The enantioselective total synthesis of (+)-laurencin (1) is accomplished in 24 steps from allyl alcohol.The synthesis features an acetal-vinyl sulfide cyclization that forms the oxocene ring and introduces, with complete control, the * 1234 unsaturation and requisite functionality at carbons 3, 4, and 9. Starting with allyl alcohol, mixed acetal 17 is constructed in seven steps and 38% overall yield (Scheme 2). Exposure of 17 to excess Bp3<)Et2 in f-BuOMe at -70 -* -40 °C affords A4-oxocene 27 in 55-65% yield (Scheme 4). Removal of the phenylthio group, followed by elaboration of the C(9) side chain and introduction of bromine at C(4), completes the construction of (-l-)-laurencin (Schemes 4 and 5).Red algae produce a breathtaking diversity of secondary metabolites.2 Distinctive members of this marine natural products group are the C15 acetogenins, many of which are halogen-containing cyclic ethers of diverse ring sizes. The prototypical member of the eight-membered cyclic ether subgroup is (+)-laurencin (1), which was first isolated from methanol extracts of Laurencia glandulifera by Irie and Masamune in 1965.3 On the basis of chemical degradation and spectroscopic studies, these researchers proposed that laurencin was a bromine-containing A4-oxocene. Four years later this proposal was confirmed and the stereochemistry and absolute configuration of (+)-laurencin were fully defined by singlecrystal X-ray analysis.4The pioneering synthetic investigations in this area were carried out also in Hokkaido and culminated in the Masamune group's total synthesis of (±)-laurencin in 1977.5 Recently, the
The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.
This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N"-(1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10(-8) M) than pinacidil (EC100 = 10(-7) M).
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