Part 3. A Novel Stereocontrolled, In Situ, Solution- and Solid-Phase, Aza Michael Approach for High-Throughput Generation of Tetrahydroaminoquinoline-Derived Natural-Product-like Architectures Michael Prakesch, † Stuti Srivastava, † Donald M. Leek, † and Prabhat Arya* ,†,‡,§ Steacie Institute for Molecular Sciences, National Research Council of Canada, 100 Sussex DriVe, Ottawa, Ontario, Canada K1A 0R6, Ottawa Institute of Systems Biology, UniVersity of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5, and Department of Biochemistry, McGill UniVersity, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6 ReceiVed April 24, 2006 With the goal of rapidly accessing tetrahydroquinoline-based natural-product-like polycyclic architectures, herein, we report an unprecedented, in situ, stereocontrolled Aza Michael approach in solution and on the solid phase. The mild reaction conditions required to reach the desired target are highly attractive for the use of this method in library generation. To our knowledge, this approach has not been used before, and it opens a novel route leading to a wide variety of tetrahydroquinoline-derived bridged tricyclic derivatives. Introduction The dissection of protein-protein interaction-based signal- ing networks using small molecules is an activity of an immense interest. 1-3 In general, these interactions are complex, dynamic in nature, and present tremendous chal- lenges in developing an understanding of their role at the molecular level. 4,5 Because small molecules have the ability to modulate these interactions in a reversible, temporal, and nondestructive manner, there is a growing desire to use small molecules to obtain a better understanding of multiple protein-protein interaction-based signaling networks. 6-8 In the absence of the structural information of a protein involved in protein-protein interactions, high-throughput generation of small-molecule chemical probes remains the method of choice. In particular, inspired by bioactive natural products that have been shown to act as inhibitors of protein-protein interactions, the development of solid-phase synthesis meth- ods leading to the high-throughput generation of natural- product-like compounds seems to be an attractive under- taking. 9-11 With the goal of having rapid access to tetrahydroquinoline alkaloid, natural-product-like, polycyclic architectures, we reveal a method that uses an unprecedented in situ aza Michael reaction to obtain this objective. The wide abun- dance of quinoline and tetrahydroquinoline alkaloid natural products showing promising properties for modulating protein-protein interactions 12 was the motivation behind the development of this method. Another objective was to validate our hypothesis that the compounds generated from this project were highly likely to yield interesting biological properties because these derivatives were anticipated to occupy the chemical space currently being championed by quinoline and tetrahydroquinoline alkaloids. 13 Results and Discussion A practical enantioselectiVe synthesis of a highly func- tionalized, tetrahydroaminoquinoline-derived artificial amino acid, 1 (Figure 1) was previously reported by us. 14,15 This scaffold is highly versatile and contains several attractive features. These include (i) the presence of orthogonally protected functional groups, (ii) - and δ-amino acid functionality, (iii) 1,2-trans-amino alcohol moiety, and (iv) 1,3-hydroxyl carboxyl ester functionality. The phenolic hydroxyl group provided a site that could be used for immobilization of the scaffold onto the solid support. Furthermore, as shown in compound 2, an extension of the side chain to obtain an unsaturated carboxyl ester functional group could be used to build the additional functionalized ring derivative that could lead to the tricyclic architecture (3) suitable for high-throughput generation of various analogs. At the time of the proposed plan, it was not clear that the desirable aza Michael reaction would lead to the additional ring in either the chair or boat form (see 3.1 and 3.2 in Figure 1). If successful in solution and on the solid phase, the approach described herein would lead to an interesting tetrahydroquinoline-derived natural-product-like tricyclic architecture that could then be subjected to com- binatorial chemistry to obtain several analogs in a high- throughput manner. Our initial approach to obtain the tetrahydroaminoquino- line-based aldehyde did not provide us the desired product, 6 (Scheme 1), from 4. In our hands, the corresponding hydroxyl derivative, 5, which was easily obtained from 4, failed to oxidize under several reaction conditions. As an alternative, compound 4 was first subjected to side-chain extension, giving the unsaturated carboxyl derivative 7. after * To whom correspondence should be addressed. Phone: (613) 993 7014. Fax: (613) 952 0068. E-mail: prabhat.arya@nrc.ca. † Steacie Institute for Molecular Sciences, National Research Council of Canada. ‡ Ottawa Institute of Systems Biology, University of Ottawa. § Department of Biochemistry, McGill University. 762 J. Comb. Chem. 2006, 8, 762-773 10.1021/cc060059n CCC: $33.50 © 2006 American Chemical Society Published on Web 08/15/2006