Macrolactam

The synthesis of (+)-N-methylmaysenine, a preliminary for the later synthesis of the antitumor agent maytansine, was accomplished by the joining of fragments A and B, chain extension and macrolactam closure using a mixed carboxylic-sulfonic acid anhydride. 

Scheme 18. Retrosynthesis for the construction of the 14-membered macrolactam ring oi Sch 38516 (fluvirucin Bj)... 

Scheme 19. Mo-catalyzed RCM in tandem with catalytic hydrogenation allows the control of C2-C6 relative stereochemistry in the macrolactam region of Sch 38516...

With the Mo-catalyzed macrolactamization secured, we turned our attention to the problem of C2-C6 remote stereochemical control. Catalytic hydrogenation of unsaturated cyclic amide 76, in the presence of 10% Pd(C), resulted in the formation of 78 in 84% yield and with >98% diastereoselectivity. 

To gain insight into this remarkably efficient cyclization reaction (77—>76), and to determine the extent to which existing stereogenic centers preorganize diene precursor 77, we examined the catalytic RCM of 79 and 82. When 79 was subjected to 25 mol% 2 (50°C, 18 h), <2% 80 was formed (Scheme 20). Instead, dimer 81 was obtained in 52% yield (3 1 mixture of olefin isomers identity of major product not determined). When diene 82 was treated with identical conditions, macrolactam 83 was obtained in 41% isolated yield [33] along with 20% of the... 

Considering the facility with which dimerization products 81 and 84 are obtained, we reasoned that, in catalytic ring closure of 77, the derived dimer is perhaps initially formed as well. If the metathesis process is reversible [17b], such adducts may subsequently be converted to the desired macrocycle 76. To examine the validity of this paradigm, diene 77 was dimerized (— 85) by treatment with Ru catalyst lb. When 85 was treated with 22 mol% 2 (after pretreatment with ethylene to ensure formation of the active complex), 50-55% conversion to macrolactam 76 was detected within 7 h by 400 MHz H NMR analysis (Eq. 8). When 76 was subjected to the same reaction conditions, <2% of any of the acyclic products was detected. Although we do not as yet have a positive proof that 85 is formed in cyclization of 77, this observation suggests that if dimerization were to occur, the material can be readily converted to the desired macrolactam, which is kinetically immune to cleavage. 

Subsequently, in the course of the total synthesis, we established that glycosyla-tion of the macrolactam alcohol or various silyl ethers by a range of protocols is not feasible. Repeated initiatives along these fines resulted in complete decomposition of the carbohydrate systems and low recovery of the macrocyclic substrate (<15%). The principal reason for such unsatisfactory outcomes proved to be the notorious lack of solubility of the parent alcohol of 76 in a wide variety of solvents the 14-membered alcohol is sparingly soluble in methanol at ambient temperatures. Clearly, out initial efforts towards the use of catalytic RCM in constructing the macrolactam segment of Sch 38516 required additional investigation. 

Scheme 6.1. Demonstration of the utility of (ebthi)Zr-catalyzed ethylmagnesation in the enantioselective synthesis of the macrolactam aglycon of fluvirucin.

Grunwald MH, Ben Amitai D, Amichai B. (2004) Macrolactam immunomodulators (tacrolimus and pimecrolimus) New horizons in the topical treatment of inflammatory skin diseases. J Dermatol 31 592-602. 

The synthesis of some alcaloids has been achieved by means of the amide version of PFR [201]. Another application is the recent synthesis of diazonamides, an unusual group of alkaloids [202]. In this case, a macrolactam was irradiated. 

Oxygen- and sulfur-assisted methods have been described to synthesize strained macrolactams by ring contraction through attack of the amine on the intermediate macro(thio)lactone [37]. 

Vasudevan A, Verzal MK (2005) A post-Ugi carbonylation/intramolecular amidation approach toward the synthesis of macrolactams. Tetrahedron Lett 46 1697-1701... 

Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei (Nocardia mediteranei). It was introduced into medical practice in 1968. Synthesis of rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions is oxidized to a new derivative of rifamicin S (32.7.4), with the intermediate formation of... 

Bis-4-arylidene-5(4//)-oxazolones are easily obtained from aromatic dialdehydes by the Erlenmeyer synthesis. Such bis(oxazolones) react with a,co-diamines to provide a convenient approach to macrolactams.Tandem Erlenmeyer condensation-macrolactamization (TECM) has been used to prepare analogues of naturally occurring, biologically active cyclic peptides such as bastadin-5. 

Macrolide-macrolactams madaneolide and laineolide A-like Lyngbya bouillonii Hoifinan and Demoulin, Nostocales, Cyabact. from PNG Klein 1999). 

In contrast, the biosynthesis of aplasmomycin in the sea and boromycin on land are expected to follow much the san pathways since actinomycetales are involved in both cases (Chart 8.3.FA/PO). Macrolactams are common metabolites in actinomycetales (Chart 8.3.FA/PO), which, as symbionts, may accoimt for the presence of these metabolites also in marine demosponges. 

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