Tertiary amide activation

The C-6 carboxamide analogues of zanamivir, represented by the general structure 24, provided an avenue to introduce more hydrophobic side-chains onto the dihydropyran scaffold to interact with the hydrophobic regions of subsites S4 and S5 (reviewed in Islam and von Itzstein 2007). The most active tertiary amides (24 = alkyl) showed comparable inhibitory activity to their glycerol side-... 

The problem of the nucleophilicity of amides in glycosylation reactions is not limited to the sulfoxide method and has been shown to result in the formation of glycosyl imidates from intermolecular reaction with activated donors. It appears that this problem may be suppressed by the prior silylation of the amide [348,349]. Accordingly, it may be sufficient to operate the sulfoxide method with an excess of triflic anhydride when amides are present so as to convert all amides into O-triflyl imidates, which are then hydrolyzed on work-up. Despite these problems, several examples have been published of successful sulfoxide glycosylation reactions with acceptors carrying remote peptide bonds [344,345] and with donors coupled to resins via amide-based linkages [346,347], with no apparent problems reported. Sulfonamides and tertiary amides appear to be well tolerated by the sulfoxide method [340,350],... 

N - Benzyl- N -p icolinoylpiperazine (EGYT-475, 4.88), a compound with potential antidepressant activity, underwent similar hydrolysis. After intravenous administration, picolinic acid (4.89) was one of its major urinary metabolites in rats the other product, A-benzylpiperazine (4.90) was also detected, but at much lower levels, since it was further transformed by A-de-benzylation [55], Since the products of direct hydrolysis of these cyclic tertiary amides (i.e., the corresponding secondary amines) were found at substantial levels, it appears that oxidative A-monodealkylation is not an essential step for hydrolysis in these compounds, in contrast to the findings for A,A-diethylbenzamide. This contradicts the hypothesis [52] (see above) that the steric bulk of the tertiary amide group impedes direct hydrolysis. Here, although the degree of steric bulk is at least comparable, direct hydrolysis clearly takes place. 

O-Protonated cations of eimides in concentrated and anhydrous acids are now well characterized by nmr spectroscopy. O-Protonated cations of N,N-dimethyl amides are most easily observed, even in 72% perchloric acid which has a water activity of about 10 , because for tertiary amides the N-protonated forms is relatively less stabilized by hydration (Liler, 1972a). O-Protonated cations of N-alkyl amides show considerable exchange of NH-protons with the solvent in 72% perchloric acid owing to the intervention of the N-protonated form. For primary amides (acetamide), however, O-protonated cations are not observable in that solvent (Liler, 1972b),... 

Tertiary amides, such as those associated with prolyl amide bonds frequently influence turn architectures. The importance of the cis Xaa-Pro bond on activity was recognized and proposed to be the source of differentiation in biological activity [86] therefore, isomerization of the prolyl amide bond is central to regulation of protein folding, immunosuppression, and mitosis. These functions are not surprisingly associated with several disease states and thus substitution of the acyl-proline amide bond with the fluoroolefin isostere has received considerable attention. 

S.J. Veenstra, K. Hauser, P. Felber, Studies on the active conformation of the NK1 antagonist CGP 49823. Part 2. Fluoro-olefin analogs of tertiary amide rotamers, Bioorg. Med. Chem. Lett. 7 (1997) 351-354. 

Sesbanine (608), a unique alkaloid isolated from Sesbania Drumondii seeds, which seems to exhibit potent antitumor activity, has been synthesized by prior carefull exploration for pyridine tertiary amide metalation (Scheme 179) (83TL2649). In the optimum case, LiTMP metalation of the diisolpropyl amide 447b for 15 min. followed by condensation with 3-... 

Imidate salts are 0-alkyl derivatives of tertiary amides. Being activated tertiary amides, they are extremely reactive towards nucleophiles. There is instantaneous reaction with hydroxide ion they also react rapidly at room temperature with water under acidic conditions. When an imidate fluoro-borate salt such as 43 reacts with sodium hydroxide, it gives sodium fluoro-borate and the tetrahedral intermediate 44 which breaks down in an irrevers-... 

A number of C-6 carboxamide analogues were prepared in which the stereo-chemically complex glycerol side-chain of Zanamivir or 4-amino-4-deoxy-Neu5Ac2en was replaced entirely by secondary or tertiary amides with the general structure of 94 or 95.95,96 These series of compounds were prepared from the C-6 carboxylate 92 (prepared by periodate oxidation of the glycerol side-chain of 91) by amide couling via the activated pentafluorophenyl ester 93 (Scheme 3). 

Scheme 1. The Kaiser-oxim resin 1 is permanently activated and can be cleaved by nucleophiles. Kenners sulfonamide resin 2 is stable against acids and bases but rendered labile against nucleophilic attack after conversion to the tertiary amide 3.

Side Note 7.1. Activation of Tertiary Amides to Make Acylating Agents... 

Table 9.1 Hot-plate Activities in Mice of Some Tertiary Amides Related to Methadone0...

Oxazoles may be used as masked forms of activated carboxylic esters since they readily form tertiary amides on reaction with singlet oxygen. Wasscrman et al. 

Table II summarizes those amino acids that contain more than an un-reactive aliphatic chain, namely a reactive site which may be a functional group in the traditional sense such as sulfhydryl, thiomethyl, hydroxyl, carboxyl, carbamide, amino, or guanido, or may be an activated aromatic ring or heterocycle such as the phenolic part of tyrosine, the pyrrole unit in troptophan, and the imidazole part in histidine. Phenylalanine would only be considered in this connection as the reactive di- or tetrahydro derivative ring. iV-Peptides derived from proline and hydroxyproline are in a separate class because they are tertiary amides carrying no proton at the nitrogen atom. It may be possible to utilize this special feature for a preferential cleavage under proper conditions.

Secondary or tertiary amides have been converted to aldehydes with Ph2SiH2 in the presence of Ti(0-f-Pr)4 (Eq. 133) [327]. It has been proposed that a species such as HTi(0-f-Pr)3 is the active reductant in this reaction. A similar reduction of lactones to lactols has also been reported [328]. 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

LiBH4 can also be activated by adding (MeO)3B or Et3B in diethylether. With this reagent, esters are rapidly reduced, tertiary amides and nitriles are also reduced, but sulfone, sulfoxide, and NO2 groups remain intact [BN3, YP2]. 

The initial attempts were the synthesis of compounds represented earlier by structure A, where the ester function was built into proximity of the propanolamine. Even though shortened duration was achieved when a short-term infusion (40 min) was carried out, their duration tended to increase considerably after the administration of the infusion itself was prolonged (ca. 3 hours). A particularly novel spontaneous inactivation mechanism independent of enzyme activity was found to occur with compounds of structure A, where n was at least three (Eq. 10.1). This intramolecular cyclization reaction (which also occurs in vitro at neutral or basic pH), while not producing a carboxylate, does result in a predictably inactive tertiary amide product. In vivo testing of the gamma-lactam derivative did in fact show it to be inactive. 

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