Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides Sarwat Chowdhury, a Niraj J. Muni, b,c Nicholas P. Greenwood, a David R. Pepperberg c,b, * and Robert F. Standaert d, * a Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7056, USA b Department of Bioengineering, University of Illinois at Chicago, 851 S. Morgan St., Chicago, IL 60607-7052, USA c Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 West Taylor Street, Chicago, IL 60612-7243, USA d Biosciences Division, Oak Ridge National Laboratory, PO Box 2008 MS 6123, Oak Ridge, TN 37831-6123, USA Received 9 March 2007; revised 4 April 2007; accepted 5 April 2007 Available online 10 April 2007 Abstract—Lithium trialkylborohydrides were found to effect rapid monodealkylation of phosphonic diesters, and this reaction was applied to the synthesis of alkylphosphonic acid 2-aminoethyl esters [H 2 N(CH 2 ) 2 OP(OH)R, 4], a little-explored class of analogs of the inhibitory neurotransmitter c-aminobutyric acid (GABA). Compound 4a (R = Me) proved to be a potent antagonist at human q1 GABA C receptors (expressed in Xenopus laevis oocytes), with an IC 50 of 11.1 lM, but is inactive at a 1 b 2 c 2 GABA A receptors. Ó 2007 Elsevier Ltd. All rights reserved. c-Aminobutyric acid (GABA) is a major inhibitory neu- rotransmitter in the central nervous system and has three major classes of receptors, designated GABA A , GABA B , and GABA C . 1 Effectors of these receptors (agonists, antagonists, and allosteric modulators) are an important class of compounds as pharmaceuticals and pharmacological probes. Compounds targeting GABA A and GABA B have been extensively studied, 2 and GABA C effectors are attracting increased interest. 3 For this reason, and because of the important role of GABA C receptors in vision, 3d,4 we have sought to devel- op new GABA C effectors. We report here the discovery of a new reaction of lithium trialkylborohydrides, the reductive monodealkylation of phosphonic diesters, and its application to the synthesis of 2-aminoethyl alkylphosphonates (4), a previously unexplored class of GABA C receptor antagonists. Phosphinic acids are the most prominent class of GABA C antagonists. 5 In the course of pursuing new synthetic approaches to 3-aminopropyl alkyl phosphi- nates (e.g., 2a–c, Fig. 1), we surveyed metal hydrides for their ability to reduce phosphonic diesters to the cor- responding H-phosphinates. Among the reagents tested, only lithium trialkylborohyrides reacted cleanly, but monodealkylation, rather than reduction at phosphorus, was observed. Partial conversion was observed with so- dium tri(s-butyl)borohydride, while little conversion was observed with the corresponding potassium reagent, suggesting a specific role for the lithium counterion. The dealkylation reaction, which likely occurs via S N 2 nucleophilic attack at carbon, was surprising in that 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.04.026 Keywords: GABA antagonists; GABA C receptors; Dealkylation; Phosphonate esters; Lithium trialkylborohydrides. * Corresponding authors. Tel.: +1 865 574 2631; fax: +1 865 574 6210 (R.F.S.); tel.: +1 312 996 4262; fax: +1 312 996 7773 (D.R.P.); e-mail addresses: davipepp@uic.edu; standaertrf@ornl.gov Figure 1. Structures of GABA and phosphorus oxyacid analogs. Bioorganic & Medicinal Chemistry Letters 17 (2007) 3745–3748