Hexacyclic indole

Moreover, polycyclic indole alkaloid-type molecules 225 with a ketopiperazine were prepared by Wang et al. using Ugi-Pictet-Spengler process [68]. Ketocar-boxylic acids 227 were used as bifunctional substrates in Ugi reaction to yield lactams of varying ring sizes (Scheme 41). A diastereomer of hexacyclic indole derivative was crystallized and yielded X-ray diffraction suitable crystal to assign the stereochemistry. 

A total synthesis of (+)-paspalicine and (+)-paspalinine took advantage of the Gassman indole synthesis. The thiomethyl ketone was treated with A-chloroaniline (prepared by mixing aniline with t-butyl hypochlorite) to afford the azasulfonium salt, which was transformed into anilinylsulfide upon treatment with triethylamine. Desulfurization with Raney nickel was followed by the acid-catalyzed cyclization to give the hexacyclic indole intermediate. 

Although these results do not rigorously exclude the possibility of the hexacyclic indole as a biosynthetic precursor to the brevianamides (poor solubiHty, cell penetration, uptake, k s, etc. may Hmit the access of the labeled, synthetic precursor to the biosynthetic machinery in the cells) enough doubt had been cast on the pathway depicted in Scheme 8 such that alternatives were pursued. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

The bromo derivative of A -mcthylsuccinimide did also undergo Suzuki coupling when treated with naphthylboronic acid in the presence of palladium acetate, triphenylphosphine and potassium carbonate (6.3.). The coupled product was deprotected under the reaction conditions and an indole derivative was isolated in good yield, which was successfully converted into the hexacyclic naphthopyrrolo[3,4-c]carbazole structure. Using the analogous trimethylstannyl-naphthalene derivative and optimised Stille coupling conditions the desired product was isolated only in 56% yield.5... 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

Securamine C from the marine bryozoan Securiflustra Securifrons family has recently been isolated and characterized by researchers at the University of Copenhagen. This interesting hexacyclic structure is an indole-imidazole alkaloid from a family of alkaloids that has yielded important biological activity. This proposal outllines a total synthesis of 1. 

Tetrahydro-jS-carboline 208 was prepared in a fashion similar to that of intermediate 189. Coupling of 208 to diphenol 209 was perhaps the most difficult step in bridging the two halves of haplophytine. Selective phenohc methylation, conversion of the acetate to the benzyloxy group, and rupture of the superfluous Af,0-acetal afforded imine 211. Hexacyclic bisenamine 212 was realized through a three-step sequence of saponification, acid chloride formation and based catalyzed cyclization. Similarly, /m-CPBA mediated rearrangement followed by DDQ oxidation afforded indole 205 (Scheme 38). 

Lundurines A-D [17, 18] are a new type of indole alkaloids characterized by the presence of a cyclopropyl moiety embedded within a hexacyclic ring system that includes a l//-azocine[5,4-h]indole ring unit (Fig. 4.4). 

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