Stereocontrolled facile synthesis and antimicrobial activity of oximes and oxime ethers of diversely substituted bispidines Paramasivam Parthiban a , Senthamaraikannan Kabilan b , Venkatachalam Ramkumar c , Yeon Tae Jeong a,⇑ a Department of Image Science and Engineering, Pukyong National University, Busan 608 739, Republic of Korea b Department of Chemistry, Annamalai University, Annamalainagar 608 002, India c Department of Chemistry, Indian Institute of Technology-Madras, Chennai 600 036, India article info Article history: Received 5 February 2010 Revised 21 July 2010 Accepted 14 September 2010 Available online 18 September 2010 Keywords: 2,4,6,8-Tetraaryl-3,7- diazabicyclo[3.3.1]nonan-9-ones Oximes O-Methyloximes 2D NMR Single-crystal XRD Antibacterial activity Antifungal activity abstract A small library of diversely substituted 2,4,6,8-tetraaryl-3,7-diazabicyco[3.3.1]nonan-9-ones, their oxi- mes and O-methyloximes were achieved in a stereocontrolled manner by an easiest synthetic strategy as single isomers with high yields. Stereochemistry of all the synthesized compounds was established by their 1D/2D NMR spectral studies, further, witnessed by single-crystal XRD analysis. Accordingly, the compounds exist in a chair-boat conformation with equatorial orientation of the substituents in the chair part and boat-axial orientation in the boat part. Finally, all the synthesized oximes and oxime ethers were evaluated for their in vitro antimicrobial activity against a panel of pathogenic bacteria and fungi, and as a result of the structure–activity correlations, some lead molecules were known for further optimization. Ó 2010 Elsevier Ltd. All rights reserved. Molecules with the bispidine nucleus are of great interest due to their presence in a wide variety of naturally occurring lupin alkaloids and various biologically active molecules. 1 In fact, bispi- dine is a piperidine scaffold, comprised by two-units of piperidine core, which is also a well-known pharmacophore, proved by their occurrence in numerous naturally occurring alkaloids and biologically active molecules as well as in drugs and active pharmaceutical ingredients. 2 Hence, synthesis of new molecules with the bio-active bispidine nucleus and their stereochemical investigation are all worthy in the field of medicinal chemistry. On the other hand, the biological activities of oxime derivatives are known as very significant, and the introduction of substituents on the oxime functionality, C@N–O–R, exhibits an advance in their antimicrobial activity. 3 In the light of above all, we synthesized a mini-library of oximes and O-methylated oximes of 2,4,6,8-tetra- aryl-3,7-diazabicyco[3.3.1]nonan-9-ones by combining the bispi- dine and oxime pharmacophores with an expectation of enhanced antimicrobial activity. Promisingly, the nature and posi- tion of the substituents were important factors toward signifi- cantly effect the biological actions. 4 Accordingly, we synthesized the target molecules with phenyl groups on both sides of the sec- ondary amino groups (i.e., C-2, C-4, C-6 and C-8 positions of the 3,7-diazabicycle). Furthermore, to find the effective structure– activity correlations, electron-withdrawing/donating fluoro/ chloro/bromo/methyl/ethyl/iso-propyl/thiomethyl/methoxy/ethoxy/ n-propoxy/n-butoxy/phenoxy/benzyloxy/allyloxy substituents were used at ortho, meta and para positions of the phenyl groups. The 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonan-9-ones 5 were synthesized by a modified and an optimized successive double Mannich condensation of acetone, substituted benzaldehydes and ammonium acetate in 1:4:2 ratio in ethanol with good yields (Scheme 1). Although a number of stereomers are possible as wit- nessed by their stereogenic centers, all bicyclic ketones were achieved as single isomers. As stereochemistry of the molecules is a major criterion for their biological response, it is of immense help to establish the structure of newly synthesized compounds. The stereochemistry of 2,4,6,8-tetrakis(2-fluorophenyl)-3,7- diazabicyclo[3.3.1]nonan-9-one and 2,4,6,8-tetrakis(3-methoxy- phenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one, respectively, an ortho and meta substituted bispidines is as shown in Figures 1 and 2, wit- nessed by their complete NMR studies. The NOE bears out the fact that both the ortho and meta isomers exhibit the same stereochem- istry as para isomers. However, 1 H/ 13 C chemical shifts of the ortho isomers vary from the meta and para isomers, whereas they are closer between them. Furthermore, in ortho isomers 2, 5 and 8, chemical shift of the benzylic (H-2, H-4, H-6 and H-8) and 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.09.079 ⇑ Corresponding author. Tel.: +82 51 629 6411; fax: +82 51 629 6408. E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong). Bioorganic & Medicinal Chemistry Letters 20 (2010) 6452–6458 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl