A Unified Strategy Targeting the Thiodiketopiperazine Mycotoxins Exserohilone, Gliotoxin, the Epicoccins, the Epicorazines, Rostratin A and Aranotin

Abstract

A unified synthetic strategy directed towards mycotoxins belonging to the thiodiketopiperazine family is reported. The building blocks for a number of natural products--including exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin--have been synthesised stereoselectively from a common precursor. This key intermediate was constructed through an efficient and highly diastereoselective [2+2] cycloaddition between a ketene and an enecarbamate derived from L-pyroglutamic acid. The annelation of the second ring was accomplished through ring-closing metathesis and enol ether-olefin ring-closing metathesis to provide both cis- and trans-annelated azabicyclic cyclohexenones, as well as an annelated seven-membered cyclic enol ether. A Pd-catalysed elimination of allyl acetate gave rise to the cyclohexadienol structure of gliotoxin. Dimerisation of one building block to afford the diketopiperazine core was demonstrated.

Graphiumins, new thiodiketopiperazines from the marine-derived fungus Graphium sp. OPMF00224

“…Type C has the five-ring system including one oxepane ring, to which apoaranotin 17 and its derivatives 15 belong. Type D has the symmetrical five-ring system, to which a number of compounds such as epicoccins, 23 epicorazines, 24 rostratins, 25 haematocins, 26 scabrosin esters, 27 brocazines, 28 exserohilones, 29 phomazine C 22 and SCH64874s 30 belong. Graphiumins A (1) to E (5) belong to type B, and graphiumins F (6) to H (8) belong to type C. Regarding the side chain extending from the central ring, all of the eight graphiumins (1 to 8) have long acyl chains.…”

A Combined Vinylogous Mannich/Diels–Alder Approach for the Stereoselective Synthesis of Highly Functionalized Hexahydroindoles

“…The applicability of our earlier method to condense two amino acids to give diketopiperazines [24] for complex hydroindole systems has already been proven in previous studies in our group. [11] …”

“…7), and Rostratin A (1). [11] This route, accomplishing the annelation of a second ring to a proline ring system by ring closing metathesis, gives 3a,7a-cis-and 3a,7a-trans-fused azabicyclic systems (for numbering and configuration see Figure 1). All of the synthesized cis-annelated substrates have a 2,3a-trans configuration.…”

Synthetic Studies on MPC1001: A Dipolar Cycloaddition Approach to the Pyrrolidine Ring System

“…To date, most synthetic approaches to the dihydrooxepin subunit in MPC1001 have only been achieved in very simple model systems. 2,3 Most model systems utilize a Cope rearrangement of cis -divinyl epoxides. Until recently, the oxepin ring had not been synthesized in a densely functionalized setting.…”