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Simple and efficient stereo-selective synthesis of exo-5-norbornene-2-carboxylic acid (NBCA) is reported. Preliminary studies on base promoted isomerization of methyl 5-norbornene-2-carboxylate (MNBC) revealed that rapid isomerization was accomplished with sodium tert-butoxide (tBuONa), and the exo-content at the equilibrium was ca. 60%. The hydrolyses of endo-rich MNBC (endo/exo = 80/20) under various conditions were carried out. The exo selectivity for resulting NBCA was improved when the hydrolysis was conducted with equimolar water at room temperature in the presence of the stronger base (tBuONa) (endo/exo: 18/82). Whereas the use of excess amount of water led to rapid and non-selective hydrolysis affording high endo content of the product. The plausible reaction mechanism involving rapid equilibrium of thermodynamic isomerization and kinetically preferred hydrolysis of exo ester is proposed.

A solid-phase synthesis of 6-sulfonylamino morphinan has been developed. The morphinan derivatives were designed as selective opioid ligands. The sulfonamide moiety was introduced by reductive amination of a ketone on solid phase, followed by sulfonylation of the resulting amine. Using this methodology, the synthesis of three combinatorial libraries was accomplished to prepare 339 morphinan derivatives with over 70% purity.Combinatorial chemistry has been shown to be an important tool that aids in the discovery of new drug leads as well as in the optimization of lead compounds. 1 For a rapid assembly of a huge number of compounds, solid-phase technology is very useful because it can simplify work up and purification. This is especially essential for the synthesis of a library whose compounds are difficult to extract with organic solvent or purify by column chromatography owing to their high polarity. For example, we have previously reported an efficient solid-phase synthesis of oligosaccharide conjugated enediynes by solid-supported coupling of hydroxyl free tri-to monosaccharides to a 9-membered enediyne. 2 Opioids receptors are generally classified to three types (m, d, and k) not only by pharmacological studies but also by molecular biological studies. Previously, there have been numerous studies for the synthesis of selective opioid ligands. 3 Recently we have been developed TRK-820(1) as a new type of k-agonist 4 on the basis of the "message-address concept" 5 and "accessory site hypothesis" 6 ( Figure 1). The message part is a morphinan skeleton having a phenol group, which is an essential moiety for elicitation of intrinsic activity on opioid receptors. The address part is an amide side-chain, which generates selectivity for subtypes of the opioid receptor. In order to discover new novel selective ligands for other subtypes, morphinan derivatives having a different side chain could be a promising candidate. Herein we describe the design of novel morphinan opioid ligands 2 having a sulfonamide side chain and the efficient library synthesis on solid-phase based on sequential diversification by reductive amination followed by sulfonylation.Our new morphinan derivatives 2 have a sulfonamide side chain. The sulfonamide derivatives 2 are expected to show different selectivity toward the opioid receptors because of a difference in conformation between the side chains. However, handling of the morphinan derivatives 2 should be relatively difficult owing to their high polarity derived from their phenol and tert-amine. In order to simplify the handling, we would apply the solid-phase technology to the library synthesis. Our strategy for the solidphase synthesis of the sulfonamide 2 is illustrated in Figure 1. Introduction of the sulfonamide chain to morphinan skeleton is based on two sequential modifications of naltrexone 4 immobilized at the phenol on Wang resin. 1) Reductive amination of ketone 4 with amine 6 would provide the bound amine. 2) The resulting amine would be converted to the sulfonamide 3 by treatment...