Synfacts 2019; 15(10): 1105
DOI: 10.1055/s-0039-1690979
Synthesis of Heterocycles
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Synthesis of Cyclic Dipeptides by Iridium-Catalyzed Hydrogenation

Victor Snieckus
John I. Trujillo (Pfizer)
Ge Y, Han Z, Wang Z, Ding K. * Shanghai Institute of Organic Chemistry, P. R. of China
Ir-Catalyzed Double Asymmetric Hydrogenation of 3,6-Dialkylidene-2,5-diketopiperazines for Enantioselective Synthesis of Cyclic Dipeptides.

J. Am. Chem. Soc. 2019;
141: 8981-8988
Further Information

Publication History

Publication Date:
17 September 2019 (online)



The 2,5-dioxopiperazine motif, also known as a cyclic dipeptide, is found in compounds possessing biological activity, such as retosiban and fumitremorgin C (see first Review below). In addition, the motif has found utility in asymmetric synthesis as a chiral auxiliary or organocatalyst (see second Review below; C. Becker et al. Eur. J. Org. Chem. 2005, 1497). The synthesis of the ring system is usually accomplished by careful cyclization of protected acyclic peptide precursors. Other methods exist, including asymmetric alkylation of 2,5-diketopiperazines and, to a limited degree, asymmetric reduction of compounds similar to 1 by cobalt catalysis in the total synthesis of an alkaloid (S. Take­uchi et al. Heterocycles 1990, 31, 2073).



In the current method, the asymmetric reduction of compounds 1 to give dioxopiper­azines 3 in high yields with ee values of up to 98% and exclusive formation of the cis diastereomer. The optimal catalyst [SpinPHOX/Ir(I)] was identified by screening a series of ligands. The scope of the reduction is exemplified by products 3ae. A mechanism that rationalizes the high ee values observed is proposed in which two C=C double bonds of the substrate are hydrogenated successively while bound to the iridium center.



1. A. D. Borthwick Chem. Rev. 2012, 112, 3641–3716; 2. E. A. Colby Davie, S. M. Mennen, Y. Xu, S. J. Miller Chem. Rev. 2007, 107, 5759–5812.