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.


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


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

Asymmetric Conjugate Addition



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

Asymmetric Hydroformylation


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

Asymmetric Allylic Alkylation

MPN ligands were found useful in selecting a highly efficient chiral ligand for the enantioselective Pd-catalyzed tandem allylic alkylation reaction. The reaction gave a critical tricyclic key intermediate with high enantiopurity for the formal total synthesis of (−)-Huperzine A, a Lycopodium alkaloid derived from the club moss Huperzia serrata that possesses potent inhibitory activity against acetylcholine esterase (ACHe) and efficacy as a medicine for helping people with neurological conditions such as Alzheimer's disease.

Asymmetric Allylic Alkylation

Asymmetric Allylic Amination

Asymmetric Allylic Amination1

1-Vinyltetrahydroisoquinolines serve as versatile intermediates for the synthesis of a variety of naturally occurring isoquinoline alkaloids. 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, developed in our laboratory.


Chien, C.-W.; Shi, C.; Lin, C. -F.; Ojima, I., Tetrahedron 2011, 67,6513-6523

Formal enantioselective total synthesis of schulzeines A‒C was accomplished, featuring highly efficient Pd-catalyzed asymmetric allylic amination using BOP ligands to provide 1-vinyltetrahydroisoquinoline key intermediates, as well as Ru-catalyzed ring-closing metathesis reaction to construct the key tricyclic cores in enantiopure form with correct absolute configurations.

Asymmetric Allylic Amination3

Pd-catalyzed asymmetric allylic amination reaction of piperonylamides and a 2-siloxymethylcyclohexenyl carbonate, using chiral BOP ligands gave the corresponding cyclohexenylpiperonylamides in excellent yield and enantiopurity (93–95% ee). These amides were applied to the synthesis of fused polycyclic alkaloids in a short sequence of steps.

Asymmetric Allylic Amination4

Asymmetric Allylic Amination

A library of BOP ligands was designed and created. These BOP ligands were applied to a Pd-catalyzed intermolecular allylic etherification reaction, which provided a key intermediate for the formal total synthesis of (−)-galanthamine with 97% ee in 97% yield.


Asymmetric Allylic Etherification


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.


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.


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




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

Novel Silylcarbotricyclization (SiCaT) of Triynes


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


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

Rh(I)-catalyzed cyclocarbonylation reaction of triyne derivatives were found to afford the fused 5-7-x (x = 5, 6, 7) tropone products. This methodology can provide direct access to novel colchicinoids in a single step.




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

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

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.


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

A high-order [2+2+2+1] carbonylative cycloaddition of ortho-phenylenetriynes with CO catalyzed by rhodium complex was developed. This reaction allows a rapid access to the novel colchicinoids. The designed triyne derivatives were synthesized and subjected to the carbonylative cycloaddition and were found to afford the desired tetracyclic fused tropone products in good to excellent selectivities and yields.

Novel [2+2+2+1] Cycloaddition Reactions-2

Associated Publications:

1.“Synthesis of Colchicinoids and Allocolchicinoids through Rh(I)-catalyzed [2+2+2+1] and [2+2+2] Cycloadditions of o-Phenylenetriynes with and without CO”, Chih-Wei Chien, Garry Yu-Han Teng, Tadashi Honda, Iwao Ojima, J. Org. Chem. 83, 11623-11644 (2018). PMID: 30129760

2. Construction of Fused Tropone Systems Through Intramolecular Rh(I)-Catalyzed Carbonylative [2+2+2+1] Cycloadditon of Triynes”, Gary Y.-H. Teng, Chih-Wei Chien, Wen-Hua Chiou, Tadashi Honda and Iwao Ojima, Front. Chem. 6, 401 (2018). PMC6139344

3. Enantioselective Pd-Catalyzed Tandem Allylic Alkylation Reaction Using Monodentate Phosphoramidite Ligands for the Formal Total Synthesis of Huperzine A”, C.-F. Lin, C.-W. Chien and I. Ojima, Org. Chem. Front. 1 (9), 1062-1066 (2014)


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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