Special Topic Presentation: Synthesis of Bis-piperidine Alkaloids Caroline Braun Townsend Group Meeting July 21, 2015

Marine Natural Products Equated with the term secondary metabolites A substance without a (known) direct role in the function of the organism that produces it Compounds of great structural variety Isolated from marine invertebrates J. Nat. Prod. 1989, 52, 1189.

Marine Sponges Rich source of pharmacologically active compounds Primitive organisms with simple internal structure Secondary metabolites may deter potential predators or may inhibit growth of other organisms Produce a variety of natural product structural classes Curr. Pharm. Biotechnol. 2009, 10, 86. Nat. Prod. Rep. 1984, 1, 551. Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

Alkaloids Primarily from plants Complex, variable structures Contains at least one basic nitrogen in a heterocyclic ring Alkaloid – “alkali-like” React with acids to form salts Classified by their structure i.e. indole, quinoline, pyrrolidines, pyridines, tropanes Also can be classified by their producing biological system or biogenetic pathway Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010. http://www.britannica.com/science/alkaloid

Bis-pyridine Macrocycles A subset of marine sponge alkaloids with a common biosynthetic precursor Exhibited biological activity Cytotoxicity, antifungal and antiviral activity, and protein kinase C inhibition Composed of 3-alkylpyridine or 3-alkylpiperidine units Org. Prep. Proced. Int. 1998, 30, 1. Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

3-Alkylpiperidine Alkaloids Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

Manzamine A Hydrochloride Reported by Higa, Jefford and co-workers in 1986 Isolated from a marine sponge (Haliclona sp.) Manzamo, Okinawa in April 1985 Inhibited growth of P388 mouse leukemia cells (IC50 of 0.07 μg/mL) J. Am. Chem. Soc. 1986, 108, 6404. Org. Prep. Proced. Int. 1998, 30, 1.

Biosynthetic Pathway “Moreover, its provenance is problematical as there appears to be no obvious biogenetic path” “…the provenance of manzamines B and C, like that of A, is biogenetically problematical” J. Am. Chem. Soc. 1986, 108, 6404. Tetrahedron Lett. 1987, 28, 5493.

Proposed Biosynthetic Pathway Proposed in 1992 by Baldwin and Whitehead 3 units: tryptophan, acrolein, and a dialdehyde Tetrahedron Lett. 1992, 33, 2059.

Proposed Biosynthetic Pathway Biogenetic precursor: bis-dihydropyridine macrocycle The reductive coupling product of two acrolein and two dialdehydes (C10 units) with two ammonias Reveals a “hidden symmetry” Tetrahedron Lett. 1992, 33, 2059. Org. Prep. Proced. Int. 1998, 30, 1.

Org. Prep. Proced. Int. 1998, 30, 1.

Proposed Biosynthetic Pathway Tetrahedron Lett. 1992, 33, 2059. Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010

A Modified Proposal Proposed by Marazano and co-workers in 1998 5-amino-2,4-pentadienal derivatives as precursors for pyridinium salts Condensation of malondialdehyde and long chain aminodialdehydes J. Am. Chem. Soc. 1998, 120, 8026. Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010

Marazano’s Modification Substitute malondialdehyde for acrolein in the condensation step with ammonia and the dialdehyde unit to produce macrocycle J. Am. Chem. Soc. 1998, 120, 8026. Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010

Biosynthesis of Related Alkaloids Keramamine C and Keramiphidin C Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010

Biosynthesis of Related Alkaloids Haliclamines and Cyclostellettamines Proposed building block of this subset of alkaloids Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010

Biosynthesis of Related Alkaloids Ingenamines and Ingamines Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

Biosynthesis of Related Alkaloids Sarain A Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

Halicyclamine A Reported in 1994 by Crews and co-workers Isolated from marine sponge (Haliclona sp.) in Biak, Indonesia Tetracyclic 3-alkylpiperidine alkaloid 3,4-linked bis-piperidine core attached to two macrocycles J. Org. Chem. 1994, 59, 3253 Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

Synthesis of Manzamine A J. Am. Chem. Soc. 1998, 120, 6425.

Synthesis of Haliclonacyclamine C >16 tetracyclic alkaloids isolated from sponges Haliclonacyclamines A-F are the largest subgroup Exhibit cyctotoxic, antibiotic and antifungal activity Differ in the # and location of cis olefins, and in the relative stereochem. within the bis-piperidine core Angew. Chem. Int. Ed. 2010, 49, 1599.

Synthesis of Haliclonacyclamine C Angew. Chem. Int. Ed. 2010, 49, 1599.

Synthesis of Haliclonacyclamine C Angew. Chem. Int. Ed. 2010, 49, 1599.

Synthesis of Haliclonacyclamine C Angew. Chem. Int. Ed. 2010, 49, 1599.

Synthesis of Haliclonacyclamine C Angew. Chem. Int. Ed. 2010, 49, 1599.

Picture References Slide 3 http://www.spongeguide.org/speciesinfo.php?species=14 http://flowergarden.noaa.gov/image_library/sponges/branchingtubesponge1elh.jpg