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Projects

Natural Product Synthesis • Diels-Alder Approach to Biaryls •
Asymmetric Selenide Oxidation / [2,3] Sigmatropic Rearrangement (ASOS Reaction)

Natural Products Synthesis

Our research group has had a long-standing interest in the synthesis of complex, biological active natural products. Each target must possess a challenging structural motif(s) that is not well addressed by current synthetic strategy. In addition, we looking a broader question or interest presented by the molecule that can be uniquely addressed through synthesis. Selected examples of broader importance include potent cytotoxic activity against cancer cell lines, shellfish toxicity and antifungal activity for patients coping with AIDS. This combination allows us to push the frontiers of organic chemistry while addressing the larger scientific issues. Our efforts in this area are funded through the National Institutes of Health (GM63723). Current synthetic targets include:

	Azaspiracid-1: This target was discovered in 1998, by when several individuals became ill after consuming mussels harvested from Killary Harbor in Ireland. The initial structure of azaspiracid was proposed based on NMR studies; however, this original structure has been recently discredited and revised. Azaspiracid-1 is known to possess considerable toxicity in vitro with a lethal dose in mice of 0.2 mg / kg and has become a significant threat to the European shellfish industry. This threat is further complicated by the absence of a reliable source of authentic azaspiracid and the lack of an effective assay to test for the presence of azaspiracid in mussels. The challenging structural architecture (20 stereocenters, 9 rings, 3 spirocenters) further attracted our attention. We were particularly drawn to the northern bisspiroketal portion as controlling elements in bisspiroketal formation is an understudied area which is present in numerous natural products. Relevant References: Zhou, X.-T.; Lu, L.; Furkert, D. P.; Wells, C. E.; Carter, R. G. "Synthesis of the Southern FGHI Ring System of Azaspiracid-1 and Investigation into the Controlling Elements of C₂₈- and C₃₆-Ketalization." Angew. Chem. Int. Ed. 2006, 45, 7622-26. Zhou, X.-T.; Carter, R. G. "Synthesis of the C₁-C₂₆ Northern Portion of Azaspiracid-1: Kinetic versus Thermodynamic Bisspiroketal Formation." Angew. Chem. Int. Ed. 2006, 45, 1787-90. Zhou, X.-T.; Carter, R. G. "Synthesis of the ABCD and ABCDE Ring Systems of Azaspiracid-1." Chem. Commun. 2004, 2138-40. Carter, R. G.; Bourland, T. C.; Zhou, X.-T.; Gronemeyer, M. A. "Controlling Influences in Bisspiroketal Formation: Synthesis of the ABC Ring System of Azaspiracid." Tetrahedron 2003, 59, 8963-74. Carter, R. G.; Graves, D. E.; Gronemeyer, M. A., Tschumper, G. S. "2. Synthesis of ABC Ring System of Azaspiracid: A Systematic Study into the Effect of C₁₆ and C₁₇ Substitution on Bisspirocyclization." Org. Lett. 2002, 4, 2181-84. Carter, R. G.; Bourland, T. C.; Graves, D. E. "1. Synthesis of ABC Ring System of Azaspiracid: Effect of D Ring Truncation on Bisspirocyclization." Org. Lett. 2002, 4, 2177-79. Carter, R. G.; Graves, D. E. "Studies directed toward the total synthesis of azaspiracid. Construction of the C₁-C₁₉ carbon backbone and synthesis of the C₁₀, C₁₃ nonnatural transoidal bisspirocyclic ring system." Tetrahedron Lett. 2001, 42, 6035-39. Carter, R. G.; Weldon, D. J. "Studies Directed Toward the Total Synthesis of Azaspiracid: Stereoselective Construction of C₁-C₁₂ , C₁₃-C₁₉ and C₂₁-C₂₅ Fragments." Org. Lett. 2000, 2, 3913-16. Recent Presentations: Liang, L.; Carter. R. G. "Synthetic studies toward the southern portion of Azaspiracid-1." 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV; Abstract #132. Kuiper, D. L.; Carter. R. G. ""Improved synthesis of C13 to C19 fragment of azaspiracid-1: Exploiting matched / mismatched relationships in Sharpless dihydroxylation on chiral oxazolidinone-containing alkenes." 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV; Abstract #134. Zhou, X.-T..; Carter. R. G. "Azaspiracid-1: synthetic efforts and adventures." 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV;Abstract #183.
	Amphidinolide B₁: This natural product was isolated extremely small quantities in the U.S. Virgin Islands and again off the coast of Japan. The relative stereochemistry of amphidinolide was determined by X-ray crystal analysis and the absolute stereochemistry was established by degradation. This target is a member of a diverse family of natural products that are potent cytotoxic agents with impressive IC50 activity in a series of screens: L1210 murine leukemia cell line (0.14 ng/mL), human colon tumor HCT 116 cell line (0.12 µg/mL) and KB cancer cell line (4.2 ng/mL). The highly substituted diene and the dense area of stereocenters further attracted our attention Relevant References: Lu, L.; Zhang, W.; Carter, R. G. "Total Synthesis of Cytotoxic Macrolide Amphidinolide B₁ and the Proposed Structure of Amphidinolide B₂." J. Am. Chem. Soc. 2008, 130, 7253-55. Zhang, W.; Carter. R. G. "Synthetic Studies Toward Amphidinolide B₁: Synthesis of the C₉-C₂₆ Fragment." Org. Lett. 2005, 7, 4209-12. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. "Unified Synthesis of C₁₉-C₂₆ Subunits of Amphidinolides B₁, B₂ and B₃ by Exploiting Unexpected Stereochemical Differences in Crimmins’ and Evans’ Aldol Reactions." J. Org. Chem. 2004, 69, 2569-72.
	Selamectin: The milbemycin and related avermectin natural products have generated and continue to generate considerable interest due to their potent anti-parasitic activity. While considerable synthetic interest has been directed toward the total synthesis of milbemycin and avermectin, relatively little attention has been paid to a synthetic route that provides rapid access to a range of C25-modified avermectins (AVM’s). To date, efforts to modify the C25 position have focused on a directed fermentation and / or derivatization approaches. The controlling effects of spiroketal stereogenic centers on neighboring stereocenters drew our synthetic attention to this target.
	Himeradine and related alkaloids: A novel member of the Lycopodium family of alkaloids isolated from the slow growing club moss. This class of compounds have been used as an herbal remedy for a wide-range of ailments. Recent members of this family have shown promise in the treatment of memory loss. The unique pentacyclic structure of the western portion of himeradine attracted our interest in this class of compounds. Relevant References: Carlson, E. K.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter, R. G. "Improved Protocol for Asymmetric, Intramolecular Heteroatom Michael Addition Using Organocatalysis: Enantioselective Syntheses of Homoproline, Pelletierine and Homopipecolic Acid." J. Org. Chem. 2008, 73, 5155-58. Yang, H.; Carter, R. G.; Zakharov, L. N. "Enantioselective Total Synthesis of Lycopodine." J. Am. Chem. Soc. 2008, 130, 9238-39.

Vacidin A: Polyene macrolides are potent antifungal agents and the primary treatment for life-threatening infections. While these compounds are effective against fungal infections, they are prone to serious side effects such as low blood pressure, headaches, vomiting, inflammation of blood vessels and kidney damage. Not surprisingly, the most commonly prescribed member of this family, amphotericin B, has been given the nickname "amphoterrible." Renewed interest toward the development of alternate fungal treatments has been recently spurned by an increased number of reported incidents, primarily related to AIDS patients. Aromatic heptaenes represent an important subclass of the polyene macrolide antibiotics. Many of these aromatic-containing macrolides have shown increased biological activity versus the more commonly employed non-aromatic polyenes such as amphotericin B. One particularly intriguing member of the aromatic heptaene family is vacidin A. Vacidin has shown significant potency for initiation of potassium release with an EK-50 of 0.025 µM (versus 0.5 µM for amphotericin B). The polyol portion of the natural product provides a nice platform for the development of novel approaches for its construction.

Diels-Alder Approach to Biaryls

	As a logical extension to our philosophy concerning target selection in natural product synthesis, our interest in the synthesis of important structural motifs not well-addressed by current methods extends to non-natural products as well. In particular, we have been drawn to the synthesis of orthogonally functionalized, highly substituted biaryls. This functionality is present as ligands in metal catalysis and as a pharmacaphore for numerous medicinally-relavent structures. While numerous advances in this field have been made using metal-catalyzed cross couplings, limitations to the cross-coupling approach exist. We have developed an efficient Diels-Alder based approach for the construction of the biaryl compounds. One major advantage to the approach is the ability to construct orthogonally functionalized substitution patterns on the aromatic rings - including halogenation and tetra-ortho-substitution (often considered the holy grail of biaryl synthesis). Our efforts in this area are funded through the National Science Foundation (CHE-0549884). Relevant References: Ashburn, B. O.; Carter R. G. “"Diels-Alder Approach to Poly-substituted Biaryls: Rapid Entry to Tri- and Tetra-ortho-substituted Phosphorus-Containing Biaryls." Angew. Chem. Int. Ed. 2006, 45, 6737-41. Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. "Diels-Alder Approach for the Construction of Halogenated, ortho-Nitro Biaryl Templates and Application to the Total Synthesis of anti-HIV Agent Siamenol." J. Org. Chem. 2007, 72, 9857-65. Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. "Synthesis of Tetra-ortho-Substituted, Phosphorus-Containing and Carbonyl-Containing Biaryls Utilizing a Diels-Alder Approach." J. Am. Chem. Soc. 2007, 129, 9109-16. Ashburn, B. O.; Carter, R. G. "Diels-Alder Approach to Tetra-ortho-Substituted Biaryls Employing Propargylic Tertiary Alcohols as Dienophiles." J. Org. Chem. 2007, 72, 10220-23. Ashburn, B. O.; Carter, R. G. "Diels–Alder approach to biaryls (DAB): Importance of the ortho-nitro moiety in the [4 + 2] cycloaddition." Org. Biomol. Chem. 2008, 6, 255-57. Ashburn, B. O; Rathbone, L. K.; Camp, E. H; Carter, R. G. "A Diels-Alder Approach to Biaryls (DAB): Synthesis of the Western Portion of TMC-95." Tetrahedron 2008, 64, 856-65. Perkins, J. R.; Carter, R. G. "Synthesis of Programmable Tetra-ortho Substituted Biaryl Compounds Using Diels-Alder Cycloadditions / Cycloreversions of Di-Substituted Alkynyl Stannanes." J. Am. Chem. Soc. 2008, 130, 3290-91. Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. "Diels-Alder Approach to Biaryls (DAB): Elucidation of Competing Tandem [2+2] Cycloaddition / [1,3] Sigmatropic Shift Pathway." J. Org. Chem. 2008, in press Recent Presentations: Ashburn, B. O.; Carter. R. G. "Diels-Alder approach to polysubstituted biaryls." 234^th American Chemical Society National Meeting (August 19-23) - Boston, MA; ORG-99. Naffziger, M. R.; Ashburn, B. O.; Carter, R. G. “Rapid synthesis and application of highly functionalized biphenyls via [4+2] cycloaddition.” 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV; Abstract #51. Ashburn, B. O.; Carter. R. G. "A Diels-Alder Approach to Tetra-ortho-Substituted Phosphorus-Containing Biaryls." 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV; Abstract #140. Perkins, J. R.; Ashburn, B. O.; Carter, R. G. “Synthesis and application of a Diels-Alder approach to 2, 2', 3-functionalized biaryls templates.” 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV; Abstract #202.
	Application of Biaryl Technology – Catalyst Development: Biaryl compounds have served as valuable ligands in metal catalysis for a wide range of applications including palladium couplings, aldol reaction and carbonyl reduction. As our Diels-Alder approach to biaryls provides access to compounds not previously available via traditional methods, we are actively exploring their use in metal catalysis. Relevant References: Ashburn, B. O.; Carter R. G. “"Diels-Alder Approach to Poly-substituted Biaryls: Rapid Entry to Tri- and Tetra-ortho-substituted Phosphorus-Containing Biaryls." Angew. Chem. Int. Ed. 2006, 45, 6737-41. Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. "Synthesis of Tetra-ortho-Substituted, Phosphorus-Containing and Carbonyl-Containing Biaryls Utilizing a Diels-Alder Approach." J. Am. Chem. Soc. 2007, 129, 9109-16.
	Application of Biaryl Technology – Studying the Fundamental Physical Properties: In addition to these avenues, our laboratory has initiated already a collaboration with Professor Wei Kong (Department of Chemistry, Oregon State University) to address some challenging and long-standing questions in experimental physical chemistry. A supporting letter is attached with this proposal from Professor Kong. The central theme of Professor Kong’s research program is spectroscopy and dynamics of excited electronic states and cationic states of non-volatile or semi-volatile compounds. Professor Kong’s group specializes in the study of both (1) long-lived (longer than picoseconds) excited states that demonstrate resolvable vibronic structures and (2) short-lived states that only exhibit broad absorption features. A unique measurement developed in Professor Kong’s laboratory is the determination of the direction of the transition dipole using polarization spectroscopy. Her method is independent of the dynamics of the upper state, and it is therefore universal regardless of the lifetime of the excited state. For long-lived systems, additional information can be obtained from vibrational analysis, particularly on the changes in the molecular frame upon electronic excitation and ionization. Using this method, her research group has investigated the photophysics and photochemistry of substituted aromatics such as chloropyrimidines, aminobenzoic acids and nitroaromatics. The application of this work to conjugation and through-space effects on biaryl compounds would appear to be a natural extension for Professor Kong’s research. The availability of sequentially substituted species would provide an ideal situation to further her studies on the effect of different substituents and the interactions among the substituents during electronic excitation and further ionization.
	Application of Biaryl Technology – TMC-95: This compound displayed nanomolar (5.4 nM) chyrotrypsin-like inhibitory activity of the 20S proteasome, which helps to regulate immune response, the cell cycle, and cell differentiation. This compound has shown reduced trpysin-like and peptidylglutamyl-peptide hydrolyzing activity of the 20S proteasome (200 and 60 nM respectively) and no inhibition of m-calpain, cathepsin L and trypsin (up to 30 µM). This activity data is indicative of a highly selective inhibitor for the 20S proteasome, thereby potentially leading to new anti-tumor and autoimmune treatments. The western biaryl portion of the molecule provided the opportunity for the application of our Diels-Alder approach to this functionality. Relevant References: Ashburn, B. O; Rathbone, L. K.; Camp, E. H; Carter, R. G. "A Diels-Alder Approach to Biaryls (DAB): Synthesis of the Western Portion of TMC-95." Tetrahedron 2008, 64, 856-65. Recent Presentations: Rathbone, L. K.; Ashburn, B. O.; Camp, E. H.; Carter. R. G. "Synthetic efforts toward TMC-95: A Diels-Alder approach to the western portion." 61^st Northwest Regional American Chemical Society Meeting (June 25-28, 2006) - Reno, NV; Abstract #203.
	Application of Biaryl Technology – Siamenol: Another application of our Diels-Alder based approach to biaryl synthesis can be found in the construction of carbazole-containing natural products. Siamenol was isolated from the Murraya siamensis L. shrub found in Southeast Asia and exhibits moderate anti-HIV activity in the XTT-tetrazolium assay (EC50 = 2.6 µg / mL). Carbazoles are readily available from ortho-nitro biaryl compounds through a Cadogan reductive cyclization. Relevant References: Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. "Diels-Alder Approach for the Construction of Halogenated, ortho-Nitro Biaryl Templates and Application to the Total Synthesis of anti-HIV Agent Siamenol." J. Org. Chem. 2007, 72, 9857-65.

Asymmetric Selenide Oxidation / [2,3] Sigmatropic Rearrangement (ASOS Reaction):

The ability to access enantiomerically enriched allylic alcohols is an important tool for the synthetic chemist due to their prevalence in natural products as well as their utility as synthons. While traditional methods have proven useful in the synthesis of the desired functionality, there are limitations to their effectiveness. For example, 3° allylic alcohols and alpha-chiral 2° allylic alcohols are often difficult to access using traditional approaches. It is the latter challenge that brought our attention to the problem during our current synthetic efforts toward the complex spirotoxin azaspiracid-1. One potential alternative to traditional methods for the construction of chiral allylic alcohols is an asymmetric selenide oxidation with in situ [2,3] sigmatropic rearrangement (ASOS Reaction). Although scattered reports of ASOS reactions have appeared in the literature, an efficient and general solution has not been reported. Our laboratory is actively developing an efficient, metal-catalyzed method for the ASOS reaction. We reported the first catalytic method for oxidation of aryl, allylic selenides with sigmatropic rearrangement using as little as 10 mol % vanadyl (IV) acetylacetonate (VO(acac)2). We have also developed a vanadium-catalyzed method for the synthesis of chiral 2° allylic alcohols in up 85:15 d.r. using a chiral oxazole template. This project is funded in part through the National Institutes of Health (GM63723).

Relevant References:

Bourland, T. C.; Carter, R. G.; Yokochi, A. F. T. "Vanadium-catalyzed selenide oxidation with in situ [2,3] sigmatropic rearrangement (SOS reaction): Scope and asymmetric applications." Org. Biomol. Chem. 2004, 2, 1315-29.

Carter, R. G.; Bourland, T. C. "The first vanadium-catalyzed oxidation of aryl allylic selenides with in situ [2,3] sigmatropic rearrangement." Chem. Commun. 2000, 2031-32.