Macrolactams synthesis

Fig. 8 Macrolactam synthesis by intramolecular reaction of an co-acyl chloride-amine...

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. 

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.

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. 

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. 

This method of amide synthesis has been applied to the construction of natural amide alkaloids and macrolactam alkaloids. Diamide (612) was prepared from the corresponding diacid (611) and then reacted with spermide to give a mixture of codonocarpine (613) and its isomer (614 Scheme 136). 

Cycloamidation has been used extensively to prepare 17-membered cycloisodityrosines. The acyclic biaryl ether precursors were prepared by methods including the Ullmann reaction 2-5 and nucleophilic aromatic substitution (SNAr)J6 7 Since these methods have all been used intramolecularly in cyclization reactions, they will be discussed in Sections 9.5.3 and 9.5.4. Evans and co-workers employed the pentafluorophenyl ester method of macrolactamization 8] to prepare 11, an intermediate in their total synthesis of OF4949-III (7) (Scheme 2)J3 In this case, the acidic removal of a Boc group was employed to release the cyclization substrate, although hydrogenolysis of a Z group is also effective 3 ... 

In the early 1990s, Smith and co-workers reported on the total synthesis of the antitumor antibiotic macrolactam (+)-hitachimycin 35 (Figure 12.1) using a Noyori three-component coupling to assemble the polysubstituted cyclopentane unit [24]. 

Such an example has been demonstrated by Johnson and Sames, who chose a platinum-mediated dehydrogenation as a key step in the synthesis of the antimitotic rhazinilam 33 (Scheme 6) [20], The key intermediate 27 was converted into the imine 28, which was allowed to react with Me Pt(//-SMe2)]2 to afford the platinum complex 29. Subsequent treatment with triflic acid resulted in elimination of methane and furnished the cationic complex 30. Upon thermolysis in trifluoroethanol, the complex lost a second methane molecule, which resulted in the activation of the ethyl group. A subsequent /1-hydride elimination gave the hydrido-Pt(n) complex 31. Treatment with aqueous KCN followed by hydrox-ylamine removed the platinum and yielded the liberated amine 32. Johnson and Sames added a homologization and a macrolactamization and completed the total synthesis of rhazinilam (33) by removal of the carboxyl group. 

The multicomponent LJgi reaction was successfully applied to the synthesis of bisamides 56, which on deprotection, followed by carbonylation and intramolecular amidation, afforded the macrolactams, 1,4-diazocines 57, as racemic mixtures (Scheme 7) <2005TL1697>. 

In 1972 Ito and Flirata reported on the isolation and structure elucidation of (-i-)-ikarugamycin as the first representative of a new class of macrolactam antibiotics [5]. Besides its remarkable biological activity, ikarugamycin is of interest because of its unusual architeeture and it represents an attractive target strueture for organic synthesis [6, 7, 8]. 

The method is useful for synthesis of five-, six- and seven-membered lactams, but not of P-lactams or macrolactams. The bridged lactam 2 was obtained from 1 in 77% yield by reaction with di-n-butyltin oxide. 

A,A-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride (BOP-Cl, 64) has been found to be an efficient macrolactamization reagent [69]. Tatsuta and coworkers [69c] used it in the synthesis of the ansamycin antibiotic rifamycin W 123). As shown in Scheme 41, amino acid 121 was cyclized to 122 using 4 equiv of BOP-Cl and 10 equiv of diisopropylethylamine in toluene at 85 °C for 3 h. Upon deprotection and oxidation 123 was obtained in 30% yield from 121. 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

Durette et al. [74] have achieved the total synthesis of the hexadepsipeptide antibiotic L-156,602 128) using the mixed phosphonic anhydride method as key macrolactamization step. As shown in Scheme 43, treatment of the linear depsipeptide 126 with n-propylphosphonic anhydride and DMAP in dichloro-methane at high dilution afforded the macrocycle 127 in more than 57% yield. 

In the first synthesis of the potent antitumor agent may famine 131) by Corey et al. [75], linear amino acid 129 was first converted to the soluble tetra-n-butylammonium salt and then slowly added to a solution of excess mesitylene-sulfonyl chloride and diisopropylethylamine in benzene at 40 °C for 28 h to afford macrolactam 130 in 71% yield (Scheme 44). 

The Mukaiyama reagent, l-methyl-2-chloropyridinium iodide (28), is also suitable for macrolactamization [85]. Jones et al. [86] achieved the first total synthesis of the important immunosupressant (-)-FK-506 (151) using the Mukaiyama method as a key cyclization step. As shown in Scheme 50, the unstable amino acid 149 was treated with 28 under high dilution to give the macrocycle 150 in... 

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