Palau-amine

Ovaman, L.E. Refers, B. Tellew, J. Traik, W.C. (1997) Stereocontrolled synthesis of the tetracyclic core of the bisguanidine alkaloids palau amine and styloguanidine. J. Am. Chan. Soc., 119, 7159-60. 

Jacquot DEN, Lindel T (2005) Challenge Palau amine Current Standings. Curr Org Chem 9 1551... 

Kinnel RB, Gehrken H-P, Scheuer PJ (1993) Palau amine A Cytotoxic and Immunosuppressive Hexacyclic Bisguanidine Antibiotic from the Sponge Stylotella agminata. J Am Chem Soc 115 3376... 

Kinnel RB, Gehrken H-P, Swali R, Skoropowski G, Scheuer PJ (1998) Palau amine and Its Congeners A Family of Bioactive Bisguanidines from the Marine Sponge Stylotella aurantium. J Org Chem 63 3281... 

Grube A, Kdck M (2007) Structural Assignment of the Tetrabromostyloguanidine Does the Related Configuration of the Palau amines Need Revision Angew Chem Int Ed 46 2320... 

Mourabit AA, Potier P (2001) Sponge s Molecular Diversity Through the Ambivalent Reactivity of 2-Aminoimidazole A Universal Chemical Pathway to the Oroidin-Based Pyrrole-Imidazole Alkaloids and Their Palau amine Congeners. Eur J Org Chem 237... 

The remarkable hexacyclic alkaloid palau-amine (10) from Stylotella agminata was reported in 1993 (Scheme 3) [8]. Its high immuno-suppresive activity - whilst being reasonably nontoxic - has provoked preclinical studies [8c]. Interestingly, the isomer styloguanidine (11) is a powerful chitinase inhibitor [8b]. 

The synthesis of palau amine (10) was addressed by Overman [21]. Its dense functionalization, with two quaternary carbons being most prominent, presents a formidable challenge to synthesis. Taking advantage of the molecules folded shape, a retrosynthesis reduces the structure s... 

Bromopyrrole alkaloids are important not only for their ecological role and for chemotaxonomic considerations, but also for the number of interesting pharmacological activities they have been shown to possess. Among them, the cytotoxicity of agelastatin (see below) and the immunosuppressive activity of palau amine (see below) are remarkable. This is probably why the interest of organic chemists in total syntheses of bromopyrrole alkaloids has strongly increased since 2000. 

The authors hypothesized the following biogenetic origin for palau amines (Scheme 10.2). 

As might be expected, the complex bisguanidine-containing hexacyclic skeleton of palau amines stimulated a series of creative synthetic efforts, but, while some moieties of the palau amine skeleton have been prepared, a total synthesis is still lacking [82-84]. 

Scheme 10.2 Postulated biogenetic origin of palau amines.

This class of cyclic oroidin derivatives also parallels the above N-7/C-11 + N-1/ C-12 class in the presence of complex derivatives in which the isophakellin skeleton appears to be conjugated with an aminoimidazolyl propene unit. These isomers of palau amines are called styloguanidines (58-60) they have been isolated from the same sponge that contains palau amines, Stylotella aurantium [90]. 

These molecules were shown to be potent inhibitors of chitinase, an enzyme involved in the ecdysis of many insects and crustaceans, whose inhibitors are supposed to control the settlement of barnacles and, therefore, could have a potential application as antifouling agents. Unfortunately, no data are available in the literature about cytotoxic, immunosuppressive, or antibacterial activities of styloguanidines and, thus, a comparison with the potently bioactive congeners palau amines is not possible. 

Different molecular mechanisms have been separately postulated for dibromo-phakellin [74], dibromoagelaspongin [91], agelastatin [92], mauritiamine [88], and palau amine [78]. A1 Mourabit and Potier proposed a universal chemical pathway, starting from the simple precursors 101 and 140 and leading to over 60 pyrrole-imidazole alkaloids [80]. A new biomimetic spontaneous conversion of proline to 2-aminoimidazolinone derivatives using a self-catalyzed intramolecular transamination reaction together with peroxide dismutation as key step has been described [166]. This work has pointed to dispacamide A as the forerunner of oroidin and compounds 101 and 140 as probable hydrolysis products of oroidin and not the precursors. In this... 

The intramolecular Pauson-Khand reaction has been extensively used as a key step in total synthesis of fairly complex polycyclic natural products. The [2 + 2 + IJcycloaddition was, for example, used in recent syntheses of magellanine (Scheme 269), tecomanine, toward palau amines and styloguanidines (Scheme 270), Sa-hydroxystreptazolone (Scheme 271), ceratopicanol (Scheme 272), 13-deoxyserratine (Scheme 273), ABC-rings of nakadomarin and manzamine (Scheme 274), cedrone (Scheme 275), (-)-dendrobine (Scheme 276), " toward kalmanol (Scheme 277), and (+)-epoxydictymene (Scheme 278). 

Mourabit AA, Potier P. Sponge s molecular diversity through the ambivalent reactivity of 2-aminoimidazole a universal chemical pathway to the oroidin-based pyrrole-imidazole alkaloids and their palau amine congeners. Fur. J. Org. Chem. 2001 2 237-243. 

Chromatograph the ethanol-soluble portion on Sephadex LH-20 (MeOH) to afford essentially pure palau amine. 

Kinnel, R. B, Gehrken, H.-P., and Scheuer, P. J (1993) Palau amine a cytotoxic and immunosuppresive hexacyclic bisguanidme antibiotic from the sponge Stylotella agminata J Am.Chem.Soc. 115, 3376, 3377. 

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