Facile Orthoester Formation in a Model Compound of the Taxol Oxetane: Are Biologically Active Epoxy Esters, Orthoesters, and Oxetanyl Esters Latent Electrophiles?

Abstract

Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday.A steroidal oxetanyl ester was synthesized in eight steps as a biomimetic model of taxol oxetane. The model compound was surprisingly reactive under acidic conditions, rearranging in the absence of H 2 O to a [2.2.1]-bicyclic orthoester. Both the oxetanyl ester and the orthoester readily hydrolyze to produce the same triol monoacetate. On the basis of the oxetanyl ester/orthoester rearrangement, a novel biochemical function is suggested for the epoxy esters and oxetanyl esters found in taxoids whereby dioxonium ions, generated from these functional groups, react with cellular proteins to form mixed orthoesters or ethers. A similar process could be involved in the mechanism of action of natural orthoesters such as resiniferatoxin.

Administering cultured Taxus cells with early precursors reveals bifurcations in the taxoid biosynthetic pathway

“…Thus, acetylation of the C5α-hydroxyl, at some stage of the pathway, is considered a prelude to oxetane (D-ring) formation via the sequential conversion of the 5α-acetoxy-4(20)-ene functional grouping to the corresponding β-epoxide, with the last step most plausibly involving intramolecular migration of the 5α-acetoxy moiety in the process of oxirane ring expansion (Figure 4) (Guéritte-Voegelein et al, 1987;Floss and Mocek, 1995;Giner and Faraldos, 2003). The question therefore arises as to when the acetylation at C5α occurs on the pathway to Taxol (1) and its congeners.…”

Sesquiterpenoids from Ligularia dentata

“…The NOE cross-peaks observed between HÀC(2) and HÀC(9), between MeO and H a ÀC (8), and between H b ÀC(8) and H a ÀC(15) implied that the 2-AngO group, the 6-MeO group, HÀC(1), and the side chain at C(9) were on the b-face of the ring system (Fig. 2, b).…”

“…1, a) implied connectivities of HÀC(5) 2 ) to both CH 2 (6) and to an OH group, of HÀC(9) to CH 2 (8), and of CH 2 (8) to HÀC (7). The HMBC spectrum of 1 ( Fig.…”

“…Accordingly, the structure of 1 was determined as (1E,5R)-3-acetoxy-9-(angeloyloxy)-5-hydroxybisabola-3,1(10),7(11)-trien-2-one 3 H-COSY spectrum of 2 ( Fig. 2, a) implied connectivities of HÀC (2) 2 ) to both HÀC(3) and HÀC(1), of HÀC(9) to CH 2 (8), and of CH 2 (8) to HÀC (7). The HMBC spectrum showed correlations between Me(12) and both C(7) and C(11), between Me(13) and both C(7) and C(11), between CH 2 (15) and both C(1) and C(9), between Me(14) and C(3), C(4), and C (5), and between the MeO group and C (6).…”

“…H-COSY spectrum of 4 (Fig. 4) implied connectivities of HÀC(9) to CH 2 (8), of CH 2 (8) to HÀC(7), and of HÀC (7) to the 7-OH group. The HMBC spectrum (Fig.…”