Discorhabdin total synthesis

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... 

Nishiyama, S., Cheng, J.F., Tao, X.L., and Yamamura, S. (1991) Synthehc studies on novel sulfur containing alkaloids, prianosins and discorhabdins total synthesis of discorhabdin C. Tetrahedron Lett., 32, 4151 154. 

Tohma, H., Harayama, Y, Hashfrume, M., Iwata, M., Egi, M., and Kita, Y. (2002) Synthetic studies on the sulfur-cross-linked core of antitumor marine alkaloid, discorhabdins Total synthesis of discorhabdin A. Arageiv. Chem. Int. Ed., 41, 348—350. 

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. 

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). 

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

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 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. 

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... 

In our total synthesis of discorhabdin A, the A,(9-acetal compound 96 acted as a key compound for the construction of the A,5-acetal compound (see Scheme 31), and was prepared by the oxidative fragmentation reaction of an a-amino alcohol 95 initially using the highly toxic lead tetraacetate. We then developed a new method using the low toxic hypervalent iodine(III) reagent. Thus, the reaction of the... 

We also completed the total synthesis of the unnatural discorhabdin A, (—)-discorhabdin A, starting from the o-tyrosine methyl ester by the same route as described for (+)-discorhabdin A (Scheme 32). 

Prianosin B is the oxidized discorhabdin A, whose C16-17 bond is double bond. We found that the detosylation and dehydrogenation reaction of the pyrroloiminoqumone unit proceeded using a catalytic amount of NaN3 in good yield. We then applied the reactions to the total synthesis of prianosin B (Scheme 33). Thus, the treatment of 98... 

In the total synthesis of discorhabdin A, the key intermediate 34 was prepared in three steps via the tin-mediated radical cyclization in 76% jdeld by Fukuyama and co-workers ... 

Scheme 8 Total synthesis of discorhabdins by tbe dearomatizing spirocyclization strategy...

For example, a variety of natural products bearing spirocyclic systems exist, and many of them are biosynthetically formed by oxidative spiroannulation processes. Hypervalent iodine(III) reagents are thus considered as one of the most effective oxidants for these oxidation processes. Several efficient methods for PIFA-induced spiroannulation reactions of phenols [48, 49] towards the total synthesis of discorhabdin alkaloids [50, 51] and their oxa-analogues have been published [52, 53], which were accomplished via hypervalent iodine oxidation of phenols or (9-trimethylsilylated phenol derivatives to the azacarbocyclic spirodienones as a key step (Scheme 8). 

Roberts, D., Alvarez, M., and Joule, J.A. (1996) Synthesis of 6-chloro-l,3,4,5-tetrahydro-7,8-dimelhoxy-l-melhylpyrrolo[4,3,2-(fe]quinoline from a quinoline formal total synthesis of batzelline C, isobatzelline C, discorhabdin C and makahivamine D. Tetrahedron Lett., 37,1509-1512. 

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. 

Roberts D, Joule JA, Bros MA, Alvarez M (1997) Synthesis of pyrrolo[4,3,2-iie]quinolmes from 6,7-dimethoxy-4-methylquinoline. Formal total syntheses of damirones A and B, batzelline C, isobatzelline C, discorhabdin C, and makaluvamines A-D. J Org (Them 62 ... 

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