Stereoselectivity chiral auxiliary approach

Two different chiral auxiliary approaches have been applied to the synthesis of NPS 1407 and it s enantiomer (119) (147). NPS 1407 is an antagonist of the glutamate NMDA receptor that has in vivo activity in neuroprotection and anti-convulsant assays. The J2-en-antiomer was synthesized in four steps from (116)with the chiral center introduced by. a completely stereoselective alkylation of hydra-zone (117). The chiral auxiliary, jS-( )-l-ami-no-2-(methoxylmethyl)pyrrolidine (SAMP), was introduced by condensation with aldehyde (116) and removed by catalytic hydro-genolysis. In the second method, the S-enan-tiomer was formed in a four-step sequence with the chiral center installed by the Michael addition of chiral amine (121) (formed in one step from the readily available a-methylben-zylamine) to benzyl crotonate (120). NPS 1407 (123) was found to be 12 times more potent than it s enantiomer (119)at the NMDA receptor in an in vitro assay. 

The Zambon synthesis of the non-steroidal anti-inflammatory agent (5)-2-(6-methoxy-2-naphthyl)propanoic acid (naproxen) is a landmark-setting application of the chiral auxiliary approach in the industrial stereoselective synthesis of an enantiomerically pure drug [51]. The chiral auxiliary employed, a (2f ,Jf )-dialkyltartrate, is a paradigmatic representative of this class of stereocontroller, being cheap, readily available, easily introduced on the substrate and removed from the product, and eventually recycled (although as its parent acid). 

Asymmetric electrocyclizations have been rarely reported in the literature, either for chiral auxiliary approaches or for asymmetric catalytic processes [73]. The main reason for this is most likely due to the generally high activation energies for these reactions, which complicates the engineering process of finding substrates and catalysts that enabled the system to react at reasonable temperatures required to obtain good stereoselectivity. 

It is this same maturity which has seen the auxiliary approach become accepted to the extent that numerous applications are now referred to as a standard procedure in many recent publications. This very fact can now make the retrieval of the actual chiral auxiliary application increasingly difficult. However, this level of maturity and reliability ensures that the chiral auxiliary approach currently remains the primary choice for many stereoselective transformations in advanced-stage, high-value synthetic intermediates. 

The powerful influence of an oxygen substituent on the rate and stereoselectivity of cyclopropanation augured well for the development of a chiral auxiliary based approach to asymmetric synthesis [54]. The design of the chiral auxiliary would take into account ... 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

In another approach to the meso problem , utilization of a chiral auxiliary attached at nitrogen appears to induce very high stereoselectivity. Reduction of the optically active imide 10a (see Appendix) with tetramethylammonium triacetoxyborohydridc in acetone/ acetic acid at 25 "C gives a 4 96 mixture of the diastcreomers 11a and 12a in 87% yield44. On changing the solvent to acetonitrile/acetic acid the diastereomeric ratio is improved to < 1 99, but the yield is lower (63%). 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

In a search for more effective approaches to the problem of stereoselective dioxygenation, alternative methods have been developed. While the inclusion of alkenes and O2 within a chiral cyclodextrin cavity furnished hydroperoxides with modest ee values, neighboring stereocenters and chiral auxiliaries could induce highly stereoselective dioxygenation. In 1987 Kropf and Reichwaldt, and three years later Adam and coworkers reported on the photooxygenation of phenyl-substituted alkenes 36 producing allyUc hydroperoxides 37 and 38 with high diastereoselectivity (dr 80/20). In the best example... 

There is increasing evidence13,7-191 demonstrating the important impact on bioactivity that (3-methylphenylalanines can have when incorporated into bioactive peptides. Asymmetric synthesis of these compounds with well-established chemistry and economic starting materials has become well developed. Among the reported syntheses, the chiral auxiliary assisted asymmetric pathway120-221 remains the most well-developed approach, while other pathways have only been briefly explored, because either too many steps were involved1231 or poor stereoselectivity was obtained.1241... 

Using a chiral auxiliary. The achiral substrate is combined with a pure enantiomer known as a chiral auxiliary to form a chiral intermediate. Treatment of this intermediate with a suitable reagent produces the new asymmetric centre. The chiral auxiliary causes, by steric or other means (see section 10.2.2), the reaction to favour the production of one of the possible stereoisomers in preference to the others. Completion of the reaction is followed by removal of the chiral auxiliary, which may be recovered and recycled, thereby cutting down development costs (Figure 10.10). An advantage of this approach is that where the reaction used to produce the new asymmetric centre has a poor stereoselectivity the two products of the reaction will be diastereoisomers, as they contain two different asymmetric centres. These diastereoisomers may be separated by crystallization or chromatography (see section 10.2.1) and the unwanted isomer discarded. 

Triethoxysilyl acetylene (51) allows a new organocatalytic approach toward the introduction of the alkyne moiety via a nucleophilic addition to aromatic aldehydes, ketones, and aldimines, with EtOK as catalyst (10 mol%). Although a catalytic asymmetric version has not yet been developed, the application of a chiral auxiliary, in the case of imines 53 (Scheme 7.9), led to an impressively high dia-stereoselectivity (20 1) [54], unparalleled by other acetylenic organometallics. 

Stereoselectivity in the Pauson-Khand reaction. For the PK reaction to be useful in synthetic chemistry, it is important that the stereochemical outcome of the reaction can be controlled. Four different approaches have been employed in attempts to control the stereoselectivity of the PK reaction, namely the use of chiral precursors, chiral auxiliaries, chiral promoters and chiral metal complexes. 

The approach of using chiral auxiliaries to control stereoselectivity has been investigated by a number of groups. Curran et al. (89JA9238) noted that development of chiral auxiliaries in these systems is a particular... 

In a different approach, chiral auxiliaries have been widely used in Reissert-type chemistry to provide practical access to enantiopure addition adducts. For example, the stereoselective addition of cyanide to isoquinoline or quinoline with a modified... 

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