Effects of solvents and water in Ti(III)-mediated radical cyclizations of epoxygermacrolides. Straightforward synthesis and absolute stereochemistry of (+)-3alpha-hydroxyreynosin and related eudesmanolides.
The Cp(2)TiCl-mediated rearrangement of 1,10-epoxy-11beta,13-dihydrocostunolide (4) was carried out using different solvents and additives to develop an expeditious procedure for the synthesis of natural eudesmanolides via free-radical chemistry. In the nonhalogenated solvents THF, benzene, and toluene the transannular cyclization, initiated by the homolytic opening of the oxirane ring, selectively led to the desired exocyclic alkene 5. When water was added to THF, however, the main product was reduced eudesmanolide 8. Experiments with D(2)O confirmed that the H-4 of 8 comes from water. To rationalize these results, a mechanistic hypothesis based on a water-solvated Cp(2)TiCl complex is proposed. Finally, the usefulness of Cp(2)TiCl for the synthesis of natural eudesmanolides has been proved using this reagent in the key step for the chemical preparation of (+)-3alpha-hydroxyreynosin (1) and (+)-reynosin (17). These syntheses confirmed the chemical structure of 1 and established the absolute stereochemistry of the natural products 1 and 17. The results obtained suggest that the combination of the biomimetic strategy employed, with Ti(III)-mediated free-radical chemistry, may come to represent a general method for the enantiospecific synthesis of more than 170 natural eudesmanolides containing an exocyclic double bond between C-4 and C-15.
Barrero
Alejandro F
AF
Department of Organic Chemistry, Faculty of Sciences, University of Granada, Campus Fuentenueva s/n, E-18071 Granada, Spain. afbarre@goliat.ugr.es
Oltra
J Enrique
JE
Cuerva
Juan M
JM
Rosales
Antonio
A
D001685:Biological Factors / Q000138:chemical synthesis / Q000737:chemistry; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
C461939:3-hydroxyreynosin; D001685:Biological Factors; D012717:Sesquiterpenes; D012997:Solvents; D014867:Water; C016715:reynosin