Home » Still In The RBF

SCH 351448   

7 June 2006 5,458 views 12 Comments

SCH351448.jpg

Crimmins and Vanier. JACS, 2006, Org. Lett. DOI: 10.1021/ol061073b

A dimeric beasty, Crimmins and Vanier have completed the synthesis of the snappily named SCH 351448 with a demonstration of some of the most powerful and useful synthetic methods in organic synthesis. A popular target (with three previous syntheses), their work was completed in 30 steps (LLS), generating the only known selective activator of LDL-R (low-density lipoprotein receptor). All but two of the stereocenters were established through chiral enolate reactions, demonstrating deft usage of a variety of chiral auxiluaries and aldol chemistry. Especially useful was the use of Ti enolatates. They also performed six alkene metatheses, including three in the following impressive transformation:

SCH351448_1.jpg

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading ... Loading ...

12 Comments

  • Klug says:

    A beautiful synthesis. Nice showcase of their glycolate chemistry.

  • Klug says:

    But does anyone know why they chose to use 5 different kinds of auxiliaries? (the acetate aldol one is immediately understandable…)

  • Tot. Syn. says:

    Hmm… I’m not sure. Perhaps it’s just a “because we could” style of thing. Afterall, the student probably learnt a lot doing this work. It certainly makes the synthesis more interesting.

  • ddd says:

    what is this Stoltz paper in Nature? Synthesis of Qinuclidone??? why was it in Nature?

  • woodward says:

    The different auxiliaries give different stereochemical results. The ones with a C=S bond give “non-Evans” syn aldols and are more easily cleaved. For the simple alkylations, you need the classic Evans oxazolidinone auxiliary.

  • NoName says:

    adding more to woodward’s comment (feel surreal. huh!).

    aldol reaction with N-acyloxazolidinethione auxilary (e.g., in paper, 7 as a fragment in scheme 1,3, and 4) gives evans-syn products using 1 equiv of TiCl4 and non-evans syn using 2 equiv of TiCl4.

    replacing O with S increases the nucleophilicity of N-acylthiazolidinethione auxilary (e.g., in paper, also named as 7 in scheme 2, i think they should fix this); one can switch the above selectivity based on amount of base using just 1 equiv of TiCl4 (i.e., 1 equiv of base to yield non-evans syn-aldol: 2 equiv of base or sparteine to afford evans-syn-aldol).

    i also think the authors should have written down the amount of lewis acid and base in the paper, which will be more helpful to readers.

    usually (honestly, as far as i remember) acylation of thiazolidinethione was performed with amine base; that of oxazolidinethine can be with amine base or BuLi (as in 21 to 7 in scheme 3)

    philips auxilary (used for acetate aldol) reminded of sammekia’s axuliary (i think they are personally related, too). if you have time, check out nagao and mukaiyama’s work in this vein (Sn-enolates).

    the choice of oxazolidinone auxilary kinda puzzled me.
    it is usually based on the cost and availability of each enantiomer (leucinol is good example; one is cheap, the other is prohibitive to most). also the ease of crystallization seems to be important for the process-people (e.g., novartis synthesis of discordermolide; i think they used seebach’s auxilary for that reason).
    pre-lithiated 18 in scheme3 is from cheaper enantiomer; however, i doubt that antipode (from R-phenylalaninol) is far more expensive to use valinol derivatives.

    i highly recommend to read first synthesis of SCH 351448 (shameless).

  • woodward says:

    Re: stoltz in nature…it is a historically very interesting result…we should be glad that any synthesis whatsoever gets into nature!

    synthetic stuff in nature is usually based on novelty, not necessarily the magnitude of the synthesis.

    No disrespect to KCN or anyone in his group, but this was a more significant result than KCN’s taxol synthesis (Holton’s was much more impressive) or the solid phase synthesis of epothioline, both of which were in nature, if my memory serves me.

  • woodward says:

    I’m a fan of the DeBrabander synthesis of SCH, but thats just me…

  • EJ Corey says:

    When are you going to come clean, Woodward? JUST ADMIT IT.

  • ddd says:

    I do not think it is a good idea to have EJ Corey handle, it is identity theft

  • Waseem Kausar says:

    can u pls mail me the photos of authors crimmins and vanier.

  • Tot. Syn. says:

    Urr, I don’t work beside them or have any face-to-face contact with them… I guess you should just look them up on google. Here’s Mike Crimmins’ website:
    http://www.chem.unc.edu/people/faculty/crimminsmt/mtcindex.html