Reduction of P-hydroxy ketones

In theory, the chiral center can be anywhere in the molecule, but in practice, reasonable diastereoselectivity is most often achieved when it is in the a position. For examples of high diastereoselectivity when the chiral center is further away, especially in reduction of P-hydroxy ketones, see Narasaka, K. Pai, F. Tetrahedron, 1984, 40, 2233 Hassine, B.B. Gorsane, M. Pecher, J. Martin, R.H. Bull. Soc. Chim. Belg., 1985, 94, 597 Bloch, R. Gilbert, L. Girard, C. Tetrahedron Lett., 1988, 53, 1021 Evans, D.A. Chapman, K.T. Carreira, E.M. J. Am. Chem. Soc., 1988, 110, 3560. 

The regiospecificity of the exclusive O-acylation [8] and O-phosphorylation [9] of P-dicarbonyl compounds (Chapter 3) also illustrates the effect of phase-transfer catalysts on the stereochemical course of reactions. Similarly, directed reduction of P-hydroxy ketones using tetramethylammonium trisacetoxyborohydride leads to the preferential formation of the anti dihydroxy system in high yield with a stereoselectivity >95% [10] (Section 11.4). 

Evans DA, Chapman KT et al (2002) Directed reduction of P-hydroxy ketones employing tetramethylammonium triacetoxyborohydride. J Am Chem Soc 110 3560-3578... 

Keck recently applied the diastereoselective reduction of ( S-hydroxy ketones in an approach to the anti-tumour natural products epothilone A and B. Sml2-mediated reduction of p-hydroxy ketone 15 in THF-MeOH gave anti- 1,3-diol 16 in 94% yield and as a 96 4 mixture of diastereoisomers.18 Attempts to carry out the reduction using common hydride reducing agents gave 16 with poor levels of diastereoselectivity (Scheme 4.10).18... 

A boat form can also be invoked 83). It should be noted that the direction of attack is opposite to that proposed for chelation controlled reduction of p-hydroxy ketones 104W. 

Trialkylboranes are also effective chelation agents in stereoselective NaBH4 reductions of P-hydroxy ketones to 1,3-syn diols. ... 

Diisobutylaluminum hydride (DIBAH) is undoubtedly one of the most common reducing agents in organic synthesis and recent interest in the synthetic utility of DIBAH has been directed toward diastereoselective reduction of carbonyl substrates. High, i-syn diastereoselectivity has been achieved in the chelation-controlled reduction of P-hydroxy ketones with DIBAH in THF [49], The choice of solvents strongly affects the selectivity. Use of CH2CI2 or toluene in place of THF did not show any diastereoselectivity. 

Claisen rearrangement The Ireland-Claisen rearrangement Stereoselective Reduction of p-Hydroxy Ketones... 

Mediation of reduction. The reduction of P-hydroxy ketones with borane-pyridine... 

Storage Moisture-sensitive store in cool, dry place away from heat, sparks, open flame store under nitrogen keep tigthly closed Uses Reducing agent in silylation-reduction-allylation sequence of p-hydroxy esters to homoallylic-substituted 1,3-diols, in silylation-hydrosilation-oxidation of allyl alcohols to 1,3-diols, reduction of p-hydroxy ketones to anti-1,3 diols... 

Table 4 Diastereoselective reduction of p-hydroxy ketone hydride QH 9 ...

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

Three years after Narasaka and Pai s disclosure, Prasad et al. developed a modified procedure to improve syn -diastereoselecti vi ty in the reduction of certain (3-hydroxy ketones6 (Scheme 4.Id). When methoxydiethylborane, in lieu of tributylborane, reacts with p-hydroxy ketones at —70 C in anhydrous methanol, the complex 5BEt2 is formed. Subsequent treatment of the complex with sodium borohydride and quenching the reaction mixture with acetic acid affords yyn-diols in excellent levels of diastereoselectivity regardless of the structure of p-hydroxy ketones. Another practical advantage of Prasad et al. s modification may be an enhanced safety feature, as methoxydiethylborane is generally less hazardous to handle than triethylborane.6... 

The 1,3-anti -reduction of (3-hydroxy ketones was utilized in the total synthesis of (+)-roxaticin (14), a pentaene macrolide isolated from streptomycete X-149944 (Scheme 4.2e). The (3-hydroxy ketone 15 underwent 1,3-anti -reduction to afford the diol 16 in 99% yield and greater than 95 5 diastereoselectivity. The resulting diol was then protected as a cyclopentylidene ketal (17) by using cyclopentylidene dimethyl ketal and pyridinium p-toluene sulfonate (PPTS). 

Stereoselective reduction of -hydroxy ketones." Boron chelates of p-hydroxy ketones are reduced by sodium borohydride stcrcoseicctivciy to, vvn-l,3-diols (equation I). Even higher, sy -selectivity obtains on similar reduction of. wn-a-substituted-p-hydroxy... 

An impressive new route to enantiopme syn- and anft-1,2-diols involves sequential diastereoselective DIBAL reduction of oxalyl-di(iV-methyl-7V-methoxyamide) following conversion to a corresponding intermediate P-keto sulfoxide a route that involved control of both reductions by the chiral sulfoxide auxiliary. Comparison of P-hydroxy ketone systems with the y-sulfoxide-) -keto systems used here showed this to be the first example of such asymmetric induction by a y-sulfoxide substituent. 

Reductive aldol reactions/ In situ aldol reaction of the tin enolates derived from the reduction of enones provides a method for the preparation of p-hydroxy ketones with the 2,3-syn isomers predominating. 

More recently, Doris et al. have described the reductive ring-opening of a-keto epoxides [16]. In this manner, p-hydroxy ketones can be obtained in high yields. The synthesis of enantiomerically pure compounds can easily be realized. The titanocene] 111) reagents are distinctly superior to samarium diiodide, which is also known to induce this transformation. 

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