Amidines natural derivatives

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

Jordan reported that cationic aluminium alkyl derivatives of amidinates (3) [10] and aminotroponiminates (4) [11] are active in ethene polymerization. The amidinate system was later shown to be more complicated, and the nature of the active species remains unclear [14],... 

Kolb and Barth 229) synthesized oc-substituted optically active amines or amino acids (223). Again the authors employed a derivative of naturally occurring (S)-proline, namely (—)-(S)-l-dimethoxymethyl-2-methoxymethyl-pyrrolidine (221) as chiral auxiliary agent. The metalation of the amidines (160) leads to azaallyl anions homologous with (222). After alkylation and hydrolysis, the desired a-substituted amines and amino acids, respectively, are obtained with some stereoselectivity. 

For these compounds, Eq. 14 was derived, in which MR-A refers to the molar refractivity of the whole group A. No role for lipophilicity was found (no 7T or C log P term). It is shown that MR-A and C log P were correlated with r = 0.597. 1-XCN, an indicator variable which takes the value of 1 for the existence of an amidino group (C(= NH)NH2) in the substituent X, was found to be significant. It shows an appreciable effect of an amidine group at X position. On the contrary, no role for the nature of the ahcyhc ring (five- or six-membered) was shown. 

That such a delicate balance exists between tautomers is not an obvious prediction based solely on ApK s. The 10 pK unit difference in 9 benzoate favors the amidine-carboxylic acid form by 0.6 eV. However, a simple electrostatic calculation [123] for a positive and negative charge at a salt bridge distance of 3.8 A translates into a stabilization energy of-0.50 eV in the solvent THF, which nearly offsets the stabilization of the amidine-carboxylic acid tautomer derived from the ApfQ. Electron-rich carboxylates such as benzoate are sufficiently basic that the amidine-carboxylic acid hydrogen bond interaction prevails while the interface retains its ionic nature for more acidic carboxylic acids and various sulfonic acids. 

Figure 29 Natural products derived from pathways containing amidinotransferase enzymes from the pentein superfamily, including streptomycin (36), bluensomycin (37), cylindrospermopsin (38), phaseolotoxin (39), gaiegine (40), and creatine (42). In each case, the amidine moiety installed by the transfer reaction is shown in blue.

The influence of the aryl substitution for derivatives bearing the aryl group at the functional carbon depends on the electronic nature of the aryl substituent. Smaller basicity is measured than for acetamidines. Bicychc amidines show larger basicity, compared to the most of simple alkyl derivatives, with the gas phase basicities in the following order DBU > DBD > PMDBD > DBN > 74. DBU has the largest gas phase basicity value of 243.4kcalmol . Five-membered ring amidines display smaller basicity than six- and seven-membered cyclic amidines. 

In a new development in alkaloid synthesis, Myers and Hellring have shown that the p-amino-carbanion from tetrahydro-p-carboline can be employed as a precursor for the ring systems (103), (104), and (105), which are found amongst natural indole alkaloids. Thus, the conversion of tetrahydro-P-carboline into the amidine derivative (101), followed by protection of the indole nitrogen and treatment with t-butyl-lithium, generated the (3-amino-carbanion (102). Addition of various electrophiles, followed by further manipulations of the functional groups, then led to the alkaloid ring-systems (103), (104), and (105). 

The nature of this amine acceptor in the case streptidine biogenesis is intriguing. Two amidine transfer reactions are necessary and hence two distinct amine acceptors are required. Assuming that the cyclohexane ring structure remains intact, two possibihties are 1. The amination and amidination of first a polyhydroxy cyclohexane derivative to form a monoguanidine hydroxycyclo-... 

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