Novel and Flexible Entries into Prostaglandins and Analogues Based on Ring Closing Alkyne Metathesis or Alkyne Cross Metathesis

• Published in: Journal of the American Chemical Society Vol. 122; no. 48; pp. 11799 - 11805
• Main Authors: Fürstner, Alois, Grela, Karol, Mathes, Christian, Lehmann, Christian W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.12.2000; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; F-SERIES; TRIPLY CONVERGENT SYNTHESIS; MOLLUSK TETHYS-FIMBRIA; 3-COORDINATE MOLYBDENUM(III); ACETYLENE METATHESIS; ALKYLIDYNE COMPLEXES; CATALYST SYSTEMS; OLEFIN METATHESIS; MARINE MOLLUSK; METAL-CARBON BONDS
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja003119g

The suitably functionalized cyclopentanone derivatives 12, 13, 19, and 37 serve as common precursors for the synthesis of various prostaglandins, prostaglandin-1,15-lactones, and unnatural analogues thereof. All of them contain a 2-butynyl entity which is elaborated into the intact α side chain of the targets either via a sequence comprising ring closing alkyne metathesis/Lindlar reduction or via alkyne cross metathesis (ACM)/Lindlar reduction. These novel approaches are distinguished by (i) the ready accessibility of the required cyclopentenone substrates via a three-component coupling reaction, (ii) the inherent flexibility which allows one to make a series of analogues starting from these common platforms, (iii) a small number of steps, and (iv) an excellent overall yield. The key alkyne metathesis reactions are efficiently catalyzed either by the tungsten alkylidyne complex (t-BuO)3W⋮CCMe3 or, preferentially, by a catalyst formed in situ from Mo[N(t-Bu)(Ar)]3 and CH2Cl2, the reactivity of which can be fine-tuned by varying the Ar substituent on the amido ligands. These organometallic tools exhibit a remarkable application profile, tolerate an array of polar groups, rigorously distinguish between different π-electron systems, and catalyze the reactions under conditions that are sufficiently mild to preserve even highly sensitive functionalities. The structures of the macrocyclic prostaglandin lactone derivatives 22 and 32 were characterized by X-ray crystallography.