Selective Reduction Between Ketones

Selective reduction of ketones.1 This reagent can be used to effect selective reduction of the more hindered of two ketones by DIBAH or dibromoalane. Thus treatment of a 1 1 mixture of two ketones with 1-2 equiv. of 1 results in preferential complexation of the less hindered ketone with 1 reduction of this mixture of free and complexed ketones results in preferential reduction of the free, originally more hindered, ketone. An electronic effect of substituents on a phenyl group can also play a role in the complexation. This method is not effective for discrimination between aldehydes and ketones, because MAD-complexes are easily reduced by hydrides. MAD can also serve as a protecting group for the more reactive carbonyl group of a diketone. The selectivity can be enhanced by use of a more bulky aluminum reagent such as methylaluminum bis(2-f-butyl-6-( 1,1-diethylpropyl)-4-methylphenoxide). 

A convenient new one-pot procedure for the selective reduction of ketones in the presence of aldehydes (the less usual chemoselectivity) is outlined in Scheme 9. ° The aldehyde is protected as an imine and the ketone is then reduced in situ with a hindred hydride reagent the aldehyde is regenerated on hydrolytic work-up. Conjugated and aromatic aldehydes are protected satisfactorily by this sequence, and moderate discrimination between aliphatic and aromatic aldehydes, with preferential reduction of the aromatic aldehyde, can also be achieved. These authors claim better selectivity than previous methods based on ketalization or hydration of aldehydes with lanthanoid cation catalysts (4,141). 

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). 

With respect to reactivity, the amine-boranes lie somewhere between BHj-THF and NaBH4. They reduce aldehydes and ketones without affecting ester, ether, SPh, and NOj groups (Section 3.2,1), The reduction of ketones can be accelerated by the addition of Lewis acids or when carried out in acetic acid [PSl], On alumina or silica supporrts, amine-boranes can selectively reduce aldehydes without affecting keto groups (Section 3.2.1) [BSl], Chiral amino acids can be reduced to amino alcohols without epimerization [PSl],... 

Aldol condensation between ketone 307 and aldehyde 298 afforded the E,E)-dienone 308 in 41% yield. Nonselective reduction of the C-9 ketone and base hydrolysis then produced a 77% yield of the seco acids 309. Lactonization utilizing the Corey thiopyridyl ester method and selective oxidation of the C-9 allylic hydroxyl group afforded the protected aglycone 310 in 59% yield. 

Chemoselectivity, for example, the differentiation between a ketone and an aldehyde, can in favorable cases be realized by capitalizing on the inherent reactivity of a specific functional group environment. Consider the conversion of 11 to 12 (Scheme 7.18). Traditionally, one tends to apply two short-term protecting groups to achieve the selective reduction of the keto function. 

This study did not investigate the transfer hydrogenation of 12 using a homogeneous catalyst. These studies would have been a useful comparison between a homogeneous catalyst and an MIP for the selective reduction in structurally similar ketones. 

Diastereoselective Reduction of Ketones by Baker s Yeast. Asymmetric microbial reduction of oc-substituted ketones leads to the formation of diastereomeilc syn-and anh -products. Because the chiral center on the a-position of the ketone is stereochemically labile, rapid in-situ racemization of the substrate enantiomers occurs via enolization ° - leading to dynamic resolution [67, 895, 896]. Thus, the ratio between the diastereomeric syn- and anti-products is not 1 1, but is determined by the selectivities of the enzymes involved in the reduction process [897]. Under optimal conditions it can even be as high as 100 0 [898]. 

---