No abstract

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

A highly convergent, enantioselective total synthesis of the aglycone of the tetrocarcins, (+)-tetronolide, is described. The synthesis highlights the use of several new methods, including camphor auxiliary-directed asymmetric alkylation and the enantioselective preparation of acyclic mixed acetals bearing chirality at the acetal center, and the highly efficient connection of the two major precursors via a ketene-trapping/intramolecular [4 + 2] cycloaddition strategy.

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).

In comparison to all carbon [4 + 2] cycloadditions, Diesl‐Alder reactions are still in their infancy. The last four decades, however, have seen intensive research in this area. The results if that synthetic organic chemists now have a powerful tool at their disposal for rapid construction of highly functionalized six‐membered nitrogen heterocycles, often in a regio‐, diastereo‐, and enantioselective manner. This chapter encompasses the topic of imine[4 + 2] cycloaddition reactions, of which there are a number of variants. This chapter is limited exclusively to imine and iminium ion dienophiles that undergo inter‐ and intramolecular Diels‐Alder reactions with acylic and cyclic all‐carbon 1,3‐dienes affording 1,2,5,6‐tetrahydropyridines as the initial cycloadducts. In situations where there is a mechanistic ambiguity, such as reactions that proceed via Mannich reactions, these mechanisms are included since it is difficult to know where to draw the line on coverage. A comprehensive discussion of each structural type of imino dienophiles covers the literature up to the middle of 2004. A general overview of mechanistic, regiochemical, and sterochemical considerations is also presented. Specific relevant exo/endo issues, remote diasteroselectivity and the use of chiral auxiliaries are discussed under each separate imine type. Separate sections have also been included that describe intramolecular reactions, as well as more recent advances in enantioselective cycloadditions involving chiral catalysts.