Reducing agent, hindered Reduction

The reduction of epoxides to alcohols has been accomplished by a variety of reducing agents. The reduction of unsymmetrical epoxides with lithium aluminium hydride in general occurs by attack of the hydride at the least-hindered side of the epoxide to form the more highly substituted alcohol. 

The copper-catalyzed chiral reduction of -substituted ,/Tunsaturated lactones with PMHS and (S)-/ -Tol-BINAP in the presence of a hindered alcohol can be carried out in moderate to good yields with moderate ee values.599 The reaction is useful for both butenolides and pentenolides. Inferior results are realized with diphenylsilane as the reducing agent. Excellent results employing PMHS and the DTBM-SEGPHOS ligand are possible (Eq. 354).598... 

In ketones having a chiral cluster next to the carbonyl carbon reduction with lithium aluminum hydride gave one of the two possible diastereomers, erythro or threo, in larger proportions. The outcome of the reduction is determined by the approach of the reducing agent from the least hindered side (steric control of asymmetric induction) [828]. With lithium aluminum hydride as much as 80% of one diasteromer was obtained. This ratio is higher with more bulky reducing hydrides [837]. 

In the presence of excess monoalkylamine, carbonyl compounds in aqueous solution are in equilibrium with the corresponding imine. In most cases these imines cannot be isolated but they are reduced at a less negative potential than the carbonyl compound. Selective reduction of such equilibrium mixtures is a useful route to alkylamines from ketones in yields of 70-90%. The process fails with hindered ketones such as camphor and with bulky amines such as fert.-butyl amine. Overall the reaction has advantages of lower costs and simpler work-up compared to the use of cyanoborohydride reducing agents. In the electrochemical reaction, protonation of carbanion intermediates occurs from the more hindered side and where two isomeric products are fomied, the least hindered amine predominates [193]. 

For reducing ozonides or sterically hindered peroxides, magnesium and methanol proved to be a better and mild reducing agent <2004JOC2851>. Thus, the bicylic ozonide prepared from 1-phenylcyclopentene, which is prone to base-mediated cleavage, was cleanly reduced by Mg/MeOH to the keto-acid with the ketonic methyl ester as a by-product, whereas reduction with zinc and acetic acid affords mainly the keto-aldehyde with the keto-acid as a by-product (Equation 7). 

The concept of in situ protection of the less hindered or more Lewis basic of two ketones to enable selective reduction of the usually less reactive groups has been successfully developed. The sterically hindered Lewis acid MAD (78) derived from BHT and trimethyl aluminum was used to coordinate preferentially to the less hindered ketone and DIBAL-H reduced the more hindered ketone that remained un-complexed. An approximate order of comparative reactivity for various classes of ketones has been established. The selectivity was improved by using the more hindered Lewis acid MAB (79) and/or di-bromoalane as the reducing agent. The discrimination between aromatic ketones is good but less successful between two dialkyl ketones. The chemoselectivity was demonstrated in the reduction of diketone (80) to keto alcohol (81) in 87% yield and excellent selectivity (equation 20). 

The reduction of d. S-imonium salts (XXXII) of substituted quinolizidines with sodium borohydride is influenced by substituents at position 3 44). The stereochemical course of the reaction is dependent upon the more stable conformation of the imonium salt. Quasiaxial hydrogen in position 3 hinders the approach of the reducing agent on that side and there result the energetically less stable quinolizidines XXXIII. 

---