|
|
 |
|
 |
|
Projects
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." 61st 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." 61st 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." 61st 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.
|

|
Amphidinolides C and
F: These macrolides were isolated by Kobayashi and
co-workers from the dinoflagellate Amphidinium sp. from within the
Okinawan flatworm Amphiscolops sp. in small amounts (0.0015% wet
weight). The absolute stereochemistry was later determined
by Kobayashi. Like many of its amphidinolide brethren,
amphidinolide C possesses potent cytotoxic activity against various
cancer cell lines. In addition to the potent biological activity,
the molecular assemblage of this 25-membered macrocycle is equally
impressive – two separate trans-fused tetrahydrofuran rings, the
interesting C15,C18 gamma-dicarbonyl moiety and
the C29 bisallylic alcohol sidearm.
Relevant References:
- Mahapatra, S..; Carter, R. G. "Efficient
Synthesis of
the C7-C20 Subunit of Amphidinolides C and F." Org. Biomol. Chem. 2009, 7, 4582-4585.
Relevant
Presentations:
- Mahapatra, S.; Carter, R.
G. "Synthetic Studies toward Amphidinolide C." 237th National Meeting
of the American Chemical Society, Salt Lake City, UT, ORGN-530.
|

|
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. C.; 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.
Relevant Presentations:
- Collett, N. D.; Carter, R.
G. "Progress toward the synthesis of himeradine A." 237th National
Meeting of the American Chemical Society, Salt Lake City, UT, ORGN-107.
- Carlson, E. C.; Carter, R
.G. "Asymmetric, intramolecular heteroatom Michael addition using
organocatalysis: Progress towards the synthesis of Cermizine D." 237th
National Meeting of the American Chemical Society, Salt Lake City, UT,
ORGN-297.
|

|
Aconitine: This densely
functionalized natural product has been known for over 100 years,
but its total synthesis remains an elusive goal. Aconitine
possesses potent analgesic and antipyretic activity. Only limited
synthetic work has been directed towards this compound – likely due to
the challenging quaternary center at C11, the presence of 15
stereogenic centers and the highly oxidized skeleton.
|
|
|
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-0848704).
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, 73, 7305-09.
Recent Presentations:
- Ashburn, B. O.; Carter. R. G. "Diels-Alder approach
to polysubstituted biaryls." 234th
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.” 61st
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." 61st
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.” 61st
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." 61st
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.
|
Hua Cat: a p-Dodecylphenylsulfonylamide-Based
Proline Derivative for Practical Solutions to Organocatalysis
|
Since the early days of enantioselective Robinson
annulations facilitated by proline, organocatalysis has garnered
the attention of the synthetic community. The explosion of
research in the area in recent years has been fueled by the general
mildness of the conditions, the relative ease of execution and the wide
variety of chemical transformations that are possible.
Proline has attracted particular attention in this area – particularly
in the role of facilitating aldol reactions. Despite proline’s
utility in facilitating an organocatalyzed process, it is not without
its shortcomings. Consequently, a range of proline mimetics
has been created to provide an improved reactivity profile. It is
important to note that the vast majority of organocatalyzed processes
involving proline or proline surrogates employ polar solvents such as
DMF and DMSO. While these solvents are commonly used in research
laboratories, their polarity creates added hurdles for product
isolation. Non-polar solvents have industrial advantages by providing
good phase splits with water and are more easily recycled on
scale. We were also cognizant of the need for any proline mimetic
to be readily accessible for inexpensive starting materials in both
enantiomeric forms. Consequently, we have recently developed a
practical solution for these challenges: a sulfonamide-based
catalyst which we have nicknamed "Hua Cat." This catalyst
has shown remarkable activity in a range of transformations - providing
some of the highest enantioselectivities and diastereoselectivities for
many transformations. This work is supported through the Oregon State
University Venture Fund.
Relevant References:
- Yang, H.; Carter, R. G.
"N-(p-dodecylphenylsulfonyl)-2-Pyrrolidinecarboxamide: A Practical
Proline Mimetic for Facilitating Enantioselective Aldol Reactions." Org. Lett. 2008, 10, 4649-52.
- Yang, H. Carter, R. G. "Enantioselective Mannich
Reactions using the Practical Proline Mimetic N-(p-dodecylphenylsulfonyl)-2-Pyrrolidinecarboxamide."
J. Org. Chem. 2009, 74, 2246-49.
- Yang, H. Carter, R. G. "Asymmetric
Construction of
Nitrogen-Containing, [2.2.2] Bicyclic Scaffolds Using N-(p-Dodecylphenylsulfonyl)-2-Pyrrolidinecarboxamide."
J. Org. Chem. 2009, 74, 5151-5156.
|
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.
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.
|
|
|