Enantioselective addition chiral initiators

When enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde 89 was examined, simple 2-butanol with low (ca 0.1%) induces a tiny chirality in the initially produced alkanol 81 and the value of the finally obtained alkanol becomes higher (73-76%) due to the asymmetric autocatalysis (Table 2). Note that the value can be further amplified by subsequent asymmetric autocatalysis, as described in the preceding section. Various chiral compounds have been proved to act as chiral initiators. 

The first example of Pd-catalyzed enantioselective allylation to be reported was the reaction of l-(l -acetoxyethyl)cyclopentene and the sodium salt of methyl benzenesulfonylacetate in the presence of 10 mol % of a DIOP-Pd complex, which led to the condensation product in 46% ee (Scheme 85) (200). This reaction used a racemic starting material, but the enantioselection was not a result of kinetic resolution of the starting material, because the chemical yield was above 80%. However, in certain cases, the selectivity is controlled at the stage of the initial oxidative addition to a Pd(0) species. In a related reaction, a BINAP-Pd(0) complex exhibits excellent enantioselectivity the chiral efficiency is affected by the nature of the leaving group of the allylic derivatives (Scheme 85) (201). It has been suggested that this asymmetric induction is the result of the chiral Pd catalyst choosing between two reactive conformations of the allylic substrate. 

However, in a comprehensive study, Seebach and coworkers have shown the usefulness of titanium and zirconium alkyls as selective nucleophilic reagents.106,107 Typically compounds of the type (RO)3MR (M = Ti, Zr) are reacted with aldehydes or ketones to yield asymmetric alkoxides (equation 32),107 The method has been extended to allow enantioselective addition using chiral organotitanium reagents where the chirality is imposed by the initial alkoxide substituents.107,108... 

The effect of enantioselectivity reversal serves as an additional experimental observation that gives a possible clue for the reaction mechanism. By the proposed additive-product interactions it was predicted that even poor stereoselectivity and discriminating capability of the catalytic additive can give rise to enantioselectivity reversal. This also gives a possible kinetic explanation for the effect of miscellaneous chiral additives in the Soai reaction and their role as potent chiral initiators. 

In this work, the synthesis of high surface densities of chlororopropyl groups covalently grafted on mesoporous micelle templated aluminosilicates (Al-MTS) of various initial pore diameters is presented. The hybrid chiral materials resulting from halogen substitution are applied in the enantioselective addition of diethylzinc to benzaldehyde. 

Most commonly used chiral Lewis acids have been derived from main group and early transition series elements. An initial attempt at utilizing optically active catalysts of late transition metal complexes for the enantioselective addition of allyltributylstannane to aldehydes was made by Nuss and Rennels [30]. Employment of Rh(COD)[(-)-DIOP]BF4 (11) as a catalyst, however, resulted in only a small degree of asymmetric induction (17% ee). 

Wynberg and co-workers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone [48], Although the enantioselectivity in the initial report was modest, a range of chiral phase-transfer catalysts, in particular based on cinchona alkaloids, were reported. 

The ratio of the products is reversed when the reaction is carried out at 110 =C and the catalyst system is generated from triisopropyl phosphite, palladium acetate and butyllithium. The diastereomers differ only in the stereochemistry at the center a to the carbonyl groups, indicating that initial addition to the unsaturated olefin is completely diastereoselective. Olefin geometry scrambling is then proposed to occur following the initial, enantioselective addition step, prior to cyclization. Indeed, removal (and recovery) of the chiral auxiliary by basic hydrolysis and diesterification of the product leads to a product with greater than 97% ee. This was determined by an ozonolysis/ ketonc reduction sequence followed by O-methylmandelate formation. 

The chiral PTC agent 63 (Fig. 7) in combination with CsOH as base, have been used for enantioselective additions of iminoglycinates or a-substituted iminoglycinates onto electrophiles for the synthesis of a-amino acids [16]. Although, initially the system was essayed for the Michael-type addition reaction, some effort also was directed to the enantioselective 1,3-DCR between 3 (R = 2-HOCeH4, R = Me) and methyl acrylate. Unfortunately, the enantioselectivity achieved for the corresponding endo-13 (R = H) was quite low (up to 25% ee) and the chemical yield moderate [58]. 

Non-fluoride initiators have been employed satisfactorily as well, including Lewis bases (amines, amine A-oxides, carbonates and phosphates," LiOAc," " f-BusF ), Lewis acids," A-heterocyclic carbenes, or even without initiator in DMSO as solvent. The addition of TMSCF3 to carbonyl compounds in the presence of a chiral initiator allows the enantioselective preparation of trifluoromethyl alcohols. For this purpose, quaternary ammonium fluorides derived from cinchona alkaloids (1) have been employed, affording moderate (up to 51% ee) " to high enantioselectivities (up to 92% ee). Also, the corresponding bromides were used in combination with an external fluoride source (KF or TMAF, up to 94% ee) or with disodium (R)-binaphtholate (up to 71% ee), or simply a cinchonidine-derived ammoniumphenoxide (up to 87% ee). Moreover, the use of a chiral TASF derivative (2) has also been reported (up to 52% ee). ... 

As described in the preceding sections, we already had experience on the enantioselective alkylation of aldehydes with dialkylzincs and the enantioselective synthesis of 3-pyridyl alkanol. In 1990, we found the first asymmetric autocatalysis of (5)-3-pyridyl alkanol 6 in the enantioselective addition of i-Pr2Zn to pyridine-3-carbaldehyde 7 to produce more of itself of 35% ee with the same S configuration (Scheme 6) [24]. Although the ee of product 6 decreased compared to that of the initial catalyst, the newly formed predominant enantiomer of the product is the same with that of asymmetric autocatalyst 6. We claim that this is the first asymmetric autocatalysis, that is, catalytic replication of chiral compound with the generation of new stereogenic centers. 

Takemoto and coworkers [32] elaborated bifunctional catalyst 27, which was found, after this initial report, to be highly versatile in promoting a large variety of transformations. The combination of a thiourea and a tertiary amine separated by a chiral scaffold, (R,l )-l,2-cyclohexyldiamine, was studied to build a new type of organocatalyst. Aminothiourea 27 was first examined as catalyst for the enantioselective addition of malonate to nitroaUcenes (Scheme 34.5). The thiourea moiety of catalyst 27 guides and activates the nitroolefin while the tertiary amine part deprotonates the malonate. 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

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