Syntheses of Combretastatin A‐4 and Related Stilbenes by Using Aqueous Conditions

Natalie G Barnes,John A Hadfield,Nadia Charafi,Patricia A Ragazzon,Amjed A Ahmed Mal Ullah

doi:10.1002/slct.202101960

Abstract

AbstractCombretastatin A‐4 (CA4) is a potent anti‐mitotic and vascular disrupting agent. Organic chemists have been working to optimize the synthesis of CA4 for the past 3 decades, with methods requiring hazardous solvents and harsh reaction conditions. Here, we report the synthesis of CA4 and a variety of stilbenes in an aqueous Wittig system. Potassium carbonate or lithium hydroxide were used as base in this Wittig reaction to give excellent yields of mixtures of E‐ and Z‐stilbenes. The synthesis of CA4 was achieved using tetrahydropyran (THP) or silyl protected phenolic aldehydes. The THP groups were removed using dilute acid whilst the silyl groups fortuitously fell off during work up.

Highlights

Until recent years, chemists have synthesised target molecules without realising the environmental impacts of the solvents and reagents required in these synthetic procedures.[1]
For these Wittig reactions both lithium hydroxide and potassium carbonate were used as a base
The methodology described has shown that the Wittig reaction using both potassium carbonate and lithium hydroxide in water can be used to synthesise the antivascular agent combretastatin A- 4 (1 a) in good yield

Summary

Introduction

Chemists have synthesised target molecules without realising the environmental impacts of the solvents and reagents required in these synthetic procedures.[1]. Methods which produce solely the Z-isomer of CA4 (1 a) have been described.[12] One method uses a Suzuki coupling starting from isovanillin (6) (Scheme 2) This method produces solely Z-CA4 (1 a) it requires protection and deprotection of the phenol to allow a good yield of the intermediate dibromo olefin (9) and the use of a toxic tin reagent and carbon tetrabromide to provide the Z-vinyl bromide (10). Suzuki-coupling of this Z-iodostyrene (14) compound with 3-hydroxy-4-methoxyphenyl boronic acid (15) produced solely Z-CA-4 (1 a) in 78 % yield, avoiding the need for protection and deprotection steps, and more importantly avoiding the use of highly toxic carbon tetrabromide and tin Another method that produces solely the Z-isomer is the Perkin condensation reaction reported by Gaukroger et al in 2001. Acid hydrolysis afforded stilbene (23) predominantly as the Eisomer (< 5 % Z) (Scheme 6).[17]

Results and Discussion

Conclusion

Conflict of Interest