Macrolactam ring

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

In summary, the obvious difference between the two Nicolaou syntheses is the reversed order of the construction of the daunting macrocyclic domains of diazonamide A (47). The initial synthesis installed the macrolactam ring first, followed by photoinduced HBr eUmination for the heterocyclic 12-membered ring. The subsequent synthesis constiucted the heterocyclic core first, which featured a... 

Confalone demonstrated another route through a C-C bond-forming process to form the 19-membered ansa-ring. Closure of this ring was designed so that a dipolar cyclo-addition could be utilized between a simple terminal olefin and nitrile oxide (-C=N -> 0 ), which was provided from a nitroalkane precursor such as 8. A macrolactam ring was cyclized in the form of the isoxazoline product 9. The maytansine model 10 was obtained after reduction and hydrolysis into a P-oxyketone followed by cyclization of the carbamate ring. 

C ompelling evidence has been presented that the enzyme responsible for activating pipecoiate in the unusual chain termination and cyclization process in rapamycin biosyn thesis is encoded by mpP (22,71). It seems likely that the polyketide chain of rapamycin is transferred from Raps3 to the amino-group of an enzyme-bound pipecolyl moiety, which in turn is attacked at the carboxyl functionality by the C22 hydroxyl-group to form the macrolactam ring. 

Cramer et have measured Dhc couplings for cylindramide and used them to refine the calculated structure of its macrolactame ring. 

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. 

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]. 

Boger and co-workers performed a detailed study on the effect of substrate structural features on the 17-membered ring macrolactamization. It was found that the substituent at the remote C4 aryl position had a profound effect on the rate and yield of the cyclization. Substrates bearing either a free phenol or no substituent were found to cyclize more efficiently, whereas those bearing methyl or benzyl ethers cyclized considerably less efficiently (Table 1)J5 ... 

Macrolactamization has limitations. All macrolactamization methods studied to date are ineffective at forming 14-membered cycloisodityrosines of the type found in deoxy-bouvardin (2) and RA-VII (3).[1° In addition, macrolactamization was not successful at preparing 16-membered rings that are structurally similar to cycloisodityrosines, such as the type found in the vancomycin family of glycopeptide antibiotics.[11 12 ... 

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... 

Macrolactamization. Closure of the 23-membered ring is the most critical step for j > nthesis of (-)-madumycin II. Using the Bop-CF in the presence of i-Pr NEt provides i volution. Despite the modest yield (32%), the method is serviceable. 

The synthesis of larger rings has also been accomplished including the fully unsaturated azolo-fused 1,3-diazepines (222) from bis(iminophosphoranes) (221) and novel cyclic carbodiimides (e.g. 223). Iminophosphoranes are also intermediates in the synthesis of macrolactams (e.g. 225) from the reaction of co-azido acid anhydrides (e.g. 224) with tributylphosphine. The synthesis of iminophosphorane-containing cryptands and a spherand-type structure have been reported. 

Esterification of 1584 with 1580 gave 1585 in excellent yield (Scheme 1.403). Sequential deprotection of 1585 unmasked the amino alcohol (not shown), which was subjected to macrolactamization using DPPA to afford the p-hydroxyamide 1586. The synthesis was then completed by cyclization/oxidation of 1586 to install the central oxazole ring of 1587. 

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). 

In contrast to his first synthesis vide supra), Nicolaou s second synthesis formed the left-side 12-membered in a late stage, through a macrolactamization process [40]. Retrosynthetic excision of the side chain and the chlorine atoms, and disconnection of the macrolactam, aminal, oxazole and bis-aryl ring system leads to fragments 76 and 77 (Scheme 12). 

Suzuki coupling and a heteropinacol coupling/oxitne-cleavage cascade reaction, followed by a similar macrolactamization for the remaining 12-membered ring. 

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. 

As such, macrolactamization was now at hand. Fortunately, several conditions could overcome the challenges imposed by this ring closure, with the use of HATU and collidine in a 1 2 mixture... 

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