Asymmetric Total Synthesis of ent-(−)-Roseophilin:  Assignment of Absolute Configuration

Abstract

An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([alpha](25)(D), CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing an unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.

Activated Zinc Dust

“…Notably, zinc dust or an amalgam thereof has been used to reduce carbonyls 2 (Clemmensen reduction), carbon-oxygen bonds, 3 carbonhalide bonds, 4 alkynes, 5 heteroatom bonds (N-N and N-O bonds), 6 and to prepare numerous organozinc reagents. In addition to various reduction reactions, zinc has been employed in several named reactions including the Reformatsky reaction, 7 Serini reaction, 8 the Knorr pyrrole synthesis, 9 and the Simmons-Smith cyclopropanation.…”

Unravelling the Reaction Mechanism of the Reductive Ring Contraction of 1,2-Pyridazines

“…9,29 Since the computational investigation of such electron-transfer reactions between metals and organic substrates is very challenging (as it entails the constraining of the orbital occupancies along reaction coordinates that lack major nuclear displacements) we analyzed the order of the reduction/protonation events by comparing the energies of the two-(or four-) electron-reduced substrate (with or without protons donated by acetic or trifluoroacetic acid) with the energies needed to remove two electrons from Zn. For these computations, we needed to compute the deprotonation energies of acetic acid (288. for the energies of the electron-transfers from zinc to the substrate, but the order of the reduction/protonation events can nonetheless be ascertained with confidence.…”

“…6 The most widely used of these ring contraction strategies is the reductive contraction of substituted 1,2-pyridazines (I) to yield 3,4-substituted pyrroles (III) first used by Kornfeld et al 7 and widely studied 8 and popularized by Boger (Scheme 1). This zinc/acetic acid-catalyzed reaction is very tolerant of additional functionality around the ring (such as aryl methyl ethers, aryl benzyl ethers, ketones, esters and carbamates), and has been used in a large number of total syntheses of biologically active natural compounds such as roseophilin, 9 ningalin D 10 and lycogarubin C. 11,12 Electrochemical investigation 13,14 of this 4-electron reaction has shown that the mechanism may involve the formation of a 1,4-dihydropyridazine intermediate (II), which is sometimes stable enough to be isolated. 9 The reaction has been reported to proceed more smoothly when using trifluoroacetic acid instead of acetic acid, 9 but neither the precise order of reduction/protonation steps nor the characteristics of the ratedetermining steps or the influence of ring substituents have been elucidated.…”

“…This zinc/acetic acid-catalyzed reaction is very tolerant of additional functionality around the ring (such as aryl methyl ethers, aryl benzyl ethers, ketones, esters and carbamates), and has been used in a large number of total syntheses of biologically active natural compounds such as roseophilin, 9 ningalin D 10 and lycogarubin C. 11,12 Electrochemical investigation 13,14 of this 4-electron reaction has shown that the mechanism may involve the formation of a 1,4-dihydropyridazine intermediate (II), which is sometimes stable enough to be isolated. 9 The reaction has been reported to proceed more smoothly when using trifluoroacetic acid instead of acetic acid, 9 but neither the precise order of reduction/protonation steps nor the characteristics of the ratedetermining steps or the influence of ring substituents have been elucidated. In this work, we have studied the reaction mechanism using computational methods and analyzed the influence of substituents on the 3-and 6-position of the pyridazine ring on the reaction profile.…”

Diene, Enyne, and Diyne Metathesis in Natural Product Synthesis

“…In the case of Fürst-ner's acyclic metathesis substrate rac-277 [129], no additional conformational assistance was necessary, and treatment with catalyst A led to the corresponding macrocycles in high yield. In Boger's total synthesis of ent-273 [130], the macrocycle was closed efficiently by treatment of the monocyclic triene 278 with catalyst A. The formation of the ansa-macrocycle prior to formation of the cyclopentanone avoids, to a large extent, the strain to be overcome in compounds 275.…”