Alkylations chiral auxiliaries, camphor

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

Asymmetric alkylation of benzylamine via the imine 6A, with ( + )-D-camphor (5 A) as chiral auxiliary is possible. Deprotonation with butyllithium and subsequent alkylation with haloalkanes, (R X) afforded the alkylated imines 7 A with reasonable yield but variable diastereo-selectivity. The diastereoselectivity depends strongly on the haloalkane with methoxy-substi-tuted halomethylbenzenes moderate to good diastereoselectivity (d.r. 80 20-90 10) is obtained, however, with haloalkanes or 3-halopropenes only low optical purities (< 50%) were observed. 

A potential method for the preparation of novel amino acids via the highly selective addition of radicals to the glyoxylic oxime derivative of Oppolzer s camphor sultam (88) has been reported.181 Both Lewis acid and non-Lewis acid-mediated reaction conditions for the addition of alkyl radicals generated from alkyl iodides and Et3B/Bu3SnH were examined. A new chiral auxiliary based upon (R,R)-2,5-diphenylpyiTolidine has been used in the addition of phenylthiyl radicals to unsaturated methacrylamides. The selectivity was found to be better than that reported for the structurally related 2,5-dimethylpyrrolidine derivative.182... 

Camphor and camphor-derived analogues are used frequently as chiral auxiliaries in asymmetric synthesis (cf Chapter 23). There have been numerous reports in the use of camphor imine as templates to direct enantioselective alkylation for the synthesis of a-amino acids, a-amino phos-phonic acids, a-substituted benzylamines, and a-amino alcohols (e.g., Scheme 5.9).43 47 Enantiomeric excesses of the products range from poor to excellent depending on the type of alkyl halides used. 

Oppolzer s camphor sultam, a well known chiral auxiliary, has been applied to the asymmetric synthesis of chial fluorine-containing amino acids <07OL2513>. Photoinduced addition of perfluoroalkyl iodides 189 to /V-acyloylcamphorsultam 188 in the presence of an aqueous solution of sodium sulfite provides alkyl iodides 190 with moderate to good stereoselectivities. Azide displacement with the major diastereomer of 190 proceeds with inversion of configuration. Subsequent removal of the sultam auxiliary and hydrogenation of the azide afford the chiral fluorine-containing amino acid 192. 

In the laboratory of T.-J. Lu, a highly stereoselective method for the asymmetric synthesis of a-amino acids was developed by the alkylation of a chiral tricyclic iminolactone derived from (+)-camphor. The iminolactone can be considered a glycine equivalent. The synthesis commenced with the Riley oxidation of (+)-camphor to obtain the corresponding (+)-camphorquinone. Amino acids are obtained by first alkylating the a-position of the lactone with various alkyl halides and then hydrolyzing the monosubstituted products. The advantage of this technique was that the chiral auxiliary could be fully recovered without the loss of any optical activity. 

Chiral auxiliaries may be applied to a-amino acid esters by forming imine derivatives. Enolates from 2-hydroxy-3-pinanone glycinate esters have been alkylated to produce mono- and di-substituted o-amino acids in good optical yields after hydrolysis. Recently, McIntosh et al reported the results of alkylations of the enolate (139) derived from the (+)-camphor imine of r-butyl glycinate with a variety of... 

A variety of methods exists for the synthesis of optically active amino acids, including asymmetric synthesis [85-93] and classic and enzymatic resolutions [94-97], However, most of these methods are not applicable to the preparation of a,a-disubstituted amino acids due to poor stereoselectivity and lower activity at the a-carbon. Attempts to resolve the racemic 2-amino-2-ethylhexanoic acid and its ester through classic resolution failed. Several approaches for the asymmetric synthesis of the amino acid were evaluated, including alkylation of 2-aminobutyric acid using a camphor-based chiral auxiliary and chiral phase-transfer catalyst. A process based on Schollkopf s asymmetric synthesis was developed (Scheme 12) [98]. Formation of piperazinone 24 through dimerization of methyl (5 )-(+)-2-aminobutyrate (25) was followed by enolization and methylation to give (35.6S)-2,5-dimethoxy-3,6-diethyl-3.6-dihydropyrazine (26) (Scheme 12). This dihydropyrazine intermediate is unstable in air and can be oxidized by oxygen to pyrazine 27, which has been isolated as a major impurity. 

Naturally occurring ketones and their readily prepared derivatives have also been used as chiral auxiliaries. Menthone ketals have been the subject of some study [373, 374], For example, enolates of compound 1.106, obtained from 8-phenylmenthone, are alkylated with a good stereoselectivity [375]. Cleavage of the chiral auxiliary is accomplished by hydrolysis. Enolates of tert-butylglycine camphor imine 1.107 are alkylated [154, 159] or suffer Michael additions [376] with a high stereoselectivity, and the auxiliary is cleaved by treatment of the prod-... 

Scheme 3.15. Controlled stereoselective enolate formation and asymmetric alkylation of a second generation camphor ester enolate chiral auxiliary [75].

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Various glycine-derived imines of camphor and other chiral ketones or aldehydes have been alkylated in a diastereoselective maimer to give nonracemic a-amino acids after the cleavage of the auxiliary [24]. A more recent concept for the alkylation of a glycinamide-derived enolate developed by Dixon and coworkers links the chiral auxiliary to the a-nitrogen atom under the form the tetrahydropy-ran 35, available from camphor in a three-step protocol. Upon deprotonation with LiHMDS, a cis-configured enolate is assumed to form wherein the metal is chelated by the tetrahydropyranyl oxygen atom. The treatment of the enolate... 

Two other alkylations were based on readily-available chiral auxiharies. PhUippe Karoyan of the Universite Pierre et Marie Curie observed Tetrahedron Lett. 2008, 49, 4704) that the acylated Oppolzer camphor sultam 20 condensed with the Mannich reagent 21 to give 22 as a single diastereomer. Andrew G. Myers of Harvard University developed the pseudoephedrine chiral auxiliary of 23 to direct the construction of ternary alkylated centers. He has now established J. Am. Chem. Soc. 2008,130, 13231) that further alkylation gave 24, having a quaternary alkylated center, in high diastereomeric excess. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

D-Amino acids (with R configuration) are only rarely found in nature and, because of their comparatively high price, their preparation may sometimes appear desirable. Resolution procedures can often be applied, but synthetic methods are also available. (/ )-Amino acids can be obtained by catalytic hydrogenation of dehydro amino acids by the appropriate choice of enantiomeric control ligands (Scheme 1, Section D.2.3.I.), and by alkylation with chiral glycine equivalents as auxiliaries, such as camphor derivatives (Scheme 2)15-16 or imidazolidinones (Scheme 3)11. Modified carbohydrates have been successfully applied in the asymmetric Ugi reaction to obtain many (R)-amino acids (Scheme 4)11. 

The most familiar of the sulfonic adds derived from camphor is 10-camphorsulfonic add (44, Reychler s acid45). Both enantiomers are commercially available and convenient procedures exist for their preparation by sulfonation of camphor (ref 46 exemplifies the racemate, but the procedure works equally well for optically active camphor). The free acid is often applied to the resolution of basic compounds such as amines. A detailed review on the use of derivatives of this acid as auxiliaries has been given3. Esters of this add are normally obtained by the reaction of the alcohols with the sulfonyl chloride which is also commerdally available (or readily obtained by the reaction of the free acid with phosphorus pentachloride or thionyl chloride46,48). Such esters with unsaturated alcohols have been used for diastereoselective [1,2] sigma tropic rearrangements (Section D.1.6.3.3.). Allyl esters have been used for enantioselective alkylation reactions, in which camphorsulfonic acid reacts as the chiral leaving group (Section D.1.1.2.2.). 

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