Reducing agent, hindered chemoselectivity

The requirement for a powerful nucleophilic hydride reagent able to reduce even very hindered ketones rapidly and quantitatively has been satisfied by lithium triethylborohydride which was screened against selected representative functional groups. The quest for increased chemoselectivity in total synthesis has led to the development of reducing agents that will discriminate between various classes of ketone or between ketones and other carbonyl groups. 

Potassium triisopropoxyborohydride, a mild selective reducing agent, rapidly converted ketones and aldehydes to the corresponding alcohols, while many common functional groups were inert.The reaction of potassium hydride with triphenylborane produced the triphenylborohydride, which is highly hindered and which exhibited excellent chemoselectivity between ketones. Cyclohexanone was reduced in preference to cyclopentanone (97 3) and 4-heptanone (99.4 0.6), while methyl ketones were more reactive than 4-heptanone (2-heptanone, 94 6 acetophenone, 97.8 2.2). 

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). 

A more versatile reducing agent is samarium diiodide, which promotes chemoselective cyclizations of functionalized keto aldehydes in a stereodefined manner to form 2,3-dihydrocyclopentane carboxylate derivatives in good yields and with diastereoselectivities of up to 200 1 (equation 38)7 The reaction proceeds via selective one-electron reduction of the aldehyde component and subsequent nucleophilic attack on the ketone moiety. Stereochemical control is established by chelation of the developing diol (19) with Sm " " which thereby selectively furnishes cis diols (equation 39). The stereoselective M/-cyclization of 1,5-diketones to cis cyclopentane-1,2-diols using TiCU/Zn has been used to prepare stereodefined sterically hindered acyclic 1,2-diols when a removable heteroatom, such as sulfur or selenium, is included in the linking chain (equation 40). 

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