Current Research Interests: Graduate Synthetic and Biological Chemistry Research at Colorado State University


Research Advisor:  Robert M. Williams

Studies Towards the Total Synthesis of
Antifungal Agents Ambiguine's E and F.




The ambiguines, Figure 1, are a series of seven tryptophan alkaloid derivatives isolated form three genera of blue-green algae; isolated and characterized by Moore, R. E. and Patterson, G. M.1,2  Ambiguines A through F were isolated from Fischerella ambigua and found to inhibit the growth of five fungi: Aspergillus oryzae, Candida albicans, Penicillium notatum, Saccharomyces cerevisiae, and Trichophyton mentagrophytes.2  These compounds are analogous to three other classes of isonitrile-containing indole alkaloids: hapalindoles, fischerindoles, and wetwitindolinones.3 

 

Figure 1:  Ambiguine Family of Indole-Derived Alkaloids.  Bold letters represents the specific ambiguine compound.

 

All four tryptophan derived alkaloids classes posses two similar, yet key, structural characteristics.  Synthetically, they are all derivatives of carvone linked through carbon 2 to carbon 3 of indole.  Order of cyclization upon indole, either at carbon 2 or 4 allows the four classes to be observed.  Biosynthetically, each of the alkaloids in the four classes can be derived from a deaminated tryptophan followed by isonitrile formation at the carboxylic acid, likely performed by a cytochromooxidase.  Cyclization onto geranyl pyrophosphate in conjunction with an electrophilic chloride affords the 3-(2-(S)-carvonyl)indole, which can be used as the metabolic precursor to derive the four indole-derived alkaloids in Blue-Green Algae. 

 

This project is dedicated to the syntheses and the elucidation of the biological syntheses of ambiguine E and F.  The synthesis of ambiguine E is the main focus of study at this point.  It is thought that the last intermediate in the synthesis of ambiguine E can also be used for the synthesis of ambiguine F, Figure 2.  From this precursor ambiguine E can be synthesized through the epoxidation by mCPBA.  The 3¡ alcohol, due to the coordination effects of mCPBA and alcohols, can direct facial selectivity for the epoxidation to afford the desired selectivity.  Synthesis of ambiguine F, at this intermediate, should be relatively trivial. 

Figure 2:  Synthesis of Ambiguine E and F from a common precursor.

 

                 

The key disconnections for the synthesis of ambiguine E are shown in Figure 3.  Of the 5 disconnection (DC) points, 1 & 5 are the subject of investigation thus far.  Three routes are being explored for DC 5 and 2 for DC 1.  DC 1 is the joining of carvone, or its functionalize counter part, to indole using chemistry development by Baran.4  Second route for the creation of this carbon-carbon bond is pallidium chemistry employed by Buchwald in similar systems.  See Scheme 1 for retrosynthesis routes attempted for this bond formation.

 

Figure 3:  Key disconnection points.  DC represents disconnection point and referred to as herein.

 

 

 

Scheme 1:  Retrosynthesis of S-carvone coupling to indole via copper radical chemistry and Pd(II) enolate chemistry.

 

In addition to the attempts at the coupling of indole to carvone, the reverse prenylated indole coupling with S-carvone was also attempted using Baran's copper (II) catalyzed radial coupling chemistry.

 

 

REFERENCES

1. Ambiguine Isonitriles, Fungicidal Hapalindole-Type Alkaloids from Three Genera of Blue-Green Algae Belonging to the Stogonemataceae.  Smitka, T. A., Moore, R. E. and Patterson, G. M.,  J. Org. Chem. 1992, 57, 857-861.

2.  Chang, C. W., Greger, H., and Hofer O.  (2000).  Naturally Occuring  isocyano/isothiocyanato and related compounds.  Springer-Verlag Wien, New York, New York.

3. Isolation of a Nitrile-Containing Indole Alkaloid from the Terrestrial Blue-Green Alga Hapalosiphon delicatulus.  Uber, U., Moore, R. E., and Patterson, G. M.,  J. Nat. Prod. 1998,  61, 1304-1306.

4. Direct Coupling of Indoles with Carbonyl Compounds: Short, Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and Fischerindole Alkaloid Families.  Baran, P. S. and Richter, J. M.  JACS, 2004, 126, 7450-7451.

5.  The Preparation and Some Unusual Chemistry of b-Allyl Derivatives of 9-Borabicyclo[3.3.1]nonane.  Kramer, G. W. and Brown, H. C.  J. Organometallic Chemistry, 1977, 132, 9-27.

6.  Short and Convergent Synthesis of Asterriquinone B1 and Demethylasterriquinone B1.  Tatsuta, K., Mukai, H., and Mitsumoto, K.  J. Antibiotics, 2001, 54(1), 105-108.

7.  Biosynthesis of Brevianamides A and B: In Search of the Biosynthetic Diels-Alder Construction.  Sanz-Cervera, J. F, Glinka, T. and Williams, R. M.  Tetrahedron. 1993, 49(38), 8471-8482.

8.  A Convenient Synthesis of 4-Ethyl-4-methyl-3-oxohexanenitrile via Pinacol Rearrangement.  Martinelli, M. J., Khau, V. V. and Horcher, L. M.  JOC.  1993, 58, 5546-5547.

9.  a.  Asymmetric Arylation of Ketone Enolates.  Ahman, J., Wolfe, J. P., Troutman, M. V., Palucki, M. and Buchwald, S. L.  JACS.  1998, 120, 1918-1919.

     b.  Highly Active and Selective Catalysts for the Formation of a-Aryl Ketones.  Fox, J. M., Huang, X., Chieffi, A., and Buchwald, S. L.  JACS.  2000, 122, 1360-1370.

10.  Rapid Access to the Welwitindolinone Alkaloid Skeleton by Cyclization of Indolecarboxaldehyde Substituted Cyclohexanones.  Baudoux, J., Blake, A. J. and Simpkins, N. S.  Org. Let.  ASAP Article.