Total Synthesis of (-)-Dendrobine

Total Synthesis of (-)-Dendrobine

Lukas M. Kreis and Erick M. Carreira

DOI: http://dx.doi.org/10.1002/anie.201108564

Dendrobine is the most abundant alkaloid isolated from an orchid which is used in traditional chinese medicine. The caged structure of this natural product is responsible for the interest of organic chemists in its synthesis. Retrosynthetically the synthesis is almost straightforward. Opening of the lactone and intramolecular amination give a precursor which is easily built up through an Ireland-Claisen rearrangement and enamine induced Michael addition.

 Scheme 1

Ester 1 which is easily accessible from commercially available material underwent a nice Michael addition with iPrNO2 to give after removal of the nitro group the cis-configured ester 2. The stereochemical outcome can be explained by using the Cornforth model. Excessive reduction with LiAlH4 was followed by benzoylation, acetonide cleavage, double TBS protection, selective mono-deprotection, and Swern oxidation of the primary alcohol to give aldehyde 3. Parallel to the latter synthesis the second fragment commenced with alcohol 4. Silylation, methylation of the alkyne, and iodination after hydrozirconation employing Schwartz’s reagent yielded iodide 5. Both fragments were combined after halogen—metal exchange with tBuLi and one-pot deprotection of the benzoyl protecting group with ethyl Grignard to furnish advanced intermediate 6.

 Scheme 2

 

Selective oxidation of the primary alcohol produced lactone 7 most likely through transitional lactol formation. After converting the ester group into the TMS-ester enolate the mixture was refluxed and underwent the crucial Ireland-Claisen rearrangement. The naked acid which resulted after work-up was protected as the methyl ester 8. Global desilylation was accomplished with HF in pyridine and followed by PCC oxidation. Aldehyde 9 was then condensed with benzylmethylamine and the resulting Michael adduct reduced with palladium on charcoal and hydrogen to give 10. N-C bond formation was accomplished by bromination/SN2 displacement and stereoselective reduction of the ketone then formed in situ dendrobine. [1]

 Scheme 3

The mechanistic rational of the enamine induced Michael addition is shown below. After formation of the enamine the unsaturated ketone is attacked from the bottom face to give presumably after some proton shifts another enamine. Reduction from the Re face delivered amine 10 while the benzyl group is cleaved off at the end of this sequence.

Scheme 4

The C-N bond formation was induced by PHT, a commercially available mild brominating reagent. It was hypothesized that the nitrogen is brominated first and delivers the bromine to the a-position of the ketone. DMAP was essential in this step because it epimerized this position and left the bromine in an ideal position for a SN2 displacement by the nearby nitrogen.

 Scheme 5

 Luckily BRSM took the Indoxamycin B synthesis from Carreira. Check it out…

[1] Big thanks to Bobby for correcting the presumed structure of PHT: it is believed known that the tribromide ion forms an ion pair with a protonated pyrrolidinone. Makes sense compared to pyridinium tribromide. Here is the corrected link to the crystal structure: ftp://ftp.oldenbourg.de/pub/download/frei/ncs/224-4/1267-2622.pdf

Big THX to Bobby for proofreading and corrections.
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6 Responses

  1. The PHT DOI doesn’t work (no idea why); to get the paper do a Google search for “hydrotribromide” “crystal structure” & it’s the first thing listed (free download).

  2. Nice one! I was worried you or Tot. Syn. would choose the same synthesis as me. Good to see the other one covered!

  3. Hehe, good teamwork 🙂

  4. Ok, corrected this one. The structure reminds me a bit of graphite-like sandwich structures.

  5. Yep, goodwork indeed…the mechanism for this synthesis is flipping great…I made a problem set from this but I also got lost somewhere between the passages…PHT it is, no more Bromination in Acetic acid..

  6. Have you tried PHT for a bromination? I almost always use NBS for bromination especially for alpha-bromination of ketones because
    bromine is really nasty for scale up. I was wondering that PHT bromination are only rarely employed.

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