Bisindoles synthesis

Additionally, there had, for many years, been a vast synthetic effort underway aimed at the synthesis of the two monomeric units, where it was anticipated that the two units could be joined to form the vinblastine-type bisindole alkaloids. Coincidentally, as it transpired, 20 years of effort in the areas of synthesis and biosynthesis converged, at almost the same time, on the compound 3, 4 -anhydrovinblastine (8). 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

With the exception of the effect on microtubules described in the foregoing paragraph, the bisindole alkaloids have little or no effect on macro-molecular synthesis at subtoxic concentrations (21,22). In experiments utilizing radiolabeled precursors ([ H]leucine, -uridine, or -thymidine) cells cultured in the presence of vinblastine showed no differential incorporation of radioactivity. Furthermore, there is no indication that treatment of cells with vinblastine or vincristine produces alterations in cellular DNA (23,24). 

In an approaeh to the synthesis of bisindole model systems developed by Magnus and co-workers, the inherent reactivity of precursor (35), activated by reaetion with phenylchloroformate, provides bisindole (37) as a mixture of diastereomers (67). In this reaction the indolenium intermediate (36) is probably the reacting species. 

Although there are many examples of bisindole derivatives that are prepared by reaction of a naturally occurring alkaloid with various reagents, there are few examples of compounds that result from chemistry that alters the skeletal features of these compounds. Much interest has been directed at the synthesis of the dimeric compounds by the coupling of the monomer units vindoline (21) and catharanthine (38), in part because of the necessity of using this strategy to prepare bisindoles by total synthesis. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

The required furanosylated indolocarbazole 1380 should be readily available by reduction of 1379, a precursor of (+)-K-252a (330). For the synthesis of (+)-K-252a (330) a single-step cycloglycosidation of the selectively protected aglycon 1381 with an appropriate furanose was planned. The protected aglycon 1381 should be readily available by a rhodium-catalyzed coupling of 2,2 -bisindole 1384 with the a-diazo-p-keto-y-lactam 1382 (Scheme 5.232). 

The 2,2 -bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsNs) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234). 

In the following year, this method was also applied to the total synthesis of tjipanazole FI (371) (784). For this synthesis, the required bisindole 1444 was obtained starting from 5-chloroindole (1440) in three steps and 47% overall yield. Acylation of 1440 with oxalyl chloride led to the glyoxylic acid chloride 1441. Transmetalation of indolylmagnesium bromide with zinc chloride, followed by addition of the acid chloride, provided the ot-diketone 1443. Exhaustive reduction of 1443 with lithium aluminum hydride (LiAlFl4) afforded the corresponding bisindolylethane 1444. Executing a similar reaction sequence as shown for the synthesis of tjipanazole F2 (372) (see Scheme 5.243), the chloroindoline (+ )-1445 was transformed to tjipanazole FI (371) in two steps and 50% overall yield (784) (Scheme 5.244). 

Kuethe et al. reported the synthesis of the tjipanazoles D (359), I (360), B (369), and E (370) starting from the nitro derivative 1496 (796). This route involves the synthesis of 2,2 -bisindoles, followed by a two-carbon insertion through condensation with (dimethylamino)acetaldehyde diethyl acetal to afford the indolocarbazole ring. 

Miyake FY, Yakushijin K, Home DA (2002) Synthesis of Marine Sponge Bisindole Alkaloids Dihydrohamacanthins. Org Lett 4 941... 

Kouko T, Matsumura K, Kawasaki T (2005) Total Synthesis of Marine Bisindole Alkaloids, (+)-Hamacanthins A, B and (-)-Antipode of cis-Dihydrohamacanthin B. Tetrahedron 61 2309... 

Kutney JP (1990) Biosynthesis and synthesis of indole and bisindole alkaloids in plant cell cultures a personal overview. Nat Prod Rep 7, 85-103. 

The structures of these bisindole maleimides were confirmed by synthesis. The reaction of indolyl magnesium bromide (10) with 2,3-dibromo-A -methylmaleimide (11) in toluene led to bisindolylmaleimide (12), which was converted into arcyriarubin A (6) through alkaline hydrolysis followed by heating with ammonium acetate (Scheme 1). The reaction of 10 and 11 in THF yielded monosubstitution product (13) which after protection of the indole NH group with the Boc residue was used to prepare unsymmetrically substituted bisindolylmaleimide, arcyriarubin B (1) [8]. 

Research by B. Jiang et al. showed that the asymmetric aminohydroxyiation of vinyl indoles can afford (S)-A/-Boc protected a-indol-3-ylglycinols in moderate to good yield and with up to 94% ee. The use of these enantiopure intermediates allowed the short enantioselective total synthesis of bisindole alkaloids, such as dragmacidin A, which contains a piperazine moiety between the indole rings. 

Yang, C.-G., Wang, J., Tang, X.-X., Jiang, B. Asymmetric aminohydroxylation of vinyl indoles a short enantioselective synthesis of the bisindole alkaloids dihydrohamacanthin A and dragmacidin A. Tetrahedron Asymmetry 2002, 13, 383-394. 

Another type of rearrangement ensues if the ATb-oxide (219) is treated with a nucleophile. This reaction can be applied to the partial synthesis of bisindole alkaloids (q.v.), but in most cases a by-product is obtained. In the simple example in which the nucleophile is acetate, the product obtained is the pentacyclic compound (222), in which the intermediate fragmentation product has cyclized on to Aa. Analogous compounds can also be obtained starting with dihydrocatharanthine or coronaridine. ... 

The Markownikov addition of the elements of water to a cleavamine derivative may also have important application in the synthesis of bisindole alkaloids. Although this appears not to have been achieved, a route to the corresponding derivative of catharanthine has been developed, by use of a modified Prevost reaction. Thus, treatment of catharanthine with iodine and silver acetate in glacial acetic acid afforded an intermediate, which was reduced to the acetate (223) by NaBH4. Although formulated otherwise this acetate must be the 20a -acetate, by reason of its later conversion into vinblastine (q.v.). 

In view of the importance of vindoline (44) as a constituent of the oncolytic bisindole alkaloid vinblastine, methods for the synthesis of both vindorosine (43) and vindoline from members of the quebrachamine and vincadifformine groups have been extensively investigated. The first results... 

Biomimetic Synthesis of the Bisindole Alkaloid Villalstonine. D.E. Burke and P.W. Le Quesne, Chem. Gommun. 678 (1972). 

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