Synthesis of Myrocin G, the Putative Active Form of the Myrocin Antitumor Antibiotics

Abstract

The antiproliferative antimicrobial fungal metabolites known as the myrocins have been proposed to cross-link DNA by double nucleotide addition. However, the nature of the DNA-reactive species is ambiguous, as myrocins have been isolated as functionally distinct 5-hydroxy-γ-lactone and diosphenol isomers. Based on literature precedent, we hypothesized that the diosphenol 7 (assigned here the trivial name myrocin G) is the biologically active form of the representative isolate (+)-myrocin C (1). To probe this, we developed a short enantioselective route to 7. A powerful fragment-coupling reaction that forms the central ring of the target in 38% yield and in a single step was developed. In support of our hypothesis, 7 was efficiently transformed to the bis(sulfide) 6, a product previously isolated from reactions of 1 with excess benzenethiol. This work provides the first direct access to the diosphenol 7, sets the stage for elucidating the mode of interaction of the myrocins with DNA, and provides a foundation for the synthesis of other pimarane diterpenes. Efforts to elucidate the mechanism of action of natural products are complicated when the metabolite can adopt two or more functionally distinct forms. This issue is exemplified by the antiproliferative antimicrobial metabolites myrocins C (1) 1 and B (2), 2,3 fungal isolates that contain a sensitive 5-hydroxy-γ-lactone residue (Scheme 1A, blue in 1 and 2). The literature indicates 4 this substructure undergoes facile ring opening to the corresponding diosphenol under mildly acidic or basic conditions, raising uncertainty about its fidelity under biological conditions. Consistent with this, the diosphenol isomer of 2, (−)-myrocin A (3), has been identified in fungal cultures. 5 Following their landmark total synthesis of (±)-myrocin C (1), 6 Chu-Moyer and Danishefsky disclosed that treatment of synthetic (±)-1 with excess thiophenol and triethylamine generated the bis(sulfide) 6 (63%, Scheme 1B). 7 The mechanism for formation of 6 was *

Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

“…[74] Accordingly, the Herzon laboratory targeted the chain isomer (À)-myrocin G( 143), which they postulated as the biologically active form of myrocin C(142). [75] TheH erzon laboratory developed af ragment coupling/ cyclization strategy to establish the C9 quaternary stereocenter and complete the central ring of (À)-myrocin G( 143) (Scheme 25). This approach led to the cyclopropyliodide 148 and the enoxysilane 147 as two synthetic precursors of similar complexity.T he first step was envisioned to involve the addition of an organometallic intermediate derived from 148 to 147.T his addition was anticipated to provide the desired C9 stereochemistry,d ue to maximization of orbital overlap (Bürgi-Dunitz approach) and minimization of nonbonding Scheme 25.…”

“…This approach led to the cyclopropyliodide 148 and the enoxysilane 147 as two synthetic precursors of similar complexity.T he first step was envisioned to involve the addition of an organometallic intermediate derived from 148 to 147.T his addition was anticipated to provide the desired C9 stereochemistry,d ue to maximization of orbital overlap (Bürgi-Dunitz approach) and minimization of nonbonding Scheme 25. Retrosynthetic analysis of (À)-myrocin G( 143)b yHerzon et al [75] Alloc = allyloxycarbonyl. interactions between the larger substituents (highlighted in gray spheres) in the transition state (Scheme 25).…”

“…Myrocin C ( 142 ) contains a γ‐hydroxylactone; related isolates deriving from opening of this ring have been characterized, and synthetic γ‐hydroxylactones are known to open under mildly acidic or basic conditions [74] . Accordingly, the Herzon laboratory targeted the chain isomer (−)‐myrocin G ( 143 ), which they postulated as the biologically active form of myrocin C ( 142 ) [75] …”

Fragmentverknüpfungen in der Totalsynthese – Bildung von C‐C‐Bindungen über intermediäre Carbanionen oder freie Radikale

“…[74] Herzon et al wollten daher das offene Isomer (À)-Myrocin G(143)synthetisieren, postulierten. [75] Dazu Diese Addition sollte wegen der maximierten Orbitalüberlappung (Bürgi-Dunitz-Annäherung) und der Minimierung nichtbindender Wechselwirkungen zwischen den grçßeren Substituenten (als graue Kugeln hervorgehoben) im Übergangszustand zur gewünschten C9-Konfiguration führen (Schema 25). [76] Die Synthese des a-Iod-a,b-cyclopropylketons 148 ging von dem b-Ketoester 149 aus, [77] der in zwei Stufen aus käuflichen Reagentien hergestellt wurde (Schema 26).…”

Controllable Si−C Bond Activation Enables Stereocontrol in the Palladium‐Catalyzed [4+2] Annulation of Cyclopropenes with Benzosilacyclobutanes

“…Thegood regio-, diastereo-, and stereoselectivity in the SiÀCb ond-cleavage-initiated functionalization/cycloaddition between three-and four-membered-ring systems were enabled by an electron-deficient phosphorus ligand and ac hiral phosphoramidite ligand, respectively.B icyclo-[4.1.0]heptane structural units are prevalent in numerous bioactive natural products. [14] Thus,t he reaction of (benzo)silacyclobutanes and cyclopropenes to give structurally diverse silacycles (silabicyclo[4.1.0]heptanes) significantly expands the potential of the silasubstitution strategy for the synthesis of bioactive molecules and natural products (Figure 1c). [15]…”