Facile one-step synthesis of 2,5-diketopiperazines Xianyu Sun a,c , Rachita Rai a , Alexander D. MacKerell Jr. a , Alan I. Faden b , Fengtian Xue a,b,⇑ a Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States b Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States c College of Animal Science and Technique, Heilongjiang Bayi Agriculture University, Daqing 163319, Heilongjiang, PR China article info Article history: Received 17 December 2013 Revised 27 January 2014 Accepted 28 January 2014 Available online 5 February 2014 Keywords: Diketopiperazine Fmoc deprotection Intramolecular cyclization Amide formation Neuroprotection abstract We report a one-step protocol for the general synthesis of 2,5-diketopiperazines from an Fmoc-protected amino acid and an amino acid ester. The application of the method is highlighted by rapid and efficient preparation of various 2,5-diketopiperazines. Ó 2014 Elsevier Ltd. All rights reserved. 2,5-Diketopiperazine (DKP) is a privileged scaffold for numer- ous bioactive molecules. 1 DKPs have been used as a key structural fragment for anticancer agents by different mechanisms such as cell-cycle inhibitors, 2 breast cancer resistance protein inhibitors, 3 plasminogen activator inhibitors, 4 and DNA binders. 5 Substituted DKPs have also been used in the development of anti-infective therapeutics including antiviral, 6 antibacterial, 7 and antifungal agents. 8 Moreover, DKPs have found application as inhibitors of phosphodiesterase-5 for the treatment of erectile dysfunction, 9 and antagonists of oxytocin for the treatment of preterm labor. 10 Recently, experimental evidence has highlighted the intriguing neuroprotective properties of DKPs in various cellular and animal models. 1c,11 Many methods are known for the preparation of DKPs. 1a A common route includes a three-step process: (i) coupling of an N-protected amino acid to an amino acid ester, (ii) deprotection of the N-protecting group (e.g., Boc, Fmoc, and Cbz), and (iii) base- assisted cyclization of the dipeptide ester (Scheme 1A). Despite the tremendous utility of this method in producing DKPs, it requires multiple-step synthesis with tedious purification processes. To date, one-pot procedure for the synthesis of DKPs is limited. 12 In the course of our research in developing multifunctional neuroprotec- tive agents, we performed a series of reactions intended to synthesize tryptophan/tyrosine-containing DKPs as potential neu- roprotective agents for the treatment of traumatic brain injury (TBI). Tertiary amines such as TEA and DIPEA are ubiquitous catalysts used for the amide bond formation. 13 They are also known to slowly remove the Fmoc group from an amino group. 14 Moreover, tertiary amines are among the common choices of bases to assist the formation of DKPs for the cyclization of the dipeptide esters. 15 Therefore, we hypothesized that a one-pot synthesis of DKPs may be achieved using Fmoc-protected amino acid and amino acid ester in the presence of a tertiary amine, which may provide a rapid and efficient synthetic method for DKPs (Scheme 1B). To implement this method, a solution of Fmoc-Trp(Boc)-OH (1a) and H 2 N-Ala-OEtÁHCl (2a) in DMF was treated with HBTU in HN * NH * O O R 1 R 2 H 2 N R 1 deprotection O H N * O OR R 2 H 2 N * O OR R 2 N H * R 1 O OH PG + N H * R 1 coupling O H N * O OR R 2 PG cyclization ii iii i H 2 N * O OR R 2 N H * R 1 O OH Fmoc + conditions HN * NH * O O R 1 R 2 B. Current work A. Previous methods Scheme 1. Synthetic methods to DKPs. (A) classical method and (B) current work. http://dx.doi.org/10.1016/j.tetlet.2014.01.133 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +1 410 706 8521. E-mail address: fxue@rx.umaryland.edu (F. Xue). Tetrahedron Letters 55 (2014) 1905–1908 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet