Total synthesis of marinomycins A-C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A.
Marinomycins A-C (1-3), and their monomeric analogues monomarinomycin A (m-1) and iso-monomarinomycin A (m-2), were synthesized by a convergent strategy from key building blocks ketophosphonate 5, aldehyde 6, and dienyl bromide carboxylic acid 7. The first attempt to construct marinomycin A [1, convertible to marinomycins B (2) and C (3) by light] by direct Suzuki-type dimerization/cyclization of boronic acid dienyl bromide 4 led to premature ring closure to afford, after global desilylation, monomarinomycin A (m-1) and iso-monomarinomycin A (m-2) in good yield and only small amounts (< or =2%) of the desired product. A subsequent stepwise approach based on Suzuki-type couplings improved considerably the overall yield of marinomycin A (1), and hence of marinomycins B (2) and C (3). Alternative direct dimerization approaches based on the Stille and Heck coupling reactions also led to monomarinomycins A (m-1 and m-2), but failed to deliver useful amounts of marinomycin A (1).
Nicolaou
K C
KC
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. kcn@scripps.edu
Nold
Andrea L
AL
Milburn
Robert R
RR
Schindler
Corinna S
CS
Cole
Kevin P
KP
Yamaguchi
Junichiro
J
D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D019281:Dimerization; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology
D000475:Alkenes; D007783:Lactones; D018942:Macrolides; C509125:marinomycin A; C509126:marinomycin B; C509121:marinomycin C