Karl B. Hansen

Regio- and Enantioselective Cyclization of Epoxy Alcohols Catalyzed by a [CoIII(salen)] Complex

The intramolecular cyclization of epoxy alcohols was catalyzed with excellent regio- and enantiocontrol by a [CoIII(salen)] complex. High endo selectivity was observed for the enantioselective cyclization of terminal epoxy alcohols [Eq. (a)], while the reaction of meso substrates produced novel cyclic and bicyclic ethers in good yields and high enantiopurity. TBME=tert-butyl methyl ether.

A Case of Remote Asymmetric Induction in the Peptide-Catalyzed Desymmetrization of a Bis(phenol)

We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 A. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure-selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.

DURCH EINEN (SALEN)COIII-KOMPLEX KATALYSIERTE REGIO- UND ENANTIOSELEKTIVE CYCLISIERUNG VON EPOXYALKOHOLEN

Mit exzellenter Regio-und Enantiokontrolle katalysieren [(salen)CoIII]-Komplexe die intramolekulare Cyclisierung von Epoxyalkoholen. Terminale Epoxyalkohole werden mit hoher endo-Selektivitat enantioselektiv cyclisiert [Gl. (a)]. Die Reaktion von meso-Substraten fuhrte in guten Ausbeuten zu neuartigen cyclischen und bicyclischen Ethern mit hoher Enantiomerenreinheit. TBME=tert-Butylmethylether.

Practical Syntheses of a CXCR3 Antagonist

Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.