Schollkopf intermediate

The Schollkopf intermediate was also used in the preparation of 2-bromo-5-hydroxytryptophan, using l-(f-butoxycarbonyl)-2-bromo-3-(bromomethyl)indole as the alkylating agent. <95TL9133>... 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

The first synthesis of lithium ynolates was reported by Schollkopf in 1975. The isoxazolyllithium 10, prepared by lithiation of 3,4-diphenylisoxazole (9), undergoes fragmentation to yield the lithium ynolate 11 (equation Tf. The dilithium ynolate dianion 14 is also synthesized by the same protocol from 3-phenylisoxazole (12) via the 3-phenyl-5-isoxazolyllithium (13) intermediate (equation 3). The maximum yields were around 80%, judged by the yields of the /3-lactones (Section IV.A). 

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. 

Schollkopf, U., Busse, U., Lonsky, R., and Hinrichs, R., Asymmetric syntheses via heterocyclic intermediates. Part 31. Asymmetric synthesis of various non-proteinogenic amino acid methyl esters (functionalized in the carbon chain) and amino acids by the bislactim ether method, Liebigs Ann. Chem., 2150, 1986. 

Schollkopf, U., Pettig, D., Busse, U., Egert, E., and Dyrbusch, M., Asymmetric synthesis via heterocyclic intermediates. Part 30. Asymmetric synthesis of glutamic acids and derivatives thereof by the bislactim-ether method. Michael-addition of methyl 2-alkenoates to the hthiated bislactim-ether of cyclo-(L-Val-Gly), Synthesis, 737, 1986. 

Taking advantage of the multifunctionalities and ready accessibility of methyl (2)-3-(dimethylamino)-2-isocyanoacrylate (Schollkopfs isocyanide) (53), Bienayme and Bouzid developed a four-component synthesis of bicyclic tetrazole 54 (Scheme 5.16) [34]. Simply stirring a methanolic solution of an aldehyde, an amine, 53, and TMSN3 afforded 54 in good to excellent yield. Trapping the nitrilium 55 by azide afforded the intermediate 56, which was subsequently cyclized to furnish the tetrazole 57. A sequence of intramolecular Michael addition followed by (3-elimina-tion of dimethylamine then provided the final product 54. The intermediate tetrazole 57 could be isolated and was found to cyclize to the bicyclic tetrazole 11 in essentially quantitative yield under the reaction conditions. 

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,... 

Nitration of aliphatic diazo compounds was studied by Schdllkopfs group (Schdllkopf and Schafer, 1965 Schollkopf et al., 1969). They nitrated ethyl diazoacetate with dinitrogen pentoxide in CCI4, at — 30°C and obtained, besides ethyl diazonitroacetate (9.2, yield 35 < 0), the nitric ester of ethyl glycolate (9.3, 27%). Scheme 9-1 explains the low yield. Stoichiometrically, only half an equivalent of the diazoacetate is nitrated the other half is the proton acceptor for the deprotonation of the intermediate with a diazonio group (9.1). 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

Scheme 12 presents a Hoppe and Schollkopf approach to the synthesis of azidoketone 49, a key-intermediate for preparation of the lincosamine derivative 15. 

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. ... 

This reaction has been modified by exchanging the lithium ion of the Schollkopf bis-lactim ether intermediate with Sn(II), Cu(I), or Ti(IV) to enhance the diastereos-electivity in Aldol Condensation and the Michael Addition. 

Besides the formation of oxazole derivatives, Schollkopf and the others have successfully extended the a-alkali metalated isocyanides to the formation of the chain-extended primary amines, 2-oxazolines, 2-thiazoline-4-carboxylic esters," 2-imidazolines, 2-pyrrolines and pyrroles, thiazoles, 2-imidazolin-5-ones," 2-imidazolinones," etc. For example, a simple reaction between lithiomethyl isocyanide with two equivalents of piperonal followed by acetylation of the intermediate with acetic anhydride affords the corresponding oxazoline. ... 

Startg. arenemanganese tricarbonyl complex allowed to react with 1 eq. Schollkopf s pyrazine in THF at —78° for 30 min - intermediate complex (Y 80%), demetalated with N-bromosuccinimide in ether at room temp, for 15 min - product (Y 60% d.e. 95%). F.e. and hydrolysis to chiral amino(aryl)acetic acid esters s. A.J. Pearson et al., J. Chem. Soc. Chem. Commun. 1989, 659-61. 

The Schollkopf reaction has found considerable use in the preparation of eompounds containing 4,5-disubstituted oxazoles. 4,5-Disubstituted oxazole 30 served as a key intermediate in DuPont s synthesis of benzamidine 31, a Factor Xa inhibitor. The Sehdllkopf reaetion has similarly found use in the preparation of 4,5-disubstituted oxazoles for P3-adrenergie receptor agonist," Fe(II)-form-selective E. coli methionine aminopeptidase inhibitor," and prostacyclin receptor antagonist programs. The robustness of this synthetic methodology has also led to the use of the Schollkopf oxazole synthesis as a test reaction in the evaluation of a number of flow-reactor systems. ... 

The Schollkopf reaction additionally serves as a useful method for the preparation of a-amino ketones (c/, 14 32 33). Aeid-eatalyzed hydrolysis of the oxazole products of the Schollkopf reaction (e.g., 18) leads initially to a-amino ketone intermediates cf, 32), which can either be isolated or—in the case of intermediates derived from oxazoles bearing C-4 ester substituents—de-alkylated and deearboxylated to provide the related a-amino ketones cf, 33). ... 

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]. 

In a variation of the Wittig reaction, the a-metallized retinyl isocyanide (98) was reacted with retinaldehyde (2) to give P-carotene via an unstable oxazoline intermediate (Schollkopf, 1977). 

Synthesis.—Schiff-base derivatives of amino-acids are readily prepared and are alkylated under various phase-transfer conditions. Schollkopf and his coworkers have continued to extend the scope of their studies on asymmetric synthesis via heterocyclic intermediates e.g. the bis(lactim) ether (263), derived... 

ScHOLLKOPF et al (360) reacted a-metallated isocyanoacetic ester with aldehydes and ketones in aprotic solvents to form formyl-enamino acid esters (24) via intermediate oxazoline carboxylic acid esters. 

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