Chirality asymmetric amplification

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

It may not be necessary to employ an optically pure chiral ligand (BINOL) for the preparation of the catalyst because a high degree of asymmetric amplification can be expected. 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

Much attention has been paid to asymmetric amplification where the enantiomeric excess ( ) of the product is higher than that of the chiral catalyst (equation 35)136. The first experiment on asymmetric amplification was reported by Kagan and coworkers in the Katsuki-Sharpless asymmetric epoxidation of allyl alcohols137. Asymmetric amplification has also been studied in the asymmetric addition of dialkylzincs to carbonyl compounds. 

In the enantioselective addition of diethylzinc to benzaldehyde, a wide variety of chiral catalysts 3, 4, 16, 23, 47, 66-73 exhibits asymmetric amplification (equation 36 and Table 1). 

Mechanistic studies of asymmetric amplification using a chiral amino alcohol catalyst have continued to dale"1 151 155. In the case of the chiral titanium complex, the observed asymmetric amplification was influenced by the method of preparation of the catalyst153. Asymmetric amplification is also observed in the catalytic addition of diphenylzinc to ketones100. 

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. 

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. 

In an effort to develop new chiral BINOL-Ti complexes, chemical modifications of the chiral complex (f )-BINOL-Ti(OPr )2 (R-2) that can easily be prepared by simply mixing ( PrO)4Ti and (/ )-BINOL in the absence ofMS4A have been studied [37c-e]. A dimeric form has been reported for the single-crystal X-ray structure of complex R-2 [38], (I )-BINOL-Ti-p3-oxo complex, prepared via hydrolysis of complex R-2 has been shown to serve as an efficient and moisture-tolerable asymmetric catalyst [37d,e]. It is noteworthy that the (/ )-BINOL-Ti-)i3-oxo catalyst [37e] shows a remarkable level of (+)-NLE (asymmetric amplification), thereby attaining the maximum enantioselectivity for this system by using (/ )-BINOL with only 55-60% ee as the chiral source (consult Scheme 8C. 14). 

Recently, examples of catalytic asymmetric synthesis have been reported in which the enantiomeric purity of the product is much higher than that of the chiral catalyst. A positive nonlinear effect, that is, asymmetric amplification, is synthetically useful because a chiral catalyst of high enantiopurity is not needed to prepare a chiral product with high enantiomeric excess (% ee) (Scheme 9.1). 

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]. 

Fu reported the enantioselective addition of diphenylzinc to ketones catalyzed by chiral amino alcohol 6, and observed a slight asymmetric amplification [13]. Bolm also reported asymmetric amplification in enantioselective alkylations using diethylzinc promoted by a chiral 2-pyridyl alkanol 7 and (1-hydroxy sulfoximine 8 (Scheme 9.6) [14,15]. 

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. 

Feringa reported an enantioselective allylic oxidation of cyclohexene to optically active 2-cyclohexenyl propionate 25 by using a chiral copper complex prepared from Cu(OAc)2 and (S)-proline, as chiral catalyst (Scheme 9.14) [32], In the absence of additives, a negative NLE was observed, whereas in the presence of a catalytic amount of anthraquinone, a positive NLE (asymmetric amplification) was observed. Moreover, higher enantioselectiv-ity was attained when enantiopure (S)-proline was used. However, the role of the additive remains elusive. 

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]. 

As described in the preceding sections, asymmetric amplification is generally a consequence of the formation of aggregates (i.e., dimers or oligomers that are homochiral or heterochiral) of a chiral catalyst. However, even a racemic catalyst can be used as a chiral catalyst with the aid of chiral additives (a simple model consisting of dimers is depicted in Scheme 9.17). If a chiral additive (R)-B is selectively associated with (S)-A in the racemic catalyst, the remaining (R)-A could operate as the chiral monomer catalyst (asymmetric deactivation). Conversely, the chiral additive (/ )-B can be selectively associated with (/ )-A in racemic catalyst to generate an active dimeric catalyst (asymmetric activation). 

Due to the intensive studies by many groups, the number of examples of asymmetric amplification has been substantially increasing. Aggregation state of the enantiomers of a chiral catalyst can be estimated based on the observation of a nonlinear effect between the enantiopurity of the chiral catalyst and that of the product. 

Palladium-catalysed hydrosilylation of reactive alkenes, such as norbornene, with silanes R3SiH, chiral at the silicon atom, has been reported to occur with asymmetric amplification.80... 

When 2-(ferf-bulylethynyl)pyrimidine-5-carbaldehyde 11, instead of the 2-methyl derivative 9, was subjected to reaction with z-P Zn in the presence of chiral leucine, highly enantioenriched pyrimidyl alkanol 12 with the absolute configuration corresponding to that of chiral leucine was also obtained. But it should be noted that the resulting alkanol 12 showed the opposite enan-tioselectivity to that of alkanol 10, i.e., L-leucine induces the production of (S)-alkanol 12 and D-leucine induces (R)-12, respectively [82]. The asymmetric amplification of 12 with an alkynyl substituent is more significant than that of the 2-methyl derivative 10 to increase to 96% ee (Scheme 11). 

Asymmetric amplification, i.e. ee of the product is higher than that of the chiral catalyst, is observed with some chiral (3-aminoalcohols 73g and 3.3° Formation of the less reactive dimeric complex from (+) and (-) catalysts increases the ee of the higher reactive monomeric catalyst. The remaining monomeric chiral catalyst with higher ee than that of the total chiral catalyst affords sec-alcohols with higher ee.3°... 

VII. Asymmetric amplification in chiral poisoning or chiral activation of a racemic catalyst... 

To amplify is defined in dictionaries as to increase or to enlarge. Its meaning is not so different from multiplication, which is defined as the action of increasing the number or the amount of things belonging to the same species. 3 The term asymmetric amplification (or amplification of chirality) has been used in the literature in various ways (for some examples see Refs. 5-8), usually to describe processes giving rise to an increase in the amount of enantioenriched material, or to the enhancement of enantiomeric excess (or enantiomeric ratio),9 or to a combination of the both. Here we will consider that there is an amplification of chirality when a reaction provides a compound with an enantiomeric excess higher than expected. The convenient but less precise expression asymmetric amplification is now widely used and will also be used in this chapter.12... 

In order to achieve an amplification of chirality, it requires that/> 1. If P = 0 (no meso catalyst) or g = 1 (same reactivity of meso and homochiral catalysts), then/= 1. The condition/> 1 is achieved for 1 + p > 1 + g ), or g < 1. Thus the necessary condition for asymmetric amplification in the above model is for the heterochiral or meso catalyst to be less reactive than the homochiral catalyst. If the meso catalyst is more reactive, then/< 1, and hence a negative nonlinear effect is observed. The size of the asymmetric amplification is regulated by the value off, which increases as K does. The more meso catalyst (of the lowest possible reactivity) there is, the higher will be eeproduct. This is well illustrated by computed curves in Scheme 11. The variation of eeproduct with eeaux is represented for various values of g (the relative reactivity of the meso complex) with K = 4 (corresponding to a statistical distribution of ligands Scheme 11, top). The variation in the relative amounts of the three complexes with eeaux is also represented for a statistical distribution of ligands (Scheme 11, bottom). 

The asymmetric amplification is a consequence of an in situ increase in the ee of the active catalyst, since racemic ligand is trapped in the unreactive or weakly reactive meso catalyst. In the reservoir effect a similar phenomenon occurs outside the catalytic cycle. Let us assume that part of the initial chiral ligand, characterized by eeaux, is diverted into a set of catalytically inactive complexes (Scheme 12). 

---