Part I: An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

Part I: An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

Ke Kong, John A. Enquist, Jr., Monica E. McCallum, Genessa M. Smith, Takanori Matsumaru, Elnaz Menhaji-Klotz, and John L. Wood


I decided to have a closer look at this and a second paper from the Martin group quite a while ago but I could not find the time to finish the write-up. I recently moved to a new place and had to get everything managed in time… Well I am not done yet but somehow I found the time to get this first piece done. The second paper on this topic will follow within the next few days.

 Scheme 1


At the outset of Wood’s work the group decided to target the different stereocenters independently. This would enable them to diversify the strategy later towards the synthesis of different members of this class of natural products. It should be noted at this point that their initial strategy made use of L-alanine which was expected to yield ent-citrinadin B. Instead it turned out this strategy actually furnished citrinadin B.

The retrosynthetic analysis is shown in scheme 2. Gold mediated oxygenation of an alkyne would introduce the side-chain ketone while the epoxide derives from Enders’ epoxidation. Sonogashira cross coupling and regioselective epoxide opening would then lead to the bromo-oxindole shown. Extrusion of one carbon via Corey-Chaykovsky epoxidation and [3+2] nitrone cycloaddition leads to the unsaturated ketone depicted. Reductive Trost enyne coupling and Heck coupling ultimately tracks back to dibromoaniline and L-alanine derived nitrone.

 Scheme 2


In the first step dibromoaniline 1 undergoes trimethylaluminum mediated amidation and TBS protection to give enamide 2 which cleanly underwent Heck reaction to give 3 as the expected racemic mixture. Benzylation of the amide nitrogen, TBS cleavage and Swern oxidation of the resulting alcohol then furnished aldehyde 4. Alkynylation and another TBS protection set the stage for a neat reductive Trost enyne coupling. Desilylation and Swern oxidation produced unsaturated spiro ketone 6. As mentioned above the group needed a racemic mixture to explore the synthesis of other members of this group of natural products containing the enantiomeric spirocyclic center.

Scheme 3


With ketone 6 in hand the crucial nitrone cycloaddition was examined. Fortunately the group found that in the presence of L-proline only two of the four possible diastereomers were formed in moderate and good yield, respectively. Though diastereomer 7b displayed the minor stereoisomer the group was able to produce enough material by this strategy.

Corey-Chaykovsky epoxidation was used to introduce the missing methylene group. This was opened by in situ generated TMSI to give ammonium salt 9 which was reduced under Clemmensen conditions yielding diol 10.

Scheme 4


Moving on with the synthesis the group transformed the diol into the corresponding epoxide 11 by chemoselective mesylation and cyclization. Sonogashira coupling and concomitant oxidative debenzylation with t-BuLi in the presence oxygen set the stage for regioselective epoxide opening with sodium azide yielding alkyne 13. Gold catalyzed oxygenation was followed by Enders’ diethylzinc mediated epoxidation and Boc protection to give a 1 : 1 mixture of epoxides 15a and 15b. Interestingly the Martin group also utilized the same strategy to introduce the unsaturated ketone and Enders’ epoxidation.

 Scheme 5


These could be elaborated by a three step sequence into ent-citrinadin B and citrinadin B. At this point the group surprisingly found that the published spectra of citrinadin B matched with the spectra of what was believed to be ent-citrinadin B.

Stay tuned for the Martin synthesis of citrinadin A.

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2 Responses

  1. Since this synthesis used racemic 6 as an intermediate why is it enantioselective? Was a resolution done somewhere?
    In Scheme 2 the arrow to the nitrone should be from the structure on the right.
    12 to 13: t-BuLi in the presence (of) oxygen? Wouldn’t that yield a fireball?
    14 to 15: Diethylzinc and oxygen? Wouldn’t that be another fireball?
    How did they know which product had structure 15a and which was 15b?

  2. Hey, thx for the questions.
    So first of all it is not racemic because the nitrone they employed derived from alanine so they got diastereomers which could be separated after the [3+2] and essentially resolved the spiroindolinone.

    To the deprotection step: most likely the carbonyl oxygen of the oxindole stabilizes an intermediate benzylic anion after deprotonation of the benzyl group by tBuLi (it might also direct the base). After the introduction of oxygen this will give a you some sort of hydroperoxide or hemiaminal which collapses to the deprotected oxindole during work-up.

    The diethylzinc method by Enders works through an in situ formed hydroperoxide anion which can undergo a Scheffer-Weitz-type epoxidation of the unsaturated ketone. One way to predict the outcome of the reaction in advance has been provided by Enders. The group therefore used an ephedrine mediated methodology which gave them a d.r. of 7 : 1 in favor of the (as later discovered) desired diastereomer. Furthermore by comparing the CD spectra of their synthetic material with the spectra provided they determined its absolute configuration.

    I do not think there are fireballs involved in any of the steps mentioned ;)

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