Catalytic, asymmetric cyanohydrin synthesis

Abstract

The aim of this project was to synthesise novel catalysts for asymmetric cyanohydrin synthesis catalysed by cyclic dipeptides, as part of an on-going research investigation into the mechanistic and synthetic aspects of diketopiperazine-catalysed asymmetric hydrocyanations. Novel derivatives of the cyclic dipeptide cyclo-[(S)-Phe(S)-His] 22, which catalyses the asymmetric addition of hydrogen cyanide to aldehydes to give enantiomerically-enriched (R)-cyanohydrins,^96,124 were synthesised via chemo-enzymatic and asymmetric methodologies, from the unnatural α-amino acids. The analogues of 22 were obtained by varying the aromatic phenyl moiety of the diketopiperazine, to give six new compounds 83-87 and 32. Eventually, only five of the target dipeptides were synthesised, and all of the presumptive catalysts tested were either inactive, or displayed very low activity. Solution state conformational analyses of four of the dipeptides were also carried out in an attempt to correlate activity (or the lack of it) to conformation. The second part of the project involved a thorough investigation into the asymmetric addition of trimethylsilyl cyanide and hydrogen cyanide to carbonyl compounds, catalysed by novel chiral (salen)Ti(IV) complexes.^51b,177 The optimal salen ligand was found to be 71, after modulating the steric and electronic properties of the ligands (68, 70-77). Products with up to 97% ee were obtained, at -80 °C, by employing these chiral titanium complexes. A mechanistic cycle has been proposed, based on the synthetic and mechanistic observations, to explain the catalysis and its various features.

Date of Award	1998
Original language	English
Awarding Institution	University of Wales, Bangor
Sponsors	EPSRC
Supervisor	Michael North (Supervisor)