Amines fragmentation

The vast majority of this type of cyclization start from pyridines. One obvious route converts o- acylaminopyridine acids, esters or their equivalents to pyridopyrimidines using a one-atom ammonia or amine fragment, e.g. (173) (174). Examples are known mainly... 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

A virtual screen of 10,000 primary amine fragments against dipeptidyl peptidase IV (a diabetes target) identified a number of hits, as determined by bioassay screening at 100 pM, e.g. 6 [21]. An X-ray structure of this fragment confirmed the predicted binding mode in the Si pocket and inspired a structure-based hypothesis that eventually led to identification of a potent series of DPP-IV inhibitors [22],... 

The secondary process of amine fragmentation (1,3-sigmatropic shift) may be used as an example of a process initiated by the charge center (Scheme 5.18). 

Undonbtedly, analogs of ampicillin that are substitnted at the amine fragment of phenyl-glycine (azolcillin, mezlocillin, piperacillin) should be included in this same gronp of com-ponnds. 

The structure of cryptowoline iodide (2) was determined by a similar set of reactions. Both O-methyl and 0-ethyl ethers were subjected to exhaustive meth-ylation, elimination, reduction, and ozonolysis. The key compounds obtained from the ethyl ether were 26 and 6-aminopiperonal. The amine fragment showed the methylenedioxy group to be at the 9,10 position in cryptowoline, and the fact that the same aldehyde 26 was obtained from 0-ethylcryptowoline iodide fixed the position of the free OH as in cryptaustoline to C-2. 

Benzofuroxans react readily with enamines, or with aldehydes or ketones in the presence of ammonia or an amine, to form quinoxaline-1,4-dioxides (44) together with the amine fragment of... 

Cleavage of amino acid esters occurs at both C— C bonds (a, b below) next to the nitrogen atom, loss of the carbalkoxy group being preferred (a). The aliphatic amine fragment decomposes further to give a peak at m/z 30. 

The vast majority of this type of cyclization start from pyridines. One obvious route converts o- acylaminopyridine acids, esters or their equivalents to pyridopyrimidines using a one-atom ammonia or amine fragment, e.g. (173) -> (174). Examples are known mainly in the pyrido[2,3-rf]pyrimidine field (e.g. 73GEP2248497, 74MI21502) but also in [3,4-d] and [4,3-rf] cases (74GEP2348U1). Sometimes pyridooxazine intermediates similar to (113) are involved, especially in the few examples with pyrido[3,2-rf]pyrimidines (65JCS4240). 

Monocyclic pyrylium salts react with azomethines according to a postulated four-centered mechanism yielding products of exchange between the oxonium atom and the amine fragment of the Schiff base (73ZOR1079 82KGS465). 

To fully interpret these details, it is necessary to refer to the User s Guide. X refers to a halogen other than fluorine Y refers to a polar fragment Fragbranch refers to the unique lowering of the hydrophobicity of chains radiating from phosphate, phosphonate, and tertiary amine fragments. The three X-C-X factors are the same as seen in chloroform the... 

Figure 9.11 Sampling the ST pocket by conformational search over amine fragments.

These results were used to screen a virtual database of primary amine fragments to enhance binding affinity in the P3 pocket using a related scaffold as shown in Figure 9.15. The virtual screening was quickly accomplished through Merck s in-house web-based tools described in Section 9.6 and was in fact a test of these tools. 

Figure 9.15 Scaffold for scanning amine fragments for P3 pocket.

Figure 3. Map of a theoretical biological activity. The biological activity has been contoured against the structures arising from a particular combination of amine and ketone fragments. If at first the amine fragment is held constant (amine A) the ketone associated with maximal activity is 1. If the ketone is held constant as 1, the most potent amine is B, resulting in the false optimum B-l (in square). The true optimum C-3 (in hexagon) is never found.

The mechanism proposed for the formation of the sepulchrates accounts for the fact that, despite seven chiral centres and six nitrogen-metal bonds, the synthesis of [Co(sep)] + cation yields only one isomer. After the formation of the first heminal diamine and second imine centre, the chiral nitrogen centre must be oriented so that the methylene unit of the amine fragment and the proton are apical and equatorial, respectively, before intramolecular cycli-zation. In this case, six-membered ring closure takes place. The same apical orientation of the six-membered chelate cycle must be retained to complete the formation of a capping group. After the completed encapsulation, the methylene unit and the proton cannot... 

In this three-step sequence, alkene 16 is first epoxidized with m-CPBA providing the a-epoxide in 87 % yield along with only minor amounts of the (3-isomer (10 %). As the aminal fragment... 

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