In this research proposal, we plan to study the application of the proline derivative-catalyzed asymmetric aldol (or Mannich) reaction of 1-ketophosphinic acid derivatives (or 1-iminophosphinic acid derivatives) and ketones/enolizable aldehydes for the enantioselective synthesis of 1-hydroxy (or amino) phosphinic acid derivatives. 1-Hydroxy and 1-aminophosphinic acid derivatives are analogs of 1-amino acids. They have very important biological activities, mainly as enzyme inhibitors. An enantioselective method is highly desirable for the medicinal chemistry and pharmaceutical industry, as it may save the cost for up to 50% and avoid the unwanted the side-effects of the other enantiomer. Nonetheless, the phosphoryl group (P=O) is normally chiral in these derivatives, which makes the enantioselective synthesis of these compounds especially challenging, because such a synthesis would have to start with racemic starting materials instead of prochiral ones. Although there are a few methods to obtain these compounds in optically active forms, none of them are catalytic AND enantioselective during the syntheses. In this project we propose to use a novel cross aldol/Mannich reaction discovered in our lab to solve this problem. The long-term goal of this project is to develop an organocatalytic highly enantioselective method, which is environmentally benign and tolerates various substrates, for the synthesis of optically active 1-hydroxy and 1-aminophosphinic derivatives, for biomedical applications, such as anti-bacterial, anti-cancer or antivirus studies.
The specific aims of this proposal include: 1) rational design of catalysts and asymmetric aldol reaction of 1-ketophosphinic acid derivatives with ketones and enolizable aldehydes;2) asymmetric Mannich reaction of 1-iminophosphinic acid derivatives with ketones and enolizable aldehydes;and 3) applications of this novel method for the synthesis of biologically important products and preliminary antibacterial studies. The rationale that underlies the investigation is that such an enantioselective synthetic method will make the desired enantiomers of the phosphinic acid derivatives readily available, which, in turn, will facilitate the screening of their biological activities, and eventually accelerate their medicinal and pharmaceutical applications. This study is strongly supported by preliminary data that validate the proposed approach. Furthermore, the investigation will be performed in an excellent research environment and research facility that are conducive to its success. ENANTIOSELECTIVE SYNTHESIS OF PHOSPHINATE DERIVATIVES In this proposed project, the asymmetric synthesis of some 1-hydroxy and 1-amino-substituted phosphinate derivatives will be studied via the asymmetric aldol or Mannich reaction of 1-keto or 1-iminophosphinate derivatives. The current approach overcomes the difficulty in handling these chiral substrates (due to the chirality of the phosphoryl group), so that racemic starting materials may be directly used for the synthesis of the desired products in high enantioselectivities, which are highly biological active compounds because of their enzyme inhibitory effects. The research will greatly enhance the PI's competitiveness in securing non-SCORE research support. Additionally, this research also offers an excellent opportunity for training the students from the underrepresented groups in the cutting-edge area of organocatalysis.
|Guang, Jie; Zhao, John Cong-Gui (2013) Organocatalyzed asymmetric Michael reaction of ?-aryl-?-ketophosphonates and nitroalkenes. Tetrahedron Lett 54:|
|Guo, Qunsheng; Zhao, John Cong-Gui (2013) Highly enantioselective three-component direct Mannich reactions of unfunctionalized ketones catalyzed by bifunctional organocatalysts. Org Lett 15:508-11|
|Guang, Jie; Guo, Qunsheng; Zhao, John Cong-Gui (2012) Acetylphosphonate as a surrogate of acetate or acetamide in organocatalyzed enantioselective aldol reactions. Org Lett 14:3174-7|
|Bhanushali, Mayur; Zhao, Cong-Gui (2012) Organocatalyzed enantioselective aldol reaction of 1H-pyrrole-2,3-diones. Tetrahedron Lett 52:359-362|
|Thimmaiah, Muralidhara; Li, Peng; Regati, Sridhar et al. (2012) Multi-component synthesis of 2-amino-6-(alkyllthio)pyridine-3,5-dicarbonitriles using Zn(II) and Cd(II) metal-organic frameworks (MOFs) under solvent-free conditions. Tetrahedron Lett 53:4870-4872|
|Abbaraju, Santhi; Bhanushali, Mayur; Zhao, Cong-Gui (2011) Quinidine thiourea-catalyzed enantioselective synthesis of ?-nitrophosphonates: Beneficial effects of molecular sieves. Tetrahedron 67:7479-7484|
|Ramireddy, Naresh; Abbaraju, Santhi; Zhao, Cong-Gui (2011) Organocatalyzed enantioselective synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates. Tetrahedron Lett 52:6792-6795|
|Rout, Laxmidhar; Regati, Sridhar; Zhao, Cong-Gui (2011) Synthesis of ýý-Arylphosphonates Using Copper-Catalyzed ýý-Arylation and Deacylative ýý-Arylation of ýý-Ketophosphonates. Adv Synth Catal 353:3340-3346|
|Li, Peng; Regati, Sridhar; Butcher, Raymond J et al. (2011) Hydrogen-bonding 2D metal-organic solids as highly robust and efficient heterogeneous green catalysts for Biginelli reaction. Tetrahedron Lett 52:6220-6222|
|Perera, Sandun; Naganaboina, Vijaya Kumar; Wang, Long et al. (2011) Organocatalytic High Enantioselective Synthesis of ?-Formyl-?-hydroxyphosphonates. Adv Synth Catal 353:1729-1734|
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