Asymmetrische Synthesen über heterocyclische Zwischenstufen, IV Asymmetrische Synthese von α‐Methylphenylalanin und seinen Analoga durch Alkylieren von 1‐chiral substituiertem 4‐Methyl‐2‐imidazolin‐5‐on

Abstract

Herrn Prof. S. Hiinig zum 60. Geburtstag gewidmet. La13t man 2-Isocyan-N-[(S)-l'-phenylethyl]propionsaureamid (3 a) mitButyllithium oder Kaliumtert-butanolat ( -70 "C, Tetrahydrofuran) reagieren, tritt erst Metallierung und dann (bei ca. -20 "C) Cyclisierung zum anionisierten 4-Methyl-l-[(S)-l'-phenylethyl]-2-imidazolin-5-on (8) ein. Dieses reagiert mit Benzylhalogeniden oder Heterobenzylhalogeniden mit weit uber 95proz. asymmetrischer Induktion (d. e. = diastereomeric excess) zu den (4S)-CBenzyl-oder (4S)-4-Heterobenzyl-4-methy1-l-[(S)-l'-phenylethyl]-2-imidazolin-5-onen 9. Deren Hydrolyse liefert a-Methylphenylalanin oder seine Analoga vom Typ 11 (nahezu optisch rein), die als N-Acetylderivate 12 charakterisiert werden. Gleichzeitig wird (S)-1-Phenylethylarnin (Za), der chirale Hilfsstoff, zuriickgewonnen. -Mit nicht benzylischen Alkylhalogeniden wie z. B. Allylbromid oder Cyclohexylmethyliodid betragt d. e. nur 17 oder 35%. -Eine Modellvorstellung zur Deutung der asymmetrischen Induktion wird diskutiert, die auch die Sonderstellung der Benzylhalogenide erklart. -Verfahren zur Darstellung von 2-unsubstituierten 4-Alkyl-2-irnidazolin-5-onen (Typ 9a, 15 -17) und 2-substituierten 4-Alkyl-2-imidazolin-5-onen (Typ 18 -20) werden beschrieben. -Die Rontgenstrukturanalyse des 4-Benzyl-4-methyl-I -(1 '-phenylethyl)-2-imidazolin-5-011s (9b) zeigt a) die ,,Phenyl-innen-Konformation" fur den C-4-Benzylrest und b) C-1' so fixiert, da13 das Wasserstoffatom der Phenylethylgruppe in der Heterocyclenebene liegt und zum Carbonylsauerstoff weist. Asymmetric Syntheses via Heterocyclic Intermediates, IV l). -Asymmetric Synthesis of a-Methylphenylalanine and its Analogues by Alkylation of 1-chiral Substituted 4-Methyl-2-imidazoline-5-oneTreatment of 2-isocyano-N-[(S)-l '-phenylethyl] propionamide (3 a) with butyllithium or potassium tert-butoxide ( -70 "C, tetrahydrofuran) initially causes metalation and subsequent (at ca.-20 "C) cyclization to give the anionized 4-methyl-1 -[(S)-1 '-phenylethyl]-2-imidazolin-5-one (8).

Isocyanoacetate Derivatives: Synthesis, Reactivity, and Application

“…The chiral amine auxiliary can be recovered. 522 Although the chemistry relevant to this section has been described in detail in the corresponding sections above, we wish to discuss some additional syntheses of natural and unnatural amino acids to further demonstrate the synthetic utility of isocyanoacetates. Thus, (-)-(2R,3S)-3-hydroxylysine 1178, a naturally occurring amino acid, was synthesized using a gold-catalyzed asymmetric aldol reaction.…”

“…He found that alkylation of N-[(S)-phenetyl]-2-isocyanopropionamides 1192 by benzyl halides proceeds with high diastereoselectivity, whereas with nonbenzylic alkyl halides, the de is much lower. 522 Furthermore, Scho ¨llkopf has described the cyclopropanation of formylaminoacrylates 1195a and isocyanoacrylates 1195b by dimethylsulfoxonium methylide, 529 a method used for the preparation of aminocyclopropane carboxylic acid (ACC) derivatives 1196 (Scheme 297). 530,531…”

“…The corresponding amino acids are obtained upon hydrolysis (see Scheme for examples). The chiral amine auxiliary can be recovered …”

Parallel Synthesis of Arrays of Amino-Acid-Derived Isocyanoamides Useful As Starting Materials in IMCR

“…Including the current approach, now four complementary synthetic pathways are available to access this important starting material class. ,, Current evaluation of this isocyanide class for use in new IMCR is ongoing in our laboratory. We are also investigating the broad use of the described compound class in the synthesis of 1-alkyl-4-carboxamidoimidazoles, 2,3,4-trisubstituted pyrroles, isoxazolinopyrroles, macrocycles, lennoxamine-type natural products, silver catalyzed imidazolidines and oxazoles, oxazolines, spiroimidazolones, 10b, peptides, 1 H -imidazole-2-thiones, 2,4-bis(arylthio)-5-[ N -alkyl- N -phenylamino]oxazoles,9b α-keto esters, mesoionic 3-alkyl-2-(arylthio)-1,3-diazolium-4-olates, 2-aminoimidazoles, optically active threo-β-hydroxyamino acids, 2-imidazolin-5-ones, 5-amino oxazoles,9a or 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives . This class of isocyanides will provide the foundation of focused and general libraries for use in the discovery of biologically active compounds.…”

Asymmetric alkylation of dimethoxyphosphoryl-N-[1-(S)-α-methylbenzyl]acetamide enolates. Synthesis of both stereoisomers from the same source of chirality by changing the equivalents of LDA

“…), the enolate geometry may be Z, in accordance with the literature precedence and favored by the coordination C-O-Li-OLP. 10 The orientation of the C-H bond of the chiral auxiliary towards the oxygen atom and the relative size of phenyl and methyl groups determines the preferred direction of benzyl bromide addition, 11 in this case for the re face, which leads to (R,S)-4 diastereomer as principal product. Additionally, the reaction appears to be operating under kinetic control, since no evidence of reversibility was observed and the diastereoselectivity was independent of reaction time (Table 1, entry 5).…”