1,4-Addition of Nucleophiles to -Unsaturated Carbonyl Compounds - Carbohydrates: Tools for Stereoselective Synthesis - page 274

substituted biphenyl-derived thioether-phosphinite 58e (41% ee, Table 12.1, entry
24).

12.3.1.3 Monodentate P- or S-Ligands
In comparison with bidentate ligands, the use of monodentate ligands in the
1,4-addition of alkyl nucleophiles to cyclohexenone is rarer. In this respect,
Diéguez, Pàmies, and Woodward synthesized phosphite ligands 59, 61, 66 with a
furanoside framework, together with some pyranoside phosphite ligands 69 and
71 derived from fructose, and tested them in the asymmetric 1,4-conjugate addi-
tion of AlCl 3 to cyclohexenone [34]. The effect of several reaction parameters were
studied using ligand 59f. The best result was obtained using dimethoxyethane
(DME) as solvent, Cu(OTf) 2 as the catalyst precursor, and a ligand-to-copper ratio
of 4 at 30 °C (Table 12.1, entry 26, 77%, 48% ee). Under the optimized conditions,

the remaining ligands, 59, 61, 66, 69, were evaluated. The results indicated that
selectivities are highly affected by the configuration of C4 of the carbohydrate
backbone, the size of the ring of the sugar, and the cooperative effect between the
configurations of C3 and that of the binaphthyl phosphite moiety, which resulted
in a matched combination for ligand 61e (Table 12.1, entry 28, 57% ee). In all
cases, however, the formation of byproducts was observed.
In addition, biphenyl phosphite ligands 59a-d were found to give (R) -configured
addition products (see, for example, Table 12.1, entry 25), while biphenyl phos-
phite ligands 61a-d (see, for example, Table 12.1, entry 27) were found to furnish
the (S) -configured products. The authors attributed this opposite sense of enanti-
oselectivity to the configuration of the biphenyl moieties of the ligands when
coordinated to the copper species, with ligands 59a-d adopting an (R) -configura-
tion while ligands 61a-d adopt an (S)- configuration.
Comparing the results using ligands 59 with 66, which differ only in the con-
figuration at C4, ligands 66 with an (S)- configuration at C4 were found to give
lower enantioselectivities than ligands 59 with an opposite configuration at this
position (Table 12.1 entry 29 versus 25 and 26). On the other hand, ligands 69 and
71, which have a pyranoside backbone, provided lower yields and enantioselectivi-
ties than furanoside ligands (2-33% ee). In summary, the best results were
obtained with ligand 61e, which contains the best combination of the ligand
parameters (ee values up to 57%; Table 12.1, entry 28).
In contrast, Spescha [35] introduced Cu-thiolate 63 for the conjugate
addition of Grignard reagents to 2-cyclohexenone. The chemical yields and
regioselectivities were in all the cases higher than 90% and 98%, respectively,
and independent of the experimental conditions. Interestingly, the enantioselectiv-
ity was dependent on the halide of the Grignard reagent and reached a maximum
of 60% when BuMgBr was used (Table 12.1, entry 30). The disadvantage of
this reaction is its low application range; low amounts of the 1,4-product or
enantioselectivities below 20% ee were obtained when applied to linear
substrates.

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