Probing chemical space with alkaloid-inspired libraries.

Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp(3)-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp(3) content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

Minimalist end groups for control of absolute helicity in salen- and salophen-based metallofoldamers.

(S)-1-Methylindan end groups are effective controllers of absolute helicity in Ni-salen- and Ni-salophen-based foldamers derived from (R,R)-trans-1,2-cyclohexanediamine and 1,2-phenylenediamine, respectively. Evidence for the helicity of the described complexes was provided through X-ray crystallography and study of chiroptical properties in solution. The chiral end groups control the absolute sense of helicity for the salen complexes, even in a case where the helical bias of the end group is mismatched relative to that of the internal diamine.

The chiral crown conformation in paddlewheel complexes.

Bimetallic paddlewheel complexes derived from imides of (S)-tert-leucine adopt 'chiral crown' configurations in which the four imide groups are projected in a chiral arrangement on one face, and the four tert-butyl groups are projected on the opposite face. In this contribution, the generality of the chiral crown conformation is examined through crystallographic studies where the metal and the nature of the chiral ligands are altered. Based upon these observations, a model is proposed to explain the factors which create bias for the chiral crown configuration.