Alkaloid Total Synthesis

In the area of alkaloid total synthesis, we have two primary areas of interest.  The first centers on the development of an enantiospecific total synthesis of the Martinella alkaloids (Figure 1).  The second is centered on the discovery of new ways to functionalize imidazoles as a means to synthesize polyguanidine and related natural products (Figure 4).

Martinella Alkaloids:

The isolation and biological characterization of the Martinella alkaloids was reported by Witherup and coworkers at Merck Pharmaceuticals in 1995.   The unique tricyclic structure and the fact that these compounds represented the first naturally occurring examples of small molecule bradykinin receptor antagonists has aroused significant attention in these alkaloids.  It was our intention to develop a concise, enantiospecific approach to this class of natural products.  In the event, we have developed two complementary approaches to these natural products, both of which rely on a [3+2] azomethine ylide-alkene cycloaddition.

Our first approach involves introduction of the C2-sidechain after construction of the pyrrolo[3,2-c]quinoline.  This was accomplished via the in situ formation of an iminium ion and its subsequent trapping with an in situ generated copper acetylide.  Global deprotection and reduction of the triple bond provided the key tricyclic triamine.

The second approach, which is out lined retrosynthetically below, involves the incorporation of the C2-sidechain prior to cycloaddition.

Figure 2: Retrosynthetic Analysis of the Martinella Alkaloids

The synthesis along these lines has been completed, however, a discrepancy in the optical rotation of the natural product and the synthetic material is under investigation.

Imidazole Functionalization:

Imidazoles in various oxidation states are prevalent structural motifs in many natural products.  However, most methods for the preparation and functionalization of imidazoles rely on the use of relatively harsh reagents or reaction conditions, clearly the natural products illustrated below would not be compatible with many of these methods.  As a result, we have initiated a program to develop new methods to functionalize imidazoles.  We have chosen to explore three areas for investigation and are described in more detail below.

Diels-Alder Reactions of Vinylimidazoles:

The presence of a six-membered ring in numerous imidazole containing natural products, would appear to suggest that a Diels-Alder reaction could be an appropriate approach.  This reaction has been little explored with imidazoles.   We have now prepared a number of 4-vinylimidazoles through Stille cross-coupling reactions of the corresponding 4-iodoimidazole and evaluated their reactivity in the Diels-Alder reaction.  Under the appropriate reaction conditions, 4-vinylimidazoles function effectively as dienes providing the benzimidazole in the enamine (A) or aromatic form (B) depending on the reaction conditions and the nature of the protecting group.  

We have found that this reaction works quite well in an intramolecular sense, providing either an enamine adduct and/or the aromatized conger, depending on the conditions employed and the nature of the substituents, primarily on the dienophile.  We have also been exploring the chemistry of these cycloadducts with a view to developing total syntheses of ageliferin, axinellamine A and palau'amine.  We expect to complete a total synthesis of ageliferin in the very near future.

Ring-Closing Metathesis of Imidazoles

In connection with approaches to the glycoside inhibitor nagstatin and the cytotoxic oroidin-derived natural product agelastatin, we became interested in applying the ring-closing metathesis reaction to imidazoles.  After some extensive experimentation it was found that imidazolium salts would participate in metathesis with the second generation Grubbs' catalyst to provide fused bicyclic imidazoles.  We are now exploring application of this chemistry to a total synthesis of nagstatin and other imidazosugars.

Oxidative Rearrangements of Tetrahydrobenzimidazoles

In connection with the palau'amine project, we needed a method to rearrange the initial Diels-Alder adducts to the corresponding spiro fused imidazole system.  Our initial approach using electrophile induced rearrangements of the enamine adducts was unsuccessful in this aim, but did provide a useful method for introducing substituents into the 4-position in stereocontrolled fashion.  Ultimately, an alternate method involving the treatment of the aromatized systems with dimethyldioxirane provided a satisfactory solution, provided a reasonable approach to the DEF-ring system of palau'amine

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