The synthesis and conformational studies of heterocyclic ureas (amides) 1-7 and their concentration-dependent unfolding to form multiply hydrogen-bonded complexes are described. Ureas 1 and 7 were prepared by reacting 2-aminopyridine and aminonaphthyridine 25, respectively, with triphosgene and 4-(dimethylamino)pyridine (DMAP). Amine 25, in turn, was synthesized by a Knorr condensation of 2,6-diaminopyridine and 4,6-nonanedione. Heterocyclic ureas 3, 4, and 16 were prepared by treating their corresponding amino precursors with butylisocyanate, whereas bisureido naphthyridines 6 and 17 were prepared by heating 2,7-diamino-1,8-naphthyridine (13) with butylisocyanate and 3,4,5-tridodecyloxyphenyl isocyanate, respectively. The hydrogen-bonding modules 2 and 5 were synthesized by reacting 13 and 2-amino-1,8-naphthyridine with valeric anhydride. X-ray crystallographic analyses were performed on ureas 1, 3, 16, and 17, indicating that these ureas are intramolecularly hydrogen-bonded in the solid state. Moreover, detailed 1H NMR solution studies of 1, 3, 4, 6, and 7 indicate that similar folded structures form in chloroform. In addition, naphthyridinylureas 3 and 7 unfold and dimerize by forming four hydrogen bonds at high concentrations, and ureas 1 and 4 unfold in the presence of their hydrogen-bonding complements, amides 2 and 5, to form complexes with three and four hydrogen bonds, respectively. Likewise, the mixing of 6 and 7 results in a mutual unfolding and formation of a robust, sheetlike, sextuply hydrogen-bonded complex. The hydrogen-bonding modules described are useful building blocks for self-assembly, and the unfolding process represents a very primitive mimicry of the helix-to-sheet transition shown by peptides and potentially shown by the hypothetical naphthyridinylurea 8.

A novel chiral Rh(II) catalyst (1) is introduced for the [2 + 1]-cycloaddition of ethyl diazoacetate to terminal acetylenes and olefins with high enantioselectivity. The catalyst 1 consists of one acetate bridging group and three mono-N-triflyldiphenylimidazoline-2-one bidentate ligands (DPTI) spanning the Rh(II)-Rh(II) metallic center in a structure that was determined by single-crystal X-ray diffraction analysis. A rational mechanism is advanced that provides a straightforward explanation for the enantioselectivity and absolute stereochemical course of the [2 + 1]-cycloaddition reactions. A key element in this explanation is the cleavage of one of the Rh-O bonds of the bridging acetate group in the intermediate Rh-carbene complex to form a new pentacoordinate Rh carbene complex (formally 1.5 valent Rh) that can undergo [2 + 2]-cycloaddition with the C-C pi-bond of the acetylenic or olefinic substrate. Reductive elimination of the resulting adduct affords the cyclopropene or cyclopropane product. The C2-symmetry of the two DPTI ligands orthogonal to the bridging acetate also contributes to the high observed enantioselectivity and mechanistic clarity. The catalyst 1, which functions effectively at 0.5 mol %, can be recovered efficiently for reuse. Its ready availability, robustness, and effectiveness suggest it as a useful addition to the list of practical chiral Rh(II) catalysts for synthesis.

A 17 step synthesis of 55, a late intermediate in Danishefsky's guanacastepene A synthesis, has been completed in 4% overall yield. Key features include the use of vinylmagnesium bromide in the Pd-catalyzed coupling with triflate 13 to give triene 16 without the formation of Heck products, a novel extension of the Stork-Jung vinylsilane Robinson annulation that provides tricyclic 2-hydroxymethylcyclohexenone 42 from 23b in four steps and 51% yield, the ability to obtain almost exclusively alpha'-alkylation of 35ba by the proper choice of protecting groups, and the ability to obtain the desired beta-alcohol selectively by reduction of keto alcohol 42 rather than keto ester 53.

The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.

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[reaction: see text] The first synthesis of (-)-dysiherbaine has been accomplished using intramolecular SN2 substitutions of a carbamate anion on an epoxide and an alkoxide on a secondary mesylate to efficiently construct the bicyclic skeleton stereospecifically from xylose. A general sequence has been developed to introduce an allyl group and convert it to the alanine side chain that should be useful for the construction of dysiherbaine analogues.

[reaction: see text] A 12-step synthesis of 26, the functionalized hydroazulenone ring of guanacastepene (1), has been completed using the EtAlCl(2)-initiated cyclization of gamma,delta-unsaturated ketone 13 to construct 2,2,3-trisubstituted cyclopentanone 14, the palladium-catalyzed coupling of vinylmagnesium bromide with enol triflate 17 to prepare triene 21, and olefin metathesis of triene 21 to form the key hydroazulene 20.