Wednesday, August 15, 2012

For Your Consideration...

A New, Improved 47-Step Synthesis of Shootmenowicene

Editor: We originally sent a 1600 x 1200
color abstract. Just picture a 15-member
macrolide, densely functionalized with
heterocycles, five stereocenters,
 and chelated iron.
Abstract: Shootmenowicene, a heterocycle-containing polyketide macrolide polyene siderophore, was originally isolated in 0.009% from immature sprouts of the Bungus bungus tree. We report herein a significantly shortened 47-step route to the natural product (down from 48), which we believe will allow for kilo-scale synthesis for future clinical trials.

Synthetic highlights include: extensive use of Yamamoto's "super-silyl" protecting group, a Sezen C-H arylation / macrocyclization, kilo-scale flash-vacuum pyrolysis (FVP), and enantioselective tributyltin hydride reduction. Efforts to adapt "green" chemical considerations have been made - the penultimate oxidation occurs by swirling flask in open air for three days over twenty equivalents iron oxide catalyst.

This streamlined route utilizes seventeen silica gel purifications, four alumina plugs, two resolutions: D(-)-tartaric acid and 1R(-)-10-camphorsulfonic acid (the expensive ones, sorry!), and a one-pot global HF / Hg / chromic acid deprotection protocol. Overall yield was 0.0008%, as a mixture of diastereomers (brsm).

Two medicinally active methylated analogues will be reported in due course.

Thanks to Derek for the initial inspiration, with a gentle nudge courtesy of Chemjobber.

15 comments:

  1. Excellent, although including a galactic magnetic field-catalyzed chiral intermediate synthesis starting from achiral materials might cut it down to 46.

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    1. We'd like to bring you on as a consultant, here at Obscurenaturalproductplex (slogan: if Nature can make it, we probably can, too!)

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  2. You forgot to mention the preparatory scale TLC you hid in the middle of it. That is going to be fun sitting there for half an hour spotting the plate.

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  3. Step 14 could also be accomplished using sodium hydroxide as the oxidant.

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    1. dangit - autocorrect messed up my lame joke. Yes, hydride.

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  4. Isn't Shootmenowicene just 7-deaza-Timewastotoxin? My group is looking at the total synthesis from benzoic acid and coal, but we're having some issues with this Wittig homologation in the middle...

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    1. You got me. Perhaps we can joint publish : )

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  5. LOL! I had difficulty reading this aloud to my wife without snickering.

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    1. I like that someone would consider this romantically inclined. Candles not included, but it supplied the whine.

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    2. After laughing at this until we startled the neighbors, we danced an Irish jig to the traditional tune "Paradimethylaminobenzaldehyde" (remember, it's dactylic tetrameter).

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  6. Oh total synthesis, how I don't miss you in the slightest...

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  7. This is very funny. And you generate quite the traffic spike these days, you know...

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  8. Am I the only one that read 'Yamamoto's "super-silyl" protecting group' as 'Yamamoto's "super-silly" protecting group'?

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