Four-membered cyclic amides

The structure is unusual in that it has a four-membered cyclic amide ring (/3-lactam). It was the first example to be discovered of a natural product with this ring structure. 

Lactams are cyclic amides and are analogous to lactones, which are cyclic esters. In contrast to their lactone counterparts, P-lactams (i.e., four-member cyclic amides) are relatively stable. The antibiotics (penicillin G and cephalexin) are examples of P-lactams. P-Lactam hydrolysis (in presence of water or a nucleophile) is known for antibiotics [9]. P-Lactams are known to form polymers under the right conditions. (An example is ampicillin, in which the primary amine (acting as a nucleophile) attacks the lactam of another ampicillin molecule to form a dimer. A third molecule of ampicillin may attack the lactam of the dimer to form a trimer, and so on). 

Azetidine-2-ones are four-membered cyclic amide commonly known as p-lactams. It is a well-known structural unit to synthetic and medicinal organic chemists. The pharmaceutical activity of famous antibiotics such as penicillin, cephalosporin, carbapenem, and so on containing p-lactam ring occupies 65% of the world total antibiotics market. Besides application as antibiotics, 3-lactams are also in clinical use as 3-lactamase inhibitor and cholesterol absorption inhibitor [29-31]. In recent years, p-lactams have emerged as powerful building blocks in organic synthesis [32]. Therefore, a lot of attention has been paid to the synthesis and chemistry of p-lactams [33]. 

Nitronate(47a) is not the only oxazete derivative. For example, sterically hindered nitroalkenes (42b-d) can be prepared by nitration and halogenation of readily available allenes (48). Compounds (42b-d) are rather smoothly isomerized into the corresponding four-membered cyclic nitronates (47b-d) by the first-order reaction equation (168). Storage of nitronate (47c) is accompanied by its slow transformation into acid chloride (47e) from which amide (47f) can be easily synthesized. 

Modification of Substituents and Functional Groups of Cyclic Nitronates At an ambient temperature, four-membered cyclic nitronate containing the chloronitromethyl group at the C-3 atom is gradually transformed into the corresponding acid chloride even under solvent-free conditions, and treatment of the latter with aqueous ammonia affords amide (168) (Scheme 3.119, Eq. 1). 

Poor nucleophiles react with acyl isoureas B so slowly that the latter start to decompose. In some sense they acylate themselves. The N atom designated with the positional number 3 intramolecularly substitutes the O-bound leaving group that is attached to the carboxyl carbon Cl. A four-membered cyclic tetrahedral intermediate is formed. When the Cl -Ol bond in this intermediate opens up, the N-acyl urea E is produced. Because compound E is an amide derivative it is no longer an acylating agent (cf. Section 6.2). 

A further good example is the difference between C=0 stretching frequencies in cyclic amides, or lactams. The penicillin class of antibiotics all contain a four-membered ring amide known as a 5-lactam. The carbonyl stretching frequency in these compounds is way above the 1680 cm 1 of the six-membered lactam, which is what you might expect for an unstrained amide. 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

Dithiophosphoric acids, (RO)2PS2H, have been used for the thionation of carbonyl groups in certain aldehydes, ketones, amides, esters, thio-carboxylates and other organics.163 The mechanism for this reaction proceeds via a reversible nucleophilic attack of the thioacid on the carbonyl compound, which can then rearrange by way of a four-membered PSCO cyclic intermediate into the desired C=S containing molecule and thiophosphoric acid (Equation 81).163... 

With five- (or four)-membered-ring cyclic imides (Scheme 16) 57 initially gives isolable eight- (or seven)-membered ring intermediates (58, 60, and 62), which can be converted readily to products 59,61, and 63. The key step appears to be transannular attack of the imine nitrogen of the intermediate on the amide carbonyl. This is followed by attack of a nucleophile and ring opening via a number of possible pathways. ... 

Diastereoselective alkylations of amides from the formally C2-symmetric cyclic amines 1, 3 and 4 have been studied to date, with the four-membered analog 2 not yet examined. The... 

Because of the presence of the cyclic four-membered amide connected to the multicyclic ring systems, an effort to define their mechanism of action would be highly important. Despite a number of synthetic efforts, a relatively small amount of research had been focused on the use of compounds related to PAHs as anticancer agents. Bair et al. [152, 153] reported a close correlation between antitumor activity and the shape of the polyaromatic system. However, his group did not make a definitive correlation between the ability of these compounds to bind to deoxyribonucleic acid (DNA) and their cytotoxic activity. Bair s group developed... 

Cyclic esters and amides are called lactones and lactams, respectively. The ring size of the heterocycle is indicated by a Greek letter. An amide in a four-membered ring is called a P-lactam, because the P carbon to the carbonyl is bonded to the heteroatom. An ester in a five-membered ring is called a y-lactone. 

Lactam (Section 22.1) A cyclic amide in which the carbonyl carbon-nitrogen o bond is part of a ring. A P-lactam contains the carbon-nitrogen o bond in a four-membered ring. 

BusSnH. Internal addition of amine to allylic acetates, catalyzed by Pd(PPh3)4, leads to cyclic products via a 8 2 reaction.Three-membered cychc amines (aziridines) can be prepared from chiral conjugated amides via bromination and reaction with an amine. Four-membered cychc amines (azetidines) have been prepared in a different way ... 

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