Positive non-linear effect

A chiral catalyst is not necessarily in enantiopure form. Deviation from the Unear relationship, namely non-linear effect , is sometimes observed between the enantiomeric purity of the chiral catalysts and the optical yields of the products (Figure 8C.2). The convex deviation—which Kagan [35a] andMikami [36) independently refer to as positive non-linear effect (abbreviated as (+)-NLE) and what Oguni refers to as [35c] asymmetric amplification —is currently attracting much attention for achieving a higher level of asymmetric induction that exceeds the enantiopurity of the non-racemic (partially resolved) catalysts. In turn, (-)-NLE stands for the opposite phenomenon of concave deviation, namely negative non-linear effect. 

Scheme 8C.14. Positive non-linear effect in asymmetric carbonyl-ene reaction.

Based on a positive non-linear effect observed for the alkylation of alanine and glycine substrates 40 and 20, active species involved in these transformation are predicted to be comprising of more than one salen-Cu(II) complex 39c [32]. Furthermore, enantioselectivity was affected by catalyst concentration, which suggested that a catalytically active dimeric form of the catalyst existed in equilibrium with catalytically inactive oligomeric and monomeric forms of the complex [36]. 

A mechanistic investigation of the Nobin-catalyzed alkylation of substrate 11a revealed that the reaction displays an extremely large positive non-linear effect [25],... 

The alkylation of substrates 16 or 34 by catalyst 33 was found to exhibit a pronounced positive non-linear effect [34]. In addition, there was an optimal concentration of catalyst 33 in these reactions, with higher or lower catalyst concentrations being detrimental to the asymmetric induction [41]. These results are consistent with a dimeric form of catalyst 33 being catalytically active and in equilibrium with catalytically inactive monomeric and oligomeric species. On the basis ofthese results,... 

R)- and (S)-pyrimidyl alcohols (78), prepared from reaction of the corresponding pyrimidylaldehyde with diisopropylzinc, are also autocatalysts starting from a near racemic seed , a large positive non-linear effect gives >99% ee.221... 

This reaction is believed to proceed via nucleophilic combination of in situ generated Cu-acetylide and iminium ion. Mechanistic studies indicate a strong positive non-linear effect based on which a catalytic cycle is proposed that involves a dimeric Cu/quinap complex as the active catalytic species. 

A positive non-linear effect is also necessary for amplifying asymmetric autocatalysis... 

Fig. 2 Illustration of a positive non-linear effect, where the enantiomer excess in the product exceeds that of the catalyst...

Soai s autocatalytic reaction appears to break a fundamental rule. The observed amplification of ee is a necessary consequence of a positive non-linear effect, and yet the typical reactant is a rigid y-aminoalcohol that cannot chelate to zinc (Fig. 5). This means that the Noyori mechanism needs to be modified in some way. Elucidation of this problem requires knowledge both... 

The first experiments carried out by Blackmond and Brown employing this technique are shown in Fig. 6 [73]. They demonstrate autocatalytic behavior as expected, and much can be learned about the reaction by analysis of the heat output from scalemic, racemic and enantiopure alcohols in separate experiments. The characteristic shapes permit testing against numerical integration of various model mechanisms. There is an excellent fit assuming what is probably the simplest solution. If the true catalyst is dimeric, and there is no selectivity between the binding constants of homochiral and heterochi-ral forms, yet the heterochiral form is unreactive, a positive non-linear effect ensues. In this case, selectivity is a purely kinetic phenomenon the positive non-linear effect arises because the statistical distribution between homo-and heterochiral forms causes the excess of (S,S)-dimer over (R,R)-dimer to exceed the formal ee. 

Positive non-linear effect when heterochiral dimer favoured... 

Fmoc HMPA Ipc KHMDS LDA MCPBA MEM Mes MOM MS- NBS NCS NIS (+)-NLE PCC PDC Ph3P Pht PMB PNB europium 9-fluorenylmethoxycarbonyl hexamethylphosphoric triamide isopinocamphenyl potassium hexamethyldisilazanide lithium diisopropylamide 3- chloroperoxybenzoic acid (2-methoxyethoxy)methyl mesityl methoxymethyl molecular sieves iV-bromosuccinimide iV-chlorosuccinimide iV-iodosuccinimide positive non linear effect pyridinium chlorochromate pyridinium dichromate triphenylphosphane phthaloyl 4- methoxyphenyl 4-nitrobenzyl... 

Noteworthy, in contrast to earlier work with the complex 2-69a in the presence of molecular sieves (MS), the MS-free system gave a better endo-selectivity and enantioselectivity. Interestingly, a positive non linear effect [(+)-NLE] [110] is observed using e.g. a mixture of (R)-2-69a and (R)/(S)-2-69 a this effect was not found in the presence of a non-racemic mixture of (R)-2-69a and (S)-2-69a in... 

Oguni has reported asymmetric amplification [12] ((-i-)-NLE) in an asymmetric carbonyl addition reaction of dialkylzinc reagents catalyzed by chiral ami-noalcohols such as l-piperidino-3,3-dimethyl-2-butanol (PDB) (Eq. (7.1)) [13]. Noyori et al. have reported a highly efficient aminoalcohol catalyst, 2S)-3-exo-(dimethylamino)isobomeol (DAIB) [14] and a beautiful investigation of asymmetric amplification in view of the stability and lower catalytic activity of the het-ero-chiral dimer of the zinc aminoalcohol catalyst than the homo-chiral dimer (Fig. 7-5). We have reported a positive non-linear effect in a carbonyl-ene reaction [15] with glyoxylate catalyzed by binaphthol (binol)-derived chiral titanium complex (Eq. (7.2)) [10]. Bolm has also reported (-i-)-NLE in the 1,4-addition reaction of dialkylzinc by the catalysis of nickel complex with pyridyl alcohols [16]. 

Uemura described use of a Ti(OiPr)4/(i )-BINOL complex for the oxidation of alkyl aryl sulfides with aqueous ferf-butyl hydroperoxide as stoichiometric oxidant [22]. At room temperature p-tolyl methyl sulfide was converted into the corresponding sulfoxide with 96% ee in 44% yield with as little as 5 mol % of the chiral ligand. The reaction is insensitive to air, while the presence of water seems to be essential for the formation of the catalytically active species, long catalyst lifetime, and high asymmetric induction. The authors observed a large positive non-linear effect which indicates that the actual catalyst consists of a titanium species with more than one (K)-BINOL ligand (11) coordinated to the metal. 

Cationic copper(II) complex 37 derived from a chiral bis(imine) ligand has also been shown to be an effective catalyst for reactions between cyclopentadiene and acylated thiazolidine-2-thione dienophiles, albeit with slightly lower se-lectivities than for the bis(oxazoline) complex 31 (Scheme 30) [93]. The bis(2,6-dichlorophenylimine) was found to be optimal among a number of electron-rich and -poor aryl imines screened. The reaction exhibits a positive non-linear effect which suggests that the minor ligand enantiomer can be sequestered by the formation of a catalytically less active (l ,l )/(S,S)Cu(II) dimer. 

As a final cautionary note regarding mechanistic interpretation of this system, Seebach has noted positive non-linear effects for the Diels-Alder reaction using Ti(IV)-TADDOL, indicating the possibility of either an aggregated transition state or the formation of catalytically inactive 1 1 (i ,i )/(S,S)-titanium complexes [119]. 

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