Theoretical study on the formation of a pentacyclo-undecane cage lactam Thishana Singh a,⇑ , Hendrik G. Kruger b , Krishna Bisetty a , Trevor D. Power c a Department of Chemistry, Faculty of Applied Sciences, Durban University of Technology, P.O. Box 1334, Durban 4000, South Africa b School of Chemistry, Faculty of Science and Agriculture, University of Kwazulu-Natal, Durban 4000, South Africa c Department of Biochemistry & Molecular Biology, Sealy Centre for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555-0857, USA article info Article history: Received 13 August 2011 Received in revised form 11 February 2012 Accepted 11 February 2012 Available online 22 February 2012 Keywords: Pentacyclo-undecane cage compounds DFT SCRF Transition state Thermodynamics abstract A quantum-chemical mechanistic investigation of the multistep mechanism of the one pot annular con- version of pentacyclo-undecane (PCU) cage lactam formation was carried out using density functional theory (DFT) level with the B3LYP hybrid functional in both the gas phase and with the self consistent reaction-field (SCRF) solvent model with the 6-31 + G(d) basis set. The kinetic and thermodynamic prop- erties of all species involved were investigated. The theoretical results suggest that the final product obtained is both thermodynamically and kinetically preferred. Moreover, the observed rate determining step compared favourably to the experimentally observed intermediate that was isolated before. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction Since the publication by Cookson and Grundwell [1] in 1958 where they describe the synthesis of the pentacyclo-undecane (PCU) dione, the focus of many research groups [2–7] has been the synthesis and chemistry of novel polycyclic cage compounds. Davies et al. [8] have been responsible for discovering the medicinal and pharmacological properties of polycyclic cage com- pounds. They discovered that 1-amino-adamantane, commonly known as amantadine, exhibits antiviral activity against a range of viruses causing influenza, hepatitis C and the herpes zoster neu- ralgia; thus realizing that polycyclic cage molecules also have the potential as biologically active agents [9]. Schwab et al. [10] later reported that amantadine was beneficial to patients with Parkinson’s disease. The hydrocarbon cage has the ability to cross the blood–brain barrier and to enter the central ner- vous system [10] due to the hydrophobicity of the ‘‘cage’’ despite the fact that the amino group is protonated at physiological pH. Drugs containing hydrocarbon cage moieties promote their trans- port across cell membranes and increase their affinity for lipophilic regions in receptor molecules [11]. While the hydrophobicity of the cage facilitates transport of the drug across membranes, the size and stability of the cage inculcate the drug with a structural property which results in controlled dos- age of the active ingredients of the drug. In addition to that, the hydrocarbon cage also induces stability towards drug degradation. In practice this translates into the slow metabolism of the drug. The important implication of this are that the intervals between drug administrations are increased [12]. Furthermore the nature of the substituent influences the specificity of the drug to antibac- terial [13], anabolic [14] and analgesic action [15]. A number of reports [16–18] have recently demonstrated the po- tential therapeutic value of novel pentacyclic cage compounds. These compounds have a promising potential as an important new class of medicinal and pharmaceutical agents and might extend the existing range [7,19–21] of bio-active pentacyclo-undecane compounds. The PCU hydantoin was investigated in our group as a potential epileptic agent [22,23], the PCU skeleton as the basis for anti-tuberculosis drugs [24,25] and recent reports focus on the PCU lactam moiety as novel HIV protease inhibitors [26,27]. How- ever, further investigation is required into the influence of the un- ique steric distribution of important functional groups around a rigid cage structure on the pharmacological activity [28]. Cyclopentadiene 1 and p-benzoquinone 2 produces the PCU dione 4 via the Diels–Alder 3 adduct (Scheme 1). The reaction in which the PCU dione 4 is synthesized is carried out by intramolec- ular photocyclization [29,30]. Treatment of the PCU dione 4 with slight variations of the Strecker reagents (HCN, NH 4 Cl NH 4 Cl and NH 4 OH) unexpectedly produced the d-lactam compounds 5a–5c (Scheme 2) [31]. Strecker reagents normally produce cyanohydrins or amino nitriles [32]. The mechanism of this unique one pot annular (Scheme 3) conversion [31,33,34] is not well understood. The mechanism initially proposed [29,31,33,34] was based on basic chemical principles and intuition. A comprehensive 2210-271X/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.comptc.2012.02.011 ⇑ Corresponding author. Tel.: +27 31 373 5272. E-mail address: singht@dut.ac.za (T. Singh). Computational and Theoretical Chemistry 986 (2012) 63–70 Contents lists available at SciVerse ScienceDirect Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc