Development of Synthetic Methodology Suitable for the Radiosynthesis of Combretastatin A-1 (CA1) and Its Corresponding Prodrug CA1P

Abstract

Synthetic methodology has been established suitable for the preparation of combretastatin A-1 (CA1) and its corresponding phosphate prodrug salt (CA1P) in high specific activity radiolabeled form. Judicious selection of appropriate phenolic protecting groups to distinguish positions on the A-ring from the B-ring of the stilbenoid was paramount for the success of this project. Methylation of the C-4' phenolic moiety by removal of the tert-butyldimethylsilyl protecting group in the presence of methyl iodide was accomplished in excellent yield without significant Z to E isomerization. This step (carried out with (12)C-methyl iodide as proof of concept in this study) represents the process in which a (14)C radioisotope could be incorporated in an actual radiosynthesis. CA1 is a natural product isolated from the African bush willow tree (Combretum caffrum) that has important medicinal value due, in part, to its ability to inhibit tubulin assembly. As a prodrug, CA1P (OXi4503) is in human clinical trials as a vascular disrupting agent.

Amine‐ and Sulfonamide‐Promoted Wittig Olefination Reactions in Water

“…[2] For example, the Wittig reaction employing ylides derived from triphenylbenzyl phosphonium salts is the most popular route to cis-and trans-stilbenes. [3] The process is typically high yielding but suffers from poor to moderate stereocontrol requiring removal of the phosphane oxide as well as separation of the stereoisomers.…”

ortho-Formylation of oxygenated phenols

“…78,79 Chemoenzymatic syntheses of CA-1 (19) and CB-1 (28) have been reported in good overall yields. 80 Also a one-pot ortho-formylation-Dakin oxidation reaction 81 developed in our group, combined with a Sonogashira coupling reaction yielded, the diaryl alkyne 47 (Scheme 3).…”

An Efficient Synthetic Strategy for Obtaining 4-Methoxy Carbon Isotope Labeled Combretastatin A-4 Phosphate and Other Z-Combretastatins

“…Substitution of a CA4P A-ring methyl group with a [ 11 C]methyl seemed to offer the fewest difficulties10b and would also utilize some of the synthetic procedures we previously developed for synthesizing combretastatin A-3, the 3-desmethyl derivative of CA4 12. When an approach based on the 3-hydroxy-4,5-dimethoxyphenyl A-ring of combretastatin A-3 was discontinued owing to geometrical isomerization problems at the stilbene stage, attention was next focused on a 3,5-dimethoxy-4-hydroxyphenyl A-ring precursor that would lead to phenol 3 and allow methylation without cis/trans isomerism.…”

“…A selection of procedures for the methylation of 4-phenol 3 were attempted using CH 3 I, as this would be a choice methylating agent for producing a [ 11 C]methylated derivative. However, all attempts to methylate the phenol ( 3 ) with CH 3 I resulted in cis/trans isomerization 10a. Therefore, a new approach that would avoid isomerization by way of direct conversion of the silyl ether to a methyl ether was examined.…”

“…A [ 11 C]methyl group was selected as the most efficient method, which required completion of an appropriate new synthesis of CA4 and now remains a most practical option. Meanwhile, a variety of other new syntheses of CA49a,b and its analogues9c–g have been reported, as well as syntheses of CA1P radiolabeled with a [14C]methyl group in high specific activity10a and [ 11 C]methyl derivatives10b of resveratrol ( 2 ), augmented by other structural modifications8j of this increasingly important naturally occurring stilbene 8h…”