July 09, 2020, 12:46:00 AM
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Topic: What is probably a good alcohol protective group for the following problem?  (Read 11343 times)

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Offline chess2007

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Hi,
I need a bulky alcohol protective group (in beta-position to a lactone) to stereoselectively introduce a methyl group in alpha position to the lactone using LDA and MeI. Can I make use of a silyl alcohol protective group such as TBDMS-OR or is there a better choice. I could not find anything about the stability of silyl protective groups under these very basic conditions. Thank you!

Offline english

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I don't know if chlorotrimethylsilane [(CH3)3SiCl] would work, but it's stable under basic conditions, and is hydrolyzed under acidic conditions.

Offline chess2007

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g_english, thank you for your answer! TMS-ether are deprotected using K2CO3 and methanol. Are there also reactions in aprotonic solvents (such as LDA inTHF)?
In my opinion the protective group is a little bit to small. What do you think?

Offline english

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Then use t-butyl dimethylsilyl chloride. (TBDMSCl)

This was the one you suggested no?  It should act the same as TMSCl, just bulkier to allow for your selectivity.


Common solvents for these would be triethylamine.  I don't know if you could use them with LDA/THF or LDA/ether.  I assume since LDA/THF is a basic solution it could work, but LDA is strongly basic. 

I question whether the silyl ether would be stable in a sufficiently strong basic solution.

Offline Sam (NG)

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silyl ethers should be fine with carbon or nitrogen bases according to my textbook.  (i.e. worry about OH-. Says that silyl ethers react with electronegative elements, but also says that N bases are ok).  Also stable against nucleophilic attack.  Acid and Fluoride sensitive.

If you are worried about the N bases being electronegative, use BuLi?

Offline kiwi

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i have a bit of experience with oxygen protecting groups, so here goes.

TMS ether: probably rubbish for this application. i personally wouldn't even try it.

TBS ether: much better choice, stable at -78 degC in the presence of these sort of situations (enolates, LDA etc) but i have seen them be cut off by ester enolates at 0 degC. probably will work still. BuLi obviously a bad idea here, will destroy your lactone.

other groups worth considering are pivalate esters (deprotection can be non-trivial) and t-butyldiphenylsilyl (a bit of extra bulk, can be tricky to get onto hindered spots though). have fun.
(edit: i forgot THP, one of my least favourite PGs. can be really annoying, but its big and rock solid toward base. the extra O might give a chelate-based directing effect too, either matched or opposed, try it and see)



Offline ziqquratu

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I know from the recent experience of a friend in my lab that TBDMS-protected alcohols remain protected after treatment with NaH at room temp. He uses tetrabutylammonium fluoride (dried of 4A sieves) for his deprotection.

Offline trufalup

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You'll be fine under basic conditions with Si groups. the real ? is, what are you conditions down the line? benzyl ethers are stable in both acidic and basic (relatively as long as it's not nasty like Me-Li or something like that). Would it not serve your purpose?

Offline Shaun

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Greene's book on protective groups is excellent.  It has tables showing the reactivity/stability of protective groups under various conditions.

However, this isn't your real problem.  You can't use LDA on a ketone or lactone that has an OH or OR beta to it.  It will eliminate.

There are lots of ways to tackle this sort of problem.  If you provide a structure I could give more info.

Offline russellm72

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I agree TMS ethers are a bit labile but TBDMS ethers much better.

The THP idea sounds good and may indeed assist in your lithiation reaction but of course may give you the wrong enantiomer! They can also be a pain to get off sometimes.

Have you thought of a PMB group? This can be removed mildly using DDQ.

Let us know how you get on.

R.




Offline Transmutation

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Re: What is probably a good alcohol protective group for the following problem?
« Reply #10 on: February 28, 2008, 04:00:30 AM »
TIPS is generally less labile than TBDMS, I believe.  More steric bulk.  I imagine you'd just take it off with HF-pyridine or TBAF; I haven't used it myself.

(Triisopropyl silyl ether is what it makes).

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