02_c2 - Chapter 2 Enantioselective Synthesis of...

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Chapter 2 Enantioselective Synthesis of 2-Aryl-4-piperidones N CO 2 Bn O N CO 2 Bn O Rh(acac)(C 2 H 4 ) 2 (3 mol%) phosphoramidite (7.5 mol%) (ArBO) 3 1,4-dioxane/H 2 O, 100 ºC R Up to 99% ee High yields Piperidones are important intermediates in the preparation of natural occurring alkaloids and synthetic pharmacophores. In this chapter the highly enantioselective synthesis of 2-aryl-4-piperidones by rhodium/phosphoramidite-catalyzed conjugate addition of arylboroxines to 2,3-dihydro-4-pyridones is described. 1 A variety of products with sterically and electronically different R-substituents have been obtained in high isolated yield and with excellent ee’s up to 99%. Part of this chapter has been published: R. B. C. Jagt, J. G. de Vries, B. L. Feringa, A. J. Minnaard, Enantioselective Synthesis of 2-Aryl-4-piperidones via Rhodium/ Phosphoramidite-Catalyzed Conjugate Addition of Arylboroxines ”, Org. Lett. 2005 , 7 , 2433.
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26 Chapter 2 2.1 Introduction The piperidine ring system ( 1, Figure 2.1) is a frequently encountered heterocyclic unit in natural compounds and drug candidates. 2 Naturally occurring piperidine alkaloids ( e.g. 2-11 ) and their synthetic analogues are of great interest to the pharmaceutical industry. N H N H CO 2 H N H piperidine 1 pipecolic acid 2 coniine 3 N H HO Me (CH 2 ) 7 CO 2 H carpamic acid 4 N H H N O O H N N H Cl Cl N H OH DKP593A 5 histrionicotoxin 6 N H N N H N N N CH 3 HO O OH O OH H 3 C anabasine 8 anabasamine 9 rohitukine 11 N C 2 H 5 O O O campedine 10 OH HO O N CH 3 morphine 7 Figure 2.1 Naturally occurring piperidine alkaloids Considering the extensive range of biological activities these compounds exhibit, it is not surprising that (according to an assertion of Watson et al. ) between 1988 and 1998 thousands of piperidine-derived compounds were mentioned in clinical and preclinical studies. 3 Piperidones serve an important role en route to substituted piperidines 4 and can also be found as a part of more complex biologically active compounds. 5 Therefore the development of short, enantioselective routes to substituted piperidones is a major goal. 6
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27 Enantioselective Synthesis of 2-Aryl-4-piperidones Although few naturally occurring piperidine alkaloids contain the arylpiperidine moiety ( 8 - 11 ), the structural unit is an integral part of many polycyclic alkaloids ( e.g. morphine, 7 ). Simple synthetic arylpiperidines have received increasing attention due to their biological activities, often resembling those of more complicated natural alkaloids. Many 3-aryl- and 4-arylpiperidines are potent opioid receptor antagonists and can be regarded as structurally simplified forms of morphine. 7 2-Arylpiperidines are of noteworthy interest as being integrated in biologically active benzo[ a ]- and indolo[2,3- a ]quinolizidine compounds. 8
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This note was uploaded on 02/17/2011 for the course CHEMISTRY 101 taught by Professor Csr during the Spring '11 term at University of Louisville.

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02_c2 - Chapter 2 Enantioselective Synthesis of...

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