Synthesis from glycine derivatives

As a result of the principal importance of a-amino acids, their synthesis from glycine or other a-amino acids by a-alkylation of a derivative with a nonracemic auxiliary has been carried out more or less successfully127. Attempts aiming at the same goal, but using heterocyclic starting materials, are described in Sections 1.1.1.3.3.4.2. and 1.1.1.3.3,4.3. 2-Hydroxypinan-3-one (5) was used to induce chirality, when its imines with a-amino acids were a-alkylated,28 l3°. 

Similar results have been obtained for the formation of 1-amidoalkyl radicals starting from A -ort/fo-halobenzyl amides. For instance, the synthesis of y-lactam from glycine derivatives was reported (Scheme 34, Eq. 34.1) [126]. A new route to spirooxindole based on 1,5-hydrogen transfer followed by cyclization onto an activated indole was recently published (Eq. 34.2) [127]. 

Evans, T.P., Cornell, L., Peterson, R.W., and Faulkner, D.). (1994) Isolation and synthesis of glycine derivatives of ilimaquinone from Fasciospongia sp. Nat. Prod. Lett., 4, 287-291. 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

These mechanisms for the synthesis of glycine present a partial barrier to the movement of FA carbons into this molecule, the most abimdant AA in collagen. On the other hand, proline is synthesized from a-keto glutarate which can be freely derived from either carbohydrates or FAs thus the synthesis of pro line does not present a barrier to entry ofFA-derived carbons into collagen. 

In a more recent study, Westman and Lundin described the solid-phase synthesis of aminopropenones and aminopropenoates, respectively30 as intermediates for heterocyclic synthesis. Two different three-step methods for the preparation of heterocycles have been developed. The first method involved formation of a polymer-bound ester from a IV-protected glycine derivative and Merrifield resin (Scheme 7.10a), while the second method employed an interesting approach utilising simple aqueous methy-lamine solution for functionalisation of the solid support (Scheme 7.10b). In this latter approach, a variety of hetero cycles were readily synthesised from the generated polymer-bound benzylamine using a two-step protocol (see Section 5.3.3). 

Another synthesis of pyrrolidines, in this case with high enantioselectivity, has seen several enones with a chiral alkoxy or amino substituent in the y-position react with azome-thine yields (derived from glycine imine derivatives) upon treatment with DBU/AgOAc (equation 171)612-614. This reaction may also be done using other alkene-containing substrates615,616. 

Asymmetric synthesis of ot-amino acids.1 This optically active phase-transfer catalyst (1) can effect enantioselective alkylation of the imine (2) derived from glycine. The highest enantioselectivity obtains with the t-butyl ester the lowest with benzylic type esters. Alkylation of 2 results in a mixture of enantiomers, but crystallization of the mixture removes the racemic product and leaves the highly pure optically active amino ester in solution. 

N-Bis(methylthio)methylene derivatives of amines (iminodithiocarbonates) were first introduced by Hoppe and Beckmann468 for the synthesis of a-amino acids from glycine. The A bis(methylthio)methyleneamines are prepared by reaction of a primary amine with carbon disulfide (HAZARD) in the presence of triethylamine and iodomethane to form a methyl dithiocarbamate derivative, which is then S-alkylated with a second equivalent of iodomethane in the presence of potassium carbonate as the base. Scheme 8,233 illustrates an alternative one pot procedure applied to the synthesis of /erf-butyl N-[bis(methylthio)-methylene]glycinate and its use in diastereoselective conjugate addition under... 

Besides stereoselective alkylations of glycine-derived enolates, enantioselective construction of chiral quaternary carbon centers from a-amino acids is one of the most challenging topics in current organic synthesis , since nonproteinogenic a,a-disubstituted amino acids often show a remarkable influence on the conformation of peptides. Moreover, they can act as enzyme inhibitors or as building blocks for the synthesis of a wide range of natural products . 

These tetrahydrofolate derivatives serve as donors of one-carbon units in a variety of biosyntheses. Methionine is regenerated from homocysteine by transfer of the methyl group ofF -methyltetrahydrofolate, as will be discussed shortly. We shall see in Chapter 25 that some of the carhon atoms of purines are acquired from derivatives of N lO-formyltetrahydrofolate. The methyl group of thymine, a pyrimidine, comes from N, N lO-methylenetetrahydrofolate. This tetrahydrofolate derivative can also donate a one-carhon unit in an alternative synthesis of glycine that starts with CO2 and NH4 +, a reaction catalyzed by glycine synthase (called the glycine cleavage enzyme when it operates in the reverse direction). 

Both enantiomers of 2-amino-3-(3-hydroxy-5-/< t/-butylisoxazol-4-yl)propanoic acid (ATPA) 69, an analogue of the neuroexcitant 2-amino-3-(3-hydroxy-5-methylisoxazoM-yl)propanoic acid (AMPA), were synthesized in 33% overall yield (from pinacolone) and 99% ee. The enantiomerically pure glycine derivative (A )-66 was coupled with 4-bromomethyl-2-methoxymethyl-5-A r/-butyl-3(2//)-isoxazolone 67 to give the intermediate (26, 5A )-68, which was hydrolyzed under mild conditions to give enantiopure (A )-69. The use of (R)-66 allowed the synthesis of R)-69 (Scheme 17) <2000TA4955>. 

These cocnxymes derived from folic acid participate in many imponant reactions, including conversion ofhomocys-Icine to methionine, synthesis of glycine from serine, purine synthesis (C-2 and C-8). and hi.stidine metabolism. 

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