Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B

Abstract

Irciniastatin A (a.k.a. psymberin) and irciniastatin B are members of the pederin natural product family, which have potent antitumor activity and structural complexity. Herein, we describe a full account of our total synthesis of (+)-irciniastatin A and (-)-irciniastatin B. Our synthesis features the highly regioselective Eu(OTf)3-catalyzed, DTBMP-assisted epoxide ring opening reaction with MeOH, which enabled a concise synthesis of the C1-C6 fragment, extensive use of AZADO (2-azaadamantane N-oxyl) and its related nitroxyl radical/oxoammonium salt-catalyzed alcohol oxidation throughout the synthesis, and a late-stage assembly of C1-C6, C8-C16, and C17-C25 fragments. In addition, for the synthesis of (-)-irciniastatin B, we achieved the C11-selective control of the oxidation stage via regioselective deprotection and AZADO-catalyzed alcohol oxidation. The synthetic irciniastatins showed high levels of cytotoxic activity against mammalian cells. Furthermore, chemical footprinting experiments using synthetic compounds revealed that the binding site of irciniastatins is the E-site of the ribosome.

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

“…The N-Boc derivatization of (rac)-16 (87% yield), followed by alkaline methanolysis (74% yield) [17] and Pinnick oxidation (43% yield) [18][19][20], delivered carboxylic acid (rac)-19. Unfortunately, an attempt to improve the oxidation yield was not fruitful; the oxidation of aldehyde (rac)-18 with TEMPO [21] resulted in a lower yield (28%). The carboxylic acid (rac)-19 was then esterified with ʟ-(−)-menthol (8) for a chiral resolution.…”

Predominately Uncultured Microbes as Sources of Bioactive Agents

“…Representative examples of these compounds have been synthesized by considerable numbers of organic chemists in the last 10 plus years. The following papers should be consulted by readers interested in the synthetic processes used (Jewett and Rawal, 2007; Jiang et al, 2007; Nishii et al, 2009; Wan et al, 2011; Wu et al, 2011, 2012; Mosey and Floreancig, 2012; Floreancig, 2014; Uesugi et al, 2015). Of these, the review by Mosey and Floreancig (2012) gives a relatively thorough overview of the isolation, biological activities, and medicinal chemistry of these agents.…”

Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents

“… 9 , 10 Finally and very recently, Usui and co-workers suggested that the irciniastatins are similar to mycalamide B, another member of the pederin family, that binds to the E-site of the ribosome to inhibit protein translation. 11 …”

“… 14 The total synthesis of the more active of the two irciniastatin congeners, (−)-irciniastatin B ( 2 ), was subsequently completed in our laboratory in 2012 18 via augmentation of our earlier synthesis of (+)-irciniastatin A ( 1 ) 14 and then recently by Iwabuchi and co-workers (2015). 11 In view of the continuing synthetic and biological interest in the irciniastatins, we undertook the design, synthesis, and biological evaluation of a structurally diminutive congener of the irciniastatins ( 6 ; Figure 3 ), as well as several C (11)-irciniastatin analogues ( 7 – 11 , Figure 3 ), available from late-stage intermediates in our total synthesis campaigns.…”