Pyrrole amides

Techniques are available for quantitative identification of the six principal types of heteroatom compounds in asphalt carboxyUc acids, 2-quinolones, phenols, pyrroles, amides, andpyridines (67). 

An efficient biocatalytic method for the production of amides in multigrara scale has been developed for the synthesis of a pyrrole-amide, which is an intermediate for the synthesis of the dipeptidyl peptidase IV that regulates plasma levels of the insulinotropic proglucagon. CALB catalyzes the ammonolysis of the ester with ammonium carbamate as source of ammonia (Scheme 7.8) [22]. The use of ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol by-products. 

Figure 3. First generation 2,5-diamido-lH-pyrrolic amide clefts.

A more recent development has been the synthesis of bisamidopyrrolylmethane based anion receptor systems (Figure 19).15 These receptors might be regarded as containing half a calix[4]pyrrole combined with die 2-amido appendages in common with the pyrrolic amide cleft. Compounds 19 and 20 were synthesized by reaction of diethyl-5,5 -methylenebis(4-ethyl-3-methyl-2-pyrrole) carboxylate with aniline or n-butylamine in the presence of trimethylaluminium in dry dichloromethane at 35°C in 40 and 43% respective yields. 

Gale, P. A., Camiolo, S., Chapman, C. P., Light, M. E., Hursthouse, M. B. (2001) Hydrogenbonding pyrrolic amide cleft anion receptors, Tetrahedron Lett. 42, 5095-5097. 

Depending on the reaction conditions, pyrrole amide 45 cyclizes either to pyrrolo[l,2- z]pyrazin-l-ones (46) or to a mixture of pyrrolo[2,3-c]pyridin-7-ones (47) and pyrrolo[3,2-c]pyridin-4-ones (48) [42], Isomers 47 and 48 are distinguishable by the lower chemical shift of the N—H proton (10.21 ppm) for 47 syn to the carbonyl) relative to that observed for 48 (9.08 ppm) and other spectral data. The cyclization leading to 47-48 is proposed to involve spiro intermediate 49. 

Fig. 20.7. Solid-phase synthesis of pyrrole amides by the split-mix method a. acetoacetylation with dike-tene b. separation of the resin into 14 aliquots, enaminone formation with 14 different primary amines ...

This rapid molecular formula determination may also be applied to complex mixtures such as those which arise from combinatorial chemistry.To demonstrate the performance of this method in this respect, a split-mix compound collection of 140 different pyrrole amides consisting of 10 subcollections of 14 compounds each was synthesized on Rink-amide-AM-resin. 

Fig. 20.11. Automated routine ESI-FT-ICR measurement of the pyrrole amide library. [Extract from...

Fig. 20.12. Completely resolved signal of compound A and B with a mass difference of solely 0.0018 Da (pyrrole amide compound library with R = amines A1 to A14 and R2R-1 = 2-bromo-4-phenylacetophe-none)...

The results of such a microHPLC/ES-FT-ICR mass spectrometric analysis of the pyrrole amide subcollection is shown in Figure 20.13 as contour plot. The separation of the subcollection was carried out on an RP C18 column (GROM-Sil ODS7 1x6 mm). For... 

Fig. 20.13. Contour plot from the HPLC/FT-ICR-MS coupling of a pyrrole amide compound collection (R2 = C6Hs, R3 = H) This method allows to prove the identity of isomers. The isotope resolution of the molecule ion peaks is recognizable.

Consequently, the MacMillan group reported a novel SOMO a-arylation reaction to achieve the total synthesis of ( )-tashiromine (165), isolated from the Asian deciduous shmb, Maackia tashiroi [67]. Organocatalytic a-arylation reaction of the pyrrole amide 163 afforded the key intermediate-bicycle 164 (72% yield, 93% ee), which was converted into ( )-tashiromine (165) by LiAHt reduction and hydrogenation using catalytic RI1/AI2O3 in 37% yield for the three steps as shown in Scheme 17.28 [66b],... 

Greger H, Zdero C, Bohlmann F (1987) Pyrrole amides from Achillea ageratifolia. Phytochemistry 26 2289-2291... 

Thus, the asymmetric catalysis of cyanoethoxycarbonylation, cyanophosphoryla-tion, epoxidation of electron-deficient olefins, Michael reactions of malonates and (3-keto-esters, Strecker reaction of keto-imines, conjugate addition of cyanide to a, (3-unsaturated pyrrole amides, ring opening of meso aziridines with TMSCN and cyanosilylation of ketones (example shown below) have been successfully carried out using these complexes as asymmetric catalysts. 

Oxygen nucleophiles Intramolecular oxa-Michael cyclization of a,/ -unsaturated carbonyl compounds (278) (e.g. thioesters, oxazolidinone imides, and pyrrole amides), catalysed by Brpnsted acids, such as camphorsulfonic acid (CSA), has been reported to afford 2,6-cis-substituted tetrahydropyrans (279) with good to excellent stereoselectivity (7 1 to >20 1 dr). The approach has been claimed to be superior to that mediated by bases and is complementary to the ruthenium-catalysed cyclization affording anal- 0 ogous products (149) discussed earlier. 

The echoes of Corey s seminal discovery with sulfonium and sulfoxonium ylides have found considerable resonance in modern investigations of enan-tioselective cyclopropanation reactions. Shibasaki showed that treatment of pyrrole amides such as 126 with trimethylsulfoxonium ylide was effectively promoted by the La-Li-(biphenyldiolate) catalyst 127 to give the cyclopropane adduct 128 in 98% ee (Equation 20) [78]. Key to the success of the transformation was the use of Nal as an additive. The investigators speculated that exchange of Li for Na occurs in 127 to some extent to give an active cyclopropanation catalyst that is more enantioselective. The observation underscored the versatility of such bifunctional heterobimetallic catalysts, the properties of which can be fine-tuned in a multitude of ways by variation of the ligand and the nature of the metals employed [79]. 

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