26 June 2017 Faculty of Chemistry B.Sc. Biomolecular Engineering Prof. Dr. Wolf-Dieter Fessner Juliane Müller, Duc Le Ngoc, Jan Krumbach, Lara Kopp

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1 PALAU AMINE 26 June 2017 Faculty of Chemistry B.Sc. Biomolecular Engineering Prof. Dr. Wolf-Dieter Fessner Juliane Müller, Duc Le Ngoc, Jan Krumbach, Lara Kopp The Structure and its Revision: Palau amin was discovered in a sea sponge family named Stylotella agminata found in the southwest Pacific Ocean. This chemical substance is believed to be poisonous and was first isolated and described in Palau amin contains nine nitrogen atoms making it very difficult to define its structure precisely. Therefore, the configuration - which has been found before - was still being researched. Until 2007, the highly complex structure of the molecule was once again pinned down and officially confirmed in Defining a 100% correct structure of an organic substance is not an easy job. It requires a combination of many researching methods such as NMR-Spectroscopy, and especially time (here, nearly a decade). In the case of Palau amin, the researchers could not interact directly with the molecule and had to work with other derivatives or substances likely to have similar atomic structures. While working with the molecule, scientists discovered that the coupling constant between the protons H11 and H12 (14,1 Hz) was too big for a cis-conjunction. However, it matched the experimental records of the already known spiro-annulated 5-rings. Considering this inconsistency, they didn t stop there, and a lot of different experiments were continuously performed. Finally, it showed that the structure published in 1993 is false - the conjunction of H11, H12 must be trans.

2 So why did they think that the cis-conjunction is more likely? The explanation for this assumption is that the energetic difference between cis- and transconjunctions is 27 kj/mol, making the cis-conjunction more stable and thus preferred by the molecule. Furthermore, not so many trans-conjunctions have been documented up to that time to make a good comparison. The revision of the atomic structure of Palau amine was done with the research of the distance between protons (H-atoms) by Dr. Achim Grube and Dr. Matthias Köck. They did some experiments on Tetrabromstyloguanidin and the results were processed and presented in form of a diagram. The distances of 1,3-protons of the revised structure strongly matched with the experimental records. Besides, the conformation of the cyclopentane ring in the new structure is in envelope form and the chlorine atom is in equatorial position. In contrast to the revised form, the conformation of the older one is in twist form and the chlorine atom is in axial position. It is very possible that this change in conformation leads to the difference of the distance between protons H12/H17, explained through the interaction of one atom to the other. Key Black Bar: Old Configuration White Bar: Revised Configuration Grey Bar: Experimental Figures

3 twisted-form old conformation envelope-form new conformation In 2010, three years later, the atomic structure of Palau amin was once again confirmed thanks to the cooperation of Dr. Köck and Dr. Volker Schmidts (AK Thiele, Technical University of Darmstadt). A method called residual dipolar couplings (in short, RDCs) was used. The molecule in question (Dibrompalau amin) is surrounded by a liquid crystal or an aligned medium (in this case: PAN Gel) leading to the interaction between the molecule and the medium. In other words, the effect is the partial orientation with respect to the magnetic field [ , 11:35 am]. The Biosynthesis of Palau amine: Up to this point the biosynthesis of Palau amine has not been studied in living organisms. The most prominent hypothesis assumes that many Pyrrole-Imidazole-Alkaloids are formed out of an intermediate product - the so called Preaxellinamine - during the synthesis in living organisms. The Preaxinellamine is most likely synthesised in three different ways: The first two mechanisms are based on ring modifications (expansion and contraction, respectively) of alkaloids; the third assumes a linear dimerization. 1) The Ring Expansion: The ring expansion of the alkaloid sceptrin consists of the assembly of a positively charged oxygen atom at the aminoimidazole-ring. In consecutive rearrangements of electrons, the neighbouring cyclobutane-ring transforms into a cyclopentane-ring.

4 2) The Ring Contraction: The ring contraction of Ageliferin is very similar to the ring expansion in its general order of reaction. A hydroxy- and chloride group are added during the process. Instead of a ring expansion of cyclobutane, the process is concluded after a ring contraction of a neighbouring cyclohexane. Ageliferin and Sceptrin have been found in organisms producing pyrrole-immidazolealkaloids, which supports the first two theses. 3) The Linear Dimerization: Two linear oroidine-molecules dimerize in an enantio- and stereoselective way. A chloride and a hydroxy-group are added and induce a cyclisation of a pentane-ring. The linear dimerization hypothesis can be seen as the missing link between relatively simple molecules (Oroidine) and complex pyrrole-imidazole alkaloids. Finally, the actual Palau amine synthesis consists of the oxidation of an amino-imidazole-ring and consecutive internal rearrangements. After the separation of a pyrrole-remnant the synthesis is concluded.

5 The chemical synthesis of Palau amine: It has been very difficult to find a way to synthesize the molecule because of its daunting structural and physical attributes, which are consisting of nine nitrogen atoms, eight contiguous stereogenic centres, a lot of reactive (hemi)aminals, oxidation-prone pyrroles and highly polar, noncrystalline morphologies. Compared to its two structural family members, the axinellamines and massadines, Palau amine additionally possesses a very unique chemical challenge: The pyrroleamide sidechain embedded in a hexacyclic core architecture containing a highly strained trans substructure (aka: the 5,5 -fused system) - which is unprecedented among natural products and has always been a problem with Palau amine (see: the revision from cis to trans). This structure possesses a high degree of strain, and thus there have been many thwarted attempts at a biomimetic or stepwise closure. In the paper Total Synthesis of Palau amine by the lab of Prof Dr Phil Baran who, after years of research, proceeded to be the first lab to synthesize Palau amine - was even written: Many well-founded and logical plans to secure the peculiar trans-5,5 core of Palau'amine in our laboratory resulted in unfortunate outcomes [p. 1, line 24 f.]. They secured their victory in the run for the chemical synthesis of Palau amine in 25 precise steps, outgoing from commercial material. Here, we describe the final and most important steps through which Baran accomplished the complicated ring closure beginning from a similar intermediate to his 2007 total synthesis of the axinellamines, which features a readily available cyclopentane core.

6 The teams first move was to install the sole hydroxyl group using silver(ii)-picolinate; this entailed the stereo- and chemoselective transformation targeting only the secondary amine. The next aim was to build the second 2-aminoimidazole ring, which has been done by adding cyanamide in brine. Other solvents would have most likely resulted into the secondary chloride of the molecule to be replaced; also, having a load of chloride ions in solution is told to favour the desired side of the reaction step equilibrium. Following this was the bromination of the new aminoimidazole ring, as it provides a functional handle for the next fragment coupling a masked pyrrole synthesis; or more specifically, done with a pyrrole surrogate and masked by the amidine tautomer of the molecule. To complete the C-N linkage, an alkylation followed by a series of acid mediated methanol eliminations to obtain the aromatic heterocycle has been done; this has been conveniently achieved with the free acid functional group.

7 A hydrogenation using palladium acetate in a hydrogen atmosphere then reduced the azide groups to a pair of primary amines, and the following treatment of the amino acid system with EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)/HOBt (N-hydrobenzotriazole) formed a macrolactone, presumably favouring the nine-member ring over the ten; this macrocycle, named macro-palau amine by Baran was the key to his synthesis. Finally, it just needed the addition of acid, which promoted a transannular cyclisation between amide nitrogen N-14 and imine C-10 - and astoundingly, this particular reaction is selective for the trans-configured 5,5 -fused system, and thereby completes the synthesis of Palau amine.

8 We want to thank Dr Volker Schmidts of the TU Darmstadt Thielelab for his help and cooperation with us for this project. REFERENCES: Research Papers: The Total Synthesis of Palau amine, Published: 29 December 2009 by Phil S. Baran Prof. Dr. et.al. in Angewandte Chemie Weblink: E150E2434FAF6317DE82C911005F3B7B.f01t01?v=1&t=j3q00g75&s=3ed52a9128aef0 5873d70ef1196dbf51954dcf9f Die Jagd auf Palau amin, Published: 24 April 2007 von Matthias Köck, Achim Grube et.al. in Angewandte Chemie Weblink: Other Articles: http news.softpedia.com/news/excalibur-compound-finally-synthesized shtml Graphics: jpg