1. New Routes To New Drugs
Ellis Hancox, Rebecca Clayton, David Fox.
Department of Chemistry, University of Warwick. URSS summer project 2016.
Pharmaceuticals and the Jocic reaction
• Many pharmaceutical drug molecules consist of an amine and/or amide functional
group. One method used to create this type of molecule is the Jocic reaction
(figure 1) .
• Experiments were carried out to determine whether there is preferable reaction of
primary or secondary amines, and at which site they each attack.
• Finally, further asymmetric reactions revealed the stereoselectivity of Jocic
reactions.
Preferred reaction of primary and
secondary amines
Starting material trichloro alcohol was synthesised from
decanal, then separately reacted with benzylamine and
piperidine via a series of Jocic reactions.1 Both of these
reactions were successful, however the reaction with
piperidine was found to give higher yield when left at 30 oC.
The trichloro alcohol was then reacted with both amines to
determine which or if both, reacted. It was found via 1H NMR and
mass spectrometry that all possible combinations of product
were created, as peaks at 337, 359 and 381 m/z, correlating to
products where 2 piperidine reacted, 2 benzylamine reacted, and
one of each reacted. Thus indicating no specific preference of
reaction between primary and secondary amines.
References
1 M. S. Perryman, M. E. Harris, J. L. Foster, A. Joshi, G. J. Clarkson and D. J. Fox, Chem. Commun. Chem. Commun, 2013, 49, 10022–10024.
2 K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya and R. Noyori, Angew. Chemie Int. Ed. English, 1997, 36, 285–288.
Figure 1. Jocic reaction.
R = C9H19
R = C9H19
R’ = C8H17
Stereoselectivity reactions via
asymmetric transfer hydrogenation
(ATH) of ketones
Synthesis of the required ketone was carried out via oxidation of
the trichloro alcohol starting material.
The above ketone was then asymmetrically reduced via ATH.2
A mixture of [RuCl2(cymene)2], (S,S)-TsDPEN and 5:2 formic
acid:trimethylamine catalyzed this reduction to give one
stereoisomer. (R,R)-TsDPEN would give the other isomer.
The trichloro alcohol isomer was then reacted with piperidine as
before, and the resulting piperidine amide could then be run
through HPLC to determine the enantiomeric excess.
The enantiomeric excess was 81.94% which shows selectivity,
however the sample was too concentrated therefore this result
should be higher.
R = C9H19
R = C9H19
R’ = C8H17