Asymmetric isopropylation, enantioselective

Soai et al. established highly enantioselective asymmetric autocatalysis in the asymmetric isopropylation of pyrimidine-5-carbaldehyde 27 (Scheme 14) [44], quinoline-3-carbaldehyde [45], and 5-carbamoylpyridine-3-carbaldehyde [46]. Among these, 2-alkynyl-5-pyrimidyl alkanol is a practically perfect asymmetric autocatalysis [47]. When 0.2 equivalents of 2-alkynyl-5-pyrimidyl alkanol 28b with >99.5% ee was employed as an asymmetric autocatalyst in the isopropylation of 2-alkynylpyrimidine-5-carbaldehyde 27b, it automultiplies in a yield of >99% without any loss of ee (>99.5% ee). When the product was used as an asymmetric autocatalyst for the next run, pyrimidyl alkanol 28b with >99.5% ee was obtained in >99%. Even after tenth round, pyrimidyl alkanol 28b with >99.5% ee was formed in a yield of >99% [47]. 

Further detailed investigations towards new chiral ruthenium catalysts that could enhance enantioselectivity and expand the substrate scope in asymmetric RCM were reported by Grubbs and co-workers in 2006 [70] (Fig. 3.24). Catalysts 59 and 61, which are close derivatives of 56 incorporating additional substituents on the aryl ring para to the ort/to-isopropyl group, maintained similar enantioselectivity than 56b. However, incorporation of an isopropyl group on the side chain ortho to the ortho-isopropyl group 60 led to an increase in enantioselectivity for a number of substrates. 

In 2004, ruthenium-catalysed asymmetric cyclopropanations of styrene derivatives with diazoesters were also performed by Masson et al., using chiral 2,6-bis(thiazolines)pyridines. These ligands were prepared from dithioesters and commercially available enantiopure 2-aminoalcohols. When the cyclopropanation of styrene with diazoethylacetate was performed with these ligands in the presence of ruthenium, enantioselectivities of up to 85% ee were obtained (Scheme 6.6). The scope of this methodology was extended to various styrene derivatives and to isopropyl diazomethylphosphonate with good yields and enantioselectivities. The comparative evaluation of enantiocontrol for cyclopropanation of styrene with chiral ruthenium-bis(oxazolines), Ru-Pybox, and chiral ruthenium-bis(thiazolines), Ru-thia-Pybox, have shown many similarities with, in some cases, good enantiomeric excesses. The modification... 

Widenhoefer and co-workers have developed an effective Pd-catalyzed protocol for the asymmetric cyclization/ hydrosilylation of functionalized 1,6-dienes that employed chiral, non-racemic pyridine-oxazoline ligands." " " Optimization studies probed the effect of both the G(4) substituent of the pyridine-oxazoline ligand (Table 7, entries 1-6) and the nature of the silane (Table 7, entries 6-15) on the yield and enantioselectivity of the cyclization/ hydrosilylation of dimethyl diallylmalonate. These studies revealed that employment of isopropyl-substituted catalyst (N-N)Pd(Me)Gl [N-N = (i )-( )-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(i )-43f and a stoichiometric amount of benzhydryldimethylsilane provided the best combination of asymmetric induction and chemical yield, giving the corresponding silylated cyclopentane in 98% yield as a single diastereomer with 93% ee (Table 7, entry 15). 

Asymmetric oxidation of formaldehyde dithioacetals with aqueous NaI04 was realized by Ogura et al. in the presence of a catalytic amount of BSA (0.005-0.02 mol equiv.) [96]. Under conditions the authors used, the starting sulfide was virtually insoluble in water (pH 9.2), and the best results were obtained at low concentrations of BSA. This result clearly indicates that the BSA/sulfide ratio is not the controlling factor of enantioselectivity. With this protocol, p-Tol-S-CH2-S-p-Tol could be transformed into monosulfoxide with 60% ee. The same protocol gave isopropyl phenyl sulfoxide with 60% ee. 

The efficiency of this method is highlighted by highly diastereoselective Michael addition arising from specific chelation control by metals. Using the concept of these catalytic reactions, asymmetric carbon-carbon bond-formation can be performed. Reactions of isopropyl 2-cyanopropanoate with vinyl ketones were conducted highly enantioselectively in the presence of RhH(CO)(PPh3)3 with (S,S)-(R,R)-TRAP [14] (R = C6H4-p-OMe 99%, 89% ee) [15]. 

An alternative and more ingenious method gave all the stereochemical information required.13 The racemic dienol 94 was subjected to Sharpless asymmetric epoxidation (chapter 25), 15 This is another kinetic resolution run to about 50% completion. Using an excess of di-isopropyl tartrate (DIPT, 1.5 equivalents) one enantiomer of the alcohol (R)-94 remained (72% ee) and one enantiomer of one diastereoisomer of the epoxide 95 (>95% ee) was formed. Once again the unreacted starting material 94 has a lower ee than the enantioselectively formed product 95. 

Catalytic asymmetric cyanation using 20 mol % of the complex of Ti(Oz-Pr)4 with diisoporpyl tartrate (10 Fig. 1) was reported by Oguni [42,43]. The mixture of Ti(Oi-Pr)4 and 10 (Fig. l)did not exhibit high enantioselectivity. Moreover, the selectivity and the reactivity were still low when the formed isopropyl alcho-hol was removed under reduced pressure using the freeze-dry method. High reactivity and an enantioselectivity of up to 90% were observed when the isopropyl alcohol was again added to the freeze-dried titanium complex. 

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