This paper was about first total synthesis of an indole alkaloid, Spirobacillene A and the key step of this approach was a Lewis acid catalyzed spirocyclization of an anisole derivative onto a tethered ynone.
I tried to replicate some of these reactions mentioned in this paper in my study towards the total synthesis of two imidazole alkaloids, spirocalcaridine A and B.
1. Sonagashira Coupling with TMS-Acetylene:
In the paper, the above reaction was done with a Iodo indole compound and I tried the above reaction with 4-iodoanisole.
- The first difference in reaction condition was the temperature, in original report, reaction temperature was 60°C and I carried out the above reaction at room temperature though duration of reaction in both cases was 2 h.
- The deprotection of TMS group was achieved using relatively expensive TBAF solution in original paper but I used less expensive K2CO3 in a mixed solvent (MeOH: THF = 1:1).
- Column chromatography was used to purify the products twice in the report but I used column chromatography only once to get the pure substituted alkyne although the yield in both cases was identical (92%).
2. Coupling with Weinreb amide:
In the original report, this reaction was carried out using alkyne (1 equiv.), Weinreb amide (0.9 equiv.) and n-BuLi (0.7 equiv.) in THF at -78°C and the yield was 76%. I tried the same reaction condition for my study but the yield was very poor (41%) in the first attempt. I was able to overcome this problem by changing the stoichiometry in the following way- alkyne (1 equiv.), Weinreb amide (1.1 equiv.) and n-BuLi (1.5 equiv.) and the final yield of my reaction was 76%.
3. TFA Catalyzed Spirocyclization:
The acid catalyzed spirocyclization of this yne-keto system was not found in literature and this report was the first example of this type cyclization using TFA as a catalyst. I tried to replicate this result using same reaction condition and I was able to synthesize desire product but the yield was 76% compared to 92% of the original report. Several attempts were made to improve the yield but led to formation of more color impurities.
4. Luche Reduction:
A selective reduction of cyclopentene-one in the cyclohexadienone moiety to form the allylic alcohol was performed at 0°C under Luche reaction condition in the report. I tried the similar reaction condition to reduced selectively the cyclopentene-one ring but even at 0°C, according to the 1H NMR of the crude material, both of cyclic ketones were got reduced. The same reaction was carried out at lower temperature (-5°C, -10°C, -20°C and -40°C) but failed to yield the desired selective reduction, both of the cyclic ketones got reduced to respective allylic alcohols.
In summary, I tried to replicate some methodology used in the above paper in a course of first total synthesis of Total Synthesis of Spirobacillene A. Although the functional group transformation was identical but the reactant molecules were different with respect to the original paper. In the article, all reactants were indole derivatives whereas in my study, all the reactants were phenyl derivatives, even though I was able to replicate the desire results with minor modification with almost similar rate of productivity and reproducibility. The modifications made by me could be attributed to the different electronics among the reactants which led to the different reactivity. In short, this article was very clear, innovative and informative and the results were reproducible in most cases even with different reactants.