Glycine derivatives

Heteroaromatic esters such as 493 and amides are produced by the carbo-nylation of heterocyclic bromides[347,348]. Even dichloropyrazine (494) and chloropyridine are carbonylated under somewhat severe conditions (120 C, 40 atm)[349]. The carbonylation of trifluoroacetimidoyl iodide (495) proceeds under mild conditions, and can be used for the synthesis of the trifluoromethyl-glycine derivatives 496 and 497(350]. 

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). 

Glycine derivatives and aUphatic sulfonates are examples of compounds that can function in this way. The use of these inhibitors in cooling systems is usually lirnited by their biodegradabiUty and their toxicity toward fish. In addition, they can form thick, oily surface films, that may severely retard heat transfer. 

Benzoic acid in the free state, or in the form of simple derivatives such as salts, esters, and amides, is widely distributed in nature. Gum benzoin (from styrax ben in) may contain as much as 20% benzoic acid in the free state or in combinations easily broken up by heating. Acaroid resin (from anthorrhoca haslilis) contains from 4.5 to 7%. Smaller amounts of the free acid are found in natural products including the scent glands of the beaver, the bark of the black cherry tree, cranberries, pmnes, ripe cloves, and oil of anise seed. Pern and Tolu balsams contain benzyl benzoate the latter contains free benzoic acid as well. The urine of herbivorous animals contains a small proportion of the glycine derivative of benzoic acid, hippuric acid [495-69-2] (CgH CONHCH2COOH). So-called natural benzoic acid is not known to be available as an item of commerce. 

In a more recent work the same research group has applied cyclic and acyclic vinyl ethers in the oxazaborolidinone-catalyzed 1,3-dipolar cycloaddition reaction with nitrones [30]. The reaction between nitrone 5 and 2,3-dihydrofuran 6 with 20 mol% of the phenyl glycine-derived catalyst 3c, gave the product 7 in 56% yield as the sole diastereomer, however, with a low ee of 38% (Scheme 6.9). 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Conden-... 

If the following glycine derived ester is deprotonated and transmetalated with the (/ ,/ )-lartaric acid derived titanium complex, and then added to butanal, the sy -a-amino-/Thydroxy ester, which is enantiomeric to the products obtained above, is formed. 

The silylated glycine derivative 1450 cyclizes spontaneously on heating to 85-140 °C to give the hydantoin derivative 1451 in 94% yield [20, 21]. The silylated hy-dantoin 1453 is obtained by reacting silylated N-carboxymethylglycine 1452 with trimethylsilyl isocyanate 327 and subsequent heating to 140°C [22] (Scheme 9.12). 

Both enantiomers of the auxiliary are available, so either enantiomeric product can be obtained. This methodology has been applied to a number of enantioselective syntheses.95 For example, the glycine derivative 14 can be used to prepare a-amino acid analogs.96... 

Ethonam (99), an imidazole derivative with a very different substitution pattern, is also reported to possess antifungal activity. To prepare it, alkylation of aminotetralin 94 with methylchloro-acetate gives the glycine derivative 95. Heating with formic acid then affords the amide 96 this compound is then reacted with ethyl formate to yield hydroxymethylene ester 97. Reaction with isothio-cyanic acid gives the imidazole-2-thiol 98. (The... 

Lemmtyinen and coworkers <01JPP835> have devised a protocol, in which the phytochlorin 37 containing a formyl group was transformed into glycine derivative 50 via reductive animation (Scheme 15). In the final step, derivative 50 was reacted with benzaldehyde and C6o, and gave rise to the phytochlorin C(,o diad 51. 

Figure 15.3 The reaction of a glycine derivative and a formaldehyde compound with a C q molecule leads to the formation of a fulleropyrrolidine.

In a more recent study, Westman and Lundin have described solid-phase syntheses of aminopropenones and aminopropenoates en route to heterocycles [32], Two different three-step methods for the preparation of these heterocycles were developed. The first method involved the formation of the respective ester from N-pro-tected glycine derivatives and Merrifield resin (Scheme 7.12 a), while the second method involved the use of aqueous methylamine solution for functionalization of the solid support (Scheme 7.12 b). The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the requisite acetophenones under similar conditions to those shown in Scheme 7.12 a, utilizing 5 equivalents of N,N-dimethylformamide diethyl acetal (DMFDEA) as reagent. The final... 

DOUBLE INSERTION IN REACTIONS OF GLYCINE DERIVATIVES REARRANGEMENT OF SYMMETRICAL ANHYDRIDES TO PEPTIDE-BOND-SUBSTITUTED DIPEPTIDES... 

Certain classes of compounds are too reactive for the present method. Ethyl mandelate produced a racemic, protected phenyl glycine derivative. Benzylic alcohols with two methoxy groups (directly conjugating in the 2 and 4 positions) gave azide of 50% e.e. 

O. A. Salach, S. Hadad, A. Haj-Yehia, S. Sussan, M. Bialer, Comparative Pharmacokinetic and Pharmacodynamic Analysis of Phthaloyl Glycine Derivatives with Potential Antiepileptic Activity , Pharm. Res. 1994, 11, 1429-1434. 

When treated with the reaction product of hippuric acid and DMF-DMA, 3-aminopyridazine was transformed into a derivative of the pyridazino-pyrimidine system 117. The same result was achieved when 3-aminopyridazine was reacted first with DMF-DMA and thereafter with the protected cyclic glycine derivative (88H903 90JHC359). 

Ma and co-workers extended use of chiral guanidine catalysts to the addition of glycine derivatives to acrylates [121], Addition products were achieved in high yield with modest enantioselectivity (Scheme 67). The ferf-butyl glycinate benzophenone imines generally provided better enantiomeric ratios than the ethyl glycinate benzophenone imines. Based on this observation, the authors hypothesized that an imine-catalyst complex determines the stereochemical outcome of the product. 

Scheme 63. Reaction of the higher-order cuprate 279 derived from 1 with O Donnell s acetoxy-glycine derivative 276 occurring with opening of a three-membered ring [156]...

One more useful synthetic application of primary Michael adducts onto 2-chloro-2-cyclopropylideneacetates 1 is the recently reported new approach to oc-tahydrospirocyclopropanepyrazinopyrazines 182. In the first step, the adducts of primary amines onto 1-Me (or 1-fBu) were coupled with AT-Boc- or N-Vmoc-protected glycine derivatives and the resulting products 178, after deprotection, cyclized under mildly basic conditions to give the spirocyclopropanehexahydro-pyrazinones 179,180 and hexahydrodiazepinediones 181 (Scheme 53) [89]. 

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