Notizen Asymmetric Syntheses via Heterocyclic Intermediates, XXIV. Enantioselective Synthesis of (R)‐α‐Methyltryptophane Methyl Ester and D‐Tryptophane Methyl Ester by the Bislactim Ether Route

Abstract

Asymmetrische Synthesen uber heterocyclische Zwischenstufen, XXIVI). -Enantioselektive Synthese von (R)-a-Methyltryptophan-methylester und D-Tryptophan-methylester nach der Bislactimether-MethodeDie Titelverbindungen wurden durch asymmetrische Synthese nach der Bislactimether-Methode hergestellt (e.e. iiber 95% bzw. etwa 90%).Recently, Brana et al.2) reported on the asymmetric synthesis of a-methyltryptophane (by methylation of the lithium derivative of N-benzylidenetryptophane methyl ester). However, in our hands this method gives -as expected -essentially racemic material3). This communication describes the asymmetric synthesis of methyl (R)-a-methyltryptophanate (8a; e. e. > 95 Yo) and of methyl D-tryptophanate (8b; e.e. ca. 88%) starting with the lithiated bislactim ethers 2 a and 2 b of cycle(-L-Val-Ala-) and cyclo(-~-Val-Gly-)4). Upon alkylation of 2a or 2 b with N-Boc-3-(bromomethy1)indole (3) the alkylation products 4 a and 4 b with (3R) configuration are formed with d.e. more than 95% and ca. 88070; respectively 1d.e. = 070 (3R) -To (3S)I.The configuration of the main (3R) isomer of the compounds 4 can be assigned by 'H NMR spectroscopy using -as in analogous cases5) -the fact that the (3R) isomer has a "folded" conformation (type 5) with the 6-H located within the shielding cone of the heteroaromatic indole ring; consequently its 'H NMR signal suffers an upfield shift.On acid hydrolysis (4a: 0.1 N HCI, 2 equivalents, room temperature, 14 days; 4b: 0.1 N HCI, 2 equivalents, room temperature, 5 days) 4a and b are cleaved to give methyl L-valinate (6), N-Boc-protected methyl (R)-a-methyltryptophanate (7a; e. e. > 95 %), and methyl o-tryptophanate (7b; e.e. ca. 90%). In both cases L-valinate 6 could be separated by fractional bulb-tobulb destillation. With 4 N HCI at room temperature the Boc protecting group is removed to give methyl (R)-a-methyltryptophanate (8a) ( Methyl (R)-a-methyltryptophanate (8a) was alternatively obtained from the lithiated bislactim ether 9 of cyclo(-~-Ala-~-Ala-)~) by the analogous route tlia 10. The bislactim ether 10 is more readily hydrolyzed than 4a, but the degree of asymmetric induction is somewhat lower (d.e. ca. 90%).

Recent Advances in the Design and Synthesis of Carbon-14 Labelled Pharmaceuticals from Small Molecule Precursors

“…Seebach's [121] oxazolidinone (136), Schollkopf's [122] dihydropiperidine (137) and as illustrated previously, the Oppolzer sultam have all been successfully used to affect this transformation.…”

“…Lodwig prepared dual-labelled L-[ 13 C 2 ]proline and L-[ 13 C 2 ]lysine in high enantiomeric excess using the bis-methylthioimine glycine sultam. Thus, (122) was alkylated with 3 equivalents of 1-chloro-3- iodopropane to give the required precursor to both L-[ 13 C 2 ]proline and L-[ 13 C 2 ]lysine (123). Intramolecular amination afforded the labelled proline, while intermolecular amination using phthalimide followed by deprotection afforded [ 13 C]lysine.…”

Important Pharmaceuticals and Intermediates

“…In Dexamethasone the hydroxyl group in position 17 is introduced by acetoxylation of the enol acetate formed from the C-20 ketone, 29 …”

“…In particular the methods of Seebach [28] and Schöllkopf [29], based on the diastereoselective alkylation of oxazolinones derived from amino acids and bis-lactim ethers of diketopiperazines, respectively, have proven their utility. More recently, the asymmetric alkylation of imines of amino acids catalyzed by chiral phase-transfer catalysts, such as those based on quaternized cinchona alkaloids has been developed as a useful synthetic method [30].…”

Herstellung enantiomerenreiner, α‐alkylierter Lysin‐, Ornithin‐ und Tryptophan‐Derivate

“…Das so erhaltene 2-Methyltryptophan (31) besass die (S)-Konfiguration, wie aus der Konfigurdtion von 30b abgeleitet und durch Korrelation mit dem bekannten 2-Methyltryptophan-methylester [20] [26] bewiesen wurde. Es gehorte also der naturlichen Reihe an.…”