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Lithium tri- n -butyl borohydride showed high selectivity in the reduction of α- and β-oxygenated ketones, giving a preponderance of the chelation controlled products.

To enhance the diastereoselectivity of the hydrogen transfer reaction of acyclic substrates bearing 1,2- or 1,3-diols, the feasibility of a strategy employing bifunctional protecting groups has been demonstrated. This strategy is based upon the “exocyclic effect” or the significant improvement of anti-selectivity exhibited by the reductions of substrates in which the two substituents (R1 and Y) at the stereogenic center α to the radical center are linked together. A rationale for the excellent facial discrimination of these exocyclic radicals is offered based on an analysis of transition state models, which considers both steric and electronic factors.

To enhance the diastereoselectivity of the hydrogen transfer reaction of acyclic substrates bearing 1,2- or 1,3-diols, the feasibility of a strategy employing bifunctional protecting groups has been demonstrated. This strategy is based upon the “exocyclic effect” or the significant improvement of anti-selectivity exhibited by the reductions of substrates in which the two substituents (R1 and Y) at the stereogenic center α to the radical center are linked together. A rationale for the excellent facial discrimination of these exocyclic radicals is offered based on an analysis of transition state models, which considers both steric and electronic factors.

Lithium tri- n -butyl borohydride showed high selectivity in the reduction of α- and β-oxygenated ketones, giving a preponderance of the chelation controlled products.

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of propionate motifs. The nature of the protecting groups on the chiral beta-alkoxy aldehyde and the type of Lewis acid used are varied to modulate the stereochemical outcome of the tandem reactions. The mode of complexation is thus controlled (monodentate or chelate) for the Mukaiyama reaction to give access to either syn or anti aldol products, precursors of the free radical reduction reaction. The endocyclic effect is subsequently capitalized upon to control the hydrogen transfer step so that the syn-reduced product may be achieved. Proceeding with excellent yield and diastereoselectivity, the synthetic sequence proposed gives access to syn-syn and syn-anti propionate motifs. Also considered is a complementary approach using a chelation-controlled Mukaiyama reaction in tandem with a free radical allylation reaction under the control of the endocyclic effect that leads to the anti-anti product.

The strategy considered herein features an iodocyclofunctionalization/hydrogen-transfer reaction sequence for the elaboration of propionate motifs. Proceeding with excellent yield and diastereoselectivity, the synthetic sequence proposed gives access to the anti-anti dipropionate motif when the reduction step is performed under the control of the exocyclic effect. The tandem sequence is applied successfully to the synthesis of the C(7)-C(16) subunit of zincophorin, and iteration of the process gives the desired anti-anti-anti-anti polypropionate stereopentad. Modifications of the reaction sequence--including phenylselenocyclofunctionalization, carbonate hydrolysis, and chelation-controlled radical reduction reactions--lead to the formation of the anti-syn dipropionate motif with remarkable diastereocontrol.