Field of Science

Panek's Leucascandrolide A

A colleague presented Panek's leucascandrolide A (LA) synthesis in a group meeting. Several interesting steps were included in the synthesis, and several interesting questions came up.

For example, in one case, when he is doing the [4+2] allylsilane cycloaddition, there is an ester group axial in a TS that gives the 'right' product. When he increases the bulk of the alkyl group on the ester, the proportion of this product actually goes up.

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A larger alkyl group will naturally have a larger A value, so why should it be preferred in an axial disposition? My surmise; as the group size increases, the ester prefers increasingly a conformation in which its carbonyl is directed inward, thus getting rid of the unfavourable interaction. Interesting how steric hindrance can cause a group to orient itself in such a way that makes the reaction more favourable.

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(The conformation to the left is prefered as R becomes larger)

Also, he used Kozmin's spontaneous macrolactonization, an entropically unfavourable event. In another step, he oxidises a secondary alcohol in the presence of a primary one using a tungsten catalyst. How does this happen? My guess; there can be a radical mechanism involved and then the secondary radical will be more stable than the primary radical obviously.

Overall an interesting, if a little long, synthesis.

J. Org. Chem., ASAP Article 10.1021/jo0610412 S0022-3263(06)01041-3
Web Release Date: September 1, 2006


  1. can you provide me some link regarding A value just to refresh my memory? thx

  2. It's the energy difference between the ground states of two conformers, one in which a substituent is axial and the other one in which it's equatorial. Therefore, the A value is for that particular substituent. Take a look at Ernest Eliel's book, or the original reference by Winstein and Holness in JACS (1955), pg. 5562

  3. If you look closely at the transition state you have drawn (if the reaction is operating under that TS) you have olefins at the 1,3-diaxial intersections. I assume that the substituents then reside in pseudoequatorial positions. Now the axial ester should actually experience no 1,3-interaction. Thus this is actually the more stable conformation and as larger groups are attached to the ester the other TS (where the ester is equatorial) is actually more destabilized.

    Would you buy that for a dollar?


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