Latent Nucleophiles Research Articles

Cyclization–oxidation of 1,6-enyne derivatived from Baylis–Hillman adducts via Pd(II)/Pd(IV)-catalyzed reactions: stereoselective synthesis of multi-substituted bicyclo[3.1.0] hexanes and insight into reaction pathways

Cyclization–oxidation of Baylis–Hillman adducts provides a convenient method to stereoselectively synthesize variety of multi-substituted bicyclo[3.1.0] ring systems via Pd(II)/Pd(IV)-catalyzed reactions. We also disclose that C–Pd(IV) intermediate can undergo reductive elimination through S N2-type attack by the latent nucleophile of vinyl acetate to afford C sp 3 – C sp 3 bond formation with inversion of configuration at the Pd(IV)-bounded carbon.

Total synthesis of linear polyprenoids. 3. Syntheses of ubiquinones via palladium-catalyzed oligomerization of monoterpene monomers

A general methodology for highly regie and stereoselective Pd(0)-catalyzed, stepwise allylic coupling of bifunctional monomers was developed, representing a practical approach for total synthesis of naturally occurring polyprenoids. As an example, the total synthesis of the cardiovascular agent ubiquinone 10 (coenzyme Qlo), as well as shorter ubiquinones, was carried out via selective coupling of monomers easily derived from geraniol that contain either one or two reacting functional end groups. One of these functionalities is a latent allylic electrophile activated by the Pd(0) catalyst and the other is a latent nucleophile activated by an appropriate base. After the desired decaprenyl carbon skeleton of Qlo was achieved, the synthesis was completed by removal of the activating groups: Methyl ester was deleted via a highly efficient demethoxycarbonylation procedure involving 4-aminothiophenol and catalytic amounts of cesium carbonate, and the allylic sulfones were deleted by Pd(0)-catalyzed allylic reduction. Finally, oxidation of the aromatic ring to quinone affords ubiquinone 10. Quinones and hydroquinones with polyprenyl side chains, such as ubiquinones, plastoquinones, phylloquinone (vitamin Kl) , and menaquinones (vitamin K2), are widely distributed in animal and plant tissues.' In addition to important biological roles in promoting electron transfer in respiratory chains and photosynthesis, these compounds exhibit various pharmacological activities. Of special interest is ubiquinone 10 (coenzyme Qlo, 1),3 which is used clinically as a cardiovascular agent and has attracted significant synthetic activity within the past two decade^.^ However, because construction of linear polyprenoid chains is still a major synthetic challenge, a practical total synthesis of ubiquinone I O has not yet been achieved. Available industrial processes for Qlo 'To whom correspondence should be addressed at the Technion, Haifa. + Weizmann Institute of Science. Incumbent of the Joseph and Madeleine Nash Career Development Chair established by Foundacion Madelon, Zurich, Switzerland. involve either biotechnological7 or semisynthetic methods, the latter employing solanesol, a nonaprenol extracted from tobacco leaves.8 (1 ) Part 2: Keinan, E.; Eren, D. J . Org. Chem. 1987, 52, 3872. (2) (a) Britton, G. Nut. Prod. Rep. 1984, 68. (b) Cainelli, G.; Cardillo, G. Acc. Chem. Res. 1981,14,89. (c) Crane, F. L. Annu. Rea. Biochem. 1977, 46, 439. (d) Isler, 0.; Schudel, P. Adv. Org. Chem. 1973, 4, 115. (e) Morton, R. A. Biol. Rev. 1971, 46, 47. (f) Morton, R. A. Biochemistry of Quinones; Academic: New York, 1955. (g) See also ref 3b,c. (3 ) For general information concerning ubiquinone I O see: (a) Yamamura, Y.; Folkers, K.; Ito, Y. Biochemical and Clinical Aspects of Coenzyme Q,,,; Elsevier: Amsterdam: 1977, Vol. I; 1980, Vol. 11; 1981, Vol. 111; 1983, Vol. IV. (b) Thomson, R. H. Naturally Occurring Quinones, 2nd ed.; Academic: New York, 1971. (c) Littaru, G. P.; Ho, L.; Folkers, K. In r . J . Vitam. Nutr. Res. 1972, 42, 291, 413. (d) Combs, A. B.; Acosta, D.; Folkers, K . IRCS Med. Sci.: Libr. Compend. 1976, 4, 403. ( e ) McCormick, D B., Wright, L. D., Eds. Methods Enzymol. 1971, 18, 137-562. (f) Bliznakov, E. G.; Hunt, G. L. The Miracle Nutrient Coenzyme Qlo; Bantam Books: New York, 1987; references cited therein. 0002-7863/88/1510-4356$01.50/0

Total synthesis of polyprenoid natural products via Pd(0)-catalyzed oligomerizations

Abstract