Asymmetric syntheses of piperidino-benzodiazepines through ‘cation-pool’ host/guest supramolecular approach and their DNA-binding studies Nagula Markandeya b , Nagula Shankaraiah c , Ch. Sanjeeva Reddy b,⇑ , Leonardo Silva Santos d , Ahmed Kamal a,⇑ a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India b Department of Chemistry, Kakatiya University, Warangal 506 009, India c National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India d Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, Talca, PO Box 747, Chile article info Article history: Received 10 August 2010 Accepted 27 October 2010 Available online 20 November 2010 abstract The asymmetric synthetic approach to piperidino-benzodiazepine 4a (a homolog of DC-81) has been developed. The absolute stereochemistry of 4 and 5 has been assigned to be (S) at C-12a position. This procedure features the use of a ‘cation-pool’ strategy and also a host/guest supramolecular co-catalysis approach. In this study, the chloroformate of 8-phenylmenthyl has been employed as a chiral auxiliary and includes one-pot conditions for anodic oxidation, which are followed by nucleophilic addition to an N-acyliminium ion. In addition, intramolecular azido reductive-cyclization and nitro reductive dithio- acetal deprotective tandem-cyclization approaches have also been utilized for the syntheses of these compounds 4a,b and 5a,b. Some of the representative compounds exhibited an enhanced DNA-binding ability in comparison to the natural product DC-81. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction A growing interest in the development of new synthetic routes for the construction of chiral N-heterocycles continues to be essen- tial for accessing natural and unnatural products, particularly in a stereoselective manner. Nowadays, chirality in organic molecules plays an enormous role in areas ranging from medicine to material science, yet the synthesis of such entities in one enantiomeric form is considered as one of the most difficult challenges that need to be addressed by the synthetic chemists. However, inspite of many developments in synthetic organic chemistry, still there is scope for the development of newer methods that could provide impor- tant insights in employing chiral auxiliaries for the stereoselective construction of predetermined moieties in certain classes of com- pounds. As part of our efforts in the field of biologically relevant N-moieties, we became interested in the development of a new asymmetric synthetic route for the preparation of imine-contain- ing piperidino-benzodiazepines and their dilactams. There has been increasing interest in the synthesis of DNA se- quence selective binding agents, particularly by low molecular weight antitumor antibiotics. Among them, the pyrrolo[2,1- c][1,4]benzodiazepines (PBDs) are a well known class of DNA-inter- active potent antitumor agents derived from Streptomycin species. Streptomycin species, 1,2 which include anthramycin 1, tomaymy- cin 2, and DC-81 3 (Fig. 1). A stereogenic center at the C11a position and a DNA-reactive imine moiety at the N10–C11 position, are char- acteristics of these tricyclic PBD’s that have been extensively inves- tigated and rationalized to obtain a snug fit into the minor groove of duplex DNA. The interaction of PBD with DNA is due to a covalent aminal bond with the N2–amino group of the guanine base 3 that pro- vides a preference for Pu–G–Pu sequences. 1 Interestingly, these compounds have also been shown to inhibit both endonuclease 4 and RNA polymerase 5 enzymes in a sequence-dependent manner. A large number of PBDs have been designed and synthesized with a view to understand their structure–activity relationship 6–8 apart from the development of a variety of synthetic approaches 9,10 both in solution-phase and on the solid-phase. 11,12 Based on this analogy we have replaced the pyrrole (five-mem- bered ring) with piperidine (six-membered ring) to evaluate their potential for DNA-binding interactions with duplex DNA by modi- fying the stereogenic position from C11a to C12a. Herein, we have developed a new asymmetric synthetic route for the piperidino- benzodiazepines (PiBDs) through a b-CD-host/guest supramolecu- lar approach using 8-phenylmenthyl chloroformate as a chiral aux- iliary for the construction of the (S)-pipecolic moiety. Takaya et al. 13 have reported the synthesis of racemic (±)-piperidino-ben- zodiazepine dilactam 5a from D,L-pipecolic acid. However, only a few methods have been reported for the synthesis of optically ac- tive pipecolic acid derivatives, mainly involving enzymatic routes, 14 alkylation of chiral glycine enolates, 15 from natural amino 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.10.030 ⇑ Corresponding authors. Tel.: +91 40 27193157; fax: +91 40 27193189 (A.K.). E-mail addresses: chsrkuc@yahoo.co.in (C.S. Reddy), ahmedkamal@iict.res.in (A. Kamal). Tetrahedron: Asymmetry 21 (2010) 2625–2630 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy