First total synthesis of dioxepine bastadin 3

Abstract

The synthesis of dioxepine bastadin 3, a tyrosine-tyramine derivative with a dibenzo-1,3-dioxepine scaffold that is rarely present among natural products, is described. The dibenzo-1,3-dioxepine ring was formed early in the sequence and the (E)-2-(hydroxyimino)-N-alkylamide was generated in the last step by oxidation of the 2-amino-N-alkylamide precursor. The presumably biogenetic late-stage ring formation starting from congener bastadin 3 failed. A new synthesis of this alkaloid was also developed. This new route requires a minimal use of protecting groups and the order of the two key steps was reversed relative to the route to dioxepine bastadin 3.

Synthesis of Biaryl‐Bridged Cyclic Peptides via Catalytic Oxidative Cross‐Coupling Reactions

“…Previous attempts to dimerize two tyrosine residues by chemoenzymatic, photochemical, electrochemical, or metal oxidation reactions have met with only limited success. A number of reasons may account for this lack of success: i) the relatively high oxidation potential of tyrosine precludes selective oxidation under mild conditions; ii) the dityrosine coupling product is more reactive than the parent tyrosine amino acid and is therefore prone to overoxidation; and iii) the tyrosyl radical can react through the ortho ‐ and para ‐positions as well as the hydroxyl group, leading to a mixture of coupling and dehydrogenation products. For example, the oxidative coupling of tyrosine 10 using 5,10,15,20‐tetraphenyl‐21 H ,23 H ‐porphine iron(III) chloride (Fe[TPP]Cl) (0.5 mol %) and urea hydrogen peroxide (UHP, 1 equiv) in HFIP (RT, 24 h, Table , entry 1), catalytic conditions that were developed in our group, afforded a complex mixture of dehydrogenative products (Figure A) from which trace amounts of dityrosine 13 were isolated.…”

Marine natural products

“…679 The synthesis of dioxepine bastadin-3 (Ianthella reticulata) 680 has been achieved. 681 A new cyclonucleoside 794 has been reported from Axinella polypoides (Calvi, Corsica, France). 611 Siphonodictyal sulfate 795 and akadisulfates A 796 and B 797 are antioxidant merosesquiterpenoids from Aka coralliphaga (Quintana Roo, Mexico), 682 while dysideavarones A-D 798-801 are cytotoxic merosesquiterpenes from Dysidea avara (Xisha Is., South China Sea).…”

Cytotoxic Compounds Derived from Marine Sponges. A Review (2010–2012)

“…The known bastadin 4 has shown strong cytotoxic activity against HCT-116 colon cancer cells with IC 50 value of 1.28 µM [ 151 ]. Total synthesis of dioxepine bastadin 3 has been performed by Pérez-Rodríguez et al [ 42 ] while the synthesis of bastadins in heterogeneous phase, starting from dopamine, has been reported by Decamps et al [ 152 ].…”

“…Given the importance of their cytotoxic effects, numerous natural products isolated from marine-sponges and their analogues and derivatives, have been synthesized to date [ 39 , 40 , 41 , 42 ]. These have proven to be—these and other bioassays—an important tool for developing potentially useful anticancer agents that are mainly naturally resistant to proapoptotic stimuli such as glioblastomas, melanomas, non-small-cell-lung cancers and metastatic cancers [ 43 , 44 ].…”