Asymmetric using chiral auxiliaries

Asymmetric Michael additions using chiral auxiliary containing donors have attracted widespread attention and various methods are now available that give high enantiomeric excess. 

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

It is worthwhile emphasising that the abovementioned syntheses using chiral auxiliaries covalently bound to the substrate bearing the prochiral center prior to the creation of the new asymmetric centre mean converting the problem of enantiofacial recognition into a problem of diastereofacial selectivity i.e. the pair of enantiomers 41 and 42 are actually obtained from hydrolysis of two different diastereomers 39 and 40. In fact, "direct enantioselectivity" can only be attained by using an external chiral catalyst,23 as shown in Figure 9.1 [26]. 

The asymmetric synthesis of a-amino acids is an important topic due to their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. The Strecker reaction is historically one of the most versatile ways to produce a-amino acids, but this method has a maximum yield of only 50% for a single enantiomer. Higher yields can be achieved by using chiral auxiliaries, but auxiliaries have other drawbacks, such as high cost, low availability, the need for purification, and high loss rates. A possible solution to these problems would be to use a chiral auxiliary in a crystallization-induced asymmetric transformation. 

The asymmetric [3 + 4] cycloaddition is readily achieved using chiral auxiliaries or catalysts [16]. The efficiency of the chiral auxiliary approach is illustrated in the [3-1-4] cycloaddition with cyclopentadiene. The vinyldiazoacetate 6, with (T)-pantolactone as the chiral auxiliary, generated the bicyclo[3.2.1]octadiene 75 in 87% yield and 76% dia-stereomeric excess (Eq. 10) [82]. Alternatively, the chiral rhodium prolinate Rh2(S-DOSP)4-catalyzed reaction of 4 generated the bicyclo[3.2.1]octadiene 76 in 77% yield and with 93% enantiomeric excess (Eq. 11) [83]. 

Another approach that relies on asymmetric induction from the alkene part, uses chiral auxiliaries of various types, thereby leading to enantiomerically enriched or pure isoxazoline products. The complexity of some of these auxiliaries is high, and more economical solutions are desirable since the competition is the resolution of racemic cycloadducts with an overall efficiency up to 50% yield. With chiral nitrile oxides, the situation is much less satisfactory since asymmetric induction of the 1,4-type (with 1-alkenes) is minimal, and hardly better with a 1,3-relationship of inducing-forming stereocenters, when 1,2-disubstituted alkenes are employed (Scheme 6.22). Upon separation of the two diastereomers, however, another entry to pure optically active isoxazolines is available. 

A special case of asymmetric induction using chiral auxiliaries has been reported for the alkylation of /1-keto esters94,106. In this approach the reaction proceeds in a diastereoselective manner via a base-catalyzed opening of the corresponding chiral 1.2-cyclohexanedioxy or 1,2-cyclohep-tanedioxy acetal, e g., acetal 50. 

Strikingly high stereoselectivities have been achieved in asymmetric syntheses with optically pure proline or proline derivatives, probably due to the rigidity of the five-membered ring. Other preferably used chiral auxiliaries include (S)-phenyl-alanine, (S)-valine and tert.-(S)-leucine. 

Asymmetric catalysis with chiral ligands [82] is commonly considered to be advantageous instead of using chiral auxiliaries. Catalytic asymmetric Michael reactions are known [83], but not with iron as the catalytically active metal. Only two reports on iron catalyzed catalytic asymmetric Michael reaction with dipeptides [84] or diamino thioethers [85] exist, but the enantioselectivities were disappointing (18% ee and 10% ee, respectively). 

A stereocontrolled synthesis of the biologically active neolignan (+)-dehydrodiconiferyl alcohol, which was isolated from several Taxus species, was achieved via Evans asymmetric aldol condensation [58] using ferulic acid amide derived from D-phenylalanine. The reaction steps are shown in Fig. 9. This stereocontrolled reaction is also useful for preparing the enantiomer of (+)-dehydroconiferyl alcohol using chiral auxiliary oxazolidinone prepared from L-phenylalanine. This reaction also enables the syntheses of other natural products that possess the same phenylcoumaran framework. 

Although asymmetric versions of aza Diels-Alder reactions using chiral auxiliaries have been reported, only one example uses a stoichiometric amount of a chiral Lewis acid [44]. The first reported example of a catalytic enantioselective aza Diels-Alder reaction employed a chiral lanthanide catalyst [45]. A chiral ytterbium or scandium catalyst, prepared from Yb(OTf)3 or Sc(OTf)3, (i )-BINOL, and DBU, is effective in the enantioselective aza Diels-Alder reactions. The reaction of A-alkylidene- or N-arylidene-2-hydroxyaniline with cyclopentadiene proceeded in the presence of the chiral catalyst and 2,6-di-rerf-butyl-4-methylpyridine (DTBMP) to afford the corresponding 8-hydroxyquinoline derivatives in good to high yields with good to excellent diastereo- and enantioselectivity (Eq. 15). 

Asymmetric total synthesis of natural products is one of the central subjects in the organic synthetic world. In order to reach this goal, there are two main strategies the first uses chiral auxiliaries and the second uses chiral starting materials. The first most important task for comple-... 

Thus far, discussion has centered around the reaction of alkenes with a source of electrophilic oxygen as a route to epoxides [the C=C + O protocol]. However, a second general approach is represented by the reaction of carbonyl compounds with amphophilic carbon centers [the C=0 + C protocol]. For example, sulfonium yhdes are known to convert aldehydes and ketones to epoxides much recent work has focused on asymmetric induction using this methodology, a topic which has been the subject of a concise review in the past year <04ACR611>. As an illustration, the D-mannitol derived chiral sulfide 42 serves as a useful chiral auxiliary in the sulfonium methylide epoxidation of aldehydes to provide terminal monosubstituted oxiranes (e.g., 44) in fair to excellent yield and good enantiomeric excess <04CC1076>. 

In Chapt. 2 of this volume the historical developments of asymmetric catalysis are reviewed. Since one of the main purposes of asymmetric catalysis is to obtain products with the highest possible ee, it appeared obvious to experimentalists to use chiral auxiliaries having the maximum ee possible. In asymmetric catalysis as well as in stoichiometric asymmetric synthesis it has been long considered that the maximum ee of the product may be safely calculated from... 

Chiral quinolines can be prepared by using chiral auxiliary. Thus, asymmetric Michael addition of the arylidenemalonate to the enhydra-zone 298, obtained from a chiral hydrazine with 1, in the presence of n-butyllithium in THF afforded the adduct 299 in high diastereomeric purity which underwent ring closure to the quinoline-2,5-dione 300 (R = H). The chiral auxiliary was removed by N-N bond cleavage with... 

Our initial improvement in the synthesis of pyrrolidine acid 3 relied on a racemic 1,3 dipolar cycloaddition followed by resolution. Attempts to devise asymmetric protocols of this reaction using chiral auxiliaries were not productive. The results from our laboratories were consistent with literature findings, with a moderate diastereoselectivity of 3 to 4 1 at best obtained even when double chiral auxiliaries were used. Several other approaches, such as Aza-Cope/Mannich reaction, intramolecular C-H insertion, and asymmetric aryl 1,4 addition, did not bear fruit. 

N,N -Dimethyl-1,2-diphenylethylenediamine and related chiral diamines are not only useful chiral auxiliaries in asymmetric synthesis, but they have also found applications as analytical reagents. They allow the resolution and the determination of enantiomeric composition of aldehydes by formation of diastereomeric aminals.31 34 Combined with PCI3, they allow determination of the enantiomeric composition of alcohols, biphenols, thiols and amines.35 36 The diamine described here is used most extensively. 

Some kinds of optically active ferrocenyl compounds have been known as useful chiral auxiliaries in asymmetrically induced synthesis. Chiral a-ferrocenylalkyl-amines have been prepared [1 — 5] and used as chiral auxiliaries for steroselective peptide synthesis by four-component condensation [6], asymmetric transamination... 

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