Discorhabdin, synthesis

Kita, Y. Tohma, H. Inagaki, M. Hatanaka, K. Yakura, T. (1992) Total synthesis of discorhabdin C a general aza spiro dienone formation from O-silylated phenol derivatives using a hypervalent iodine reagent. J. Am. Chem. Soc., 114,2175-80. 

Tohma H, Harayama Y, Hashizume M, Iwata M, Egi M, Kita Y (2002) Synthetic Studies on the Sulfur-Cross-Linked Core of Antitumor Marine Alkaloid, Discorhabdins Total Synthesis of Discorhabdin A. Angew Chem hit Ed 41 348... 

Harayama Y, Yoshida M, Kamimura D, Wada Y, Kita Y (2006) The Efficient Direct Synthesis of N.O-Acetal Compounds as Key Intermediates of Discorhabdin A Oxidative Fragmentation Reaction of a-Amino Acids or P-Amino Alcohols by Using Hypervalent Iodine(III) Reagents. Chem Eur J 12 4893... 

Oxidative cyclizations of 3-(/ -azidoethyl)indoles with BTIB afford pyr-roloiminoquinones 15, compounds that appear as sub-structures in biologically active marine alkaloids such as the makaluvamines and discorhabdins (Scheme 22) [67- 69]. In fact, BTIB-mediated sulfide and azide cyclizations, and a-azido-nation of the cyclic sulfide with PhIO/TMSN3, were incorporated into the first total synthesis of ( )-makaluvamine F [68,69]. 

Several efficient methods for PIFA-induced spiroannulation reactions of sily-lated phenol derivatives [44] or phenols [45] toward total synthesis of dis-corhabdin alkaloids having potent cytotoxicities and unique structures have been developed by Kita and co-workers. Utilizing these methodologies, total syntheses of discorhabdin C (30) [106] and discorhabdin A (31) [107] have been accomplished (Scheme 20,21). 

Nucleophilic attack of the electron-rich aromatic ring 124 to the cationic complex 123, and intramolecular amination afforded the intermediate 125 for the synthesis of discorhabdin and prianosin alkaloids [29]. 

Of physiologically active substances isolated from marine sources, the pyrroloimino-quinone alkaloids family exhibits antitumor activities derived from the unique highly-fused structure. The first synthesis of discorhabdin C (127) was performed by means of an electrochemical method as a key step . The key substrate 128, efficiently prepared starting from 4,4-dimethoxy-5-nitrobenzaldehyde, was submitted to constant current electrolysis (3 mA 4-1.2-1.8 V vi. SCE) in anhydrous MeCN to give rise to discorhabdin C in 24% yield, together with a minor compound 129 (6%) (Scheme 24). After a while, discohabdin C was also synthesized by using PhI(OCOCF3)2-promoted oxidation as a key step. ... 

At the early stage of Heathcock s biomimetic total syntheses of discorhabdins [108], a 5-ejco Heck cyclization was employed for the synthesis of 3,6,7-functionalized indole. As highlighted in Scheme 42, when precursor 237 was exposed to catalytic palladium acetate, tri-o-tolylphosphine, and stoichiometric base, indole 238 was smoothly produced in 89% yield. Subsequently, the total syntheses of discorhabdin C (239) and discorhabdin E (240) were accomplished using indole 238 as the common intermediate. 

Scheme 42. 5-exo Heck cyclization in the total synthesis of discorhabdins... 

Yamamura et al. developed an efficient route to the synthesis of the A, B, C, D, and E rings of the prianosins and discorhabdins, which led them successfully to synthesize discorhabdin C (Scheme 59) (210-212). Because their route involves the synthesis of the pyrroloquinoline skeleton of the pyrroloquinoline type alkaloids (213-217), they have also achieved the synthesis of batzelline C and isobatzelline C (213,214). Their synthesis involved first the construction of the C, D, and E rings as in 505, starting from 502, which was synthesized in three steps (212). Reaction of 502 with... 

A synthetic methodology has been under investigation for the synthesis of discorhabdins and prianosins by Confalone et al. using intramolecular... 

Among these alkaloid metabolites, the alkaloids containing the pyrroloimino-quinone 4 core skeletons comprise about 60 metabolites including makaluvamines, isobatzellines, discorhabdins, tsitsikammamines, and wakayin. There are several reviews of the structures, biological activities, and synthesis of the pyrroloimino-quinone alkaloids and their analogs [6-9]. 

Our group accomplished the total syntheses of discorhabdin C in 1992 [38], makaluvamine F in 1999 [39, 40], and discorhabdin A in 2002 [41, 42]. We also accomplished the first total synthesis of prianosin B in 2009 [43]. We now report the progress towards the synthesis of pyrroloiminoquinone alkaloids, mainly since 2000 including our studies, in this chapter. 

Discorhabdin alkaloids have the richest structure-diversity among the marine pyrroloiminoquinone alkaloids, and new discorhabdins are still being discovered. Although many synthetic studies have been carried out, only a few total syntheses of the natural discorhabdins have been reported. The total synthesis of discorhabdin C was accomplished by our group and Yamamura s group at almost the same time, and later by the Heathcock group. Heathcock et al. also synthesized discorhabdin E at the same time. Those discorhabdins are rather simple. The more complex discorhabdins, discorhabdin A and prianosin B, were synthesized only by us. 

Scheme 17 shows the final steps of each synthesis of ( )-discorhabdin C. For the details of our synthesis, see Sect. 4. In Yamamura s synthesis, discorhabdin C was obtained in 24% yield upon anodic oxidation of the bromophenol derivative 60 (R=H) [72, 73]. In Heathcock s synthesis, discorhabdin C was obtained by a phenolic coupling reaction of 60 (R=Ts) with CuCl2 and EtsN under bubbling O2 followed by detosylation [74]. 

Scheme 18 shows Heathcock s total synthesis of ( )-discorhabdin E by the same procedure as discorhabdin C [74]. The reaction of the imine 62, derived from 61, and o-bromotyramine furnished 63. The treatment of 63 with three equivalents of CUCI2 and four equivalents of EtsN under bubbling O2 gave the W-tosyldiscorhabdin E 64, the detosylation of which with NaOMe resulted in the formation of ( )-discorhabdin E. 

In 2006, Copp et al. reported the semi-synthesis of discorhabdins P and U from the natural discorhabdins C and B (Scheme 20). Discorhabdin C was reacted with CH3I in dry acetone to yield discorhabdin P in 54% yield. Discorhabdin B was reacted with CH3I in dry acetone to yield two products, discorhabdin U and 66. The order of the methylation of discorhabdin B preferentially favors the thio group, and a large excess of CH3I enables the methylation at the Ai-13 pyrrole position [75]. 

We synthesized discorhabdin C in 1992 [38]. For the total synthesis of discorhabdin C, two approaches were studied (Scheme 21). One approach involves the imine... 

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