Asymmetric Synthesis of Oxygen Heterocycles via Pd-Catalyzed Dynamic Kinetic Asymmetric Transformations: Application to Nucleosides

• Published in: Chemistry : a European journal Vol. 9; no. 18; pp. 4442 - 4451
• Main Authors: Trost, Barry M., Brown, Brian S., McEachern, Ernest J., Kuhn, Oliver
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 22.09.2003; WILEY‐VCH Verlag; Wiley
• Subjects: Alcohols - chemical synthesis; Alcohols - chemistry; asymmetric catalysis; asymmetric synthesis; Catalysis; Chemistry; Chemistry, Multidisciplinary; Cyclization; Epoxy Compounds - chemical synthesis; Epoxy Compounds - chemistry; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Kinetics; metathesis; Models, Chemical; Molecular Structure; nucleosides; Nucleosides - chemical synthesis; Nucleosides - chemistry; Organometallic Compounds - chemistry; Oxygen - chemistry; palladium; Palladium - chemistry; Physical Sciences; Ruthenium - chemistry; Science & Technology; Stereoisomerism; SUBSTITUTION; REAGENTS; ENTRY; THYMIDINES; STRATEGY; OLEFIN METATHESIS; asymmetric catalysis; ENANTIOSELECTIVE CONSTRUCTION; ALCOHOLS; nucleosides; ETHERS; asymmetric synthesis; metathesis; RING-CLOSING METATHESIS; palladium
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200304949

Racemic butadiene and isoprene monoepoxide react with unsaturated alcohols in the presence of a chiral palladium catalyst and a boron co‐catalyst to give 3‐alkoxy‐4‐hydroxy‐1‐butene and 3‐alkoxy‐4‐hydroxy‐3‐methyl‐1‐butene, respectively, with excellent regio‐ and enantioselectivity in a dynamic kinetic asymmetric transformation whereby both enantiomers of the starting epoxides provide the same enantiomeric product. In the case of 2‐phenylbutadiene monoepoxide, easily available from phenacyl chloride and vinylmagnesium bromide, the reaction proceeds by kinetic resolution. A model to rationalize the result is presented. The bis‐olefin products are ideal substrates for the Ru catalyzed ring closing metathesis. In this way, five‐, six‐, and seven‐membered oxygen heterocycles are readily available enantiomerically pure. The value of this very simple two step process is demonstrated by the use of the five‐membered ring heterocycles to form unnatural and unusual nucleosides that cannot be easily accessed by other means. The sequence involves a Ru catalyzed isomerization of the initial 2,5‐dihydrofuran to a 2,3‐dihydrofuran followed by a selenium promoted addition of a pyrimidine or purine base. One advantage of this strategy is the easy access to either enantiomeric series, both of which have important biological applications. A palladium‐catalyzed dynamic kinetic asymmetric transformation of racemic epoxides with unsaturated alcohols followed by ring‐closing metathesis provides a facile entry into five‐, six‐, and seven‐membered‐ring oxygen heterocycles. The utility of this methodology is highlighted by a non‐carbohydrate‐based route to nucleosides and analogues of either enantiomeric series in only five steps (see scheme).