Dialkylated Glycines

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° (< >) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205... 

Benedetti E, Barone V, Bavoso A, Di Blasio B, Lelj F, Pavone V, Pedone C, Bonora GM, Toniolo C, Leplawy MT, Kacz-marek K, Redlinski AS. Structural versatility of peptides from C ,-dialkylated glycines. 1. A conformational energy computation and X-ray diffraction study of homo-peptides from C -diethylglycine. Biopolymers 1988 27 357-371. 

Chruma, J.J., Liu, L., Zhou, W. and Breslow, R., Hydrophobic and electronic factors in the design of dialkyl-glycine decarboxylase mimics, Bioorg. Med. Chem., 2005, 13, 5873-5883. 

Ethyl (bornylideneamino)acetate (2) and the imines of (-)-(lf ,2, 5 )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were particularly successful as Michael donors. The chiral azaallyl anions, derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 C, add to various a,/i-unsaturated esters with modest to high diastereoselectivity (see Section 1.5.2.4.2.2.5.). Thus, starting with the imine 2, (R1 = CH,) and ethyl ( )-2-butcnoate, the a,/i-dialkylated glutamate derivative 3 is obtained as a single diastercomer in 90% yield91-92. 

Commercially available ethyl nitroacetate is an interesting pronucleophile, because it can serve as the synthetic equivalent of either nitromethane or glycine. The ethoxycarbonyl group can also be considered as a protecting group against dialkylation. The allylic alkylation with ethyl nitroacetate did not require an additional base (salt-free conditions). As a consequence of the high acidity of the chirality center a to N, 1 1 mixtures of epimers were formed. 

Ethyl 7V-[2-(/er/-butoxycarbonylamino)ethyl]glycinate (4) can be purchased or easily prepared from 3-aminopropane-l,2-diol (1) as shown in Scheme 4J24 Any nucleobase can then be coupled to this backbone. Alkaline hydrolysis then gives the PNA Boc monomer. The temperature should be kept below 120 °C during distillation of 3 to avoid decomposition. If 3 is used in excess compared to HC1 H-Gly-OEt, dialkylation will occur. 

Since the aldimine Schiff base 21 can be readily prepared from glycine, direct stereoselective introduction of two different side chains to 21 by appropriate chiral phase-transfer catalysis would provide an attractive, yet powerful, strategy for the asymmetric synthesis of structurally diverse a,a-dialkyl-a-amino acids. This possibility of a one-pot asymmetric double alkylation has been realized by using N-spiro chiral quaternary ammonium bromide le (Scheme 5.21). 

In view of the observation that A-o-nitrophenyl derivatives of glycine and other a-amino acids could be converted into benzimidazolones by the action of heat, and the assumption that iV-oxides were intermediates in the thermolysis [156], it was thought tliat flash vacuum pyrolysis with a very short reaction time might allow isolation of the IV-oxides. This approach, however, did not turn out to be as synthetically efficient as the base treatment method [97]. Indeed, heating such compounds in sand at 200° C is probably of more use for making benzimidazoles or benzimidazolones [156]. Benzimidazole iV-oxides can be made from acid-catalysed thermal or photochemical reactions of AyV-dialkyl-o-nitroanilincs, but not from purely thermal reactions. 

Piperazine-2,6-diones have been prepared as follows. A group of 3,3-dialkyl-piperazine-2,6-diones were obtained by treating 7V-(l-cyanoalkyl)glycine esters... 

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. 

A phase-transfer-catalyzed direct Mannich reaction of glycinate Schiff base 5 with a-itnino ester 78 was achieved with high enantioselectivity by the use of N-spiro chiral quaternary ammonium bromide 9e as catalyst (Scheme 11.21) [62]. This method enabled the catalyhc asymmetric synthesis of differentiatly protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate, the utility of which was demonstrated by the conversion of product (sy -79) into a precursor (80) of strep-tohdine lactam. 

Another attractive, though limited, route to fully protected (o-amino-(n-(hydroxycarbonyl)alkylphos-phonic acids involves the addition of sodium acetamidomalonate or potassium A-(diphenylmeth-ylene)glycine esters to dialkyl vinylphosphonates (Scheme 8.80). ° - ... 

Intermediate (5)-l is simply yV-benzyl-4-fluorophenylglycine that has been capped with an ethylene unit. The original synthesis in which 4-fluorophenylacetic acid was transformed to the corresponding chiral oxazolidinone 6 is depicted in Scheme 2. Masked a-azido acid 7 was formed diastereoselectively from this intermediate. Hydrolysis and azide reduction afforded enantiomerically pure (5)-4-fluorophenyl glycine (8). Reductive amination with benzaldehyde introduced the V-benzyl unit and subsequent A, 0-dialkylation with ethylene dibromide provided chiral oxazinone 1. 

Scheme 17.23 Synthesis of a,a-dialkyl-a-amino acids by double alkylation of glycine Schiff base.

Coldham et alP reported the one pot iV-alkylation and [2,3]-Stevens rearrangement of A -allyl a-amino esters 27 and 29 in DMF in the presence of potassium carbonate and DBU to afford JV -dialkylated allyl glycine derivatives 28 and 30. 

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