Lactams macrocycles from

Scheme 4.11 Cu-catal5 ed s nthesis of macrocycles from /1-lactams.

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

Amfidinolides (unique macrolides from marine dinoflagellates) 97H(44)543. Antitumor N-, N,S-, and S-heterocycles and macrocyclic lactams from ascidi-ans 97M122. 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Macrocyclic lactams making use of the double reaction of bisimidazolides — in this case, prepared from the corresponding dicarboxylic acids by in-situ reaction with C6H5POIm2 - were obtained in acceptable yield considering the unfavorable ring sizes of the products 1-1295... 

Rzasa, R. M., Shea, H. A., and Romo, D. (1998). Total synthesis of the novel, immunosuppressive agent (-)-Pateamine A from Mycale sp. Employing a b-lactam-based macrocyclization. J. Am. Chem. Soc. 120, 591—592. 

Macrocyclic 14-membered lactams, lactones, and thiolactones 211 have also been prepared from 3-amino-l,2,5-thiadiazole-4-carboxylic acids 210 (Equation 47) <1996CHE975>. 

Bacterial metabolites include novel alkaloids, peptides, and macrocyclic lactams. The most unusual metabolites from dmoflagellate are polyethers, both linear and macrolides. The latter were also found abundantly in brown seaweeds (Chart 7.6.FA/PO). Filamentous fimgi have afforded new isoindole and quinazoline alkaloids, as well as new-skeleton steroids (Chart 7.6.A/P/I). 

In a similar way, formation and subsequent hydrolysis of bis-p-lactams provide a route to peripheral functionalization of macrocyclic imines. For example, racemic bis-p-lactam 15, Scheme 5, which is formed upon Staudinger reaction of imine 14 and the ketene originated from phenoxyacetyl chloride and triethylamine, led to C2 symmetric amino acid 16 in high yield [59]. 

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

Ansamycins are a class of macrocyclic compounds in which non-adjacent positions on an aromatic ring system are spanned by the long aliphatic bridge (Latin ansa = handle). The aromatic portion may be a substituted naphthalene or naphthaquinone, or alternatively a substituted benzene ring. The macrocycle in the ansamycins is closed by an amide rather than an ester linkage, i.e. ansamycins are lactams. The only ansamycins currently used therapeutically are semi-synthetic naphthalene-based macrocycles produced from rifamycin B. 

In an extension of the approach, the dihydropyrrolizinone (26) was prepared in similar yield from the bicyclic lactam (25) (Scheme 6). Both (+)- and (-)-forms of (26) are present as part of macrocyclic diesters in Senecio species (cf. Vol. 10, p. 54). 

Gunasekera, S. P, Gunasekera, M., and McCarthy, P. J., Discodermide a new bioactive macrocyclic lactam from the marine sponge Discodermia dissoluta, J. Org. Chem., 56, 4830, 1991. 

Enantiopure fused oxopiperazino-/3-lactams have been produced by application of the Staudinger reaction with 5,6-dihydropyrazin-2-(l/7)-ones and the /3-lactams were converted to the 2-oxopiperazine-3-acetic acid esters in good yield with no epimerization (Equation 86) <2006TL8911>. Fused /3-lactams have been formed from macrocyclic imines by use of the Staudinger reaction (see Section 2.04.9.7). When phenoxyacetyl chloride and triethylamine were used, the best yields (45-52%) of the fused /3-lactams were obtained with dry dichloromethane as solvent <2006TL8855>. 

As can be seen from Scheme 2.1, under appropriate equilibrating conditions, the macrocycle will be produced as the thermodynamic product. This dearly appears in the following example (Scheme 2.2). During the synthesis of the 14-membered lactam fluvirudn Bj by Hoveyda and coworkers from diene 1, only the dimer 2 resulting from the head-to-head coupling between the less substituted double bond... 

This strategy allows the preparation of macrocyclic carbinols, lactones, and lactams. For example, highly regioselective and stereoselective macrocyclization has been found for ketoprofen-tetrahydrofuran (THF) conjugates, due to exclusive H-abstraction from the less-substituted carbon and a preferred cisoid ring junction over the transoid junction (Scheme 9.40) [67]. 

A second period of macrocyclic chemistry was signaled by the isolation of the first macrolide antibiotic from an Actomyces culture in 1950. Brockmann and Henkel [6][7] named it picromycin (Pikromycin) (1/4), because of its bitter taste. This antibiotic contains a 14-membered ring. Since then a large number of macrocyclic lactones, lactams and cycloalkane derivatives have been discovered. Some of these compounds have a considerable physiological importance for humans and animals. Because of these physiological properties it was necessary to prepare larger quantities of these macrocylic compounds by chemical syntheses [8]. 

Another method employed for the synthesis of these types of macrocycles involves the reaction of a Ws-acid chloride with a diaminoether. Weber and Vogtle have reported the synthesis of a series of these macrocycles and their complexes. The first examples included ligands 166-171 137), which were obtained in yields varying from 3% to 61 % no metal complexes have as yet been reported for these lactam-type macrocycles 117 137>. 

Mono- and diazamacrocycles can be conveniently prepared by a catalyzed ([Cl2(PCy3)2Ru(=CHPh)]) RCM from bis(olefinic) precursors. The reaction is very general and affords monounsaturated macrocycles in reasonable yields. Furthermore, lactam formations by closure of amino-carboxyl derivatives or by Beckmann rearrangement are also methods of the choice however, in the first case, the yields are in general low since polymers are usually produced, as the main product. 

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