Asymmetric Synthesis of Amino Acid Derivatives

Recently, a,p-dehydroamino add derivatives have been found to be suitable substrates for ene reductases of the OYE family [53]. Although methyl 3-methyl-2-acetamidoacrylate (P-methyl-a-alanine precursor) and methyl 3-acetamidoacrylate (P-alanine precursor) were unreactive, N-acetyl precursors of alanine and aspartic add methyl ester were reduced by YqjM to the corresponding (S)-enantiomers 

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A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192], The (+)- or (-)-lO-(N, Af-dicyclohexylsulfamoyl)isobomeol was used as chiral auxiliary in the intramolecular cyclization of /V-(/>methoxybenzyI)-/V-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the (1-lactam ring (Scheme 85). 

Scheme 8.1 Asymmetric synthesis of amino acid derivatives.

A general approach towards the asymmetric synthesis of amino acid derived... 

FIGURE 1.35. Enantiomeric forms of enolates with axial, planar, and central chirality in asymmetric synthesis of amino acid derivatives. 

Bamish FT, Corless M, Dunn PJ, Ellis D, Finn PW, Hard-stone JD, James K. Asymmetric synthesis of -amino acid derivatives by Michael addition to chiral 2-aminomethyla-crylates. Tetrahedron Lett. 1993 34 1323 1326. 

The first 3,6-dialkoxy-2,5-dihydropyrazine used in asymmetric synthesis of amino acids 7 10 was the symmetrical derivative 2, derived from cyclo(L-Ala, L-Ala) (1). This dihydropyrazine can be prepared by direct condensation of the methyl ester of L-alanine and subsequent alkylation with trialkyloxonium tetrafluoroborate7. Although the condensation process results in partial racemization of the alanine moiety, recrystallization yields almost optically pure cyclo(L-Ala, L-Ala) (1). 

A group at the Academy of Sciences in Moscow 197) has synthesized chiral threonine. Derivatives of cyclic imino acids form copper complexes with glacine and carbonyl compounds. Hydroxyethylation with acetaldehyde and decomposition of the resulting complexes produced threonine with an optical purity of up to 97-100% and with threo/allo ratios of up to 19 1 197). The chiral reagents could be recovered and re-used without loss of stereoselectivity. The mechanism of this asymmetric synthesis of amino acids via glacine Schiff base/metal complexes was also discussed 197). 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Very recently the Shibasaki group extended the range of application of their asymmetric two-center catalysts 31 to the synthesis of amino acid derivative intermediates for aeruginosin 298-A and analogs thereof [39]. Aeruginosin has a tetrapeptide-like structure and contains non-standard a-amino acids. The synthesis of the key intermediate (S)-20r, bearing a bulky substituent, is shown in Scheme 3.17 [39]. In the presence of the catalyst R,R) 31 the desired amino acid derivative (S)-20r was obtained in 80% yield and with 88% ee [39]. The catalyst 31, which is very stable under basic conditions, could be recovered in 80-90% yield and re-used efficiently [39]. 

Asymmetric Catalytic Aminoalkylations New Powerful Methods for the Enantioselective Synthesis of Amino Acid Derivatives, Mannich Bases, and Homoallylic Amines... 

D-Arabinosylamine 10 is more reactive and shows even higher asymmetric induction than D-galactosylamine 2 in this case [19b]. A variation of this method was reported by Ugi et al., who used 2-acetamidoglucosyl imine derivatives for the synthesis of (/ )-amino acid derivatives [46]. 

Akiyama T, Saitoh Y, Morita H, Fuchibe K (2005b) Adv Synth Catal 347 1523 Akiyama T, Tamura Y, Itoh J, Morita H, Fuchibe K (2006a) Synlett 2006 141 Arend M (1999) Asymmetric catalytic aminoalkylations new powerful methods for the enantioselective synthesis of amino acid derivatives, Mannich bases, and homoallylic amines. Angew Chem Int Ed Engl 38 2873-2874 Arend M, Westermann B, Risch N (1998) Angew Chem Int Ed Engl 37 1045 Avemaria F, Vanderheiden S, Brase S (2003) Tetrahedron 59 6785 Babu G, Perumal PT (1998) Tetrahedron 54 1627... 

Sheehan, S. M. Preline-catalyzed asymmetric Mannich reactions The highly enantioselective synthesis of amino acid derivatives and 1,2-amino alcohols. Chemtracts 2002, 15, 384-390. 

Schdllkopf and cowoikers have pioneered the development of anions of another type of masked carboxylic acid derivative, i.e. bislactim ethers such as (159), derived from (5)-valine and glycine or alanine, for the asymmetric synthesis of amino acids. As shown in Scheme 78, compounds such as... 

O-Alkylation of dioxopiperazines with oxonium salts yields bislactim ethers, e.g. 4, which are used as reagents for the asymmetric synthesis of amino acids (bislactimether method, Schollkopf 1979). The chiral bislactim ether 4 is converted into the 6 r-anion 5 (under kinetic control) by n-butyllithium. Alkylation proceeds with high stereoselectivity (greater than 95%). Acid hydrolysis of the alkylation product 6 leads to (unnatural) (R)-mnno acids 7 and recovery of the chiral auxiliary (5)-valine, from which the starting material dioxopiperazine 3 was derived [160]. 

The addition of cyanide to imines forms the basis of the Strecker reaction, and can be used in the synthesis of amino acid derivatives by hydrolysis of the nitrile to the acid. The asymmetric variant of this reaction can be achieved using both metal-based catalysts and organocatalysts. ... 

The reaction of organoboranes with carbon-nitrogen multiple bonds always leads to aminoborane derivatives through a hard-hard interaction. Hydro-boration of nitriles with optically active diisopinocampheylborane (43) constitutes a key step in an asymmetric synthesis of amino acids (44). Carbonyl compounds are deoxygenated via hydroboration of their tosylhydrazones (45). 

Several synthetic methods have appeared in which derivatives of amino-acids have been reacted with strong base and then with carbon electrophiles. This process has been used in the a-hydroxymethylation of SchifI bases derived from a-amino-acid esters and good yields of /3-hydroxy-a-amino-acids are obtained. This type of compound is also prepared using the optically active imine (183) the t/trco-product was obtained with selectivity ranging from 58 to 92% and optical purity between 43 and 71% (Scheme 88). The jS-hydroxy-a-amino-acid (185) is a constituent of the antibiotic bleomycin and its preparation from L-rhamnose has been described. Studies on the asymmetric synthesis of amino-acids by alkylation of various lactim ethers (186) have continued. L-Alanine, L-valine, and (S)-0,0-dimethyl-a-methyldopa have been used to prepare the heterocyclic intermediates (186), which give a range of amino-acids in high yield and enantiomeric excess. Earlier work has also been extended to the alkylation of the imidazolone anion (187). ... 

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. 

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