Asymmetric PTC Alkylation of Glycine Imines: Variation of the Imine Ester Moiety

Abstract

Studies into the enantioselective phase-transfer alkylation of a series of glycine imine esters are presented. Using a quaternary ammonium salt catalyst derived from a-methylnaphthylamine, high enantioselectivities were obtained in reactions involving imines containing tert-butyl, benzhydryl, and benzyl esters. In contrast, a quaternary ammonium salt catalyst derived from dihydrocinchonidine gave highest enantioselectivities with tert-butyl and ethyl esters. Application of the benzhydryl ester alkylation in the preparation of a differentially protected aspartic acid derivative is also presented.Key words: amino acids, asymmetric alkylation, phase-transfer catalysis, quaternary ammonium salts In recent years the asymmetric phase-transfer catalyzed alkylation of glycine imines (Scheme 1) has emerged as a highly effective method for the enantioselective synthesis of a-amino acids. 1-4 This chemistry has now been developed to the point that it is regularly being exploited in target synthesis. 5 Throughout the development of this methodology most work has focused on the identification of highly effective phase-transfer catalysts and the optimization of reaction conditions. In contrast, relatively little variation in the nature of the glycine imine ester function has been reported, with the vast majority of studies involving only tert-butyl ester 1a. 3 With this in mind, we have recently examined the enantioselective alkylation of alternative glycine imine esters and in this paper report preliminary results arising from this work. Scheme 1We have examined the asymmetric alkylation of four different glycine imine esters 1 (a: R = t-Bu; b: R = CHPh 2 ; c: R = CH 2 Ph; d: R = Et). These particular imines were selected because they are straightforward to prepare 6 and because they incorporate synthetically versatile ester functions. In particular, the benzhydryl and benzyl esters were of interest to us because of they are readily cleaved via hydrogenolyzis, thus offering a useful alternative to the strong acid or base normally employed in the hydrolytic cleavage of esters 2a. 7Pioneering studies by the O'Donnell group included investigations into the C-benzylation of these four imine esters using N-(4-trifluoromethylbenzyl)cinchoninium bromide as the phase-transfer catalyst. 8 This work established tert-butyl ester 1a as the optimal substrate for reactions of this type, the product 2a (R¢ = Bn) being generated in 56% ee with this particular catalyst. Interestingly the benzyl and benzhydryl esters gave the lowest levels of enantioselectivity (28% ee and 14% ee respectively) in this study. Similar trends have also been reported for reactions involving C 2 -symmetric binaphthyl derived phase-transfer catalysts. 4a

In the Golden Age of Organocatalysis

“…The substitution pattern of the glycine derivative also has a major impact on the stereoselectivity of the alkylation. Recent studies demonstrated that the tert ‐butyl ester of the glycine reagent can be advantageously replaced by a diphenylmethyl ester when the catalyst 126 (Figure 14) is used 202…”

Fortschritte bei asymmetrischen Phasentransferkatalysen

“…Beispielsweise lieferte die Alkylierung von 51 mit tert ‐Butylbromacetat in Gegenwart von ent ‐ 50 unter ähnlichen Bedingungen quantitativ und mit hohem Enantiomerenüberschuss das gewünschte Produkt 52 . Damit eröffnet sich ein Zugang zu einem differenziell geschützten L ‐Asparaginsäure‐Derivat (Schema ) 41. Diese Umsetzung ist mit Cinchona‐Alkaloid‐Katalysatoren wie 26 k vermutlich nur schwer zu erreichen.…”

Two Highly Effective Phase-Transfer Catalysts for the Enantioselective Synthesis of ?-Amino Acid Derivatives

“…[36] This led to the development of a α -methylnaphthylamine- derivedP TC 18,w hich has provedt ob e equally effective in the alkylation of imine 1 ,but which is more tolerant of variation in the ester moiety. [37] Quaternary ammonium salt 18 can be prepared from the commercially available phenol 15 via the six-step sequence outlined in Scheme 5. This catalyst is significantly more active than cinchona-alkaloid derivedc atalysts such as 11,a nd this allows for lower catalyst loading to be employed.…”

“…[37] This opens up the possibility of generating orthogonally protected amino acid esters within as ynthetic sequence, and this feature has recently been exploited in as hort, stereoselective construction of the marine peptide renieramide (Scheme 6). [39] This synthesis features twoasymmetric alkylation steps, the first utilizes the enantiomer of catalyst 18 for the enantioselective introduction of the first amino acid benzhydryl ester,and the second employs the cinchonidine-derivedc atalyst 11 to introduce an amino acid tert-butyl ester.Both of these reactions proceed with ahigh levelofstereoselectivity,and it is also interesting to note that the first alkylation proceeds with high selectivity for the bromomethyl function.…”