A practical and scalable synthesis of a PDE4 inhibitor KW-4490 (1) was developed. This improved synthesis features the construction of the 1-arylcyclohexene ( 9) by the Diels-Alder reaction followed by a newly established Brønsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution enabled the high-yield production of the desired cis-isomer (cis-8). The synthesis was achieved in seven steps in 37% overall yield.

A short and practical synthesis of the PDE4 inhibitor K-34 (1) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production.

Chemoenzymic large-scale synthesis of the calcium salt of (6s) -5-formyltetrahydrofolic acid [ (-)leucovorin, (6S)-5] was achieved from folic acid 1 via (6s)-tetrahydrofolic acid [(6S)-3] by using dihydrofolate reductase (DH FR) produced by Zscherichia coli, harbouring a high-expression plasmid, pTP64-1. On the other hand, for the diastereoselective reduction of 7,8-dihydrofolic acid 2 to tetrahydrofolate (6S)-3, a new NADPH recycling system was constructed by coupling with glucose dehydrogenase from Gluconobacter scleroides. Having these enzymic systems to hand, compound 1 was reduced by zinc powder in alkaline solution to give compound 2 which, without isolation, was reduced enzymatically to afford tetrahydrofolate (6s) -3 (94% de). The pH adjustment of the reaction mixture containing dihydrofolate 2 was done with phosphoric acid in order to remove zinc ion which inhibited the following enzymic reduction. The formed tetrahydrofolate (6s) -

RES-1214-1 and -2, Novel Non-peptidic Endothelin Type A ReceptorAntagonists Produced by Pestalotiopsis sp.-Both title compounds (I) inhibit the ET-1 binding to endothelin type A receptor with IC50 values of 1.5 µM and 20 µM, respectively. Taxonomy of producing strains, fermentation, isolation, structural determination, and biochemical properties of (I) are described. -(OGAWA, T.; ANDO, K.; AOTANI, Y.; SHINODA, K.; TANAKA, T.; TSUKUDA, E.; YOSHIDA, M.; MATSUDA, Y.; J.