Total Synthesis of Stipiamide and Designed Polyenes as New Agents for the Reversal of Multidrug Resistance

Abstract

The synthesis of (−)-stipiamide (1) is reported together with the designed enynes 2 (6,7-dehydrostipiamide) and 3 that are now shown to reverse the multidrug resistance (MDR) of human breast cancer cells (MCF-7adrR). Stipiamide was assembled using a Stille coupling with (E)-vinyl iodide 17 and (Z)-stannyl amide 16 in 78% yield. (E)-Vinyl iodide 17 was made using a Takai reaction and a selective dihydroxylation of the terminal olefin of nonconjugated diene 7 using the Sharpless AD-mix reagent. The precursor to 16, (E,Z)-stannyl diene ester 13, was assembled with high selectivity in a single operation using a tandem syn-addition of tributyltin cuprate to acetylene followed by conjugate addition to ethyl propiolate. Structural variants 2 and 3 were assembled using palladium-catalyzed Sonogashira couplings with vinyl iodides 17 and 35 and acetylenes 22 and 26 in high yield at near 1:1 stoichiometry. Compound 2 was found to be far less toxic than stipiamide and performed much better as an MDR reversal agent. Compound 3 was better still due to even lower toxicity.

Synthesis of a C-9 to C-18 Building Block of the Phenalamides

“…5 A common building block for the synthesis of the phenalamides is the aldehyde 6. 1,5,6 We describe here our route to generate this aldehyde 6, using an allylation with the chiral (E)-a-chlorocrotylboronate (4) as key step to create the stereogenic centers at C-12 and C-13 (phenalamide numbering) (Scheme 2).…”

“…This seemingly simple transformation was quite difficult, giving a poor yield of 40% when carried out in THF. Andrus 6 used toluene at 90°C for the same transformation and obtained 55% of an 8:1 E:Z-mixture of 14. We found that the reaction carried out in refluxing CH 2 Cl 2 or in benzene at r.t. is higher yielding (93% to 96%) and furnishes product 14 free of the corresponding Z-isomer.…”

“…For the chain extension of the aldehyde 3 to generate the next two stereogenic centers, Andrus used Brown's crotylboration 6 reaction with (-)-(ipc) 2 -(E)-crotylbo-rane, 13 which proceeded with 7:1 diastereoselectivity. The minor diastereomer likely resulted from insufficient reagent control of diastereoselectivity.…”

Total Synthesis of the Callipeltoside Aglycon

“…Conventional coupling conditions ([Pd(PPh 3 ) 4 ], CuI, n BuNH 2 in benzene)22 failed to generate any of the desired product 29 . However, conditions developed for the coupling of electron defficient alkynyl amides23 [(Ph 3 P) 2 PdCl 2 ], CuI, i Pr 2 NH, in ethyl acetate) proved successful, affording the protected aglycon 29 in 93 % yield with retention of double bond geometry. Finally, deprotection of the TBS ether with TBAF, followed by treatment with catalytic PPTS in wet acetonitrile to hydrolyse the methyl acetal, provided the callipeltoside aglycon 30 .…”

Organotin Reagents in Cross‐Coupling Reactions

“…[97] made a vinylidene dibromide moiety react with the required vinyltin; the coupling was immediately followed by HBr elimination (Scheme 6.32); Trost et al [98] The more conventional vinyl-vinyl coupling methodology has been used in a total synthesis of stipiamide [99], for the completion of the side chain in a total synthesis of (−)-pateamine A [100], and in attaching the tetraenyl moiety (from the tin component) in syntheses of retinoic acid and some ring-modified analogs thereof [101]. A catalyst system first used by Negishi [102] a quarter of a century ago [(Ph 3 P) 2 PdCl 2 /Dibal-H] (Dibal-H, diisobutylaluminum hydride) was employed [103] in the completion of the lower side chain in (+)-manumycin A.…”