A stereoselective
protection-free asymmetric total synthesis of
(+)-chamuvarinin (1), a potent anticancer and antitrypanosomal
agent, has been accomplished. The adjacently linked [bis(tetrahydrofuran)]tetrahydropyran
(THF–THF–THP) core of this natural product with seven
stereogenic centers was constructed in a completely substrate-controlled
fashion. The inter-ring stereochemistry (threo,threo,threo) of the oxatricyclic core was established in a stereoselective fashion
by a chelation-controlled Keck allylation, whereas the intraring cis or trans relative stereochemistry was
controlled by a stereoselective internal alkylation.
A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.Key words phosphodiesterase 5 inhibitor; bisprehomotadalafil; bisprecyclopentyltadalafil; bisprenortadalafil; dietary supplement Tadalafil (1, Cialis ® ), a phosphodiesterase 5 (PDE5) inhibitor, has been widely used for the treatment of erectile dysfunction (ED). In spite of its excellent efficacy and safety profile, the administration of tadalafil (1) to patients who are concurrently using any form of organic nitrates or guanylate cyclase stimulators is contraindicated due to its hypotensive effects.
1-3)Tadalafil (1) should also not be prescribed in patients with Stevens-Johnson syndrome or exfoliative dermatitis because hypersensitivity reactions to this ED drug have been reported in such patients. 4) However, tadalafil (1) and its analogues have been detected in a number of dietary supplements over the last decade. These illegal products are mainly advertised as sexual enhancement products and sold without any declarations on the label of the pharmacological and toxicological effects arising from the PDE5 inhibitory activity. Most of the tadalafil analogues detected in illegal dietary supplements were generated by removal of an N-methyl group or its replacement by another group such as amino, ethyl, butyl, octyl or cyclopentyl.5-14) Epimeric tadalafil analogues 5,15) and precursor-related analogues of tadalafil (1) have also been identified.16-18) These analogues were presumably designed for use in adulteration to avoid identification by authorities. Recently, we found a new type of tadalafil analogues in dietary supplements, exemplified by 2a,b and 3, which bear two (pre) tadalafil moieties (Fig. 1). We have named these trans-bisprehomotadalafil, trans-bisprecyclopentyltadalafil and bisprenortadalafil, respectively. 5,19,20) The relative stereochemistry of these dimeric analogues was tentatively assigned based on no observation of nuclear Overhauser effect (NOE) between the protons at stereogenic centers in the molecules and by comparison of their spectral data with those of monomeric tadalafil der...
A highly stereoselective asymmetric total synthesis of (−)-jimenezin (1), a potent anticancer acetogenin, was efficiently completed with the key feature being a sequential intramolecular amide enolate alkylation (IAEA). Our investigation to probe the origin of the complete stereoselectivity in the second IAEA step to form the conformationally flexible tetrahydrofuran with perfect stereocontrol identified the presence of the oxygen atom in the adjacent tetrahydropyran ring to be crucial.
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