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
Key words
cyclic dipeptides - piperazinediones - iridium catalysis - asymmetric hydrogenation
- asymmetric catalysis
Significance
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).
Comment
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 3a–e. 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.
Reviews
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.
