• 10.1021/ol4013958
  • Organic Letters
  • Volume 15
  • July 2013
  • pp 3306-3309

Total Synthesis of Spirobacillene A

Replicable (w/ Minor Modifications)

Details


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.

  1. 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.
  2. 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). 
  3. 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.



Comments

Reactions in the review aren't consistent with the paper

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

 I am not convinced that the review accurately assesses the original paper.

1. Sonagashira Coupling with TMS-Acetylene:

In the original paper, Iodo indole was used but 4-iodoanisole in its place can not really belittle the need of 60 oC in case of the former.

Why do you consider the reaction of 4-iodoanisole at room temperature to be a better method than reaction of iodo indole at 60 oC?

Clearly, the 4-iodoanisole has the electron donating -OCH3 group which propell the reaction at RT. So, the comparison is not correct.

The same argument follows for the use of TBAF by the authors of the paper. K2CO3 can not be used to deprotect the compound 3-((trimethylsilyl)ethynyl)-1H-indole (in original paper), but it can be in case of ((4-methoxyphenyl)ethynyl)trimethylsilane (as synthesised by you), again, because of the electron donating ability of  -OCH3 group.

The third point is about column chromatography.

The product 19, reported in the paper is different from what you have prepared. So, it is quite possible that you can get the pure product by running one column, while the actual process needs 2 runs. So, I don't consider this a valid point either.

2. Coupling with Weinreb amide:

The process you mention in the review, is totally inconsistent with the 1st point you wrote about Sonagashira Coupling with TMS-Acetylene. If you did not synthesize the compound 19 in 1st place, how could you even try the compound 21 in this step?

3. TFA Catalyzed Spirocyclization:

4. 4. Luche Reduction:

Both the steps 3 & 4 are inconsistent since the very first reaction is inconsistent with the original paper. So, none of the comparisons are justified.

Can you clarify the inconsistency ?

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