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20 July 2006 6,678 views 22 Comments


Gin, Eckelbarger and Wilmot. JACS, 2006, ASAP. DOI: 10.1021/ja063304f.

Ring expansion-action in this latest paper from David Gin, regarding the total synthesis of (-)-deoxyharringtonine, an anti-leukemia alkaloid. Starting from simple starting materials, they created the complex 7,5,5 system very quickly, using the ring-strain inherant in aziridines to open to a 7-member ring via a cyclisation.


This was then N-alkylated with Me3SiCH2I, which permited O-acylation with PivCl. The silyl group was then removed, generating a short-lived nonstabilized azomethine ylide. A stereo- and regioselective 1,3-dipolar cyclisation onto the PhSO2CH=CH2 led to the spiro-pyrrolidine. Phew! An impressive set of steps, creating two rings and completing the carbocyclic core of the target.

Other cool steps include a Yb(OTf)3 mediated mono-acylation of the free diol, and use of SmI2 to remove the sulfonate group. The side-chain (a non-trivial component, which produced in an impressive sequence) was then attached using Yamaguchi conditions, resulting in the desired product. The work is full of interesting reactions, and is a great read.

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  • JohnMark says:

    Wow, Gin is pushing out impressive total syns like a fire sale right now.

  • Hap says:

    Gin has been at this for some time now – he gave a talk that mentioned this in 2002 at the ACS nat’l meeting. It still looks nice, though.

  • SJB says:

    Oooh, funky, looks like some of my work may have wider application after all (the triflate acylation stuff ;) )

  • rb says:

    Gin is the shit.

  • alex says:

    I think you have the aziridine N in the wrong place – should be bonded directly to the ring

  • Tot. Syn. says:

    Yup; thanks for that – fixed now.

  • azomethine ylide chemist says:

    I’d me more impressed with this if Gin were intellectually honest enough to cite the people who actually developed the desilylation method for azomethine ylide generation twenty-five years ago, most especially Vedejs and Padwa.

  • Portnoy says:

    So is Gin at Sloan-Ketttering or what? The email and address suggests so, but there’s no update at the Illinois web page, and he doesn’t show up on the SK directory!

  • Curious guy says:

    azomethine ylide chemist:

    Dave is usually extraordinariy careful and deliberate with the references he cites so I am curious which passages you feel were underreferenced? Were the same conditions previously used? Desilylation is well known enough and old enough that nobody thinks this methodology is completely novel.

    Yes, Dave is moving to SKC and should be there around the first week in august.

  • Hap says:

    sorry to point elsewhere – Dylan Stiles’ blog has a pointer to the total synthesis of hexacyclinol by Porco et al., which surprisingly (or not) fits the structure calculated by Rychnovsky (who is also an author on the paper). Dr. LaClair’s site renames the previous structure for hexacyclinol and says that they are trying to reconfirm/reproduce the “unconventional” work done previously. This might be fodder for a post here in the near future.

  • NoName says:

    considering this is two-page JACS communnication: no space left at the end of the paper, i can live with sparse citations.

  • ddd says:

    how did you guys feel after your PhD completed? I feel myself a kinda emptied…I had a goal, and I am done now…more freedom but it is confusing…

  • azomethine ylide chemist says:

    NoName’s point is valid. However, if I were using methodology that was almost identical to work reported in another lab (see Padwa, TL 1983, 4303), I would consider citing that earlier precedent, along with my own paper that was published 19 years later. If necessary, I would trim a sentence out of my text to make room for it. But that’s just me–I happen to think that sparse citations can reflect spin-control or carelessness at least as often as space management.

  • Curious guy says:

    As a personal note, I am a fan of overciting rather than under. However, I would make the following point. The alkylation of a vinylogous amide and subsequent desilylation is secondary to the paper at hand because this methodolgy has been previously reported by the Gin group (ACIE 2002, 1778) and is appropriately cited by the JACS communication. In the original report, the azomethine literature is heavily cited by way of many reviews (it is a large field). In addition, the Padwa TL example of the use of azomethines via vinylogous amides is directly referenced. So yes, more relevant direct literature citations might have been worthwile, but this lack is much more of a case of redundancy with the ACIE 2002 paper than a result of intellectual dishonesty as azomethine chemist suggests.

  • NoName says:

    nature publishing group tries so called “open peer-review”; it recruits informal comments and collegial advices prior to publications probably with author’s permission. this might help to resolve some issues mentioned above (citation) in the future.
    if interested, check out nature podcast (june 15th).

  • azomethine ylide chemist says:

    I don’t want to overstate this issue. It’s true that Dave did a thorough job of citing the prior art in his 2002 paper. Citing the most relevant of the earlier work in this second paper is a judgement call. Since synthesis often seems to display a rather short collective memory, I tend to err on the side of giving as much credit as possible to the progenitors of the ideas I am seeking to publish. Others may differ with me on this. Bottom line: it’s a great synthesis, and I regret it if this digression has distracted anyone from that fact.

  • Tot. Syn. says:

    Hap (and others who are interested); I have indeed seen the ACIE regarding the total synthesis of hexacyclinol. The paper itself has yet to reach the web, but you can trust me to blog it, and comment upon the work in my usual, unbiased fashion. But I do think it’s fair to say (paraphrasing my groupmate, Andy) that LaClair is about to have his arse handed to him.

  • secret milkshake says:

    …more like kicked up to his shoulderblades

  • ddd says:

    STOP blogging and get back to yoru hoods! ;)

  • Tot. Syn. says:

    ddd: just cause we have hoods. You miss it, don’t you? You want to smell the ether, get the taste of silica again, and get confused by the bloody mess at 2ppm. Now, if you ask nicely, and give me 50 quid a week, you can do my work-ups for me…

  • [...] Also, this synthesis was highlighted over at Totally Synthetic. Go and enjoy reading Paul’s Chemdraw skills and comments on this post. [...]

  • pasupathy says:

    Are there any precedents to make non stabilized nitogen ylide by deprotonation of N-CH3 in a quaternary ammonium compound and subsequent reaction with alkyl halides to create N-CH2R