Chiral auxiliary based approaches reaction

Substantial progress has also been made in the chiral auxiliary-based approach to an enantioselective intermolecular Pauson-Khand reaction. Initial studies utilizing alkynes substituted with fra s-2-phenylcyclohexanol produced cyclopentenones with low drs, however, the diastereomers were easily separable... 

Another chiral auxiliary-based approach was documented by Davies (Equation 5) [8, 34]. These studies involved diazo compounds that incorporate vinyl and C=0 substitution and revealed that these stable carbene precursors participate in a variety of useful transformations, including diastereoselective cydopropanations. Importantly, Davies found that the cydopropanations with 33, in contrast with those of their simpler diazoacetate counterparts, are highly diastereoselective. The reaction with styrene and chiral diazo compound 33 is representative treatment of styrene with 33 in the presence of a simple Rh catalyst resulted in the formation of product 34 with high asymmetric induction dr 98.5 1.5) and in 84% yield. In this example, the panto-lactone auxiliaiy is a convenient, readily available chiral alcohol. 

A chiral auxiliary-based approach utilizing oxazepinediones has been reported by Trost [108]. The reaction between 142 and 143 in the presence of Pd(OAc)2/P(Ot-Pr)j furnished cycloadduct 144 in 85% yield (Scheme 18.25). The optically pure cyclopentanone 145 was obtained after hydrolytic cleavage of the auxiliary and was converted into the anticancer agent rocagla-mide (146). 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

The virtue of performing the PKR in an enantioselective manner has been extensively elaborated during the last decade. As a result, different powerful procedures were developed, spanning both auxiliary-based approaches and catalytic asymmetric reactions. For instance, the use of chiral N-oxides was reported by Kerr et al., who examined the effect of the chiral brucine N-oxide in the intermolecular PKR of propargylic alcohols and norbornadiene [59]. Under optimized conditions, ee values up to 78% at - 60 °C have been obtained (Eq. 10). Chiral sparteine N-oxides are also able to induce chirality, but the observed enantioselectivity was comparatively lower [60]. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.71 72 Avery useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1-3, which are readily available in enantiomerically pure form. 

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. 

Pyrrolidines are an important class of five-membered heterocycles with noteworthy biological properties [46]. In addition to pharmaceutical applications, the pyrrolidine moiety has also been widely used as a chiral auxiliary for asymmetric synthesis [47]. Although many elegant syntheses of chiral nonracemic pyrrolidines have been reported within the past decade or so [48-50], an alternative approach based on the intramolecular reaction of an azide and organoborane has been developed very recently [51-53], This approach utilizes the hydroboration-azide alkylation tandem reaction as a key sequence, taking advantage of the efficient stereocon-trolled steps. Scheme 20 shows an application of the synthesis of 3-substituted 5-(2-pyrrolidinyl)isoxazole which has been found to have nanomolar activity, comparable to (5)-nicotine, against whole rat brain [54]. 

Chiral oxazolidinone auxiliaries based on D-glucose were used for aldol reactions by Koell et al. [160]. The highest select vities were observed with auxiliaries equipped with the pivaloyl protecting group. The pivaloylated oxazolidinone 228 was transformed into the boron enolate according to the procedure of Evans [161] and subsequently reacted with aliphatic and aromatic aldehydes. The best results were obtained with isobutyric aldehyde (Scheme 10.77). The syn-dldo 229 was formed in 16-fold excess over the a/i Z-diastereomer and with an acceptable yield of 59%. The authors explain the stereoselectivity by a chair-like transition state according to Zimmermann-Traxler. The electrophile approaches at the less hindered r -face of the (Z)-configured enolate double bond. For A -phenacetyl substituents, an inversed stereoselectivity was observed as described above for these oxazolidinone auxiliaries. 

The first enantioselective total synthesis of (-)-denticulatin A was accomplished by W. Oppolzer. The key step in their approach was based on enantiotopic group differentiation in a meso dialdehyde by an aldol reaction. In the aldol reaction they utilized a bornanesultam chiral auxiliary. The enolization of A/-propionylbornane-10,2-sultam provided the (Z)-borylenolate derivative, which underwent an aldol reaction with the meso dialdehyde to afford the product with high yield and enantiopurity. In the final stages of the synthesis they utilized a second, double-dlastereoditferentiating aldol reaction. Aldol reaction of the (Z)-titanium enolate gave the anf/-Felkin syn product. The stereochemical outcome of the reaction was determined by the a-chiral center in the aldehyde component. 

Williams " has reported an enandocontroUed approach by low temperature formation of a six-membered coordination complex of chiral Af-enoyl-l,3-oxazolidin-2-ones with ZrCU- Conjugate Se additions of a variety of substituted allylic stannanes occur with moderate to high stereoselectivity based on the oxazolidinone auxiliary, as shown by the conversion of 176 to 177 (Scheme 5.2.38). The precise role of the chiral auxiliary for determining the facial selectivity in the reaction is not fully understood. 

One stoichiometric method that avoids the use of an expensive chiral auxiliary and allows for the use of nonpyrophoric bases is based on diketopiperazine chemistry. The use of this system as a chiral auxiliary is associated with a method that was developed for the preparation of the sweetener aspartame. At the same time, we were looking at the alkylation reactions of amino acid derivatives and dipeptides. These studies showed that high degrees of asymmetric induction were not simple, were limited to expensive moieties as the chiral units, and required the use of large amounts of lithium [25,26]. The cyclic system of the diketopiperazine has been used successfully by other investigators [27,28], and we also chose to exploit the face selectivity of this unit. L-Aspartic acid was chosen as the auxiliary unit because it is readily available and cheap. All of the studies were performed with sodium as the counterion because it is a more cost-effective metal at scale. Finally, we concentrated in the use of aldehydes rather than alkyl halides to allow for a general approach and so as not to limit the reaction to reactive alkyl halides. 

In the last few chapters we have started with a prochiral molecule having enantiotopic features the faces of an alkene for instance - and differentiated these faces with enantiomerically pure reagents or catalysts. In this chapter we explore the alternative approach. The enantiotopic faces are transformed into diastereotopic faces by the covalent attachment of a chiral auxiliary. It seems inevitable that this auxiliary must be stoichiometric but you will even see that catalytic substrate methodology is starting to emerge. It also seems inevitable that two extra reactions will be needed the attachment and the removal of the chiral auxiliary. In spite of this, one of the most important methods of asymmetric synthesis, centred around Evans s amino acid-based chiral auxiliaries, uses this approach. 

The methods that we have just discussed can be used to control the ratio of syn and anti diastereomeric products. It is often desired to also control the reaction to provide a specific enantiomer. Nearby stereocenters in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Much effort has also been devoted to the use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions." A very useful approach for enantioselective aldol additions is based on the oxazolidinones 4,5, and 6. 

Two approaches have been studied to access non-racemic products a chiral nucleophile and a chiral auxiliary. In an approach based on Pearson s earUer work with dienyliron and dienemolybdenum complexes [79],Miles used a chiral enolate derived from AT-acyloxazolidinones in a reaction with a prochiral Mn(arene)(CO)3+ complex to give a 3.5 1 mixture of chiral q -dienylmanganese... 

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