O’Donnell imine

One of the interesting application of 12 (R= allyl, X=Br) will be the synthesis of cyclic amino acid, (S)-pipecolic acid, as its tert-butyl ester 271251 Monoalkylation of the O Donnell imine 23 with l-chloro-4-iodobutane afforded the alkylated product 26 with 99 % ee. The conversion of 26 to the tert-butyl ester of pipecolic acid 27 was achieved in high yield by the sequence imine reduction, cyclization, and hydrogenolytic removal, as shown in Scheme 8. 

Figure 3. The tight ion pair 28 in the asymmetric alkylation of the O Donnell imine 23.

Bis-a-amino acid esters 35 were prepared by use of the N-anthracenylmethyl catalysts 12 (R=H, X=C1) or its dihydro derivative 12 (R=H, X=Br, 10,11-dihydro) with high diastereo and enantioselectiv-ities via alkylation of two equivalents of the O Donnell imine 23 with appropriate dibromides 33, as summarized in Table 3.130311... 

The efficient enantioselective alkylation of the P/y-unsaturated ester 39 was achieved1351 by use of the N-anthracenylmethyl catalyst 12 (R=benzyl, X=Br) together with CsOH-H20 under phase transfer conditions analogous to those in the alkylation of the O Donnell imine 23, as shown in Scheme 13. The enantioselectivity of the alkylation correlates with Hammett o constants, and the N,N-dimethylamino substituents in 39 showed the most effective enantioselectivity. The tight ion pair in which the enolate... 

O Donnell imine 23 with various aldehydes, giving P-hydroxy-a-amino acid esters 44 with high enantiomeric excess,1401 as shown in Scheme 15. 

Some chiral quaternary ammonium salts are also effective in Michael addition reactions. The Merck catalysts 7 (R=4-CF3, X=Br) and 9 (R=4-CF3, X=Br, 10,11-dihydro) were used tor the Michael additions of 59,61, and 64 to vinyl ketones to give the adducts 60,62, and 65 (isolated as 66), respectively,148,491 with excellent enantioselectivity, as shown in Scheme 19. The Michael addition of the O Donnell imine 23 to the a,(3-unsaturated carbonyl compounds also efficiently proceeded by use of the N-anthracenyl-methyl catalyst 12 (R=allyl, X=Br), giving the Michael adducts 67 (Scheme 20).1251... 

The solid-phase synthesis of a-amino acids via alkaloid-catalyzed alkylation has been investigated by the O Donnell group [64, 65]. The solid-phase based synthetic approach is particularly useful for rapid preparation of a-amino acids for combinatorial application. The concept of this solid-phase synthetic approach, which comprises three key steps, is shown in Scheme 3.22 (for formation of (R) enantiomers). First, solid-phase bound glycine, 51, is converted into its benzophenone imine de-... 

In 1992, O Donnell succeeded in obtaining optically active a-methyl-a-amino acid derivatives 49 in a catalytic manner through the phase-transfer alkylation of p-chlorobenzaldehyde imine of alanine tert-butyl ester 48 with cinchonine-derived la as catalyst (see Scheme 4.16) [46]. Although the enantioselectivities are moderate, this study is the first example of preparing optically active a,a-dialkyl-a-amino acids by chiral phase-transfer catalysis. 

O Donnell MJ (2001) The preparation of optically active a-amino acids from the benzophenone imines of glycine derivatives. Aldrichim Acta 34 3... 

O Donnell, M. J. The Preparation of Optically Active a-Amino Acids from the Benzophenone Imines of Glycine Derivatives, Aldrichim. Acta 2001,34, 3-15. 

In 1978, O Donnell and coworkers developed the benzophenone imines of glycine alkyl esters 4 as glycine anion equivalents, which have been found to be perfed to use in the phase-transfer catalysis [10]. An essential feature of this reaction system lies in the selective mono substitution of the starting Schiff base, the O Donnell substrate 4. This can be possible because of the significant difference in acidity of a-hydrogen between starting substrate 4 p/C,(DMSO) 18.7 (R=Et)] and a-monosubstituted produd S p/C,(DMSO) 22.8 (R=Et, E = Me), 23.2 (R=Et, E = CH2Ph)] [11]. This dramatic acidity difference makes it possible for selective formation of only monoalkylated product without concomitant production of undesired dialkylated produd or racemization. 

The first example of preparing ophcaHy achve a a-dialkyl-a-anhno acids by chiral PTC was reported by O Donnell in 1992 [36], giving moderate enanhoselec-hvities for the alkylation of p-chlorobenzaldehyde imine of alarhne tert-butyl ester 39a with cinchonine-derived Ic as catalyst (entry 1, Table 11.4). Subsequenhy,... 

The point of attachment of the solid support could play a signihcant role in steering the stereoselection of the reaction course. In 1989, O Donnell et al. observed that a tertiary butyl group was required for achieving high enenatioselectivity in the phase transfer alkylation of diphenylmethyleneglycinimine ester. As a consequence, Park et al. (Scheme 7.15) linked the solid support to the substrate (72) onto the imine moiety to... 

Lipkowitz KB, Cavanaugh MW, Baker B, O Donnell MJ. Theoretical studies in molecular recognition asymmetric induction of benzophenone imine ester enolates by the ben-zylcinchoninium ion. i. Org. Chem. 1991 56(17) 5181-5192. 

Phase-transfer catalysis is a vast area of organic chemistry, and there are many different examples of the applications of phase-transfer catalysts to asymmetric synthesis, particularly in the area of enantioselective a-ami-noacid synthesis. This area has been extensively reviewed by Maruoka, Lygo and O Donnell. However, there are limited examples where asymmetric phase-transfer catalysis has been applied to drug discovery. One notable example is the asymmetric allylation of glycine imine 337, catalysed by quaternary ammonium bromide 340, which has been used by Kumar et al, as the key step in the synthesis of local anaesthetic levobupivacaine " (339) (Scheme 14.102). 

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