Total Synthesis of cyclo‐Mumbaistatin Analogues through Anionic Homo‐Fries Rearrangement

Abstract

The structurally unique polyketide mumbaistatin is the strongest naturally occurring inhibitor of glucose-6-phosphate translocase-1 (G6P-T1), which is a promising target for drugs against type-2 diabetes mellitus and angiogenic processes associated with brain tumor development. Despite its high relevance, mumbaistatin has so far withstood all attempts towards its total synthesis. In the present study an efficient total synthesis of a deoxy-mumbaistatin analogue containing the complete carbon skeleton and a spirolactone motif closely resembling the natural product in its cyclized form was elaborated. Key steps of the synthesis are a Diels-Alder cycloaddition for the construction of the fully functionalized anthraquinone moiety and an anionic homo-Fries rearrangement to build up the tetra-ortho-substituted benzophenone core motif, from which a spiroketal lactone forms in a spontaneous process. The elaborated strategy opens an entry to a variety of new analogs of mumbaistatin and cyclo-mumbaistatin and may be exploited for the total synthesis of the natural product itself in the future.

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…Schmalz et al [202] recently reported a tandem anionic homo-Fries rearrangement/ lactonization [203] for the synthesis of cyclo-mumbaistatin analogue 436 (Scheme 105).…”

“…Thus, the reaction sequence was optimized to maximize the yield of 439, proposed to arise from dehydration of the intermediate hemiacetal 441, followed by Ferrier rearrangement (Scheme 107). By inclusion of Scheme 105 Anionic homo-Fries rearrangement in the synthesis of a spiroacetal [202] Scheme 106 Unexpected Ferrier rearrangement in the synthesis of the southern hemisphere of spirastrellolide B [28] Scheme 107 Optimization of the Ferrier rearrangement in the synthesis of the southern hemisphere of spirastrellolide B [28] PTSA in the reaction sequence, the yield of the unsaturated spiroacetal 443 could be improved from 24 % to 62 %.…”

Advanced Routes in Synthesis and Reactions of Lawsone Molecules (2‐Hydroxynaphthalene‐1,4‐dione)

“…Stirring compound 1 with acetic anhydride in ethyl acetate in the presence of triethylamine for 4.5 h at 5–10°C gave 1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl acetate ( 307 ) in yield 80% . Refluxing compound 1 with SO 2 Cl, oxyalyldichloride in DMF , Br 2 or any bromating agent in AcOH afforded 2‐halonaphthalen‐1,4‐dione 308 . Also, heating 1 with 1‐bromo‐3‐methylbut‐2‐ene in DMSO in the presence of sodium hydride (NaH) at 45°C for 2 h produced 2‐((3‐methylbut‐2‐en‐1‐yl)oxy)naphthalen‐1,4‐dione ( 309 ) .…”

Influence of coordinating groups of organotin compounds on the Fries rearrangement of diphenyl carbonate

“…16,17 Fries rearrangement has been extensively used in the synthesis of organic pharmaceuticals and gradually become a research hotspot in recent years. [18][19][20][21][22] In the synthesis of DPC, organotin, organotitanium and other Lewis acids are usually used as catalysts, and the pilot-scale amplication reaction is carried out under high temperature and high pressure.…”