2.
Development of new efficient methods for organic synthesis
We have been developing new carbonylations
and carbocyclizations as efficient and useful methods
in organic synthesis. We have discovered silylformylation
of alkynes and silylcarbocyclizations (SiCaCs) of alkenynes, dialkynes, and alkynals which are
catalyzed by Rh and Rh-Co
clusters or bimetallic complexes.
Further work in this area has led to cascade reactions using either triynes (SiCaT) or enediynes (COCaT) as substrates.
The products of these reactions provide various versatile synthetic building
blocks for alkaloids, terpenes, steroids, fluoroamino acids, etc. We are also looking into the
mechanism of these catalytic reactions based on organometallic
chemistry. These catalytic reactions have a high potential as future industrial
processes.
I. Cyclohydrocarbonylations
Total syntheses of enantiopure
heterocyclic natural products using cyclohydrocarbonylation
in the key step have been accomplished. Cyclohydrocarbonylation
reaction of alkenamides, alkenamines
or alkenols catalyzed by transition metals proceeds
via hydroformylation followed by condensation of the
resulting aldehyde with amide, amine or alcohol
moiety. This reaction provides efficient routes to various nitrogen and oxygen heterocycles.
A.
Synthesis of azabicycloamino acids
Azabicyclo[X.Y.0]alkane amino acids,
as conformationally restricted dipeptide
surrogates, have recently been recognized as important structural backbones for
the design of peptides and peptidomimetics for enzyme
inhibitors and receptor antagonists or agonists. We have succeeded in
developing a highly stereospecific and extremely diastereoselective methods for the synthesis of 1-azabicyclo[4.4.0]decane amino
acids using Rh-BIPHEPHOS-catalyzed cyclohydrocarbonylation.
The scope of this process has been extended to the
formation of 1-azabicyclo[4.3.0]-, and
1-azabicyclo[5.4.0]-alkane amino acids systems. These bicyclo-b-turn dipeptide motifs are very
useful for the development of efficient enzyme inhibitors. 1-azabicyclo[5.4.0]-,
and 1-azabicyclo[5.3.0]-alkane amino acids skeletons
have served as the structural backbone of
many therapeutic molecules.
B. Application of CHC to the Synthesis of Enantiopure Homokainic acids.
Glutamate plays an important role in memory and
learning process and neuronal degradation in the central nervous system of
mammalian. At present it is known that
the metabotropic Glutamate Receptors (mGluRs) are involved in synaptic plasticity, which
is important for the formation of memory and learning. In order to explore and
distinguish the role of different kind of receptors, it is necessary to prepare
and use different agonists to test their pharmacological activity.
Kainic acid, a naturally occurring cyclic glutamate
congener, is known to possess a powerful neuroexcitatory
effect on GluRs, but its neurotoxicity
has prohibited the pharmacological applications. Accordingly, we are currently
synthesizing homokainic acids in enantiopure
form by using the cyclohydrocarbonylation methods and
investigate their neuroexcitatory activity, receptor
specificity, and toxicity in collaboration with Dr. Andre Mann (Laboratory of Pharmacochemistry and Cellular Communication, Faculty of
Pharmacy,
II.
Cascade Carbocyclizations.
In
the course of our investigation into the development of silicon-initiated cyclization processes, intramolecular
silylformylation, silylcyclocarbonylation
(SiCCa), silylcarbocyclization (SiCaC), silylcarbobicyclization (SiCaB), and silylcarbotricyclization
(SiCaT) have been
discovered. The development of cascade reactions has been an active area of
research in this group. Work in this area has led to the discovery of novel
catalytic carbocyclization reactions. The reaction of
triynes has allowed for the rapid construction of
5-6-5, 6-6-5, and 6-6-6 fused tricyclic skeletons.
Under
optimized conditions, the reaction of enediynes allows the very
efficient formation of 5-7-5 ring systems with
incorporation of a carbonyl moiety. This novel silicon-initiated carbonylative carbotricyclization
(CO-SiCAT) of unsymmetrical enediynes
promoted by rhodium-catalyst has been developed and its scope has been
successfully expanded for the rapid construction of various 5-7-5 tricyclic ring systems.
During the course of our investigation, we
serendipitously discovered a novel intramolecular [2
+ 2 + 2 + 1 ]-carbonylative cycloaddition reaction of enediynes
catalyzed by rhodium complex. This carbonylative
process has similarly proven to be efficient for the construction of 5-7-5
fused tricyclic compounds, starting from substrates
having substituents on the terminal acetylene
moiety. It is noteworthy that these
substrates usually failed to form the desired 5-7-5 tricyclic
compounds under the general CO-SiCaT conditions. The
scope of this reaction has been successfully applied to a broad range of
substrates having different functionalities.
The CO-SiCaT and
[2+2+2+2+1]-cycloaddition reactions proceed through
two distinctive catalytic cycles, the later involving the formation of a metallacycle.
We are currently working on expanding the scope of
these efficient catalytic processes for the synthesis of 5-7-6, 5-7-6-6 fused polycyclic
structures. 5-7-5 and 5-7-6 tricyclic ring systems
are structural skeletons that are found in many bioactive natural products.
Application of these higher order carbocyclization
processes could provide a rapid and powerful method for the construction of
complex polycyclic skeletons that serve as key-step for the synthesis of
natural products.
III.
Novel ligand synthesis for Asymmetric Catalysis.
Recently,
chiral monodentate
phosphorus ligands have been attracting increasing
interest because of their structural simplicity as well as excellent efficiency
in a variety of catalytic asymmetric transformations. The emergence of chiral monodentate ligands comes after three decades of predominance by chiral bidentate ligands with C2-symmetry, which was often considered as a
prerequisite for efficient asymmetric induction. Currently, the simplicity and
ease of the synthesis and structural modification of chiral
monodentate ligands can be
considered as highly advantageous because these characteristics fit very well
to a combinatorial approach to finding the most suitable ligand
for a particular catalytic asymmetric transformation.
We have been developing
a new class of chiral monodentate
phosphite and phosphoramidite
ligands derived from readily accessible enantiopure axially chiral biphenol units
(Fig. 1).
One of the
salient features of these novel monodentate
phosphorus ligands is their fine-tuning capability
through modifications of the R1, R2, and R3
groups. This feature is of critical importance because it
allows a combinatorial approach to finding the most efficient ligand for a specific reaction or process.
These ligands have
permitted to achieve high catalytic activity as well as enantioselectivity
in various catalytic asymmetric transformations.
Chiral monophosphite
ligands
Chiral monophosphite ligands have been applied to the Rh-catalyzed
asymmetric hydrogenation of dimethyl itaconate.
Z. Hua, V. C. Vassar and
Rh-catalyzed
hydroformylation of allyl
cyanide
A library of new monophosphoramidite
ligands have been developed and applied to the
asymmetric Rh-catalyzed hydroformylation
of allyl cyanide and Cu-catalyzed asymmetric
conjugate addition to a,b-unsaturated
systems.
Z. Hua, V. C. Vassar, H. Choi, and I. Ojima, Proc.
Nat. Acad. Sci. 101,
5411-5416 (2004).
Cu-catalyzed conjugate addition of diethyl zinc to a,b-unsaturated
cyclic ketones
In the catalytic reactions
mentioned above, the critical rule of the nature of the R2 substituent of the biphenol
moiety of the ligand has been clearly characterized.
Pd-catalyzed allylic alkylation :
Synthesis of enantiopure (+)-Lycorane
A short total synthesis of enantiopure (+)-g- Lycorane has recently
been reported. The key-step of this synthesis involved the Pd-catalyzed
asymmetric allylic alkylation
of meso-dibenzoate 1 for which we have
been applying our library of chiral monophosphoramidite ligands.
Optimization of a lead ligand through modification of
the chiral amine moiety of the ligands
has permitted to achieved up to 99.7% ee.2
Having achieved excellent enantioselectivity,
the total synthesis of enantiopure (+)-g-Lycorane has been
completed in 4 steps and 41% overall yield from 1.
Catalytic reactions using enantiomerically pure phosphorus ligands
bearing perfluoroalkyl tethers have been explored. Ligands with high fluorine content can be used in reactions using either scCO2 or a fluorous biphase system
(FBS). Fluorinated ligands
with lower fluorine content can be recovered from reactions (using normal
organic solvents) by separation using fluorinated silica gel.
Phone: (631)632-7947 or
(631)632-7890 (Patricia Marinaccio, Project Staff
Assistant)
Fax: (631)632-7942
Email: iojima@notes.cc.sunysb.edu