Asymmetric biaryls

Another possibility is the use of Cu(I) for the oxidative coupling of aryllithium compounds at low temperatures. This method can also be used to generate asymmetric biaryls, after addition of the appropriate halide. 

This synthetic plan, which initially involved an efficient asymmetric biaryl synthesis, suffered from two weaknesses, namely in the manipulation of configurationally fragile intermediates and in the epimerization at the biaryl axis during the decarboxylation step. These... 

The Ullmann reaction (Figure 13.4) represents another synthesis of substituted biphenyls. In this process an aryl iodide or—as in the present case—an aryl iodide/aryl chloride mixture is heated with Cu powder. It is presumed that under standard conditions the aryl iodide reacts in situ with Cu to form the aryl copper compound. Usually, the latter couples with the remaining aryl iodide and a symmetric biphenyl is formed. In a few instances it is also possible to generate asymmetric biaryls via a crossed Ullmann reaction. In these cases one employs a mixture of an aryl iodide and another aryl halide (not an iodide ) the other aryl halide must exhibit a higher propensity than the aryl iodide to couple to the arylcopper intermediate. It is presumed that the mechanism of the Ullmann reaction parallels the mechanism of the Cadiot-Chodkiewicz coupling, which we will discuss in Section 13.4. 

Of the various possible asymmetric cross-coupling reactions, (1) asymmetric alkylation with secondary alkylmetals, (2) asymmetric biaryl synthesis, and (3) asymmetric allylation with allylic electrophiles have been most extensively studied with chiral Ni and Pd complexes [166]. The initial study in this area was reported as early as 1974 by Kumada and his co-workers, but only a meager range of 8-15% ee was reported [167]. By the end of the 1970s, however, the cross-coupling reaction had been sufficiently developed so that its application to the asymmetric synthesis was already practically attractive, as indicated by an asymmetric total sythesis of (R)-(—)-a-curcumene in five steps in 66% ee and 34% overall yield shown in Scheme 1-47 [168]. 

An interesting example of asymmetric induction from an asymmetric biaryl system to a stereo-genic carbon atom has been described for the [1,2] Stevens rearrangement of the (M)-ammoni-um salt 1452 53. The product of this reaction, (.S, M)- 5 undergoes slow mutarotation about the biaryl linkage in solution, yielding an equimolar mixture of the (5,/>)-diastereomcr. 

Recently, the use of a chiral catalysts in the asymmetric biaryl synthesis has received some attention. Unsymmetrical chiral binaphthyls can be obtained in high enantiomeric excess by SnAt reactions of naphthylimines such as 39 with lithium bromide free 1-naphthyllithium catalysed by a chiral ether ligand 40 (ref. 29). Another example is the Ni(0) catalysed cross coupling of naphthyl Grignard reagents and naphthyl bromides in the presence of a chiral ferrocene ligand (ref. 30). 

In non-enzymatic asym. synthesis, centre stage goes to homochiral reagents with C2-symmetry . Chiral stein (1,2-diamino-1,2-di-phenylethane) derivatives, for example, are prominent in a variety of standard transformations, although the dimethoxy-analog evidently is superior for asym. 1,4-addition to a,P-unsatd. azome-thines" . Equally valuable are axially asymmetric biaryl and binaphthyl derivs. which (like stein derivs.) may coordinate a metal template for enhancement of enantioselectivity or incorporation of... 

SCHEME 13.17. Asymmetric biaryl Suzuki coupling in the synthetic studies toward vancomycin. 

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