Organocatalytic enantioselective syntheses of alpha-hydroxy phosphinates/phosphonates, 3,4-Dihydro-2H-pyran derivatives, and Mannich bases

Date
2013
Authors
Perera, Wijesooriya Gunawardhana Mahawaduge Sandun
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Abstract

Organocatalysis has now become a well-established approach for asymmetric organic synthesis. This dissertation describes high enantioselective syntheses of alpha-hydroxyphosphinate and alpha-hydroxyphosphonate derivatives, 3,4-dihydro-2H-pyran derivatives, and Mannich bases using organocatalytic methods.

alpha-Hydroxyphosphinate and alpha-hydroxyphosphonate derivatives are known for their important biological activities. Some of these compounds are clinically used as antiviral, antibacterial, and antifungal agents. Several commercial pesticides, plant growth regulators, and herbicides are hydroxyphosphonate derivatives. 3,4-Dihydro-2H-pyran scaffold is found in numerous natural products and biologically and/or medicinally important compounds. However, its importance as a pharmacophore is not apparent. 3,4-Dihydro-2 H-pyran derivatives have been identified as versatile synthetic intermediates in the synthesis of a multitude of important chiral compounds. Mannich bases have long been known as highly important chiral synthons for the synthesis of medicines and other commercially important compounds and important natural products.

In this study we employed cross-aldol reaction between alpha-formyl/ketophosphinates and ketones for the synthesis of alpha-hydroxyphosphinates. Proline and several proline derivatives were found to be very efficient organocatalysts for the title reaction. The synthesis of alpha-hydroxyphosphonates was achieved using cross-aldol reaction between aldehydes and alpha-ketophosphonates. A quinine-derived primary amine in combination with a suitable amount of a weak acid was found to catalyze the reaction. Inverse electron demand hetero-Diels--Alder reaction (IEHDA) of beta,gamma-unsaturated-alpha-ketoesters/phosphonates and aldehydes was used in the synthesis of 3,4-dihydro-2H-pyran derivatives while a Mannich reaction of aldehydes with pre formed glyoxylate imines was used to access the Mannich bases. Bifunctional organocatalysts generated in situ via ionic interaction between two different pre-catalyst modules were used to promote the aforementioned IEHDA and Mannich reactions.

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Keywords
Biological activity, Modularly designed organocatalysts, Organocatalytic Asymmetric Synthesis, Proline derivatives, Quinidine derived thiourea, Quinine derived amine
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Department
Chemistry