Avrainvillamide

Fig. 27 Suggested stephacidine B formation by artificial not enzyme-dependent dimerisation of avrainvillamide...

More complicated alkaloid structures like stephacidine B exhibiting the impressive number of 15 rings and 9 stereogenic centres may have originated by spontaneous, not enzyme-catalysed dimerisation of avrainvillamide. The efficient bio-mimetic conversion of the precursor molecule avrainvillamide into its dimer stephacidine B under diverse experimental conditions by two Michael additions and additionally the retro-dimerisation of the dimer would support a self-assembly mechanism for formation of the dimer B [153-155]. 

Wulff JE, Herzon SB, Siegrist R, Myers AG (2007) Evidence for the rapid conversion of stephacidin B into the electrophilic monomer avrainvillamide in cell culture. J Am Chem Soc 129 4898 1899... 

These studies, combined with observations that cells treated with avrainvillamide underwent increased p53 expression and that cells silenced with siRNA against nucleophosmin increased sensitivity to avrainvillamide, provided strong evidence that this event was indeed relevant to the cellular response and downstream entry into apoptosis. 

While an abundant nucleolar protein, this was the first study to identify a small molecule ligand to nucleophosmin. But although binding has been identified, the role in which dimerisation of avrainvillamide (to stephacidins)... 

Figure 3.15 Structures of (+ )-avrainvillamide, stephacidin B, notoamide B, a reduced analogue of avrainvillamide, and related affinity and fluorescent probes and controls. 

Myers AG, Herzon SB (2003) Identification of a novel Michael acceptor group for the reversible addition of oxygen- and sulfur-based nucleophiles. Synthesis and reactivity of the 3-alkylidene-3H-indole 1-oxide function of Avrainvillamide. J Am Chem Soc 125 12080-12081... 

Biosynthetically, 125 is considered to be a dimer of 127, which itself could be an oxidation product of 126. The manner in which two avrainvillamide units are linked strongly indicates a dimerization mode that has not yet been described for indole alkaloids. Initiation of the dimerization by a hetero-Michael addition reaction sets the stage for the synthesis of 125. Until now, three syntheses of stephacidin B (all based on the dimerization of avrainvillamide) have been accomplished, by Myers et al. [55], Baran et al. [57, 58], and Williams et al. [59]. 

Retrosynthetically, a base-catalyzed dimerization of 127 would afford stephacidin B. Avrainvillamide (127) was simplified as vinyl iodide 128 by cleavage of the dihydropyrano [2,3-g]indole-l-oxide moiety and palladium mediated coupling. An aminoacyl radical addition from 129 gave access to 128, while 129 could be derived from cyanide 130 through a hemiaminal formation/dehydration and conjugate addition. Finally, Strecker-like reaction of ketone 131 would fulfill nitrile 130 [55] (Scheme 22). 

Avrainvillamide (127) Scheme 23 Total synthesis of stephacidin B by Myers and coworkers... 

The approach of Baran and coworkers features the fact that stephacidin A (126), which is a reduced monomer biogenetically related to stephacidin B (125), can be oxidized to avrainvillamide (127). The retrosynthetic analysis fundamentally differs from that of Myers in that the indole nucleus is already present in the starting material. Thus, one stereocenter is in the starting material and the other two stereocenters are installed simultaneously [54, 58] (Scheme 24). 

Fenical W, Jensen PR, Cheng XC (2000) Avrainvillamide, a cytotoxic marine natural product, and derivatives thereof. U.S. Patent 6,066,635... 

Escolano C (2005) Stephacidin B, the avrainvillamide dimmer a formidable synthetic challenge. Angew Chem Int Ed 44 7670-7673... 

Baran PS, Guerrero CA, Hafensteiner BD, Ambhaikar NB (2005) Total synthesis of avrainvillamide (CJ-17, 665) and stephacidin B. Angew Chem Int Ed 44 3892-3895... 

Two sohd-phase syntheses of Af-hydroxy(alkoxy)indoles have been reported by Roy (equation 1) [91] and Wu (equa-tion2) [92] respectively (Scheme 15).TheAf-hydroxyindoles in equation 2 were alkylated regioselectively to give a library of 1,2-dialkoxyindoles after cleavage from the SynPhase lanterns [92]. In a program toward the synthesis of the alkaloids avrainvillamide and stephacidin B, Myers and Herzon synthesized 3-alkylidene-3//-indole 1-oxide (equation 3), which is the keystone unit of these novel alkaloids [93]. 

Scheme 14.12 Baran s syntheses of avrainvillamide (73) and the stephacidins (72 and 74) via domino deprotection/cyclization/rearrangement.

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