Leucine derivatives

Prasad RS, Anderson CE, Richards CJ, Overman LE (2005) Synthesis of tert-leucine-derived cobalt oxazoline palladacycles. Reversal of palladation diastereoselectivlty and application to the asymmetric rearrangement of N-aryl trifluoroacetimidates. Organometallics 24 77-81... 

Chiral surfactants have been used in the aqueous chiral micellar catalysis of a Diels-Alder reaction using an (5)-leucine-derived surfactant (Figure 12.4) to catalyze the reaction between cyclopentadiene and nonyl acrylate.65... 

This interpretation was also supported by the spectra of the corresponding N-methyl-leucine derivative in which the H-donor of the selectand was substituted by a methyl group and therefore not available for hydrogen bonding. Both complexes showed a similar spectral behavior as the weak 5-complex of DNB-Leu The C=0 stretch was always shifted from 1725 (uncomplexed autoassociated selector) to 1739 cm (indicative for disrupted H-bonds) in the 5-complex and R-complex as well. These FT-IR data may be regarded as an unequivocal proof for the existence of a stereoselective H-bond between the NH of DNB-Leu and the selector s carbonyl group (Figures 1.10 and 1.11). 

Desymmetrizations by C—H insertion using diazo decomposition strategies is well established. Chiu and coworkers have recently applied this strategy to the oxabicyclic system 195. A ferf-leucine-derived Rh(II) catalyst provided the best results [Eq. (10.58a)]. Wardrop and coworkers have applied a similar strategy en route to sordidin unfortunately, both yield and ee proved to be suboptimal [Eq. (10.58b)] ... 

Cyclohexanone imines derived from a-(methoxyniethyl)benzeneethanamine7 8, erythro-fl-methoxy-a-phenylbenzeneethanamine 6, and the tert-butyl esters of valine and rm-leucine3,17, as well as valine and h /-/-leucine derived enamines of /i-oxo esters3, are prepared by refluxing the amine and the carbonyl compound in benzene solution under azeotropic water removal, in 80-100% yield (see Table 1). 

In summary, of the many chiral auxiliaries used in the asymmetric synthesis of carbonyl compounds via imines, those able to form a methoxymethyl-chclated azaenolate show the best enantioselectivities (see Tabic 7). The same is true for valine and im-leucine derivatives which form rigid chelates via their carboxyl groups. In particular, quaternary centers (see Table 6) and a-alkvl-/i-oxo esters arc effectively prepared using these chiral auxiliaries. 

Valine and tert-leucine derived cyclohexanone imines were hydrolyzed with 5% aqueous citric acid in an ice bath under vigorous stirring for 25 minutesi-17. From the acidic layer 67% of the chiral auxiliary was recovered3. Aldimines13. acyclic ketimines10, and cyclic polymer-... 

Alkylation of this derivative and subsequent hydrolysis provides optically pure or almost pure 2-alkylated 2-amino-4-methylpentanoates 3 (a-alkylated leucine derivatives)14. However, hydrolysis of the alkylated dihydrodimethoxypyrazines 2 to the amino acid methyl esters proceeds rather slowly compared to the mono-substituted systems, and even fails in some cases. 

The (S)-leucine derivative (215) was allowed to react with diene (216) to afford the threo isomer (217) as the major product (d.s. = 80%) 213). Mukaiyama et al. 215) have reported the total synthesis of the sesquiterpene (-l-)-farnesiferol, starting from (R)-phenylglycinol, a derivative of the amino acid (R)-phenylglcine. They key step of this synthesis was an asymmetric Diels-Alder reaction. 

The asymmetric addition of organomagnesium and organolithium reagents to a,P-unsaturated carbonyl compounds and especially imines can be achieved in situations where rigid chelation controls the geometry of the transition state. Stereospecific alkyl addition occurs in the case of a chiral leucine-derived imine to provide overall asymmetric alkyl addition to an a,P-unsaturated aldehyde (Scheme 107).380 381... 

The group of Podlech has reported that trans-substituted (3-lactams (dr 70 30) can be prepared treating an Fmoc-protected leucine-derived diazoketone with a benzylidene-protected glycine ester in a photochemically induced Staudinger-type reaction [173]. Separation of the isomers, deprotection, and attachment of Fmoc-proline using the pentafluorphenyl ester activation protocol yielded the protected peptidomimetic in 93% yield, (Scheme 74). Deprotection and amidation resulted in formation of the /ram-substituted (3-lactam. 

The effect of mobile phase composition, including pH and organic modifiers, was carried out on the chiral resolution of leucine derivatives on the fert-butyl carbamoylated quinine-based CSP [2], The results of these findings are given in Table 2. This table shows that the best resolution was obtained at pH 5, 2mM concentration of buffer, 60% methanol, and 80% acetonitrile concentrations, separately. In another study, the same authors [4] studied the influence of the mobile phase, pH, and temperature on the chiral resolution of leucine derivatives. The effect of temperature on the chiral resolution of leucine derivatives is shown in Figure 2. It is clear from this figure that the chiral... 

TABLE 2 Effect of Mobile Phase Composition (pH and Organic Modifiers) on the Chiral Resolution of Leucine Derivatives... 

Since the stereochemistry of the newly created quaternary carbon center was apparently determined in the second alkylation process, the core of this method should be applicable to the asymmetric alkylation of aldimine Schiffbase 42 derived from the corresponding a-amino adds. Indeed, di-alanine-, phenylalanine- and leucine-derived imines 42 (R1 = Me, CH2Ph, i-Bu) can be alkylated smoothly under similar conditions, affording the desired non-coded amino acid esters 43 with excellent asymmetric induction, as exemplified in Table 5.7 [19]. 

Figure 22-23. ORTEP plot of a 1 1 complex between the proUne CSP and the leucine derivative. (Reprinted from reference 96, with permission.)...

By separating vacuoles isolated from mesophyll and epidermal tissue of Sorghum leaves, Kojima and co-workers (1979) showed that the cyanogenic glucoside, dhurrin, is preferentially localized in the epidermal layer. The epidermal localization of leucine-derived cyanogenic glucosides was also reported for barley leaves (Pourmohseni et al, 1993). 

Lechtenberg, M., Nahrstedt, A. and Fronczek, F.R. (1996) Leucine-derived nitrile glu-cosides in the Rosaceae and their systematic significance. Phytochemistry, 41, 779-85. 

Nielsen, K.A., Olsen, C.E., Pontoppidan, K. and Muller, B.L. (2002) Leucine-derived cyano glucosides in barley. Plant Physiol, 129,1066-75. 

Other approaches to chiral aziridines have been reported. For example, treatment of cycloheptadiene 725 with the leucine-derived (A)-3-acetoxyamino-2-(3-hydroxy-2,2-dimethylpropyl)quinazolin-4(3//)-one 724 in the presence of titanium(iv) /-butoxide (TTB) in methylene chloride leads to formation of the chiral aziridine 726, in which the chiral auxiliary (Q) is in the o-position, as the only isolated product in 29% yield (Scheme 175) <2001J(P1)1518>. 

A mixture of amino acids was reacted with -iodobenzene sulfonyl chloride ( pipsyl chloride) labeled with I to produce the radioactive pipsyl derivatives of the individual amino acids. The specific activity of the pipsyl chloride was 4.23 x lO CPM//i.mole. After the reaction, 250 mg of unlabeled pipsyl derivative of leucine were added to the mixture. A small amount of the leucine derivative was reisolated and purified to a constant specific activity of 1700 CPM//iJnole. Calculate the amount of unlabeled leucine in the original mixture. 

Y butenolides 22 were obtained in good yields and as essentially single stereoisomers (Table 5.2). In these studies, the tat leucine derived SchifTbase ligand 18a gave rise to the best diastereo and enantioselectivities, and even with the less expensive valine derived Schiffbase ligand, the products were formed with 97% ee. Removal of the N aryl group was readily accomplished with cerium ammonium nitrate followed by acidic hydrolysis of the intermediate aza quinone. 

A highly diastereoselective acetate aldol reaction that uses an L-tert-leucine-derived N-acetyl thiazolidinethione auxiliary 125 and dichlorophenylborane has been reported <04OL23>. Thiazolidinethione reagent 127, pseudoenantiomeric to 125, is also found to be effective in diastereoselective asymmetric aldol reactions, thus obviating the expensive D-tert-leucine <04OL3139>. Asymmetric aldol additions of A-propionyl thiazolidinethione... 

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