Reduction hydroxy ketone

Nicolaou hydroxy-ketone reductive cyclic ether formation... 

Reduction of jl-hydroxyketones through chelated transitions states fovors syn-1,3-diols. Boron chelates have been exploited to achieve this stereoselectivity.86 One procedure involves in situ generation of diethylmethoxyboron, which then forms a chelate with the /1-hydroxy ketone. Reduction with NaBH4 leads to the syn diol.87... 

The stereocontrolled reduction of optically pure P-keto sulfoxides (60) with DIBAL-H anti selective, >93 7) or DlBAL-H in the presence of zinc chloride (syn selective, >95 5) provided an entry to enantio-merically pure alcohols after desulfurization (Scheme 9). The stereoselectivity may be rationalized by consideration of transition states analogous to those described for P-hydroxy ketone reduction (31 and 32), cyclic chelation by zinc chloride and external hydride delivery giving the syn isomer, and coordination of the DIBAL-H to the sulfoxide and internal hydride delivery giving the anti product. 

Reduction of a-Ketolsf Carbonyl compounds containing a-hydroxy, a-acetoxy, or a-halo groups react with excess TMS-I to give the parent ketone. a-Hydroxy ketone reductions proceed via the iodide, which is then reduced with iodide ion to form the parent ketone (eq 32). 

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. 

The synthesis of hydroxy ketone A, via a different reduction process as shown below ... 

Borohydrides reduce a-substituted ketones to the corresponding a-substituted alcohols, and such products can be further reduced to olefins (see section VIII). Other reagents serve, through participation of the carbonyl group, to remove the substituent while leaving the ketone intact. The zinc or chromous ion reduction of a-halo ketones is an example of this second type, which is not normally useful for double bond introduction. However, when the derivative being reduced is an a,jS-epoxy ketone, the primary product is a -hydroxy ketone which readily dehydrates to the a,jS-unsaturated ketone. Since... 

The milder metal hydnde reagents are also used in stereoselective reductions Inclusion complexes of amine-borane reagent with cyclodexnins reduce ketones to opucally active alcohols, sometimes in modest enantiomeric excess [59] (equation 48). Diisobutylaluminum hydride modified by zmc bromide-MMA. A -tetra-methylethylenediamme (TMEDA) reduces a,a-difluoro-[i-hydroxy ketones to give predominantly erythro-2,2-difluoro-l,3-diols [60] (equation 49). The three isomers are formed on reduction with aluminum isopropoxide... 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

Scheme 10. Synthesis of compound 49 by the reductive hydroxy ketone cyclization method.

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

Scheme 11. Bis(oxepane) synthesis using a photochemical dithioester cyclization and a reductive hydroxy ketone cyclization.

Metalation ofa-sulfinyl dimethylhydrazones with terf-butylmagnesium bromide, butyllithium or lithium diisopropylamide, and reaction of the generated azaenolates with aldehydes, provides aldol adducts (e.g., 6) as mixtures of diastereomers. Reductive desulfurization leads to fi-hydroxy dimethylhydrazones (e.g., 7) which are cleaved to the desired /(-hydroxy ketones in 25% overall yield10 u. The enantiomeric excesses are about 50%, except for (- )-3-hydroxy-4-methyl-1-phenyl-1-pentanone (8) which was obtained in 88% ee. 

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. 

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