Enones asymmetric reduction

The intermediate enolate or enol ether from the initial reduction of an enone may be alkylated in situ (Eq. 281).455 / -Substituted cyclopentenones may be asymmetrically reduced and alkylated459 (see section on asymmetric reductions of enones). Enolates may also be trapped with an aldehyde in a reductive aldol condensation of an enone with an aldehyde,455 permitting a regioselective aldol condensation to be carried out as shown in Eq. 282.455 This class of reductive aldol condensation reactions can also occur in a cyclic manner (Eq. 283).460... 

Another method for ketone reduction, BINAL-H asymmetric reduction, can also be used in co-side chain synthesis. An example of applying BINAL-H asymmetric reduction in PG synthesis is illustrated in Scheme 7-27. This has been a general method for generating the alcohol with (15. -configuration. The binaphthol chiral auxiliary can easily be recovered and reused. As shown in Scheme 7-27, when the chiral halo enone 91 is reduced by (S -BINAL-H at — 100°C, product (15S)-92 can be obtained with high enantioselectivity. 

Asymmetric reduction of a,fi-enon s. This combination of reagents (1 1) in conjunction with N-cthylaniline (2 equivalents) reduces alkyl aryl ketones to alcohols with high stereoselectivity.1 Under these conditions 2,/1-unsaturated ketones arc reduced to optically active (S)-allylic alcohols. Optical yields of 80 98% have been reported for open-chain enones. Reduction of cyclic enones is somewhat less efficient. The method was used to reduce 1 to 2, which has been used as an intermediate in an anthracyclinone synthesis.2... 

Asymmetric reduction of oi, -enones. Prochiral cyclic and acyclic a,p-enones are reduced by lithium aluminum hydride complexed with 1 to (S)-allylic alcohols in optical yields of 30-100% (equation 1). 

In general, structural variations to the backbone of the Chirald ligand have not led to the development of more selective or reliable LAH complexes for use in asymmetric reductions. Other complexes of amino alcohols with LAH have been studied for their ability to achieve enantioselective reduction of prochiral ketones. However, in most cases the selectivities observed have been moderate. The complex of LAH with the amino alcohol (IS) reduces some enones, such as cyclohexenone and cyclopentenone, to the corresponding (5)-alcohols in high optical purities (100% and 82% ee, respectively). ... 

The difference is that there was already a chiral centre in the enone, but there wasn t in the amide because the nitrogen atom is flat. All the stereochemistry in the amide product is induced in the hydrogenation. For the enone, if the starting material was racemic, the product will be racemic too. If, on the other hand, the enone starting material was a single enantiomer, then we don t need asymmetric reduction. In either case, asymmetric reduction is too late. 

Chiral reductions are now quite common with these reagents when used either in stoichiometric amounts [CT4, MT6, SCI] or in catalytic amounts in the presence of BH3 THF, catecholborane [G6, GB6, QWl, SK5], or BH3 Me2S as achiral reducing co-reagent [DS6, JM3, N5, S5, SCI, SM6, TA3, TBl, YL4]. The asymmetric reduction of aldehydes, various ketones, a-enones, and a-ynones usually take place with an excellent enantiomeric excess [BB13, CL2, CL6, CR2, CT4, DS5, DK2, GB6, MT6, NNl, PL2, S4, SM6, WM2] (Figure 3.24). The reduction of ketones is carried out between -20°C and r.t., while that of aldehydes requires - 126°C for a good asymmetric induction. 

Other related examples are provided in the literature [KY3, NS5, SM8, TH2, WKl, YK6]. The reductions of substituted cyclopentenones, functionalized vi-nylketones, and carbacyclin precursors by NaBH4-CeCl3 in MeOH have also provided interesting stereoselectivities [BA4, GLl, Jl, MH5, SG3]. The asymmetric reduction of a-enones by oxazaborolidines-BH3 has been described in Section 3.2.3. 

Conjugate addition of the complete allylic alcohol fragment is possible with the mixed cuprate reagents 33 prepared by asymmetric reduction (chapter 26) of acetylenic ketones 29 to give the alcohols 30, protection as a silyl ether 31 and hydroboration-iodination. Lithiation and reaction with hexynyl copper (I) gives the mixed cuprate 33 from which the less stable anion is transferred selectively to an enone.3 This approach has been widely used in the synthesis of prostaglandins. 

Should the starting material 53 be enantiomerically pure Yes, as there is virtually no kinetic resolution. The asymmetric centre in 53 is evidently too far from the alkene that reacts by AE to have more than a minor effect on the stereoselectivity. Enantiomerically pure alcohol 53 was already available from asymmetric reduction (using CBS, see chapter 26) of the corresponding enone. Sharpless epoxidation does have limitations but it is supremely practical. 

When asymmetric reduction of the ketone of an enone such as 39 is wanted, the catalyst must be further modified14 by using the very crowded BINAP derivative XYLBINAP 41 and the diamine additive DAIPEN 42. The results are then excellent but this example makes the point that it is essential to follow closely related examples when attempting the asymmetric reduction of any but the simplest alkene. 

More recent efforts to effect metal-free hydrogenations have fallen in the realm of organo-catalysts. For example, the hydrogenation of enones, imines, unsaturated a,P-aldehydes, and quinolines have been achieved without a metal, however, in these cases the stoichiometric source of H2 was a Hantzsch ester (Scheme 11.3) [10-14], Such a protocol can be applied to asymmetric reductions, as substituted enones can be reduced with reasonable enantiomer excesses between 73 and 91%. A variety of organocatalyst systems have been reviewed [15, 16]. 

The encouraging result of the trans-epoxy acylates with the chiral spiro compounds was appUed to the optically active system (Scheme 15). Asymmetric reduction of the enone 31 by Corey s method [72] afforded the allyl alcohol (-)-34 (90% ee). Epoxidation of (-)-34 by the stereoselective Sharpless epoxidation [73] afforded the cts-epoxy alcohol, cfs-(-)-35, as the sole product. The Mitsunobu reaction [74] of czs-(-)-35 with benzoic acid gave the trans-epoxy benzoate, trans- -)-36, (90% ee) in 89% yield. Treatment of trans-(-)-36 with BF3-Et20 afforded the optically active spiro compound (+)-37 in 89% yield with retention of the optical purity (90% ee). This means that the rearrangement occurs stereospecifically. The optically pure epoxy camphanate (-)-38 could be obtained after one recrystallization of the crude (-)-38 (90% de), which was obtained by the Mitsimobu reaction of cfs-(-)-35 with D-camphanic acid. The optically pure spiro compoimd (+)-39 (100% de) was obtained from the optically pure (-)-38 in 89% yield. 

The first compound is an ester derived from a cyclic secondary alcohol that could be made from the corresponding enone by asymmetric reduction. 

Alkylated oxazaborolidines such as (3.123) and (3.124) are more stable to air and moisture than (3.115) and exhibit better selectivities in some cases. BHs-THF is not the only borane carrier used and both BHs-DMS and catecholborane can be used as the stoichiometric reductant. As the latter reagent is effective at low temperature and is less reactive than BH3 it can be used to effect reduction of the ketone group of a,(3-enones such as (3.125) with no hydrobora-tion of the alkene moiety. Catecholborane can also be used as a stoichiometric reductant in the asymmetric reduction of halogenated ketones (3.126) and (3.127). 

Gondai, T, M. Shimoda, and T. Hirata, 1999. Asymmetric reduction of enone compounds by Chlorella min-iata. Proceedings of the 43rd TFAC, pp. 217-219. 

Shimoda, K., S. Izumi, and T. Hirata, 2002. A novel reductase participating in the hydrogenation of an exocy-clic C-C double bond of enones from Nicotiana tabacum. Bi Chem. Soc. Jnn... 75 813-816. Shimoda, K., N. Kubota, H. Hamada, and M. Kaji, 2003. Cyanobacterium catalyzed asymmetric reduction of enones. Proceedings of the 47th TEAC, pp. 164-166. 

Shknoda, K., N. Kubota, H. Hamada, and M. Kaji, 2003. Cyanobacterium catalyzed asymmetric reduction of enones. Proc. 47th TEAC, pp. 164—166. 

Scheme 16 Copper-catalysed asymmetric reduction of p,p-disubstituted enones...

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