Ketones, cyclic reduction with Selectride

Lithium tri-sec-butylborohydride, also known as L-selectride, is a metal hydride reagent that contains three sec-butyl groups bonded to boron. When this reagent is used to reduce cyclic ketones, one stereoisomer often predominates as product. Explain why the reduction of 4-ferf-butylcyclohexanone with L-selectride forms the cis alcohol as the major product. 

In contrast to the facile MAD- or MAT-mediated alkylation of cyclic ketones with primary organolithium or Grignard reagents, reduction takes precedence over alkylation with hindered alkylation agents such as fert-butylmagnesium chloride in the presence of MAD [131], This amphiphilic reduction system seems to be complementary to existing methodologies which use L-Selectride to obtain axial selectivity (Sch. 94). 

The principal interest of these reagents resides in their bulkiness. The reductions of slightly hindered cyclic ketones and imines occurs on the equatorial face (Sections 3.2.2, 3.3.1), and aliphatic carbonyl compounds are reduced with a high stereoselectivity (Section 3.2.2). The Li and K Selectrides selectively reduce the carbon-carbon double bond of a-enones and a,p-ethylenic esters unless the p position is disubstituted (Section 3.2.9) in the latter case, the carbonyl of the a-enones is reduced. 

Other cyclic or bicyclic ketones do not have a convex side but only a less concave and a more concave side. Thus, a hydride donor can add to such a carbonyl group only from a concave side. Because of the steric hindrance, this normally results in a decrease in the reactivity. However, the addition of this hydride donor is still less disfavored when it takes place from the less concave (i.e., the less hindered) side. As shown in Figure 10.10 (top) by means of the comparison of two reductions of norbomanone, this effect is more noticeable for a bulky hydride donor such as L-Selectride than for a small hydride donor such as NaBH4. As can be seen from Figure 10.10 (bottom), the additions of all hydride donors to the norbomanone derivative B (camphor) take place with the opposite diastereoselectivity. As indicated for each substrate, the common selectivity-determining factor remains the principle that the reaction with hydride takes place preferentially from the less hindered side of the molecule. 

Finally, a recent noteworthy development is the use of molecular mechanics calculations to rationalize and predict the stereoselective reduction of large-ring ketones. This has been of particular interest to chemists working on the synthesis of macrolide antibiotics. An example is the reduction of the cyclic oxolactone 3-methyl-2-oxa-l,7-cyclotetradecanedione with LS-Se-leetride or L-Selectride to give the /ram-alcohol with d.r. (transjcis) 90 10131. 

---