Total Synthesis of (−)-Zampanolide and Questionable Existence of (−)-Dactylolide as the Elusive Biosynthetic Precursor of (−)-Zampanolide in an Okinawan Sponge

Abstract

A new and concise total synthesis of (-)-zampanolide, (-)-1, and (-)-dactylolide, (-)-2, is described. Synthetic highlights include (i) a mild Horner-Wadsworth-Emmons reaction providing the seco acid, (ii) an unusual stepwise cross-coupling reaction of a 1,1-dibromodiene with inversion of olefin geometry, and (iii) specific O-Michael reaction conditions using catalytic LHMDS with TMEDA for the synthesis of functionalized 2,6-cis-tetrahydropyran. A marine sponge extract was analyzed for the presence of (-)-2 as the biosynthetic precursor of (-)-zampanolide.

Synthesis and Cytotoxic Activity of N,N′-(Arylmethylene)bisamides

“…1 Hz, 1 H), 6.99 (t, J = 7. 5 Hz, 1 H), 6.93 (dd, J = 9.1, 3. 2 Hz,1 H),6.80 (d,J = 15.5 Hz,2 H), 3.80 (s, 3 H), 3.75 (s, 3 H).…”

“…5,6 In the construction of the aminal unit of (-)-1, the assembly of the (-)-dactylolide as the macrolactone part with the dienoylamide not only gave the desired (-)-1, but also gave a proportion of the N,N′-methylenebis(dienamide) (-)-2 as a byproduct. The cytotoxicity of (-)-2 was 10 -3 times weaker than that of (-)-zampanolide, although it still possessed an activity in the low micromolar range.…”

“…The cytotoxicity of (-)-2 was 10 -3 times weaker than that of (-)-zampanolide, although it still possessed an activity in the low micromolar range. 5 The specific structure and the potent cytotoxic activity of (-)-2 led us to design a new N,N′-bisalkenamide. We hypothesized that simplification of the N,N′-methylenebisamide segment of (-)-2 to an N,N′-arylmethylenebis(cinnamamide) might provide a new and unique functional small molecule with cytotoxic activity.…”

Asymmetric synthesis of the C(6–18) bis(tetrahydropyran)spiroacetal fragment of the lituarines

“…Among over 90 publications referring to the transformation (with enoates), examples include applications to: ambructin, 9 aspergillides A and B, 10 bistramides A and D, 11 brevetoxin B, 12 ciguatoxin fragments, 13 clavosolides A and B, 14 decarestrictine L, 15 gambierol, 16 goniothalesdiol A, 17 halichondrins, 18 herboxidiene, 19 lasonolide A, 20 leucascandrolide A, 21 miyakolide, 22 montanacin, 23 mucocin, 24 neopeltolide, 25 phorboxazoles A and C, 26 polycavernoside A, 27 pyranicin, 28 spirastrellolide A, 29 spongistatin 1, 30 vermiculine 31 and zampanolide. 32 In general, the geometry of the enoate double bond dictates the stereochemical outcome although the stereoselectivity may vary depending on the reaction conditions. Thus, the most common outcome is for E-enoates to cyclise kinetically to give the trans-2,6-disubstituted tetrahydropyrans, with the cis-diastereomers predominating under equilibrating conditions.…”

The Catalytic Synthesis of Carboniolamide: The Role of sp 3 Hybridized Oxygen

“…22 In 2009, Tanaka and his co-workers reported the p-TsOH-catalyzed addition of amide to aldehyde in their total synthesis of (-)-zampanolide, where carboniolamide was generated as a minor product along with the bisamide as the major outcome. 23 The only example of chemoselective direct addition of amide to aldehyde is presented by Ghosh employing chiral phosphate as catalyst. 24 So far the factor that stabilized the carboniolamide instead of its overreaction to bisamide is not clear.…”