Pyroglutamate preparation

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (5)-a-chloroboronic esters. Aminolysis of the chloride yielded... 

A rich family of diazaphospholes 260-262 having hcxahydro- l//-pyrrolo [l,2-c][l, 3, 2]diazaphosphole backbone was readily prepared by the reaction of phenylphosphorodichloridite or another P(III) precursor with anilides of (iS )-proline, (S)-pyroglutamic acid, and (S)-indoline carboxylic acid in high yields diastereoselectively [95],... 

The symmetrical anhydride is prepared using dicyclohexylcarbodiimide in dichloromethane, the urea and solvent are removed, and the anhydride is dissolved in dimethylformamide and added to the peptide-resin (see Section 2.5). The anhydride is a more selective acylating agent than the 0-acylisourea and, thus, gives cleaner reactions than do carbodiimides, but twice as much amino-acid derivative is required, so the method is wasteful. It avoids the acid-catalyzed cyclization of terminal glutaminyl to the pyroglutamate (see Section 6.16) and is particularly effective for acylating secondary amines (see Section 8.15). 

Both anodic oxidation reactions proceeded well. As illustrated in Scheme 44, an anodic methoxylation of menthyl pyroglutamate followed by the trapping of an incipient A-acyliminium ion with allyl-silane in the presence of Lewis acid led to (138) [86]. While the stereoselectivity of this reaction was not high, the major product from the reaction could be fractionally crystallized from hexane and the route used to conveniently prepare (138) on a scale of 10 g. In this case, a platinum wire anode was used in order to keep the current density high. This was required because of the high oxidation potential of the secondary amide relative to the methanol solvent used in the reaction. 

An angiotensin-converting enzyme inhibitor 64 was prepared in several steps from L-pyroglutamic acid. The formation of the bicyclic system was achieved with methylene glutaric anhydride (89TL3621). 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

In the synthesis of the alkaloid gephyrotoxin, L-pyroglutamic acid was used as a starting material for the preparation of intermediate 85 (81TL4197). A related pyrrolooxazine 86 was also obtained from pyroglu-tamic acid after A-substitution and ring closure in the presence of silica... 

During synthesis of the hormone rf-aldosterone, 20,21-dihydroxy-lip,18-epoxy-5a-pregnan-3-one diacetate was oxidised to the 3-oxo acid by stoich. RuOy CCl [78, 79], Oxidation of a substituted pyrrolidine to a pyroglutamate, part of the total synthesis of the antibiotic biphenomycin B, was effected by RuO /aq. Na(lO )/ EtOAc [102], Oxidation of a number of A-5 steroids to enones was effected by RuClj/TBHP/cyclohexane [391] safety aspects of these large-scale reactions were examined, as in the preparation of the antibacterial squalamine [186],... 

The electrophilic fluorination of chiral bicyclic lactams (prepared from the epimers of pyroglutamic acid) by means of A-fluoro sulfonimide (NFSI) yields l- and d-4, 4-difluoroglutamic acids and 4,4-difluoroglutamines (Figure 5.21). They have also been prepared with a good ee starting from ethyl (/ )-bromodifluoroalaninate. ... 

In 1996, Mori reported the total synthesis of (—)-stemoamide through a ruthenium-catalyzed enyne metathesis developed by theit group (Scheme Enyne 83 prepared from (—)-pyroglutamic acid is reacted with Ic in... 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

The pyrrolidine is prepared from ethyl (S)-N-(ethoxycarbonyl)pyroglutamate. 

Scheme 31. Preparation of triazolium salts 123 derived from pyroglutamic acid...

It was of interest to examine the use of chiral bi-2-naphthol to resolve the racemic amino alcohol 11 that can be prepared starting from pyroglutamic acid (Scheme 9). Preliminary studies revealed that die resolution can be readily carried out using B(OH)] and chiral bi-2-naphthol (Scheme 9).17 Further optimisation of the results and structural analysis of the borate complex involved in this reaction are under way. 

A substantial proportion of biologically active peptides carry an acylated A-terminus or A-terminal pyroglutamic acid and are therefore not amenable to chemical degradation from the A-terminus (Edman sequence analysis). However, these A-blocked peptides and A-protected peptides, prepared through laboratory peptide synthesis for which one needs routine checks on structure, can be studied by MS. 

Ibesc ligands are generally prepared from D- or i.- pyroglutamic acid. An attractive short synthesis is shown in equation I. Several 5 aza-semicorrins such as 1 arc known and... 

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