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

2. 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.

3. 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.

4. 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.

5. 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.

6. 3-Alkylpiperidine Alkaloids
Smith, B. J. “Total Synthesis of Haliclonacyclamine C.” Thesis. Vanderbilt University, 2010.

7. 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.

8. 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.

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

10. 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.

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

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

13. 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

14. 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

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

16. 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

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

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

19. 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.

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

22. 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.

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

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

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

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

28. Picture References
Slide 3