Palladium and silver catalyzed synthesis of (Z)-γ-alkylidenebutenolides and palladium-catalyzed syntheses of terminal alkynes, conjugated diynes, and terpenoids
Abstract
An antibiotic lissoclinolide has been synthesized in 9 steps and 32% overall yield via (i) hydrogen transfer hydrozirconation of TBS-protected propargyl alcohol with i-BuZrCp2Cl, (ii) Pd-catalyzed trans-selective cross coupling of the hydrozirconation product with a key 1,1-dibromoalkene intermediate, and (iii) Ag-catalyzed lactonization of a trienynoic acid precursor. Xerulin, an inhibitor of cholesterol biosynthesis, has been synthesized from commercially available (E )-1-bromopropene, acetylene, and propynoic acid in five steps (longest linear sequence) in 30% overall yield and >96% stereoselectivity. The preparation of (E)-bromoiodoethylene and its use in the Pd-catalyzed cross coupling are two of the novel aspects of this synthesis. A direct synthesis of terminal alkynes via Pd-catalyzed cross coupling of aryl and alkenyl halides with ethynylmetals containing Zn, Mg, and Sn has been developed. HC≡CZnBr is generally the most favorable and widely applicable reagent that can often help alleviate the difficulties associated with Mg. The procedure has been applied to an efficient synthesis of a thiophenelactone from Chamaemelum nobile L. A strictly “pair”-selective synthesis of conjugated diynes via Pd-catalyzed cross coupling of 1,3-diynylzincs has been developed. The perfect “pair”-selectivity permitting high-yield production of the desired conjugated diynes promises to make this protocol superior to the Cadiot-Chodkiewicz reaction in many cases. The intermolecular trapping of acylpalladium and related acylmetal derivatives with active C-H compounds provides the corresponding enol carboxylates formed via trapping with O-enolates. An unprecedentedly general, efficient, and selective methodology for the synthesis of geometrically defined 1,5-dienes and 1,5-oligoenes, especially of terpenoid origins is developed. This method has been applied to the synthesis of (2 Z,6E)-, (2E,6Z)-, and (2Z,6Z)-farnesols, (2E, 6Z,10E)-geranylgeraniol, menaquinone-3, coenzyme Q3, and coenzyme Q10.
Degree
Ph.D.
Advisors
Negishi, Purdue University.
Subject Area
Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.