New Synthetic Methods and Asymmetric Synthesis

The Ojima Laboratory has been exploring and developing new methodologies, especially based on catalytic organic transformations, including enantioselective processes, cyclohydrocarbonylations and higher order cycloadditions and carbocyclizations, which provide the basis for the efficient syntheses of biologically active substances of medicinal interest, such as those anticancer and antibacterial agents mentioned above. Mechanisms of these reactions are also studied based on spectroscopic methods including advanced NMR techniques, computer-assisted molecular modeling, and X-ray crystallography.

Biphenol-based Monodentate Phosphorous Ligands

  • Possess 3 different modifiable substituents for fine-tuning capabilities.
  • R1 substituent can be modified for catalyst recovery.
  • R2 and R3 substituents are important for enantioselectivity, reactivity, regioselectivity, etc.

asymm1

Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831-3834

Choi, H.; Hua, Z.; Ojima, I. Org. Lett. 2004, 6, 2689-2691

Chapsal, B. D.; Ojima, I., Org. Lett. 2006, 8, (7), 1395-1398

Shi, C.; Ojima, I., Tetrahedron 2007, 63(35), 8563-8570

 

Applications to Asymmetric Reactions:

Asymmetric Hydrogenation

asymm2

Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831-3834

Asymmetric Conjugate Addition

asymm3

asymm4

Choi, H.; Hua, Z.; Ojima, I. Org. Lett. 2004, 6, 2689-2691

Asymmetric Hydroformylation

asymm5

Hua, Z.; Vassar, V. C.; Choi, H.; Ojima, I. PNAS 2004, 101, 5411-5416

Asymmetric Allylic Alkylation

asymm6

Chapsal, B. D.; Ojima, I., Org. Lett. 2006, 8, (7), 1395-1398

Asymmetric Allylic Amination

asymm7

Shi, C.; Ojima, I., Tetrahedron 2007, 63(35), 8563-8570

asymm7

Shi, C.; Chien, C.-W.; Ojima, I. Chem. Asian J. 2011, 6, 674-680

1-Vinyl-6,8-dimethoxytetrahydroisoquinoline 4 and 1-vinyl-5,6,7-trimethoxytetrahydroisoquinoline 6 with >90% ee by means of Pd-catalyzed intramolecular asymmetric allylic amination reactions, using MPN and BOP ligands.

asymm8

Chien, C.-W.; Shi, C.; Lin, C. -F.; Ojima, I., Tetrahedron 2011, In Press

Cyclohydrocarbonylation

Total syntheses of enantiopure heterocyclic natural products using cyclohydrocarbonylation in the key step have been accomplished. Cyclohydrocarbonylation reactions 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.

CHC1

Ojima, I.; Vidal, E.S. J. Org. Chem. 1998, 63, 7999-8003

The synthesis of pipecolic acid derivatives from allylglycinates has been accomplished via the CHC reaction. The CHC reaction begins with an extremely linear and selective hydroformylation, followed by an intramolecular attack of the nitrogen atom on the electrophilic carbonyl carbon. Depending on the nature of the solvent, the N-acyliminium ion intermediate species may then undergo nucleophilic attack or elimination.

CHC2Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60 (22), 7078-7079.

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 highly stereospecific and extremely diastereoselective methods for the synthesis of 1-azabicyclo[4.4.0]decane amino acids using Rh-BIPHEPHOS-catalyzed cyclohydrocarbonylation.

CHC3Chiou, W.; Mizutani, N.; Ojima, I. Journal of Organic Chemistry 2007, 72 (6), 1871-1882

The CHC reaction has recently been utilized as a key step in the synthesis of the potent antitumor natural alkaloid, crispene-A.

CHC4

Chiou, W.; Lin, G.; Hsu, C.; Chaterpaul, S. J.; Ojima, I.. Organic Letters 2009, 11 (12), 2659-2662

 

Cascade Carbocyclizations and Higher Order Cycloadditions

We have been developing new carbonylations and carbocyclizations as efficient and useful methods in organic synthesis. In the course of our investigation into the development of silicon-initiated cyclization processes, intramolecular silylformation, silylcyclocarbonylation (SiCCa), silylcarbocyclization (SiCaC), silylcarbobicyclization (SiCaB), and silylcarbotricyclization (SiCaT) have been discovered. The development of cascade reactions has been an active area of reasearch 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.

Novel Silylcarbocyclization (SiCaC) of Enediynes

cyclo1

 

cyclo2

Ojima, I.; McCullagh, J.; Shay, W.R. J. Organometallic Chem., 1996, 521, 421 - 423.

Novel Silylcarbotricyclization (SiCaT) of Triynes

cyclo3

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.

Novel Carbonylative Silylcarbotricyclization (CO-SiCaT) Reactio n

cyclo4

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 thsi reaction has been successfully applied to a broad range of substrates having different functionalities.

Discovery of Novel [2+2+2+1] Cycloaddition Reactions

cyclo5

Bennacer, B.; Fujiwara, M.; Lee, S. Y.; Ojima, I. J. Am. Chem. Soc., 2005, 127, 17756 - 17767

The CO-SiCaT and [2+2+2+1]-cycloaddition reactions proceed through two distinctive catalytic cycles, the later involving the formation of a metallacycle.

       cyclo6     cyclo6

We are currently working on expanding the scope of these efficient catalytic processes for the synthesis of 5-7-6-5 fused polycyclic structures. These tetracyclic ring systems are structural skeletons that are found in many bioactive natural products. Application of these higher order cycloaddition processes could provide a rapid and powerful method for the construciton of complex polycyclic skeletons that serve as key-steps for the synthesis of natural products.

cyclo6

                                         Kaloko, J. J.; Teng, Y-H.; Ojima, I. Chem. Comm., 2009 , 30, 4569 - 4571.

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Biphenol-based Monodetate Phosphorous Ligands

Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400 Phone: (631) 632-7890