Amino acid derivatives diastereoselective alkylation

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Novel highly functionalized dipeptide isosters were synthesized via diastereoselective alkyl-arylation protocol of a glucose-derived (R)-tert-butanesulfinylimine. One of these novel sugar amino acid derivatives, a D-Ala-Ser/Thr isostere, was applied in a peptide synthesis protocol to afford a cyclic tetramer (Fig. 53).69... 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Highly diastereoselective alkyl radical addition to Oppolzer s camphorsultam derivative (33) of oxime provides enantiomerically pure a-alkyl-a-amino acid derivative (34) at — 78 °C by the same method as shown in eq. 10.16. Moreover, enantioselective tandem radical 1,2-difunctionalization of cinnamamide (35) can be carried out with high stereoselectivity, using the chelation manner of the cinnamamide and a chiral bisoxazoline ligand on Mgl2, as shown in eq. 10.17. 

VIII. MEMORY OF CHIRALITY IN DIASTEREOSELECTIVE a-ALKYLATION OF fi-BRANCHEI) a-AMINO ACID DERIVATIVES... 

Scheme 70 Chiral Auxiliaries Used in the Derivatization of Glycine Equivalents and Diastereoselective Alkylation of Chiral A -Alkylidene Amino Acid Derivatives ...

For other examples, the diastereoselectivities range from 1.5 1 to 3 1 502. The oxazole method is limited to a-alkyl a-amino acid derivatives as the a-unsubstituted substrates 11 (R = H) lead to 1 1 mixtures of diastereomers as a result of facile epimerization of the intermediate oxa-zolone502. For applications of the oxazole method see refs 526-530. 

Rh-catalyzed cyclohydrocarbonylation of functionalized homoallyic amine has been successfully applied to the synthesis of (+)-prosopinine (97) and (-)-deoxyprosophyline (98) (Figure 2-4). Both (+)-prosopine and (-)-deoxyprosophyline have been shown to possess both antibiotic and anesthetic properties. This synthesis uses amino acid derivatives that are subjected to CHC conditions to generate the desired substituted piperidine intermediates. The piperidine intermediates are then further converted to the desired alkaloid by subsequent diastereoselective introduction of the alkyl chains at the C-6 position. 

The Naito laboratory has investigated the applicability of radical reactions in solid-supported chemistry. A pronounced effect of the solid support on the stereochemical outcome of a radical reaction was reported for the addition of an alkyl radical onto the chiral oxime 139, delivering a-amino acid derivatives 140 in good yield and with high stereoselectivity (Scheme 6.32). Higher diastereoselectivities were observed with the substrate 139 immobilized on the solid support (>90% de), compared to comparable solution-phase reactions of 139 (72-85% de). This effect was rationalized based on the lower reactivity and reduced reaction rate of the immobilized oxime, inducing an enhanced selectivity. ... 

Various enones could he employed, and only minor electronic effects were observed for R2 substituents. Arylbromide and arylchloride R2 substituents could be used without diminished yields (80-94%). Aryl/alkyl, aryl/aryl, and alkyl/alkyl combinations for R2 and R3 were well tolerated providing functionalized azalactones in good to excellent yields (65-96%) and with high enantio- and diastereoselectivities (75-99% ee, <98 2 dr) (eq 77). Additionally, postfunctionalization of the azalactone products could be explored to generate unnatural quaternary amino acid derivatives and bicyclic dipeptides. 

Meyers reported one of the first approaches to diastereoselective alkylations of enolates derived from carboxylic acids through the use of optically active amino acid-derived oxazolines [67-69]. As an example, alkylation of 79 with ethyl iodide gave 80 with high stereoinduction (Scheme 3.13) [70]. Subsequent hydrolytic opening and cleavage of the oxazoline auxiliary furnished optically active u-substituted carboxylic acid 81 in 80 % ee. 

Other uses of oxazinone enolates have been described by Williams, including the boron enolate 60, in the synthesis of diaminopimelic acid (62), the penultimate precursor of the essential amino acid i.-lysine (Scheme 10.8) [59], Acylated derivatives of Oppolzer s camphor sultam 63 can readily be alkylated in a highly diastereoselective fashion (Scheme 10.9) [60]. Thus, the imide derived from the condensation of 63 and 64 undergoes enolization and subsequent alkylation to furnish protected amino acid derivatives with high selectivity (cf 65, dr > 99 1) [61],... 

An efficient enantioselective total synthesis of (—) -cis-clavidpitic acid was reported by Park and coworkers (Scheme 12.3) [103]. The asymmetric phase-transfer catalytic alkylation of 65a with 68 was employed as the key step, producing the urmatural oi-amino acid derivative 69 for the introduction of the 5S chirality. Starting from a glycine derivative 65a, Maruoka and coworkers successfully developed a strategy for the asymmetric synthesis of cyclic amino acids having a piperidine or azepane core structure by the combination of a phase-transfer catalytic asymmetric alkylation and a subsequent diastereoselective reductive amination. This approach allows the... 

Diastereoselective preparation of a-alkyl-a-amino acids is also possible using chiral Schiff base nickel(II) complexes of a-amino acids as Michael donors. The synthetic route to glutamic acid derivatives consists of the addition of the nickel(II) complex of the imine derived from (.S )-,V-[2-(phenylcarbonyl)phenyl]-l-benzyl-2-pyrrolidinecarboxamide and glycine to various activated olefins, i.e., 2-propenal, 3-phenyl-2-propenal and a,(f-unsaturated esters93- A... 

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