Preparation and Evaluation of 1,3-Diaminocyclopentane-Linked Dihydropyrimidinone Derivatives as Selective  1a -Receptor Antagonists James C. Barrow, a, * Kristen L. Glass, a Harold G. Selnick, a Roger M. Freidinger, a Raymond S. L. Chang, b Stacey S. O'Malley b and Carla Woyden b a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA b Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA Received 30 May 2000; accepted 16 June 2000 AbstractÐSeveral 1,3-diaminocyclopentane linked a 1a -receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their eect on a 1 -receptor binding. # 2000 Published by Elsevier Science Ltd. Recently, dihydropyrimidinone/piperidines such as 1 1 (Fig. 1) have been disclosed as selective a 1a -receptor antagonists, and these compounds have the potential to be eective therapy for treatment of benign prostatic hyperplasia. 2 As part of a strategy to design potent and selective antagonists of the a 1a -receptor, constraints in the ¯exible linker between the piperidine and dihy- dropyrimidinone heterocycle of 1 were examined. Con- straining a ¯exible section of an enzyme inhibitor or receptor antagonist often results in enhanced binding anity due to reduced entropic penalties on binding when the constraint mimics the bioactive confor- mation. 3 While there are several conceivable ways to constrain the 3-carbon chain of 1, 1,3-substituted cyclopentanes such as 2 were chosen for this study. It was hoped that, in addition to improving the potency at the a 1a -receptor, the four stereochemical permutations of this cyclopentane system might reveal new strategies for gaining selectivity among the a 1a -, a 1b -, and a 1d - receptor subtypes. 4 Below is described a novel method for synthesis of stereochemically de®ned 1,3-diamino- cyclopentanes and evaluation of each con®guration at the three a 1 -receptor subtypes. The most rapid and convergent method for construction of each possible stereoisomer of 2 would be a non- selective reductive alkylation of a piperidine with enan- tiopure ketone 3. At the outset of these studies, the only preparation of optically active analogues of 3 was the chiral auxillary-based approach of Miller. 5 A more ¯exible approach that would provide entry into all ste- reochemical permutations involves resolution of a 3- amino cyclopentanol derivative 5 6 in analogy to the known desymmetrization of 4a. 7 Deardor has reported the palladium catalyzed opening of epoxide 6 (Scheme 1) with several oxygen nucleo- philes 8 as well as displacement of 4b 9 with NaN 3 which aorded azide (+)8 in 44% yield as a 4:1 mixture with the trans-isomer. 10 It is possible to combine these two procedures so that 6 can be opened with azide under Pd(0) catalysis to give 8. Further, it was found that replacing NaN 3 with TMSN 3 improved the yield and selectivity of this reaction, most likely because the steric bulk of the TMS group helps direct attack of azide toward the distal end of the Pd-allyl system. Further- more, the large TMS group stabilizes the allylic azide 7 from decomposition via sigmatropic rearrangements. 11 Removal of the silyl protecting group from 7 (1 M aq HCl/EtOAc, 15 min) aorded the more labile allylic azide 8 in racemic form. To minimize the number of operations involving these somewhat unstable allylic azide intermediates, a resolution procedure based on a selective enzyme catalyzed acylation was chosen rather than an acylation followed by selective hydrolysis. In analogy to the work of Theil 7 we employed the convenient pancreatin/vinyl acetate system in THF. 12 Using 10 equiv of vinyl acetate and 0.5 g of pancreatin/mmol of substrate, the selective acylation of 8 proceeded to 0960-894X/00/$ - see front matter # 2000 Published by Elsevier Science Ltd. PII: S0960-894X(00)00374-7 Bioorganic & Medicinal Chemistry Letters 10 (2000) 1917±1920 *Corresponding author. Tel.: +1-215-652-4780; fax: +1-215-652-3971.