Enantioselective reduction, using

Enantioselective Ketone Reduction. Following Itsuno s lead for enantioselective reductions using diphenylvalinol, Kraatz was the first to describe the use of a 1 2 mixture of (5)-diphenylprolinol (1) and Borane-Tetrahydrofuran for the stoichiometric enantioselective reduction of ketone (2) to obtain the plant growth regulator triapenthenol (3) (eq 1). Although not characterized at the time, the species responsible for the enantiose-lectivity observed was presumed to be an oxazaborolidine-borane complex. ... 

Another approach to enantioselective reductions involves reactions with chiral tin hydrides. The helical chirality of the binaphthyl group has been taken advantage of in the design of chiral tin reagents. An example of an enantioselective reduction using chiral tin hydride 88 is shown in Eq. (13.26) [38]. The reduced products are formed in low enantiomeric excesses (41 % ee) and low chemical yields (often under 50%). These factors and the difficulty in synthesizing the chiral tin hydride reagents serve to diminish the utility of these types of enantioselective reductions thus far. 

Enantioselective Reduction Using Polymer-Supported Catalysts. . 17... 

A prochiral radical intermediate is generated from a-methoxymethyl-a-iododihy-drocoumarin (la) which is coordinated via the carbonyl oxygen to the chiral Lewis acid/ligand combination of MgL and 2. Enantiomeric excesses of up to 62% and yields of 88% have been obtained in this enantioselective reduction using tributyltin... 

The intermediate sulfonimide derived from saccharin by addition of an alkyllithium compound is also the starting material for sultams mimicking the behavior of camphorsultams. The sultams arc readily obtained from, e.g., 3-methylbenzisothiazole 1,1-dioxide, by ruthenium-catalyzed enantioselective reduction, using BINAP as a chiral ligand, in enantiomerically pure form 79. Thus, both enantiomers can be obtained by using the appropriate enantiomer of the control ligand. Like the camphorsultams, the saccharin derivatives readily form amides with carboxylic acids which can be alkylated via the carbanion (Section D.1.1.1.3.1.) or, if unsaturated carboxylic acids are used, may react as chiral dienophiles in Diels—Alder reactions (Section D.l.6.1.1.1.). 

Valerolactones. - Enantioselective reduction using Baker s yeast, a method most often associated with chiral 3-hydroxy-ester preparation, has also been applied to generation of the... 

Bringmann and co-workers have reported highly efficient atropo-enantioselective reduction using OABs as chiral inducers to give one atropisomer with high enantiose-lectivities [76]. For example, the reduction of biaryl lactones 51 with BH3 THF (4 equiv.) in the presence of 2b (3 equiv.) in THF at 30 °C provided chiral biaryl alcohol 52 with up to 97% ee (Scheme 11.15). 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

By an alternative approach, the enantioselective reduction of 1,2-diketimines was achieved by using hydride reagents in the presence of stoichiometric amounts or an excess of enantiopure carboxylic acids. An... 

Figure 5.1 Mass indices and environmental factors E of the enantioselective reduction steps A-D (top) and synthesis sequences via A-via D (bottom) using EATOS according to Blaser etal. (Figures 10 and 8 in reference [1 0]). Auxiliaries (isolation) are solvents.

Chloroboranes have also been found useful for enantioselective reduction. Di-(isopinocampheyl)chloroborane,144 (Ipc)2BCl, and /-butyl (isopinocamphcylj... 

Catalytic Enantioselective Reduction of Ketones. An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most developed is the oxazaborolidine 18, which is derived from the amino acid proline.148 The enantiomer is also available. These catalysts are called the CBS-oxazaborolidines. 

Scheme 5.6. Enantioselective Reduction of Ketones Using CBS-Oxazaborolidine... 

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