Enantioselective reactions asymmetric amplification

Enantioselective conjugate addition of diethylzinc proceeds in the presence of №( ) complex104. Asymmetric amplification was observed in reactions using chiral ligand l156, 66157, 47107 and 3 (equation 38)109. 

As described in the preceding section, asymmetric amplification has been reported in the non-autocatalytic enantioselective addition of dialkylzincs. In asymmetric autocatalysis, amplification of has a more significant role, because the product of the asymmetric autocatalysis itself is capable of acting as the asymmetric autocatalyst. Once the product, i.e. the asymmetric autocatalyst with an enhanced , is formed in the asymmetric autocatalytic reaction, the product catalyzes the formation of itself with higher . From the viewpoint of the molecule, an asymmetric autocatalyst with dominant absolute configuration catalyzes... 

An amino alcohol was found to accelerate the addition reaction of diethlylzinc to aldehyde [8], and then chiral amino alcohols were proved to be efficient chiral catalysts for asymmetric alkylation by using dialkylzinc reagents [9], Oguni reported a remarkable asymmetric amplification in chiral amino alcohol-promoted alkylation (Scheme 9.4). In the presence of (-)-l-piperidino-3,3-dimethyl-2-butanol (5) of 11% ee, benzaldehyde is alkylated enantioselectively to give (/ )-l-phenylpropanol with 82% ee [10]. Asymmetric amplification was also observed by Noyori using partially resolved (2.S )-3-exo-(dimethylamino)isobomeol (6) [11]. 

Tanaka reported the synthesis of (/ )-muscone (10) by an enantioselective conjugate addition of chiral alkoxydimethylcuprate, which was prepared from chiral ercdo-3-[(l-methylpyrrol-2-yl)methylamino]-l,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (9), methyllithium, and copper iodide (Scheme 9.7) [16]. In this reaction, convex deviation from a linear correlation was observed when the chiral ligand had a higher enantiopurity. This positive NLE was probably induced by the formation of a reactive homochiral dinuclear copper complex to give (R)-muscone. Rossitter also observed asymmetric amplification in a copper-catalyzed conjugate addition of methyl-... 

Mikami reported a highly enantioselective carbonyl-ene reaction where a chiral titanium complex 11 prepared from enantiomerically pure binaphthol (BINOL) and Ti(0-i-Pr)2Br2 catalyzed a glyoxylate-ene reaction with a-methylstyrene to give chiral homoallyl alcohol 12 with 94.6% ee [22]. In this reaction, a remarkable asymmetric amplification was observed and almost the same enantioselectivity (94.4% ee) was achieved by using chiral catalyst prepared... 

Keck reported an asymmetric allylation with a catalytic amount of chiral titanium catalyst [24]. The enantioselective addition of methallylstannane to aldehydes is promoted by a chiral catalyst 13 prepared from chiral BINOL and Ti(0-i-Pr)4 (Scheme 9.10). An example of asymmetric amplification was reported by using (R)-BINOL of 50% ee, and the degree of asymmetric amplification was dependent on the reaction temperature. Tagliavini also observed an asymmetric amplification in the enantioselective allylation with a BIN0L-Zr(0-i-Pr)2 catalyst [25]. 

Asymmetric amplification has also been observed in lanthanum-catalyzed nitro-aldol reaction, Shibasaki used a chiral lanthanum complex 15 prepared from LaCl3 and dilithium alkoxide of chiral BINOL for the enantioselective aldol reaction between naphthoxyacetaldehyde 14 and nitromethane (Scheme 9.11) [26]. When chiral catalyst 15 was prepared from BINOL with 56% ee, the corresponding aldol adduct 16 with 68% ee was obtained. This result indicates that the lanthanum 15 complex should exist as oligomer(s). 

Kobayashi reported an asymmetric Diels-Alder reaction catalyzed by a chiral lanthanide(III) complex 24, prepared from ytterbium or scandium triflate [ Yb(OTf)3 or Sc(OTf)3], (Zf)-BINOL and tertiary amine (ex. 1,2,6-trimethylpiperidine) [30], A highly enantioselective and endose-lective Diels-Alder reaction of 3-(2-butenoyl)-l,3-oxazolidin-2-one (23) with cyclopentadiene (Scheme 9.13) takes place in the presence of 24. When chiral Sc catalyst 24a was used, asymmetric amplification was observed with regard to the enantiopurity of (/ )-BINOL and that of the endoadduct [31 ]. On the other hand, in the case of chiral Yb catalyst 24b, NLE was affected by additives, that is, when 3-acetyl-l,3-oxazolidin-2-one was added, almost no deviation was observed from linearity, whereas a negative NLE was observed with the addition of 3-pheny-lacetylacetone. 

Uemura reported a highly enantioselective oxidation of sulfides to sulfoxides using a chiral titanium complex prepared from chiral BINOL and Ti(0-i-Pr)4, and this reaction exhibits a remarkable asymmetric amplification (Scheme 9.15) [33]. 

Highly enantioselective asymmetric autocatalytic reactions have been reported using chiral pyrimidyl-lla,b and quinolylalkanols (Scheme 12.2).Uc (5)-2-methyl-l-(2-methyl-5-pyrimidyl)-l-propanol (14b, 99.9% ee) autocatalyses the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde to afford 14b itself of the same configuration with 98.2% ee.ll Moreover 14a shows asymmetric autocatalytic reaction with amplification of ee. Thus, starting from (5)-14a with only 2% ee, four successive autocatalytic reactions afford (5)-14a with 88% ee.ub... 

Asymmetric amplification in reactions involving partially resolved chiral auxiliaries is now a well-established phenomenon that is very attractive since it gives improved enantioselectivities witb respect to expectations based upon the ee of the auxiliary. It may have practical application in that enantiomerically pure chiral auxiliaries are not always required for highly selective asymmetric synthesis. Asymmetric amplification is also of fundamental importance in order to achieve efficient asymmetric autocatalysis. Finally, evidence of an asymmetric amplification is a very useful piece of information in mechanistic studies. 

The reaction of methallyltri-n-butylstannane 117 with achiral aldehydes is also effectively promoted by the binol-Ti complex [89 c]. In all but one case (cyclo-hexanecarboxaldehyde), the yields and enantioselectivities observed with the methallylstannane are identical or higher than those obtained in the reactions with allyltributylstannane with only 10 mol% of the binol-Ti complex (Scheme 10-50). Insight into the nature of the titanium catalyst is provided by the observation of asymmetric amplification [89 b] and chiral poisoning [89 g]. An intruiging hypothesis on the origin of enantioselection in allylation and related reactions [89 h]. 

Non-linear effects were discovered in 1986 [5]. They are now widely recognized in many catalytic reactions, and provide a useful tool for mechanistic investigations. Moreover, they can have some practical applications. For example, in the case of asymmetric amplification it is not necessary to perform a costly complete resolution of a chiral ligand if the reaction involves a strong (-i-)-NLE. The concept of non-linearity has been extended to mixtures of diastereomeric ligands (vide supra). Finally, asymmetric amplification is very useful in reactions which display asymmetric autocatalysis, giving high levels of enantioselectivity after initiation with a catalyst of very low ee. 

Double AD of dienes is an interesting way to enhance the enantioselectivity of the first dihydroxylation reaction. This amplification process, which has been applied to many other asymmetric reactions, usually results in significant improvement of the enantiopurity of the bis dihydroxylated product. Momose [ 140] has studied in detail the double AD of several non-conjugated dienes, during his elegant synthesis of a range of optically active nitrogen heterocycles (Scheme 62). 

The high value of catalytically performed reactions as compared to non-catalytic variants is particularly evidenced in the field of enantioselective reactions. Chemists cannot complete enantioselective reactions without certain chiral information in the reacting system. This information is regularly derived from the chiral compounds present in nature, collectively named the chiral pool of the nature. Their availability is often limited, which is not an issue when they are used as catalysts, but causes significant costs of non-catalytic reactions when they are needed in equimolar quantities. The practical value of the catalytic approach to enantioselective processes cannot be overestimated. Asymmetric catalysis characterizes the amplification of chirality one chiral molecule of the catalyst generates an enormous number of chiral molecules of the product in the optically pure form. This results with high chiral economy of catalytically performed enantioselective syntheses. 

In the enantioselective addition of diethylzinc to aldehydes catalyzed by nonracemic amino alcohols, the phenomenon named asymmetric amplification has been well recognized as a consequence of an in situ increase in the enantiopurity of the active catalyst, as the racemic ligand is trapped in the more stable, unreactive meso species [3, 11]. Although the reaction will definitely give racemic product if only racemic Hgands are used alone, the addition of an easily accessible alternative... 

These schemes have been frequently suggested [105-107] as possible mechanisms to achieve the chirally pure starting point for prebiotic molecular evolution toward our present homochiral biopolymers. Demonstrably successftd amplification mechanisms are the spontaneous resolution of enantiomeric mixtures under race-mizing conditions, [509 lattice-controlled solid-state asymmetric reactions, [108] and other autocatalytic processes. [103, 104] Other experimentally successful mechanisms that have been proposed for chirality amplification are those involving kinetic resolutions [109] enantioselective occlusions of enantiomers on opposite crystal faces, [110] and lyotropic liquid crystals. [Ill] These systems are interesting in themselves but are not of direct prebiotic relevance because of their limited scope and the specialized experimental conditions needed for their implementation. 

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