Total synthesis of laulimalide: synthesis of the northern and southern fragments.
The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. bmtrost@stanford.edu
Barry M
BM
Trost
W Michael
WM
Seganish
Cheol K
CK
Chung
Dominique
D
Amans
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
D000475:Alkenes; D000480:Alkynes; D018942:Macrolides; C117305:laulimalide