Amino ethers chiral auxiliary

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

O-Alkylation gives the bis-lactim ether shown at the top right of Scheme 3.11. After deprotonation, alkylation occurs stereoselectively such that the electrophile approaches the anion anti to the isopropyl. Typical selectivities for this process are listed in Table 3.2. Advantages of this process are that selectivities are high and that it makes chiral quaternary carbons. Disadvantages are that the electrophiles must often be activated (Le., allylic, benzylic), and that the alkylated amino ester and the amino ester chiral auxiliary must be separated at the end. 

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

The reduction of phenyl mesityl ketone was studied with LAH modified with amino alcohols 65 to 72 in ether (the ratio LAH alcohol ketone = 1.1 1.1 1) (83). Optical yields were modest, with the highest 39%, obtained with 65 as the chiral auxiliary reagent. It was observed that there is a relationship between the preferred enantiomeric product and the structure and absolute configuration of the carbons carrying the hydroxy and amino groups. Thus the threo... 

To recover the chiral auxiliary, the aqueous phases are made basic with 2 M sodium hydroxide. After extraction with dielhyl ether, the amino alcohol is recycled in >80% yield. 

Symmetrical hw-Iactim ethers of type (187) — built up from two identical amino acids — do have one disadvantage, inherent in the system only 50% of the chiral auxiliary — in this case (S)-alanine — is recovered the other 50 % is first racemized via (188) and finally incorporated in the product (189). To avoid this disadvantage Schollkopf et al. have developed methods to synthesize mixed bw-lactim ethers, starting from two different amino acids, e.g. (S)-valine and (R,S)-alanine. Thus, the authors obtained cyclo [(S)-val-(R,S)-ala] and prepared the related h/.s-lactim ether... 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

An enantioselective synthesis of CR)-amino acids has been developed which utilizes L-valine as the chiral auxiliary (81AG(E)798). The diketopiperazine cycZo-(L-Val-Gly) (780) was converted to its bis-lactim ether (781) by methylation with Meerwein s salt, and the ether metallated in the glycine portion by n-butyllithium. Alkylation of the delocalized... 

With an amino acid-derived chiral auxiliary employed in the chloroformate, reaction of silyl enol ethers with isoquinolinium salts showed not only regiospecificity, but some stereoselectivity as well (Equation 61) <1999SL1154>. The addition of ketene silyl acetals to an W-acylpyridinium salt containing a chiral 2,2-dimethylox-azolidine at C-3 gave 1,4-dihydropyridines with excellent stereoselectivity <2002JA8184>. 

This article deals with results achieved with the 2,5-dimethoxy-3,6-dihydropyra-zines, the heterocycles of type I. Results obtained with the imidazolinones III are discussed elsewhere 6). At first glance the heterocycles I look rather esoteric. However, the yare nothing but the bis-lactim ethers of the well known 2,5-diketopiperazines, the cyclic dipeptides. — At first, experiments with the symmetrical bis-lactim-ether (6) of cyclo(L-Ala-L-Ala) (5) are described and then results with several mixed bis-lactimethers. Symmetrical bis-lactimethers — i.e. those, build up from two identical amino acids — do have one disadvantage, inherent in the system, namely, only one half of the chiral auxiliary is recovered, the other half is incorporated in the product. But they are easily prepared and, hence, are good models to commence a study. 

Of course, the (3S)-compounds would also be formed if D-valine would be employed as chiral auxiliary. Hence, this method with valine as chiral auxiliary reagent solves the problem of enantioselective synthesis of a-methyl amino acids satisfactorily. Probably it can also be used — mutatis mutandis — for the asymmetric synthesis of a variety of a-alkyl amino acids, provided, the corresponding bis-lactim ether (type I) with valine as C-6 is regiospecifically metallated by butyl-lithium. This, for instance, is not be case with the mixed bis-lactim ether (20c) of cyclo(L-Leu-D,L-Ala)17). 

The ionic chiral auxiliary approach was also applied to the enantioselective photocylization of tropolone. Irradiation of salt crystals of tropolone ether carboxylic acid 29 with several chiral amines afforded the enantiomerically enriched secondary products 31 [52]. The best results were obtained with optically pure 1-phenylethylamine and l-amino-2-indanol, which gave optical yields in the 60-80% ee range depending on the extent of conversion. 

Metallation-alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquin-oline provides optically active 1-alkyl-1.2,3,4-tetrahydroisoquinolines. The formam-idines of 10 optically active amino alcohols have been examined as the chiral auxiliaries and of these, the bistrimethylsilyl ether 2 (S.S-BISPAD) of 1 proved to be the mc>st efficient as well as consistent (equation II). The configuration (S) was established by synthesis of the benzoquinolizine (S)-5, a degradation product of an alkaloid. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

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