Anthramycin synthesis

Anthracene, 9,10-dihydro-9,9-dimethyl-as antidepressant, 1, 169 Anthracene, 1,4,5,8,9-pentamethyl-synthesis, 2, 537 Anthracyclinones synthesis, 1, 414, 4, 700 Anthramycin synthesis, 7, 614 Anthranil, 3-acyl-rearrangement, 5, 93 Anthranil, 3-aiyl-acridones from, 2, 93 thermolysis, 5, 91 Anthranil, 3-(imidazol-2-yl)-rearrangement, 5, 433 Anthranil, 6-nitro-reactions... 

Scheme 1-38. Introduction of a BOC-protected amino group into o-cresyl methoxymethyl ether as a crucial part of a new Anthramycin synthesis.

Stille employed a Heck reaction on triflate 136 to install the acrylamide side chain in his synthesis of anthramycin and analogues, as illustrated below [79, 80]. Ironically, a Stille reaction was less efficient in this transformation. 

Table II compiles melting points, optical rotations, and methods used for the structural elucidation of the known benzodiazepine alkaloids. Intensive studies of the degradation of the molecules as well as attempts at total synthesis have been undertaken only with members of the cyclopenin and the anthramycin-tomaymycin groups. In the following a short summary is given of the reactions and intermediates that provided essential information about the structures of the basic skeletons of the alkaloids.

Fig. 4. (a) Degradation of anthramycin-11-methyl ether (25) and tomaymycin ethyl ether (28) to anthranilic acid derivatives (28). (b) Formation of the trioxo compound (33) by degradation of tomaymycin (12) and by total synthesis (26). 

Pd(OAc)2] in the presence of PPhs was used as catalyst. The use of vinyl bromides in lactam formation has also been reported." Imides were obtained from aryl bromides. The method has further been applied to the synthesis of diazepam and 1,4-benzodiazepines and to a-methylene lactams and lactones. " In connection with the synthesis of natural products, the reaction has been employed in the preparation of hexadehydrohimbane, anthramycin and berbine derivatives. The catalyst was prepared in situ from [Pd(OAc)2] (106) and PPhj in all cases. The mechanism of lactam formation is analogous to that for amides (Scheme 42). 

Lithiation of both A/-phenyl- and 0-phenyl-urethanes has been reported. The ortho lithiadon of /V-r-bu-toxycaibonylaniline and subsequent addition to carbonyls, nitriles and several other electrophiles was first reported by Muchowski in 1980. In some cases the adduct cyclized by attacking the urethane carbonyl. Typical examples are shown in Scheme 17. Lithiation of an /V-r-butoxycarbonylaniline derivative served as one of two directed lithiation steps in Snieckus synthesis of anthramycin (17 Scheme 18). Treatment of phenothiazines with 2 equiv. of butyllithium affords an A(,o-dilithium species, but reaction with electrophiles occurs at both sites. Katritzky has shown that the sequence of N-lithiadon, car-bonation and o-lithiation protects the nitrogen from alkylation (Scheme 19). ... 

Using the same procedure as for the synthesis of the related five- and six-membered benzolactams, the benzoazepinone derivatives (27) have been synthesized in good yield. This palladium-catalyzed procedure has more recently been extended to the synthesis of a number of antibiotics. A key step in the synthesis of anthramycin, for example, is the palladium-catalyzed insertion of CO into the amine (28). ... 

Design, synthesis, and biological evaluation of DNA minor-groove binders, ligands structurally related to CC-1065, distamycin, and anthramycin 03PAC187. 

Sequential directed ortAo-metallation reaction has been utilised in the synthesis of anthramycin... 

Anthramycin (95), produced by Streptomyces refuineus [171], is active in vivo against sarcome 180, Ehrlich solid and Ehrlich ascites carcinomas, Waker 256 carcinosarcoma and human epithelioma no. 3 [172]. As mentioned before, anthramycin (95) inhibits nucleic acid synthesis through covalent attachment via Cl 1 to DNA at N2 of guanidine [173]. The right-handed twist of anthramycin (95) allows it to fit entirely within the minor groove of DNA [174]. Its synthesis has been carried out by two groups [170,175],... 

Azetido[2,l-c]-[l,4]benzodiazepine 19 has been synthesi.sed as an analogue of the anthramycin type 20 antitumour antibiotic <97TL5839>. A crystal structure for 21 is available <96MI639>. 

Anthramycin 4.43) which readily undergoes covalent hydration (Section 2.5, p. 47), inhibits the synthesis of RNA by binding to the DNA template in RNA polymerase, which could account for its anti-tumour and anti-microbial action (Horwitz and Grollman, 1968 Kohn and Spears, 1970). 

Anthramycin was isolated from the fermentation beer of Streptomyces rejuineus [1], its chemical structure determined [2], and total synthesis achieved [3]. In contrast, tomaymycin was isolated from the fermentation broth of S. achromogenes [4]. 

Scheme 10.2 Application in the synthesis of Anthramycin, Prothracarcin and Tomaymycin...

The use of secondary amides as nucleophiles has been also documented by Mori et al.f Synthesis of imides by this method is not always satisfactory, but phthalimides are prepared in high yield (Scheme 44). An interesting modification of this method consists of the double carbonylation of o-aryl diiodides and proceeds via an initial intermole-cular amidation, followed by the intramolecular one described by Mori (Scheme 45). ° The formation of seven-membered rings was demonstrated by the synthesis of diazepam and a number of anthramycin alkaloids, including Prothracarcin and Tomaymycin (Scheme 46). As mentioned above, for seven-membered rings direct amination is observed as a side reaction. Secondary ureas are also substrates for this reaction, yielding seven-membered cyclic ureas. ... 

Mori and Ban then reported a novel synthesis of benzodiazepine derivatives by Pd-catalyzed carbonylation of o-haloaniline derivatives 10, which was prepared from o-haloanilines 8 (Scheme 4) and amino acid derivatives 9. They succeeded in the total synthesis of many benzodiazepine antitumor aulibiotics. A toluene solution of o-bromoani-line derivative 10a, which was prepared from 2-hromo-4-methoxy-5-tosyloxyaniline and 4-hydroxy-/-proline, Pd(OAc>2, PPhs, and BU3N, was heated at 110 °C for 48 h under carbon monoxide (5 atm) to produce benzodiazepiue derivative 11a. Compound 11a was converted into 12, which was a key intermediate for the synthesis of anthramycin (ISa). Using a similar procedure, they succeeded iu the total synthesis of tomaymycin (13b), prothracarcin (13c),t pretomaymycin (13d),t neothramycin (13e)t and SEN 215 (13f). ... 

Anthramycin selectively inhibits RNA and DNA synthesis in mouse leukaemia cell suspension [134], The more stable anthramycin methyl ether... 

The synthesis of diazepam and related 1,4-benzodiazepines has been accomplished by means of a palladium-catalysed carbonylation reaction. Similarly, this reaction has been employed as the key step for the construction of benz-lactams, in syntheses of anthramycin and of the lycorine ring system. Palladium-mediated macroheterocyclization has been used in an impressive synthesis of indandenin-12-one in a remarkable 23.3% overall yield from butadiene monoepoxide. The key step provided the necessary 21-membered ring in nearly quantitative yield in a highly chemo-, regio-, and stereo-selective fashion (Scheme 41). ... 

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