Homochiral auxiliary

Scheme 3-56 shows an example of the generation of chiral amines via nucleophilic attack onto an imine substrate in the presence of an external homochiral auxiliary. Moderate ee can be obtained from 161-induced reactions, and moderate to high ee can be expected from 162-induced reactions. For instance, when 161 (R1 = Et, R2 = t-Bu) is involved in the reaction, nucleophilic attack of RLi (R = Me, -Bu. and vinyl) on imine 163 gives product 164 with 81-92%... 

The solution to this problem is straightforward either chemically attach a homochiral auxiliary to the achiral reactant or cocrystallize the achiral reactant with an external homochiral auxiliary. In botlreases, the crystals formed must be non-centrosymmetric, i.e., chiral, because it is not possible for homochiral objects to pack with a center of symmetry between them. In our research, we have pioneered the use of internal, built-in chiral auxiliaries to generate chiral... 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

Figure 1-31. Strategy for generation of new chiral centers on a chiral substrate. A and B must be homochiral. A-C(x), chiral substrate B-C(y), chiral reagent I, desired transformation II, double asymmetric induction III, removal of the chiral auxiliary. Reprinted with permission by VCH, Ref. 88.

The application of a chiral auxiliary or catalyst, in either stoichiometric or catalytic fashion, has been a common practice in asymmetric synthesis, and most of such auxiliaries are available in homochiral form. Some processes of enantiodifferentiation arise from diastereomeric interactions in racemic mixtures and thus cause enhanced enantioselectivity in the reaction. In other words, there can be a nonlinear relationship between the optical purity of the chiral auxiliary and the enantiomeric excess of the product. One may expect that a chiral ligand, not necessarily in enantiomerically pure form, can lead to high levels of asymmetric induction via enantiodiscrimination. In such cases, a nonlinear relationship (NLE) between the ee of the product and the ee of the chiral ligand may be observed. 

Homochiral molecules readily available from inexpensive sources are useful synthetic building blocks and chiral auxiliaries. 1,4-01-0-benzyl-L-threitol has been used in construction of homochiral crown ethers that are useful as enzyme model systems. Topologically controlled diastereoselective delivery of the Simmons-Smith reagent for 2-cycloalken-l-one 1,4-d1-0-benzyl-L-threitol ketals was recently reported. ... 

To this point, all the examples presented have been ones in which the origin of the asymmetric induction has been unimolecular in nature, that is, the molecules adopt homochiral conformations in the solid state that favor the formation of one enantiomer over the other, usually through the close intramolecular approach of reactive centers bimolecular crystal packing effects appear to play little or no role in governing the stereochemical outcome of such reactions. This raises the interesting question of whether the soUd-state ionic chiral auxiliary approach to asymmetric synthesis could be made to work for conformationally unbiased reactants, i.e., those possessing symmetrical, conformationally locked structures. Two such cases are presented and discussed below. 

The intramolecular Michael reaction of chiral acetoacetate derivatives (124) proceeds with excellent selectivity when the alcohol (125) is used as the chiral auxiliary (Scheme 48),141 leading to valuable intermediates for the synthesis of homochiral 11-keto steroids.142 The stereochemical outcome suggests a reactive conformation as shown in (126). 

This research group further carried out an asymmetric version of the solid-phase Staudinger reaction using a chiral auxiliary at C-3 for the generation of active carbacephems and other multicyclic (3-lactam. Thus, the homochiral (,S )-4... 

It was soon recognized that in specific cases of asymmetric synthesis the relation between the ee of a chiral auxiliary and the ee of the product can deviate from linearity [17,18,72 - 74]. These so-called nonlinear effects (NLE) in asymmetric synthesis, in which the achievable eeprod becomes higher than the eeaux> represent chiral amplification while the opposite case represents chiral depletion. A variety of NLE have been found in asymmetric syntheses involving the interaction between organometallic compounds and chiral ligands to form enantioselective catalysts [74]. NLE reflect the complexity of the reaction mechanism involved and are usually caused by the association between chiral molecules during the course of the reaction. This leads to the formation of diastereoisomeric species (e.g., homochiral and heterochiral dimers) with possibly different relative quantities due to distinct kinetics of formation and thermodynamic stabilities, and also because of different catalytic activities. 

Chiral catalysts do provide high degrees of asymmetric induction.61-265 272 Double asymmetric induction was observed in the synthesis of homochiral pyranose derivatives using a chiral auxiliary-chiral catalyst combination.273-274... 

Fig.24 Overview of the synthesis and resolution of solution stable, chiral tetrahedron 6 [119]. a Formation of racemic, homochiral (AAAA)-6 and (AAAA)-6 b Chiral resolution and separation upon addition of s-nic ions (38) by formation of diastereomeric ion-pair (AAAA)-6-38 c Ion-exchange of chiral auxiliary 38 by achiral counterions such as NMe4+ and NEt4+ maintains the chirality of the resolved tetrahedra (AA AA)-6...

Oxocarbenium ions bearing a chiral auxiliary are useful for asymmetric allylation with 10. For example, oxocarbenium ions generated from aldehydes and homochiral Me3Si ether 15 are allylated with high diastereoselectivity (Scheme 104,104a,104b rp e resultant homoallyl ethers can easily be converted into homoallyl alcohols without epimerization. This two-step procedure is applicable to enantioselective allylation of ketones.105,1053... 

Since acidic hydrolysis would cleave both the heterocyclic rings, the method may potentially be applied to the auxiliary-induced diastereoselective synthesis of /i-amino alcohols, provided that the starting azido ethers are prepared optically pure from homochiral aldehydes. 

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