Total Synthesis of Herbimycin A

Abstract

[structure: see text] Hsp90 has recently emerged as a promising biological target for treatment of cancer. Herbimycin A and other members of the benzoquinoid ansamycin class of natural products are known to inhibit Hsp90 activity. The total synthesis of herbimycin A was achieved from the commercially available Roche ester 1 by using allylmetals to control the stereogenic centers at C6, C7, C10, C11, and C12 and a ring-closing metathesis to control the (Z)-double bond of the (E,Z)-dienic moiety.

Dinuclear Zinc‐Catalyzed Asymmetric Desymmetrization of Acyclic 2‐Substituted‐1,3‐Propanediols: A Powerful Entry into Chiral Building Blocks

“…[10] In order to demonstrate our method as a general entry into other 2-substituted-1,3-propanediols we chose to optimize our desymmetrization protocol on the next simplest 2-ethyl-1,3-propanediol 3, whose ester analog is not commercially available. Furthermore, the enzymatic desymmetrization of diol 3 has proven to be problematic.…”

“…A significant advantage of using such synthetic processes is that both enantiomers of the desymmetrized product can be obtained from the same starting material by simply reversing the chirality of the desymmetrizing element. [10] Fukumoto and coworkers developed the first synthetic method to obtain desymmetrized 2-substituted-1,3-propanediols in high enantiomeric purity by employing chiral auxiliaries. [11,12] Oriyama and coworkers developed the first non-enzymatic catalytic desymmetrization using a proline-derived diamine to desymmetrize meso 2-alkyl-1,3-propane diols.…”

Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides

“…Oxidation of 9 with Dess–Martin periodinane produced 3 in 88% yield. Similarly, the enantiomeric aldehyde 4 40 was synthesized from Roche ester 10 .…”

Macrocyclic Inhibitors of Hsp90

“…The molecule was termed herbimycin A due to its potent herbicidal activity against mono-and di-cotyledonous plants; this molecule also exhibits antifungal, anti-angiogenic and anti-tumor activities [22]. The absolute structure and configuration of HA was confirmed by Omura et al who reported that HA is a 19-membered macrocyclic lactam with seven stereogenic centers, a carbamate, an isolated tri-substituted (E)-double bond, and (E,Z)-diene and a benzoquinone ring system [111]. Structurally, this molecule resembles GA (Fig.…”

“…14), and it was logical to test its ability to modulate Hsp90, perhaps inhibiting its client proteins from binding to Hsp90, as well as its cytotoxicity against cancer cell lines. The first total synthesis of HA was reported in 1991 by Tatsuta et al [112], with other synthetic routes reported by Panek et al in 2004 [113] and Cossy et al in 2007 [111]. …”