Macrolactam, formation

The f.Z-diene of the seco acid 2 would result from Horner-Emmons and Wittig reactions from aldehyde 3 (Scheme 2). The trimethoxyaniline functionality is carried along as a stable nitrobenzene that would be unmasked at a late stage prior to macrolactam formation. The syn methoxy-hydroxy functionality at C6-7 in 3 is installed using the newly developed glycolate aldol reaction with enal 4 and norephedrine glycolate ester auxiliary 5. This new method is an application of Masamune s recent work with propionate norephedrine aldol reactions.The CIO methyl is installed using the aforementioned hydroboration reaction,... 

JV-Methylmaysenine is the simplest congener among maytansinoids, since it lacks both of the epoxide and the C3 hydroxy group. This compound has often been chosen as the first target to examine the validity of synthetic methodology (strategy) thus, the macrolactam formation and the carbamate ring could be examined properly. The process is summarized in Scheme 5. 

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. 

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. 

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... 

Kato, N. Shimamura, S. Khan, S. Takeda, F. Kikai, Y. Hirama, M. Convergent approach to the maduropeptin chromophore aryl ether formation of (R)-3-aryl-3-hydroxypropanamide and cyclization of macrolactam. Tetrahedron 2004, 60, 3161-3172. 

Macrocyclic motifs are usually essential for the unique biological properties of natural products. In most cases, linear NRP and PK scaffolds are cyclized to form macrolactones or macrolactams prior to further post-modification. Macrocyclization is usually carried out by cyclases towards the end of elongation. For example, in the biosynthesis of the antibiotic tyrocidine A, a linear enzyme-bound decapeptide is cyclized via an intramolecular SN2 reaction between the N-terminal amine nucleophile and the C-terminal thioester, which is covalently linked to the synthase [reactions (a) and (b), Scheme 8.3] [22], This cyclase shows great versatility. Not only does it catalyze the formation of macrolactams of ring sizes from 18 to 42 atoms from... 

Grubbs catalyst 86a efficiently produced 16- or 21-membered lactone 90a-c in good yields (Scheme 14) [59], The method was further applied to the synthesis of (4-)-12-methyl-13-tridecanolide (91), a minor musk-odor component. Lasiodiplo-din (94) was efficiently synthesized via the formation of 12-membered lactone 93 by RCM of 92 with 86a as the key step [60]. Schrock catalyst 85 was successfully applied to the synthesis of fluvirucin Bi (Sch 38516) (97). Reaction of the fully functionalized diene 95 with 85 afforded macrolactam 96 as a single (Z)-olefin [61]. RCM has been also utilized in the total synthesis of epothilones (5) (Section... 

Shortly after Harran s structure revision of diazonamide A (47), Nicolaou and coworkers reported the first total synthesis [39]. Retrosynthetically, assembly of fragments 63-67 could lead to diazonamide A through side-chain excision, chlorination, macrolactamization, aminal and oxazole formation, and bis-aryl ring realization (Scheme 10). 

The intramolecular esterification of simple m-hydroxy-acids (for example, those containing only a saturated hydrocarbon chain) or of its co-halogeno derivative can be realized easily (Fig. 5), but the harsh reaction conditions are not compatible with the numerous sensitive functions present in the seco co-hydroxyacids of natural origin. The necessity to perform the lactonization in a smoother way has been an efficient motor for progress. The same considerations apply for the macrolactamization or the formation of macrocarbocycles of natural origins. 

In contrast to syntheses of epothilone A, Hoveyda et al. disclosed the highly Z-selective formation of the 14-membered macrolactam 27 by the Schrock complex [Mo]-I... 

Many of the early examples of maerocyeles in drug discovery relied on these classical reaction types for the formation of the ring and they remain in regular use. This was due, in part, to the peptidomimetic nature of many of these structures, which often were targeted at protease enzyme inhibition, and thus lent themselves readily to macrolactamization for amide bond formation or macrolactonization for cyclic depsipeptide-like compounds. Representative examples of these two general transformations are shown in Scheme 11.1 (BOP (benzotriazol-l-ylo5ytris(dimethylamino)-phosphonium hexafluorophosphate, Castro s reagent), EDC (l-ethyl-3-(3-dimethylamino-propyl)-carbodiimide), DMAP (4-dimethylamino-pyridine)) for the matrix metalloproteinase (MMP) inhibitor template 2 and the renin inhibitor scaffold 4. °... 

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