[kriggy]

Hi, im going to run some wittigs soon(ish) and probably need some help with planning my stuff.

My issue is, that if I use the Boc-protected coupling partners, then the NH acidity will cause problems with forming the ylid since the acidity is similar: 25 ish for the carbamate and 22 for phosphonium and 27 for phosphonate. Should I be worried or is the 3 pka units good enough difference?

If there is no protecting group, do you think the amine would react with the aldehyde preferentially over the ylid yielding imine over alkene?
How long does the ylid formation take place? Can it be monitored by TLC? I did HWE once and I just mixed all together but this wont work here since I have base labile protecting group in my aldehyde.

[rolnor]

It could be a problem, the Boc containes a carbonyl and you create a nucleophile in the same molecule. Use some other PG, Trityl maybe. If you have a Fmoc in the aldehyde this can cleave, you have alkaline conditions. Change this PG.

[kriggy]

It could be a problem, the Boc containes a carbonyl and you create a nucleophile in the same molecule. Use some other PG, Trityl maybe. If you have a Fmoc in the aldehyde this can cleave, you have alkaline conditions. Change this PG.

Thanks, I might try trityl, it doesnt matter that much if its boc or trityl. I need the Fmoc since its for SPPS therefore I might be stuck with reprotecting later. Thats unfortunate but guess its fine

[rolnor]

Can you change the Fmoc on the aldehyde to Boc?

[kriggy]

Im starting with fmoc protected AA but I can make the Boc derivative thats no problem. its just I need the fmoc for later steps (SPPS). Not having it there, would require introduction later and possibly add many steps with protecting group manipulations which is something I want to avoid.

I think having trityl there and introducing fmoc back if it falls is probably the simplest solution

[rolnor]

I understand. Be carefull, you have a methylester so a free amino can attack  that.you could use a trimethylsilylethoxycarbonyl instead, cleaves by  TBAF.

[Babcock_Hall]

We have had good results with the Masamune-Roush (Blanchette MA et al., Tetrahedron Letters 1984 25(21):2183-86) variation of the HWE, which is suitable for substrates that would not tolerate a strong base.  Typically people use LiCl or LiBr as the catalyst, and DIPEA or TEA may be used.  If the lithium ion chelates the phosphorus-containing molecule (there is a second oxygen that can bind the Li⁺ ion in all of the examples I can think of offhand), the pK_a is lowered.  However, your reactants are considerably different versus ours, and our experience is probably not applicable.  I have also seen an FMOC-protected amino acid used in a HWE reaction with LiHMDS.  IIRC the yield was not great.  One wonders if there was some loss of the FMOC-group.

[rolnor]

As you can see, this ylide is very alkaline, not stabilized. The amino group may make it worse. You have a sulphone that makes it much less alkaline.

[Babcock_Hall]

I agree and implied as much, but I was also thinking about the structure in which the amine is protected.  I realize that it is quite optimistic to imagine that the carbonyl group within the Boc-group will help to bind lithium, but I am not 100% sure that it won't.  Regarding LiHMDS and FMOC-protected compounds, I was thinking of Lee 2009 doi:10.1016/j.bmcl.2009.07.045.  There is also a closely related reaction that used NaH.

[kriggy]

Thanks for the references. I know of the TEA+Li/Mg salts method but Im afraid since my compound is not a (basically) 1,3-dicarbonyl it wont work.
There is a paper that deals with the similar reaction

(1) Mali, S. M.; Bandyopadhyay, A.; Jadhav, S. V.; Kumar, M. G.; Gopi, H. N. Synthesis of α, β-Unsaturated γ-Amino Esters with Unprecedented High (E)-Stereoselectivity and Their Conformational Analysis in Peptides. Org. Biomol. Chem. 2011, 9 (19), 6566–6574. https://doi.org/10.1039/c1ob05732d.

but they dont describe the synthesis of the ylid

[rolnor]

I agree and implied as much, but I was also thinking about the structure in which the amine is protected.  I realize that it is quite optimistic to imagine that the carbonyl group within the Boc-group will help to bind lithium, but I am not 100% sure that it won't.  Regarding LiHMDS and FMOC-protected compounds, I was thinking of Lee 2009 doi:10.1016/j.bmcl.2009.07.045.  There is also a closely related reaction that used NaH.

When it comes to PG-chemistry, I lika to exclude all obvious possible problems. There are other PG-s thar are more base-stable.

[rolnor]

I think not even t-BuOK can pick these protons to create the ylide you need dimsylsodium, LDA or n-BuLi…

[kriggy]

Sooo I did the reaction today with the unprotected aminogroup and KHMDS (had it available and shouldnt deprotonate the NH2) anyway, phosphonium turned yellow and then the color dissapeared after a while (checked after 1 hrs in ice bath). HPLC/TLC doesnt show much except of the phosphonium and my aldehyde (no Fmoc cleave) and possibly trace of product. I think im gonna run it ovn and then add more base to see what happens

I suppose the yellow wasf rom the ylid being formed but the discoloration means decomposition back to the phosphonium salt? Are ylids moisture/air sensitive?