Lactam ring closure with

Decarboxylative acylation—Lactam ring closure with N-dealkylation s. 17, 898... 

N-Dealkylation, lactam ring closure with — 17, 898 O-Dealkylation (s. a. Ethers, cleavage)... 

Acetic anhydride Lactam ring closure with N-deaikylation... 

The formal total synthesis of the novel /3-lactam antibiotic thienamycin has been accomplished from an isoxazoline derivative generated by [3 + 2] dipolar cycloaddition <79H(l2)l 183). Reaction of the nitrile oxide derived from 3-nitropropanal dimethyl acetal with methyl crotonate gave the isoxazoline (477) regio- and stereo-selectively. The isoxazoline was converted to amino ester (478) by hydrogenation and then to /3-lactam (479) by ester saponification and ring closure with DCC. Treatment of (479) with p-nitrobenzyl chloroformate and reaction of the derived acetal (480) with excess N-p-nitrobenzyloxycar-bonylcysteamine gave thioacetal (481), a compound which has previously been converted into ( )-(8S )-thienamycin (Scheme 106). 

A new route to ( )-trachelanthamidine (6) and ( )-isoretronecanol (5) has been reported by Nossin and Speckamp.12 Cyclization of the ethoxy-lactam (28), which is formed on reduction of the imide (27), led to ring-closure with the acetylene to give, after hydrolysis, a 4 1 mixture of the epimers (29) and (30) (Scheme 7). The preferential formation of the five-membered ring is considered to be due to stabilization of an exocyclic vinyl cationic intermediate by the phenylthio group. Reduction of the separated diastereoisomers (29) and (30) yielded ( )-trachelanthamidine (6) and ( )-isoretronecanol (5), respectively. 

Various cyclization techniques have been used in the past, which include disulfide bond [61], side-chain lactam [59], and head-to-tail amide bond formation [62], In most cases, the readiness of an open-chain precursor to cyclize depends on the size of the ring and the sequence of the peptide to be cyclized. Usually, ring closure with hexa- and pentapeptides is somewhat hampered however, the cyclization may be enhanced by the presence of turn structure inducing amino acids such as glycine, proline, and D-amino acids, etc., as was the case in the study of McBride et al. [63], Spatola et al. [64] have recently conducted extensive studies in these aspects and several cyclic penta-, hexa-, and heptapeptide libraries were prepared and analyzed. Their results showed that rapid cyclization rates can be achieved with optimized synthesis and cyclization procedures, and many combinations of cyclic peptides can be formed in high quality if they contain structural features that make cyclization more facile. 

DCC is also used to prereact carboxyl groups with 0-benzylhydroxylamine prior to /8-lactam ring closure. A water soluble carbodiimide in combination with HOBt is used in several steps of the total synthesis of nisin, a pentacyclic polypeptide. Carbodiimides are also used for amide bond formation in the synthesis of the antiviral antibiotic distamycin Similarly, carbodiimides are used in the synthesis of a model depsipeptide lactone related to quinoxaline antibiotics. In the last synthesis, DCC in the presence of pyridine is used in the depsipeptide bond formation. 

Penam derivatives with different C-2 and C-3 substituents were synthesized by the group at Astra Lakemedel Co. [19,20] (14) using a new /3-lactam ring-closure, but they do not report any activity data either. 

On-resin lactam (amide) formation or cyclization can be achieved via HOBt active esters using a number of reagents. Carbodiimide and phosphonium activation have all been used for ring closure with minimal loss of chiral integrity of the activated amino acid residue. The choice of reagent and auxiliary nucleophile (i.e. HOBt, HOAt) is at the discretion of the operator (see Chapters 2 and 3). However, it is worth noting that successful peptide cyclization is, to an extent, sequence dependent. Nominal ring closure is not uncommon and is due in part to the spatial orientation of the peptide backbone and steric hindrance. 

N-Condensed lactams from isocarbostyrils Ring closure with acetals... 

Formation of the /3-lactam (161) by reaction of the dianion (160) with methylene diiodide provides an example of a [3 + 1] type of ring closure (79TL2031). The insertion of carbon... 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

Optically active, a-branched lactams 30 have been built by means of Meyers chiral auxiliaries [ 10]. The key step included the diastereoselective a-alkylations of the initially formed co-i -sulfonamido oxazolines 26. The R or S configuration in the product 27 was obtained reacting the appropriately configured intermediate aza enolates with alkyl halides, high diastereoselectivities have been reported. Several attempts to achieve a complete ring closure to the lactams 30 (via 29) by an acidic cleavage of the oxazolines 27 failed. Varying mixtures of... 

Reaction of 2-129 with NaCN followed by treatment with NaH and TIPSC1 led to the anthracene 2-130 in 68% yield (Scheme 2.30). The desired lactam 2-131 was then obtained by reduction of the cyano group and ring closure using CoCl2/ NaBH4. Quite recently, this procedure has also been used for a formal total synthesis of tetracenomycin [63]. 

A Hungarian research group observed a nonexpected formation of a tetrazolo[l,5- ]derivative <2001J(P 1) 1131 >. These authors found that treatment of the /3-lactam-substituted tetrazolylmethyl ketone 135 with lead tetraacetate results in a ring closure to pyridine ring fused to tetrazole, and product 136 was formed as a mixture of diastereomers in low yield (Scheme 33). 

The earliest synthetic method for 1-benzazepine derivatives was a ring closure of -substituted anilines by C-N bond formation. Cyclization of 4-(2-aminophenyl butanoic acid and the corresponding butyl chloride gave the lactam (1, R1 = R2 = H) [1] and the 2-deoxo analogue [93], respectively. Thermal cyclization of (41, R1 = R2 = Me R3 = OH) gives 2,5-dioxo-benzazepines (38, R1 = R2 = Me R3 = R4 = R5 = H) [94]. Treatment of analogous esters with sodium hydride gives the derivatives of (38) [9, 95],... 

Several classes of antibiotics, e.g., tetracyclines [86], fluoroquinolones [87, 88], and p-lactams [89] were observed to react with chemical oxidants such as chlorine dioxide (CIO2) and free chlorine. Oxidation with CIO2 yields hydroxylated and oxygenated products in the case of tetracyclines, and leads to dealkylation, hydroxylation, and intramolecular ring closure at the piperazine moiety of the fluoroquinolones [86, 88]. 

Polyphosphoric acid (PPA) has recently been used for the intramolecular reaction of a properly positioned amino group with the carbonyl group of the lactam function of a pyridazin-3(2//)-one unit as exemplified by the ring closure of 2-(2-aminophenyl)phthalazin-l(2//)-one <2006T10018>. 

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