• 10.1021/jm301323k
  • Journal of Medicinal Chemistry
  • Volume 55
  • December 2012
  • pp 10662-10673

Bile Acid-Based 1,2,4-Trioxanes: Synthesis and Antimalarial Assessment(1)

Decarboxylative oxidation of lithocholic acid

Details


Summary:

A new series of bile acid-based trioxanes have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route.

The Reaction of Interest:

Decarboxylative oxidation of the O-acylated lithocholic acid derivative 11 into alkene 12.

3α-Acetyl-24-nor-5β-chol-22-ene (12). Pyridine (50.0 mL) and

cupric acetate (1.66 g, 8.3 mmol) were added to a solution of 11 (10.0

g, 23.9 mmol) in dry benzene (100 mL), and the reaction mixture was

heated to 90 °C under N2 atmosphere. Lead tetraacetate (30.0 g, 67.7

mmol) was added in portions during and the reaction mixture was

refluxed for additional 12 h. It was cooled to room temperature and

filtered through Celite; the residue was washed with benzene (75 mL).

Addition of water (100 mL) and extraction with benzene yielded an

organic layer that was further stirred with 1N HCl (200 mL) for 30

min. The benzene layer was separated and washed with water (100

mL) followed by saturated aq NaHCO3 (100 mL). The organic layer

was dried over anhyd Na2SO4, concentrated in vacuo at rt, and the

crude product was purified by column chromatography over silica gel

using EtOAc−hexane (2:98) to furnish 12 (6.15 g, 69% yield) as a

white solid; mp 80−82 °C.

According to the described procedure, the O-methylated lithocholic acid was converted into the corresponding alkene in 40% yield (15 mmol scale).

Practical Observations:

  • The reaction is reproducible and scalable up to 15 mmol.

Recommendations:

  • An efficient stirring is required for this reaction.
  • Freshly purchased Pb(OAc)4 is required for efficient conversion
  • Benzene was replaced with toluene for extraction of the product.


Comments

A much more greener approach is needed

Arnab Bhattacharya
(13)
PhD, Inorganic & Computational Chemistry, Tripura University, 4yrs

The original paper reports the use of benzene & you have used toluene for extraction of the product. But the reaction medium was still benzene.

Apart from benzene, the other chemicals used like Cupric acetate, pyridine and lead acetate. Is it possible to replicate the reaction using milder reagents?

The yields are also nothing to speak of. Hence, it will be better if greener methods are used. I would like to know of any alternative method you might have tried.

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