Reduction hydride delivery from carbon

R. M. Kellogg, Reduction of C=X to CHXH by Hydride Delivery from Carbon, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 8, 79, Pergamon Press, Oxford, 1991. 

Reduction of C=X to CHXH by Hydride Delivery from Carbon... 

These trends agree with the frontier orbital analysis. In particular, the delivery of hydride from carbon breaks a relatively unpolarised bond, making the hydride notably soft, as we saw earlier in its capacity to attack pyridinium salts preferentially at the 4-position. The metal hydrogen bond will be more polarised, and metal hydrides should therefore be harder. Similarly, the delivery of hydride from boron will make it softer than when it is delivered from the more electropositive metal, aluminium. It also seems that, among a,(3-unsaturated carbonyl compounds, the susceptibility to conjugate reduction increases in the sequence ketones < esters < acids < amides but there are too few examples to be sure. 

The general message from these reductions is to enhance the hydride donor capacity of a Lewis acid reagent by a neighboring basic center, or to hook the hydride donor into a proper position relative to the epoxide to direct hydride delivery into the desired carbon atom. 

Enyne cycloisomerizations can also be exploited to annulate a cyclopentane onto an existing ring system. An example drawn from Trost and co-workers asymmetric total synthesis of picrotoxinin (119) is the conversion of bridged bicyclic intermediate 117 into tricycle 118 (Scheme 6-20) [46]. The optimal cyclization conditions in this case were unusual, requiring an internal proton delivery and a bidentate phosphine. A related example is the conversion of 120 to 121, which was the pivotal step in Trost s synthesis of (—)-dendrobine (122) [47]. An all-carbon tether is not required, as is exemplified by the conversion of 123 to 124 in the total synthesis of ( )-phyllanthocin (125) [48]. Note that in-situ reduction of the o-palladium species prior to /5-hydride elimination has occuined in this latter-example. The enyne disconnection in the synthesis of ( )-phyllanthocin was... 

Because of electronic repulsion, nucleophilic attack on the carbonyl function does not occur perpendicular (90° angle) to the tr bond, but at an angle (107°) away from the negatively polarized oxygen. Consequently, the nucleophile approaches the target carbon in relatively close proximity to its substituents. For this reason, hydride reductions can be stereoselective, with the delivery of hydrogen from the less hindered side of the substrate molecule. Predict the likely stereochemical outcome of the treatment of compound A with NaBH4. (Hint Draw the chair form of A.)... 

Figure 2 Delivery of the hydride from NADH to the re or si side of a prochiral ketone yielding either (S)- or (/ )-alcohols. Depending on the dehydrogenase involved either the pro (/ )- or the pro (5)-hydrogen at C-4 of the nicotinamide moiety of NAD(P)H is selectively transferred in the course of the reduction. L denotes the larger and 5 the smaller substituent at the central carbon.

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