediate. This methodology was effectively applied in the total synthesis of the polyene macrolide roflamycoin (Scheme 15) [23]. Noteworthy is the formation of the entire protected polyol segment of roflamycoin by treatment of a late-stage intermediate with Li/ NHa to effect a simultaneous decyanation/debenzylation. 

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