Schollkopf chiral auxiliary

Undoubted, 2-haloaniline derivatives still maintain most vored precursor status for the preparation of the indole nucleus. Larock now reports the frill details of his examination of the asymmetric addition of IV-tosyl-2-iodoaniline (63) to allenes 64 (e.g. 1,2-undecadadiene) in the presence of palladium catafysts and chiral bisoxazoline ligand to afford chiral indolines 65 in up to 88% ee <99JOC7312>. Cook has utilized the palladhjm-catafyzed heteroannulation of iodoanilines with alkynes derivatized with the Schollkopf chiral auxiliary as a reliable route to optically active ring-A substituted tryptophans <99TL657>. 

The total synthesis of (-)-fuchsiaefoline was accomplished in the laboratory of J.M. Cook using the Larock indole synthesis to prepare the key precursor 7-methoxy-D-tryptophan in enantiopure form. The propargyl-substituted Schollkopf chiral auxiliary was reacted with 2-iodo-6-methoxyaniline in the presence of 2 mol% Pd(OAc)2 to give the expected indole in good yield. Interestingly, the Bartoli indole synthesis gives /-substituted indoles only in moderate yield. 

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. ... 

The synthesis of 11-methoxymacroline 350 (239) required 6-methoxy-D-tryptophan 359, which was prepared by Larock s Pd-catalyzed heteroannulation of iodoaniline 360 and the propargyl compound 361 (prepared in turn from the Schollkopf chiral auxiliary derived from L-valine), followed by removal of the chiral auxiliary, and N(l)-methylation (Scheme 28). The 6-methoxy-D-tryptophan 359 was then transformed into the pentacyclic sarpagine derivative 362, via the 11-methoxytetracyclic ketone 354, following the same protocol as that employed in the A -methylsarpagine synthesis (vide... 

The chiral auxiliary (the a-amino ester 4) is regenerated and can be separated from the desired amino ester 3 by distillation or chromatography. (S)- or (/ )-Valine (R2 = z -Pr) is commonly used as the chiral auxiliary. The corresponding bis-lactimether (with R3 = H or CH3) is commercially available as the Schollkopf-Hartwig reagent 6. 

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... 

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. 

The reactions of enolates bearing chiral auxiliaries with formaldehyde or symmetrical ketones can be stereoselective. After removal of the auxiliary, nonra-cemic primary or tertiary alcohols are obtained. The reaction of lithium enolates of Schollkopfs lactim ethers 1.114 with symmetrical carbonyl compounds are highly stereoselective, as are the reactions of enolates of Seebach s imidazolidinone S.39 (R = Ph). In both cases, the enolate reacts from its least hindered face [154, 261] (Figure 6.11). After acidic hydrolysis, P-hydroxy-a-aminoacids are obtained with a high enantiomeric excess. However, when R = H, some unwanted epimerization can take place. 

Another example of the use of Schollkopf s method is for the synthesis of 4-fluoro-3-nitrophe-nylalanine methyl ester (15) (Scheme 9.14). In this example, valine is the amino acid used as a chiral auxiliary. 

Schollkopf, U., Nozulak, J., Groth, U. (1982). Asymmetric syntheses via heterocyclic intermediates XV. Enantioselective synthesis of (R)-(-)—hydroxyvaline unsing L-valine or (S)-0,0-dimethyl-—methyldopa as chiral auxiliary reagents. Synthesis,... 

O-Alkylation of dioxopiperazines with oxonium salts yields bislactim ethers, e.g. 4, which are used as reagents for the asymmetric synthesis of amino acids (bislactimether method, Schollkopf 1979). The chiral bislactim ether 4 is converted into the 6 r-anion 5 (under kinetic control) by n-butyllithium. Alkylation proceeds with high stereoselectivity (greater than 95%). Acid hydrolysis of the alkylation product 6 leads to (unnatural) (R)-mnno acids 7 and recovery of the chiral auxiliary (5)-valine, from which the starting material dioxopiperazine 3 was derived [160]. 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

The cyclic diamides formed by the cyclodehydration of a-amino acids are known trivially as 2,5-diketopiperazines, and are the important element of an asymmetric synthesis of a-methyl substituted amino acids developed by Schollkopf.Ii l The anion (55) resulting from deprotonation of the bis-lactim ether of a diketopiperazine undergoes alkylation with very high diastereofacial selection, especially if the chiral auxiliary is derived from (5)-valine. 

An excellent source of readily available chiral auxiliaries is to be found in amino-acids, and Schollkopf and co-workers have once again used them to prepare lithiated dihydropyrazines (11). In particular, they have used L-valine, tert-leucine, and (5)-0,0-dimethyl-a-methyldopa in the synthesis of (i )-a-amino-acids from, for example, glycine. "" The same authors have also used the oxazinones (12) to give chiral (S )-a-alkyl-a-phenylglycines from DL-phenyl-glycines however, in this case 2-hydroxyalkanoic acids are used as the chiral auxiliaries. In a quite different approach, protected and lithiated glycine is converted into alanine by the methyl sulphate (13) in enantiomeric excesses approaching 40... 

Schollkopf has developed chiral auxiliaries in order to synthesise ot-amino acids in high enantiopurity via diastereoselective alkylation of masked glycine.Schollkopf reagents 258 are formed by cyclisation of a chiral amino acid 256 with glycine 257 followed by di-O-all lation (Scheme 14.84). 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

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