Palau'amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here we report the total synthesis of palau'amine characterized by the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N–N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation) and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The synthetic palau'amine is confirmed to exhibit excellent immunosuppressive activity. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity.

The pyrrole-imidazole alkaloids, which comprise a large family of natural products, 1 have received a great deal of attention due to their potent biological activities and tremendous structural diversity. Palau'amine (1a) was originally isolated from a sponge, Stylotella agminata, in 1993 by Scheuer as a novel class of the pyrrole-imidazole alkaloid. 2 Since the initial disclosure of its proposed structure (1a), palau'amine (1) has been an attractive synthetic target because of its intriguing molecular architecture and significant biological properties such as antifungal, antitumor, and immunosuppressive activities. However, according to several groups, the originally proposed structure 1a was recently revised as 1b, which possesses the indicated the trans-D/E ring junction and the β-chlorine substituent. 3, 5e, 5gThe noteworthy structural features of palau'amine include: two guanidine moieties, fused polycyclic system with a spiro cycle, complex all carbon substituted cyclopentane ring, nitrogen-substituted quaternary carbon center, and eight contiguous stereogenic centers. Not surprisingly, many attempts to synthesize palau'amine and related natural products have been reported so far, 4, 5 and the first total synthesis of the related natural products axinellamines A and B (2) was recently accomplished. 6 However, a total synthesis of palau'amine itself has not yet been reported. Efficient construction of the complex cyclopentane core with the correct stereochemistry at each carbon center, including a quaternary carbon center, is definitely one of the most difficult synthetic challenges for the synthesis of palau' amine. Herein, we describe an efficient synthesis of the cyclopentane core of palau'amine by the application of a highly efficient novel Hg(OTf) 2 -catalyzed reaction developed in our laboratory. 7 In 2008, the Hg (OTf) 2 -catalyzed alkyne cyclization reactions were expanded to the alkene cyclization reactions by using allylic alcohol or vinyl methyl ether substrates that, after cyclization, undergo a smooth proto-demercuration to give the cyclized products and the regenerated Hg Correspondence to: Kosuke Namba, namba@mail.sci.hokudai.ac.jp. Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author.)) NIH Public Access Author ManuscriptChemistry. Author manuscript; available in PMC 2010 March 12. Published in final edited form as:Chemistry. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript (OTf) 2 catalyst. 8 For instance, Hg(OTf) 2 -catalyzed cyclization of N-tosylanilino allylic alcohol 3 provided 2-vinylindolines 4 in high yield (Scheme 1). 8b Thus, the cyclization of cyclopentylidene alcohol 5 is expected to give 6 by constructing a quaternary carbon center that corresponds to the C16 of palau'amine. However, the catalytic cyclization of amide 5 is also possible to give the O-cyclized product 7 in preference to the N-cyclized product 6. Indeed, we confirmed this was the case. The conventional methods for N-selectiv...

Palau amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and signi cant immunosuppressive activity. Here, we report the total synthesis of palau amine characterized by the Hg(OTf) 2 catalyzed construction of tetra substituted carbon center at the C16 position and the construction of an ABDE tetracyclic ring core including a trans bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D ring formation), and the condensation of pyrrole with methyl ester (B ring formation) in a single step. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity.