Ruthenium-Catalyzed Alder Ene Type Reactions. A Formal Synthesis of Alternaric Acid

• Published in: Journal of the American Chemical Society Vol. 120; no. 36; pp. 9228 - 9236
• Main Authors: Trost, Barry M, Probst, Gary D, Schoop, Andreas
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.09.1998; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; ALCOHOLS; ALKENES; ACETYLENES; CROSS-COUPLING REACTIONS; ASYMMETRIC DIHYDROXYLATION; STEREOCHEMISTRY; CHEMISTRY; ALKYNES; DINOFLAGELLATE AMPHIDINIUM SP
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja981540n

Alternaric acid, a nanomolar fungal germination inhibitor, is typified by a 1,4-diene, consisting of a terminal methylene and an (E)-1,2-disubstituted alkene. A new strategy for the synthesis of natural products containing such functionality stems from the development of a ruthenium-catalyzed addition of terminal alkenes with terminal alkynes. The alkyne substrate, 4-pentynoic acid, is commercially available or can be prepared in two steps by alkylation of tert-butyl acetate. The alkene substrate is prepared from commercially available (S)-2-methyl-1-butanol. This synthesis involves formation of a geometically defined trisubstituted alkene by involving Pd-catalyzed cross-coupling and asymmetric dihydroxylation. The ruthenium-catalyzed coupling proceeds best in the absence of alcohol protecting groups to maximize regioselectivity. The examples of this addition illustrated herein help elucidate some of the important factors controlling regioselectivity. They also illustrate the excellent chemoselectivity. The acyclic unit of alternaric acid, which is simply coupled to a dihydropyrone fragment to complete the synthesis, is available in only 11 steps and 27% overall yield compared to the one extant synthesis also starting from (S)-2-methyl-1-butanol which proceeds in 26 steps and 0.003% overall yield. This new reaction provides a powerful tool in streamlining this synthesis and should prove more generally useful.