Chiral Auxiliary Modified Substrates

Chiral amines were always considered important targets for synthetic chemists, and attempts to prepare such compounds enantioselectively date back to quite early times. Selected milestones for the development of enantioselective catalysts for the reduction of C = N functions are listed in Table 34.1. At first, only heterogeneous hydrogenation catalysts such as Pt black, Pd/C or Raney nickel were applied. These were modified with chiral auxiliaries in the hope that some induction - that is, transfer of chirality from the auxiliary to the reactant -might occur. These efforts were undertaken on a purely empirical basis, without any understanding of what might influence the desired selectivity. Only very few substrate types were studied and, not surprisingly, enantioselectivities were... 

Asymmetric cyclopropanations of Michael acceptors with ylides have been explored for a number of substrates modified with chiral auxiliaries. The reactions of 47 with Ph3P=CMe2,48 (equation 119)259 and of 49 with 50 (equation 120)260-261 proceed with excel-... 

Isosorbide (3) and isomannide (4) act as chiral auxiliaries for the sodium borohydride reduction of some prochiral ketones optical yields of up to 20% were achieved. It seems that the isohexides form chiral complexes with sodium borohydride, whereby the chiral information is transferred to the substrate.219 Optical active alcohols were obtained by reduction of appropriate ketones with sodium or lithium borohydride in the presence of isosor-bide.219 Asymmetric reduction of propiophenone using sodium borohydride, modified with (+)-camphoric acid and isosorbide, resulted in C -phenylethylcarbinol in 35% enantiomeric excess.2,9b... 

A number of techniques are now available allowing the preparation of enantiomerically pure (or at least enriched) compounds via asymmetric nucleophilic addition to electron-deficient alkenes. Some of these transformations have already been successfully applied in total synthesis. In most cases, the methods are based on diastereoselective reactions, employing chirally modified substrates or nucleophiles. There are only very few useful enantioselective procedures accessible so far. The search for efficient en-antioselective methods, especially for those which are catalytic and do not require the use of stoichiometric amounts of chiral auxiliaries, remains a challenging task for the future. 

Ramamurthy and coworkers have utilized zeolites modified with chiral organic compounds [17,18]. Zeolites are crystalline aluminosilicates with open framework structures. In this approach, the zeolite is first loaded with a chiral inductor and the compound to be photolyzed is then added in a second, separate adsorption step. Asymmetric induction ensues as a result of the close proximity enforced between reactant and chiral inductor in the confined space of the zeolite supercage. The zeolite method has the disadvantage that the size of the substrate is limited by the pore size of the zeolite being used. Most of the work using the chirally modified zeolite approach was compared with the ionic chiral auxiliary method by Scheffer and coworkers. The enantiodifferentiations by the zeolites are usually low to moderate. 

The desire to produce enantiomerically pure pharmaceuticals and other fine chemicals has advanced the field of asymmetric catalytic technologies. Since the independent discoveries of Knowles and Homer [1,2] the number of innovative asymmetric catalysis for hydrogenation and other reactions has mushroomed. Initially, nature was the sole provider of enantiomeric and diastereoisomeric compounds these form what is known as the chiral pool. This pool is comprised of relatively inexpensive, readily available, optically active natural products, such as carbohydrates, hydroxy acids, and amino acids, that can be used as starting materials for asymmetric synthesis [3,4]. Before 1968, early attempts to mimic nature s biocatalysis through noble metal asymmetric catalysis primarily focused on a heterogeneous catalyst that used chiral supports [5] such as quartz, natural fibers, and polypeptides. An alternative strategy was hydrogenation of substrates modified by a chiral auxiliary [6]. 

A different approach to enantioselective electrophilic fluorination is the use of chiral auxiliary groups on the substrate this converts the problem into a diastereo-selective fluorination. The ground-breaking work in this field was done since 1992 by the Davis group [207], by fluorination of imide enolates modified by Evans oxazolidinone chiral auxiliary [208] using N-fluoro-o-benzenedisulfonimide (NFTh) as the electrophilic fluorination agent (Scheme 2.94). 

The most important heterogeneous systems for the hydrogenation of C=N groups have been reviewed by Blaser and Muller [8]. Neither the use of soluble modifiers nor of chiral supports led to heterogeneous catalysts with useful enantioselectivities. The interaction between adsorbed substrate, the active site and the chiral auxiliary employed until now was probably not sufficient for a good discrimination. 

In asymmetric synthesis, the use of enantiomerically pure chiral auxiliaries involves the temporary introduction of a chiral group G onto an achiral substrate R-Y. This modified substrate R-Y-G is subsequently transformed, ideally through a highly diastereoselective process, into a new product R-Z -G. After cleavage of the chiral auxiliary, the final product R-Z, bearing a new stereocenter, is formed. 

Directed and Asymmetric Oxidation The traditional method of asymmetric synthesis involves modifying the substrate with a resolved chiral auxiliary and finding a reagent that introduces an asymmetric center in a defined way relative to the auxiliary. The auxiliary is then removed, ideally leaving a single enantiomer of the product. This method requires a mole of auxiliary per mole of product formed. A more sophisticated approach is to mimic Nature s own solution the use of an enantiomerically pure catalyst. In this case the handedness of the product is decided by the handedness of the catalyst, and only a small amount of resolved catalyst produces a large amount of asymmetric product. 

Carbohydrates are inexpensive chiral compounds. In one molecular unit they contain numerous chiral informations. Despite of these striking properties, carbohydrates have been applied only in isolated cases as chiral auxiliaries in stereoselective syntheses. First, asymmetric reductions were studied with carbohydrate-modified reducing reagents. More recently, aldol reactions and Diels-Alder reactions with carbohydrate-linked substrates have been described. 

Most reactions have been conducted using readily available, naturally occurring, chiral modifiers. The auxiliaries employed for the modification of LAH are classified into three types (i) alcohol modifiers (ii) dialkylamino alcohol modifiers and (iii) primary or secondary amines and amino or monoalkylamino alcohol modifiers. Most asymmetric reductions have been investigated with acetophenone (1) as the substrate. Structures (3) to (24) summarize the chiral modifiers, enantiomeric excesses ee) and absolute configurations of the 1-phenyl-1-ethanol (2) produced. 

The first applications of nickel-catalyzed [3 + 2] cycloaddition to asymmetric diastereose-lective synthesis of metbylenecyclopentanes employed acrylic ester substrates chirally modified with menthol-4 or camphor-derived41,42 auxiliaries. The adducts were obtained in good yield with diastereomeric ratios up to 99 141-42. After hydrolysis, optically active 3-methylene-l-cy-clopentanecarboxylic acids 4 were obtained. 

---