Synthesis of Benzoquinone Ansamycin‐Inspired Macrocyclic Lactams from Shikimic Acid

Abstract

One is not like the other: The title approach proceeds by stepwise coupling of three relatively simple substrates. Three natural product‐inspired agents are described, one of which has natural product‐like toxicity for HeLa and MCF7 cells. It is isoform‐selective, thus targeting Hsp90α/β over Grp94, and adopts a conformation similar to that of geldanamycin when complexed with Hsp90.

(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones

“…Because of this, the required azadiene, 13 was obtained from the (-)-shikimic acid, according to the synthetic pathway shown in Scheme 1 . Firstly, the (-)-shikimic acid ( 6 ) was transformed to 10 using reaction conditions reported by Jeso et al [ 35 ]. Later, 10 was treated with diisobutylaluminum hydride solution (DIBAL-H) in toluene at −78 °C and gave the corresponding allylic alcohol, 11 , in a 92% yield.…”

“… Conditions and reagents : (a) REF [ 35 ]; (b) DIBAL-H, toluene, −78 °C, 2 h (92%); (c) PCC, CH 2 Cl 2 , r.t., 1 h (51%); and (d) NH 2 NMe 2 , MgSO 4 , CH 2 Cl 2 , r.t., 24 h (42%). …”

Metallacycle-mediated cross-coupling in natural product synthesis

“…This chemistry fueled an SAR study that ultimately led to the discovery of valerjesomycin (Figure 8A) as a benzoquinone ansamycin-inspired agent with exquisite paralog selectivity for Hsp90α and Hsp90β over Grp94. 29 As illustrated in Figure 8B, these investigations targeted the construction of the C7–C8 bond by metallacycle-mediated cross-coupling between 15 and 16 . After hydrolysis of the ester, this sequence delivered seco-acid 17 in 52% yield as an 8:1 mixture of regioisomers.…”

Rh-Catalyzed Reactions of 1,4-Benzoquinones with Electrophiles: C–H Iodination, Bromination, and Phenylselenation

“…9 Finally, geldanamycin, a benzoquinone-based member of the ansamycin family, is a potent inhibitor of Hsp90 and has provided inspiration for the development of new anti-tumor compounds. 10,11 Unsurprisingly, there has been significant recent interest in the development of methodologies for the C-H functionalization of benzoquinones, especially as such approaches might allow analogue synthesis by late stage derivatization. 12 Predominant efforts have focused on C-C bond forming strategies that exploit the high electrophilicity of the quinone core.…”

“…Recently, embelin, a naturally occurring quinone isolated from Embelia ribes , has been described as an effective photodynamic therapeutic candidate for the treatment of tumors. , Memoquin is of interest as a multitarget-directed ligand for the development of Alzheimer’s therapeutics . Finally, geldanamycin, a benzoquinone-based member of the ansamycin family, is a potent inhibitor of Hsp90 and has provided inspiration for the development of new antitumor compounds. , …”